2024 EASD Senior Vice President, Francesco Giorgino, discusses the organisation's main objectives Interview:
Hyperkalaemic Paralysis by Addisonian Crisis: A Near Fatal Accident Article:
Welcome
Foreword
Congress Review
10 Review of the European Association for the Study of Diabetes (EASD) Annual Meeting 2024, 9th–13th September 2024
Congress Features
19 AI and Diabetes Technology in Diabetic Complications
Aleksandra Zurowska
23 Youth-Onset Type 2 Diabetes: An Awakening Epidemic
Ada Enesco
Abstract Reviews
28 Meal Timing: Its Relation to Metabolism and Heritability in German Adult Twins
Pivovarova-Ramich et al.
30 Screening and Monitoring for Presymptomatic Type 1 Diabetes: The DiaUnion Project
Klæbel et al.
32 Sex-Specific Differences of Human Skeletal Muscle: A Multi-Omics Exercise Study
Dreher et al.
34 Abstract Highlights
Congress Interview
44 Francesco Giorgino
Interviews
50 Philippe Froguel 53 Samuel Seidu
Articles
57 The Potential Impact of Gestational Diabetes Mellitus on Long-Term Kidney Disease: A Narrative Review
Siddiqui and George
65 Hyperkalaemic Paralysis by Addisonian Crisis: A Near Fatal Accident – A Case Report
Bertlla et al.
72 A Case of Mauriac Syndrome Caused by Social Inequities in Healthcare: A Call to Action
Iglesias et al.
76 Consequences of Disintegrated Care for Dual Tuberculosis and Diabetes in Tanzania: A Case Report on Recurrent Tuberculosis with Severe Haemoptysis in a Patient with Dysregulated Diabetes
Chamba et al.
"The event celebrated six decades of groundbreaking progress in diabetes research and care, showcasing exciting new data aimed at transforming the future of diabetes care and prevention"
Editorial Board
Editor-in-Chief
Dr Martin Whyte
University of Surrey, UK
Dr Martin Whyte undertook his medical degree at King’s College Hospital, after which he complete a PhD exploring the metabolic effects of insulin in critical illness at Guy’s & St Thomas’ Hospital, London, UK. He became the Associate Professor in Metabolic Medicine at the University of Surrey, UK in 2021. His areas of research interest include non-alcoholic fatty liver disease and the effect of insulin resistance on cardiovascular disease.
Prof David Simmons
Western Sydney University, Australia
Dr Gijs Goossens
Maastricht University Medical Centre+, the Netherlands
Mrs Anne-Marie Felton
Foundation of European Nurses in Diabetes, UK
Dr Mohammad Alhadj Ali
Cardiff University School of Medicine, UK
Prof Henning Beck-Nielsen
Odense University Hospital, Denmark
Dr Hassan Shora
Port Said University, Egypt
Prof Ellen Blaak
Maastricht University Medical Centre+, the Netherlands
Dr Muthuswamy Balasubramanyam
Madras Diabetes Research Foundation (MDRF), India
Dr Lorenzo Pasquali
Germans Trias i Pujol University Hospital and Research Institute, Spain
Prof Nikolaos Tentolouris
Dr Yehuda Handelsman
Metabolic Institute of America, USA
National and Kapodistrian University of Athens, Greece
Dr Dario Rahelic
Prof Dr Baptist Gallwitz
University of Tübingen, Germany
Dubrava University Hospital, Croatia
Prof Anne Phillips
Birmingham City University, UK
Dr Sampathkumar Rangasamy
Translational Genomics Research Institute (TGen), USA
Dr Jonathan Bodansky
Leeds Teaching Hospitals, UK
Aims and Scope
EMJ Diabetes is an open-access, peer-reviewed eJournal committed to helping elevate the quality of healthcare in diabetes globally, by informing healthcare professionals on all aspects of the condition and its evolving treatment landscape.
The journal is published annually, 6 weeks after the European Association for the Study of Diabetes (EASD) Congress and features highlights from this event, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. The journal also covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.
EMJ Diabetes also publishes peer-reviewed research papers, review articles, and case reports in diabetes. In addition, the journal publishes features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous doubleblind peer-review process, maintains high standards of copy editing, and ensures timely publication.
EMJ Diabetes focuses on topics that are relevant to healthcare professionals in the field. We do not publish veterinary science papers or laboratory studies that are not linked to patient outcomes. We have a particular interest in topical studies that advance knowledge and inform of coming trends affecting clinical practice in diabetes.
Further details on coverage can be found here: www.emjreviews.com
Editorial Expertise
EMJ is supported by various levels of expertise:
• Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.
• Invited contributors who are recognised authorities in their respective fields.
• Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on their knowledge of a specific topic.
• An experienced team of editors and technical editors.
• A team of internal and independent medical writers.
Peer Review
On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review.
Editorial staff, following consultation with a member of the Editorial Board if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.
All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.
Editorial staff have final discretion over any proposed amendments.
Submissions
We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects. We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.
We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com
To submit a paper, use our online submission site: www.editorialmanager.com/e-m-j
Submission details can be found through our website: www.emjreviews.com/contributors/authors
Reprints
All articles included in EMJ are available as reprints (minimum order 1,000). Please contact hello@emjreviews.com if you would like to order reprints.
Distribution and Readership
EMJ is distributed through controlled circulation to healthcare professionals in the relevant fields globally.
Indexing and Availability
EMJ is indexed on DOAJ, the Royal Society of Medicine, and Google Scholar®.
EMJ is available through the websites of our leading partners and collaborating societies. EMJ journals are all available via our website: www.emjreviews.com
Open Access
This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license.
Congress Notice
Staff members attend medical congresses as reporters when required.
This Publication Launch Date: 2013 Frequency: Yearly Online ISSN: 2054-3174
All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (EASD 2024) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Madrid, Spain the location of EASD 2024.
Helena Bradbury, Ada Enesco, Katrina Thornber, Katie Wright, Aleksandra Zurowska
Creative Director
Tim Uden
Design Manager
Stacey Rivers
Senior Designer
Steven Paul
Designers
Fabio van Paris, Owen Silcox
Junior Designers
Dillon Benn Grove, Shanjok Gurung
Senior Performance & Insight Lead
Darren Brace
Project Manager
Devan Parmer
Marketing Director
Kristina Mestsaninova
Chief Content Officer
Justin Levett
Chief Commercial Officer
Dan Healy
Founder and Chief
Executive Officer
Spencer Gore
Welcome
Dear Readers,
It is a great pleasure to welcome you to this year’s issue of EMJ Diabetes, bringing you all the latest advancements in diabetes research from the European Association for the Study of Diabetes (EASD) Annual Meeting, which took place in Madrid, Spain. This year saw the celebration of six decades of groundbreaking progress in diabetes research and care, showcasing exciting new data that will shape the future of diabetes care and prevention whilst also taking a turn towards patient-centred care, with a newly formed patient committee taking an active role in the development of new guidelines.
In our exclusive interviews with diabetes experts, among whom is the EASD Senior Vice President, we discussed the current state-of-the-art and future outlook for Type 1 and Type 2 diabetes research, gaps in research, and the role of obesity and genetics as risk factors.
Among our peer-reviewed content is an excellent narrative review on the impact of gestational diabetes on long-term kidney disease. This article highlights the importance of monitoring and interventions to reduce the risks associated with this condition.
In closing, I would like to thank all of our contributors, peer reviewers, and of course our Editorial Board for helping us deliver this high-quality issue. Until next year’s issue, we welcome your feedback, and we look forward to your submitted content!
Editorial enquiries: editor@emjreviews.com
Sales opportunities: salesadmin@emjreviews.com
Permissions and copyright: accountsreceivable@emjreviews.com
Editor
Reprints: info@emjreviews.com Media enquiries: marketing@emjreviews.com
Evgenia Koutsouki
Foreword
The European Association for the Study of Diabetes (EASD) Annual Meeting 2024, held in Madrid, Spain, showcased advancements in diabetes research and care. For Type 1 diabetes, the data presented indicated that males have a higher risk of developing Type 1 diabetes after early childhood compared to females. Evidence was also presented for maternal protection against Type 1 diabetes in children, compared to paternal transmission.
Advances in once-weekly insulin came from Lilly's QWINT global Phase III clinical trial programme for efsitora alfa. High doses of insulin were used for the initial loading phase, suggesting clinicians would need to become skilled with this to reduce the risk of hypoglycaemia.
Incretin drugs continued to feature prominently in the Congress. The FLOW trial found that semaglutide reduced the risk of the composite kidney outcome (persistent ≥50% reduction in estimated glomerular filtration rate, kidney failure, kidney death, or cardiovascular death) by 24%, with consistent benefits across subgroups and no significant differences in effect based on background medications, including SGLT2 inhibitors. Results of incretins and
weekly insulin examined together were also discussed in the Congress. The onceweekly combination of insulin icodec plus semaglutide (IcoSema) could benefit people with Type 2 diabetes who don't reach target glycaemic goals with either of the single agents alone.
The guidance highlighted the need for coordinated care between hepatology and the diabetes community
Finally, important EASD/European Association for the Study of the Liver (EASL) guidance on metabolic-associated steatotic liver disease was presented. This stressed the importance of early detection and comprehensive management and echoed the ever-greater interdisciplinary approach to cardiorenal metabolic disease. The guidance highlighted the need for coordinated care between hepatology and the diabetes community.
Martin Whyte Associate Professor of Metabolic Medicine, University of Surrey, UK
EASD 2024
The event celebrated six decades of groundbreaking progress in diabetes research and care, showcasing exciting new data aimed at transforming the future of diabetes care and prevention
Review of the European Association for the Study of Diabetes (EASD) Annual Meeting 2024 Congress Review
ATTENDEES were warmly welcomed to a "feast of science" at the 60th European Association for the Study of Diabetes (EASD) Annual Meeting in Madrid, Spain, by President Chantal Mathieu. The event celebrated six decades of groundbreaking progress in diabetes research and care, showcasing exciting new data aimed at transforming the future of diabetes care and prevention. Mathieu invited the audience to attend the Plaza de Toros de Las Ventas (a bullfighting arena in Madrid) to celebrate the 60th anniversary with drinks, nibbles, and music, joking that there would be "no bulls" present.
Looking back on 60 years of EASD, Mathieu spoke a little about the origins of the Annual Meeting. In July 1964, the founding meeting brought together just 66 participants from 11 European countries. It was here that the decision to establish the EASD was made, with headquarters in Geneva and an official European journal. The first official meeting followed in April 1965, in Montecatini Terme, Italy. Fast forward to last year, and the creation of the Global EASD Council was announced, and in September 2024, the council came together for the first time. The goals of the council are to raise global awareness of diabetes and related metabolic diseases, advise on global activities, whilst addressing specific regional needs, and enhance communication between the EASD Board and the leadership of national and regional organisations, fostering stronger partnerships across the world.
Now, with 12,117 participants from 130 countries, this is the biggest annual meeting yet. This year, for the 60th Meeting, the Congress has grown to impressive amounts: there are 62 symposia, 48 oral sessions, 8 late-breaking oral sessions, 102 short oral discussions, 5 late-breaking short oral discussion sessions, 19 study group and NGO sessions, and 51 industry sessions.
Mathieu proudly announced that, out of 2,089 abstracts selected this year, 275 have been classed as late-breaking, highlighting the significant volume of groundbreaking research in the field.
Mathieu acknowledged the contributions of study groups who work closely with EASD, with research focusing on a range of areas such as artificial insulin delivery, the link between diabetes and cancer, genetics, pregnancy, and more. She emphasised that research alone is not enough, and thus, the EASD has actively engaged in shaping policy through the European Diabetes Forum.
One key initiative is the forum’s pledge for the 2024 European elections, outlining key priorities for advancing diabetes care in Europe.
She also highlighted the work of the Guideline Development Committee, which is dedicated to creating thorough and scientifically rigorous guidelines. In the pipeline are guidelines on ‘Diabetes Distress’, and ‘Technology in Type 2 Diabetes’, while noting that the topic of a third guideline is still being finalised, urging everyone to stay tuned.
This year, the EASD has taken an important step forward by ensuring that the voices of people with diabetes are heard. They have commissioned a patient advisory committee, which will include individuals living with diabetes to participate in the development of new guidelines. On the topic of patient-centred care, Mathieu encouraged all attendees to support the pledge to ‘End Diabetes Stigma’, which has already garnered over 2,700 signatures from more than 230 organisations across 107 countries.
The EASD [...] have commissioned a patient advisory committee, which will include individuals living with diabetes to participate in the development of new guidelines
Mathieu concluded the Presidential Address by encouraging attendees to join the EASD, emphasising that collaboration is essential to produce groundbreaking research and enable policy changes that will ultimately "shape the future of diabetes". She also stressed the importance of collaborations between academia and industry, noting the critical role of industry in transforming academic discoveries into real-world innovations, therapies, and insights that will one day lead to the prevention and cure of diabetes.
To learn more about some of the groundbreaking research and innovative developments in diabetes healthcare, read on for key highlights presented at the 2024 Annual Meeting, and return next year for our coverage of EASD 2025 in Vienna, Austria!
Research Confirms Link Between Microvascular Complications and Periodontitis
NEW research presented at EASD 2024 revealed that there is a higher risk of periodontitis in individuals with microvascular complications of diabetes.
In patients with diabetes, inflammation can lead to periodontitis, in which the buildup of bacterial plaque triggers an immune response that damages the gums and supporting bone structures, often leading to tooth loss if left untreated. Previous research has suggested a link between diabetes-related microvascular complications, such as retinopathy and neuropathy, and an increased risk of periodontitis. However, previous studies have often been limited in scope and have failed to account for confounding factors like smoking, diabetes duration, and socioeconomic status, and therefore have reported inconsistent findings.
Therefore, researchers from Steno Diabetes Center Aarhus, Denmark, and National Dental Centre Singapore, analysed data from over 15,000 individuals with Type 2 diabetes as part of the Health in Central Denmark study. The analysis included 15,922 participants with an average age of 63.7 years. The study accounted for a wide range of confounding factors, including lifestyle habits and sociodemographic variables. The analysis revealed that there was a significant association between microvascular complications and moderate/ severe periodontitis. In particular, diabetic retinopathy increased the risk of periodontitis by 21%, and diabetic neuropathy increased the risk by 36%. In individuals with both complications, the likelihood of gum disease was 51% higher. Moreover, the presence of dyslipidaemia further heightened the risk of developing periodontitis.
These findings suggest that oral health evaluations should be prioritised in patients with diabetes as part of a multidisciplinary approach when treating individuals with Type 2 diabetes, particularly those with microvascular complications. Additionally, the authors highlighted that dentists should be aware of the link between oral health and microvascular complications and recommend screening for these conditions. Furthermore, the authors noted that periodontitis can lead to difficulties with nutrition, communication, and social interactions. Therefore, identifying those as high-risk is crucial for both oral health and psychological well-being.
Oral health evaluations should be prioritised [...] as part of a multidisciplinary approach when treating individuals with Type 2 diabetes
Diabetic retinopathy increased the risk of periodontitis by 21%, and diabetic neuropathy increased the risk by 36%. In individuals with both complications, the likelihood was 51% higher.
Real-World Analysis Confirms Tirzepatide’s Safe Profile for Diabetes and Obesity Treatment
A LARGE-SCALE analysis of real-world data from the FDA Adverse Event Reporting System (FAERS) confirms a reassuring safety profile for tirzepatide (TZP), a new medication used for Type 2 diabetes and obesity.
The research examined 7,460 reports, referring to 286 adverse events related to gastrointestinal, pancreatic, biliary, eye, and thyroid issues
The study, presented at EASD 2024, found that TZP had similar gastrointestinal tolerability compared to other glucagonlike peptide-1 receptor agonists (GLP1RA), without an increased risk of serious complications such as diabetic retinopathy, pancreato-biliary disorders, or medullary thyroid cancer.
The research examined 7,460 reports, referring to 286 adverse events related to gastrointestinal, pancreatic, biliary, eye, and thyroid issues. TZP showed a higher risk of some gastrointestinal side effects, including nausea, dyspepsia (indigestion), and constipation, compared to insulin and SGLT-2 inhibitors, but these risks were similar to those seen with GLP1RAs. Notably, eructation was reported 30 times more frequently with TZP than with other drugs. However, TZP did not show a disproportionate increase in the risk of pancreatitis or gallbladder-related conditions compared to other medications in the analysis.
Additionally, reports of diabetic retinopathy (based on 12 diabetic retinopathy events) were over three times more likely with TZP compared to all other drugs. However, TZP was associated with a similar risk of medullary thyroid cancer as other GLP1RAs and SGLT-2 inhibitors, and a greater risk compared to insulin. Importantly, TZP did not show a significantly higher risk of gallbladder issues except for biliary colic, which was consistent with other GLP-1RAs.
The lead author of the study highlighted that, while the results are promising, the study’s observational nature and the limited time frame of TZP’s real-world use suggest caution when interpreting the findings. Despite these limitations, the research underscores TZP's potential as a safe and effective treatment for managing blood sugar levels and promoting weight loss in patients with Type 2 diabetes and obesity.
Semaglutide May Reduce Heart Risks in People with Impaired Kidney Function
A NEW study presented at EASD 2024 showed results from the SELECT trial, which has revealed that the anti-obesity drug semaglutide effectively reduces the risk of heart attacks, strokes, and other major cardiovascular events in people with impaired kidney function.
Over the course of more than 3 years, participants treated with semaglutide experienced a 20% reduction in MACE
The SELECT trial involved over 17,000 adults with obesity or overweight who did not have diabetes but had established cardiovascular disease. Results showed that over the course of more than 3 years, participants treated with semaglutide experienced a 20% reduction in major adverse cardiovascular events (MACE), which include heart attacks, strokes, and cardiovascular deaths, compared to those on a placebo. Importantly, the drug was equally effective in participants with impaired kidney function, who saw a 31% reduction in MACE and a 33% lower risk of MACE or death from any cause compared to those taking a placebo.
In addition to its cardiovascular benefits, semaglutide contributed to a significant average weight loss of 9.4% of body weight over the study period. The drug, a GLP-1 receptor agonist, works by mimicking incretin hormones in the body, which help regulate blood sugar levels and reduce appetite, leading to lower calorie intake and weight loss.
The analysis also examined kidney function markers, such as estimated glomerular filtration rate and urinary albumin-to-creatinine ratio, to further assess semaglutide’s impact. The drug showed robust cardiovascular protection in participants with impaired kidney function, measured by an estimated glomerular filtration rate below 60 mL/min/1.73m². Similarly, those with higher levels of albumin in their urine experienced significant reductions in cardiovascular risk with semaglutide.
These findings suggest that semaglutide, a drug that is traditionally prescribed for Type 2 diabetes and weight loss, may also play a key role in managing cardiovascular health in people with obesity, particularly those with compromised kidney function. While the results are promising, the lead study authors caution that further research is needed to confirm its effectiveness in patients with severe kidney failure.
Semaglutide and Tirzepatide Aid Weight Loss in Type 1 Diabetes
NEW research presented at EASD 2024 has found that the drugs semaglutide and tirzepatide can significantly improve blood sugar control and lead to substantial weight loss in individuals with Type 1 diabetes (T1D) who are overweight or obese. The findings suggest that these medications, typically prescribed for Type 2 diabetes and weight loss, could be a valuable addition to insulin therapy in managing T1D.
The study was led by researchers from the University of Colorado Anschutz Medical Campus, USA, and reviewed the medical records of 100 adults with T1D, 50 treated with semaglutide and 50 with tirzepatide. Results showed that both drugs were found to cause significant weight loss compared to a control group of patients with T1D who were not on weight-loss medications.
Participants on semaglutide lost an average of 9.1% of their body weight over 12 months, equating to about 19.2 lbs (8.7 kg). In comparison, those on tirzepatide saw an average weight loss of 21.4%, or 49.4 lbs (22.4 kg), more than double the weight loss achieved with semaglutide. Almost all participants using the drugs (77% on semaglutide, 93% on tirzepatide) lost at least 5% of their body weight, with many losing more than 10%.
Both drugs also improved blood sugar control in patients, regardless of whether they used insulin pumps or injections. Notably, patients on tirzepatide were able to reduce their daily insulin dose by an average of 18%, suggesting a decrease in insulin resistance, which is a challenge for overweight and obese individuals with T1D.
The findings of the study are particularly relevant as more patients with T1D are living with obesity, which complicates blood sugar management and increases the risk of complications like heart disease. The weight
Both drugs also improved blood sugar control in patients, regardless of whether they used insulin pumps or injections
loss and improved glycaemic control offered by semaglutide and tirzepatide could help reduce these risks.
While the results are promising, the researchers emphasised the need for larger trials to further evaluate the safety and effectiveness of these drugs in patients with T1D. Nonetheless, the study suggests that semaglutide and tirzepatide could become valuable tools in managing T1D, particularly for those struggling with obesity and insulin resistance.
Fear of Hypoglycaemia Hinders Exercise in People with Type 1 Diabetes
FEAR of hypoglycaemia (FOH) remains a significant barrier to regular physical activity for people with Type 1 diabetes (T1D), despite widespread use of advanced glucose-monitoring technologies, according to research presented at EASD 2024.
Physical activity is known to offer numerous health benefits for people with T1D, including better blood glucose control and overall fitness. However, many with the condition fail to meet recommended activity levels. To examine barriers to exercise in T1D, the study recruited 463 adults with T1D through the National Health Service (NHS) Research Scotland Diabetes Network and via social media to complete an anonymous 61-point online questionnaire. The reported median age of respondents was 45–54 years, median disease duration 21–25 years, and median HbA1c 50–55 mmol/mol.
Participants were asked to rate on a 7-point Likert scale (from 1, "extremely unlikely" to 7, "extremely likely") the likelihood that each of 13 factors would prevent them from exercising regularly in the next 6 months. Factors included loss of control over diabetes, FOH, the fear of being tired, the fear of getting hurt, a low fitness level, and the lack of social support.
The study showed that the overall score for barriers to exercise was relatively low, with a mean of 2.72 out of 7. However, FOH scored significantly higher at 3.60, marking it as the most prominent concern for those with T1D.
In addition, the study revealed that people who discussed exercise during their diabetes clinic visits were less likely to experience FOH (P=0.002). Furthermore, better knowledge of insulin and carbohydrate adjustments before and after exercise was associated with lower FOH (P<0.001). Exercise confidence emerged as the strongest predictor for reducing perceived barriers, accounting for 48.3% of the variance in scores.
The team found that 78.8% of participants were using continuous or flash glucose monitoring, 63.7% were using multiple daily injections, and 36.3% were relying on continuous subcutaneous insulin infusion, emphasising that technological advances alone are not enough to overcome FOH. The researchers concluded that improved education and more frequent discussions about exercise in clinical settings could help alleviate patients' fears and encourage greater physical activity.
Overall, this study highlights the need for healthcare providers to focus on empowering people with T1D through better education and support for integrating exercise into their diabetes management.
78.8 of participants were using continuous or flash glucose monitoring %
63.7 were using multiple daily injections %
36.3 were relying on continuous subcutaneous insulin infusion %
Marathon Runners with Type 1 Diabetes Aided with Hybrid Insulin Technology
A SERIES of case reports, presented at EASD 2024 in Madrid, showcased how hybrid closed-loop insulin technology enabled three adults with Type 1 diabetes (T1D) to run marathons in Tokyo, Santiago, and Paris.
This advanced automated insulin delivery (AID) system uses an algorithm integrated with an insulin pump to adjust insulin doses every 5 minutes based on real-time glucose readings, significantly improving blood sugar management during physical activity.
The first case report highlighted a 50-year-old man with a history of T1D for 22 years who ran the Tokyo Marathon in 3 hours and 34 minutes
For patients with T1D, managing blood sugar levels during aerobic exercise, such as marathon running, can present a significant challenge. Traditional insulin delivery methods often struggle to maintain optimal glucose levels during strenuous exercise; however, this new hybrid closed-loop system allows for more precise control by delivering both basal and correction bolus insulin automatically. It also enables patients to set temporary glucose targets to reduce the risk of hypoglycaemia during exercise.
The first case report highlighted a 50-yearold man with a history of T1D for 22 years who ran the Tokyo Marathon in 3 hours and 34 minutes. He maintained excellent glycaemic control throughout the race, spending 96% of the time within the target glucose range and achieving an average blood glucose level of 107 mg/dl. Adjustments to his insulin doses before the
race, along with carbohydrate consumption via glucose gels, helped maintain his blood sugar within this desired range.
A second report described a 40-year-old man with T1D for 4 years who completed the Santiago Marathon in under 5 hours. He also demonstrated effective blood sugar management, with 100% of the race spent within the target range, aided by careful pre-race insulin adjustments and carbohydrate intake.
The final case detailed a 34-yearold woman with T1D for 27 years who completed the Paris Marathon in under 4 hours. However, her glucose levels remained elevated throughout the race, thought to be due to an overconsumption of carbohydrates and a lack of autocorrection boluses.
These case reports highlight the potential of automated insulin delivery systems to help individuals with T1D lead active lives, even during intense physical activities like marathon running. However, they also emphasise the need for personalised approaches and proper education to optimise glucose control.
These case reports highlight the potential of automated insulin delivery systems to help individuals with T1D lead active lives
AI and Diabetes Technology in Diabetic Complications
Author: Aleksandra Zurowska, EMJ, London, UK
Citation: EMJ Diabet. 2024;12[1]:19-22.
https://doi.org/10.33590/emjdiabet/YNXZ8573.
IN AN INSIGHTFUL session presented at the European Association for the Study of Diabetes (EASD) Annual Meeting 2024, the speakers discussed the advances in diabetes technology, offering solutions like continuous glucose monitoring (CGM) and hybrid closed-loop insulin pumps to help manage the condition. Tomas Griffin, Galway University Hospital, Ireland, explored how these tools can benefit people on dialysis or with impaired vision, highlighting their potential to improve glycaemic control. Meanwhile, Sufyan Hussain, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, addressed the limitations of these technologies for patients with severe complications, such as gastroparesis or those on dialysis, and stressed the need for further innovation and research to meet the needs of disadvantaged populations with diabetes.
CAN WE USE DIABETES TECHNOLOGY IN PEOPLE ON DIALYSIS OR WITH IMPAIRED VISION?
A talk delivered by Tomas Griffin, Galway University Hospital, Ireland, explored whether diabetes technology can be used in people on dialysis or with impaired vision, focusing on the complexities of managing diabetes. Firstly, Griffin described diabetes as the leading cause of end-stage renal disease (ESRD), which accounts for approximately 45% of all cases of people with ESRD in the USA.1 For patients with diabetes who are on dialysis, managing blood glucose levels is complex due to several factors, such as limited medication options, lack of awareness on hypoglycaemia, and fluctuating glucose levels during and after dialysis, contributing to increased cardiovascular risk. Griffin noted that HbA1c, a blood test used to diagnose Type 2 diabetes, may inaccurately reflect glucose control, making CGM necessary. Griffin went on to describe a study that assessed glycaemic control by CGM and HbA1c in patients with ESRD and 'burnt-out' diabetes. The results of this revealed that the number of people with
diabetes on dialysis has increased from 41% to 81% over the recent years. The findings also showed that CGM has proved to be more effective than HbA1c in detecting undiagnosed hyperglycaemia, particularly in patients with burnt-out diabetes, where traditional monitoring may fail.2
Griffin also described several studies on the use of hybrid closed-loop insulin pump therapy. One multicentre study in particular on patients with Type 2 diabetes on haemodialysis showed that after 3 months of CGM-guided basal-bolus insulin therapy, HbA1c levels significantly decreased, without increased hypoglycaemia.3 A randomised control trial further demonstrated that closed-loop insulin delivery reportedly helped patients achieve better glucose control during dialysis, with more time spent in the target glucose range and reduced hypoglycaemia.4
Griffin explained that for individuals with impaired vision, managing diabetes can be particularly difficult, as diabetic retinopathy along with other complications, can significantly affect a person’s ability to manage their condition. Griffin presented several tools such as magnifiers, voice-
enabled glucose meters, and CGMs integrated with voice assistants like Siri (Apple Inc., Cupertino, California, USA) and Alexa (Amazon, Seattle, Washington, USA), that are meant to aid visually impaired people in managing their condition. These smart assistants allow people with visual impairments to receive their glucose data audibly, making it easier for them to manage their condition on their own. As an example, Griffin described the app SugarMate (Tandem Diabetes Care Inc., San Diego, California, USA), which integrates with CGM systems like Dexcom (San Diego, California, USA), providing users with features such as real-time monitoring, personalised alerts, and trend analysis. It can even provide reminders for insulin injections and meal planning through voice commands. To support his point, Griffin described a study by Akturk et al.5 where legally blind patients who used a Dexcom G6 CGM combined with Siri voice assistant showed significant improvements in glycaemic control over 12 months. Furthermore, the patients reportedly experienced reductions in HbA1c and a decrease in episodes of
severe hypoglycaemia. This highlights how voice-enabled CGMs can improve diabetes management for people with visual impairments.5
To conclude, Griffin emphasised how diabetes technology has evolved and its potential to be a useful tool in improving outcomes for people on dialysis or with visual impairment. He noted that hybrid closed-loop insulin pumps and CGM systems can provide better glycaemic control, while technological advancements offer increased accessibility and independence for people with visual impairments.
HbA1c, a blood test used to diagnose Type 2 diabetes, may inaccurately reflect glucose control, making CGM necessary
WHAT CAN WE DO WHEN TECHNOLOGY DOES NOT HELP?
Sufyan Hussain, Guy’s and St Thomas’ NHS Foundation Trust, London, UK, delivered an insightful talk that aimed to address the limitations of current diabetes technology and what more is needed to improve care for people with diabetes, particularly those with complications such as dialysis, gastroparesis, or microvascular issues. Hussain explained the importance of ensuring equitable access to technology, as those who come from lower socioeconomic or minority backgrounds tend to present with the most severe complications and tend to be excluded from the benefits of advanced technologies, either due to systemic barriers or lack of inclusion in clinical trials.
Hussain emphasised that hybrid closed-loop insulin systems have shown promise in managing Type 1 diabetes; however, their impact is often limited, especially in people with complications. Hussain also pointed out that clinical trials of closed-loop systems typically report
modest improvements in HbA1c (0.3% to 0.6%) and focus on people without advanced complications, while real-world evidence in a recent study demonstrated that people with poorer glycaemic control experience larger drops in HbA1c and greater improvements in time in range (TIR).6 Access to these devices is often limited to people of higher socio-economic status, even in public healthcare systems like the NHS in the UK.
Hybrid closed-loop insulin systems have shown promise in managing Type 1 diabetes; however, their impact is often limited
In individuals with advanced complications, such as those of dialysis or with gastroparesis, closed-loop systems are not effective due to the delayed pharmacokinetics of subcutaneously administered insulin. Gastroparesis and dialysis are situations in which glucose levels can rapidly fluctuate, as such, closed-
loop systems cannot adjust quickly enough, leading to poor glucose control in these individuals. Furthermore, the algorithms that power these systems are designed based on data from people without complications, which limits their applicability in patients with diabetes complications.7
One of the key research needs that Hussain highlighted is the need for further studies and product development, especially for algorithm design and options to control the duration of insulin action. Hussain continued to mention the over-represented themes in people with complications like technology rejection, psychological challenges, and anxieties from technology and alarms, which makes it very difficult for patients to manage their condition. Hussain explained that this is a common theme that’s being over-represented in people; therefore, more thought needs to be given to how we manage diabetes distress and technology rejection effectively.
Finally, Hussain touched on the future of diabetes management, pointing to emerging therapies such as cell therapy. While still in the early stages, cell therapy offers hope
References
1. Griffin TP et al. Burden of chronic kidney disease and rapid decline in renal function among adults attending a hospital-based diabetes center in Northern Europe. BMJ Open Diabetes Res Care. 2021;9(1):e002125.
2. Kaminski CY et al. Assessment of glycemic control by continuous glucose monitoring, hemoglobin A1c, fructosamine, and glycated albumin in patients with end-stage kidney disease and burnt-out diabetes. Diabetes Care. 2024;47(2):267-71.
for improved long-term outcomes in people with diabetes, particularly those with severe complications.
To conclude, Hussain noted that more studies are needed in populations with complications to aid optimal device design, algorithm development, features, and simplicity. He highlighted that trials should demonstrate the safety and efficacy of licensing and renumeration. As well as providing better HPC education on the optimal use of hybrid closed-loop systems in those with complications, he also highlighted the issues around staffing and capacity.
CONCLUSION
While diabetes technology offers promise, particularly for those on dialysis or with impaired vision, it has limitations, especially for patients with severe complications. Both Griffin and Hussain emphasised the need for further research, improved algorithms, and more equitable access to ensure these tools can fully benefit all individuals with diabetes.
3. Kepenekian et al. Continuous glucose monitoring in hemosialyzed patients with type 2 diabetes: a multicenter pilot study. Clin Nephrol. 2014;82(4):240-6.
4. Bally et al. Fully closed-loop insulin delivery improves glucose control of inpatients with type 2 diabetes receiving hemodialysis. Kidney Int. 2019;96(3):593-6.
5. Akturk HK et al. Continuous glucose monitor with siri integration improves glycemic control in legally blind
patients with diabetes. Diabetes Technol Ther. 2021;23(1):81-3.
6. Knoll C et al. Real-world evidence on clinical outcomes of people with type 1 diabetes using open-source and commercial automated insulin dosing systems:a systematic review. Diabet Med. 2022;39(5):e14741.
7. Peacock S et al. A systematic review of commercial hybrid closed-loop automated insulin delivery systems. Diabetes Ther. 2023;14(5):839-55.
Youth-Onset Type 2 Diabetes: An Awakening Epidemic
THE RISING global prevalence of youth-onset Type 2 diabetes (Y-T2D) is a serious public health concern. With an aggressive clinical course and debilitating complications by young adulthood, there is an urgent need for effective strategies to inform prevention and treatment of Y-T2D. In a key symposium presented at the 60th European Association for the Study of Diabetes (EASD) Annual Meeting, three leading experts in diabetes shared alarming data on Y-T2D, calling for concerted efforts to improve understanding and management of this emerging epidemic.
EARLY PRESENTATION AND LONG-TERM COMPLICATIONS
For the first time, as of 2018, the incidence of T2D among adolescents aged 15–19 years in the USA exceeded that of Type 1 diabetes (T1D; 19.7 per 100,000 versus 14.6 per 100,000), stated Orit Pinhas-Hamiel, Sheba Medical Center, Tel-Aviv University, Israel. “The data are undeniable […] Y-T2D is an awakening epidemic.”
Hamiel presented two pivotal studies examining T2D in youth: the SEARCH for Diabetes in Youth (SEARCH) Study,1 an observational study initiated in 2000 at five sites in the USA, designed to estimate the prevalence, incidence, and complications of both T1D and T2D in youth; and the Treatment Options for T2D in Adolescents and Youth (TODAY) study,2 an interventional study on adolescents with T2D aimed at assessing various treatment options for disease management.
A key characteristic of Y-T2D is the early presentation of complications, with obesity, hypertension, and dyslipidaemia often evident at diagnosis. In the TODAY study,2 11.6% of adolescents with T2D were hypertensive at baseline. After 1.5 years of follow-up, the SEARCH study found that 27% of youth with T2D were hypertensive,
27% had low high-density lipoprotein, and 25% had elevated triglycerides.1 In a cohort of 500 adolescents with T2D in the TODAY study, 50% of young adults were hypertensive within 10 years after diagnosis, and male participants had almost a 50% higher risk than females of developing hypertension.3 After 13 years, 51.6% of participants had dyslipidaemia.3
However, management of hyperlipidaemia in Y-T2D continues to be suboptimal, and adherence to medication is poor. Only 5% of youth with T2D and lipid abnormalities are prescribed lipid-lowering medications, and only half of youth with hypertension are taking blood pressure-lowering medication, said Hamiel.
A key characteristic of Y-T2D is the early presentation of complications
A primary microvascular complication in Y-T2D is diabetic kidney disease, which is associated with rapid progression and poor prognosis. Beginning with hyperfiltration as a consequence of obesity and impaired glucose tolerance, the second stage is reduction in glomerular filtration rate, typically accompanied by changes in kidney structure, which Hamiel noted are
detectable among most adolescents within 1.5 years of T2D diagnosis. However, these changes are reversible, making this a critical time for intervention and risk factor reduction.
After 15 years, almost 55% of adolescents with Y-T2D are diagnosed with diabetic nephropathy. The SEARCH study found that, after 8 years of diagnosis, the prevalence of diabetic nephropathy was 19.9% among adolescents with T2D compared with 5.8% in those with T1D.1 Alarmingly, a recent meta-analysis also found that the age of T2D onset among those with macroalbuminuria was as young as 6.5 years.4
After 12 years of diagnosis, diabetic retinopathy was present in over ≥50% of SEARCH and TODAY participants, continued Hamiel, and after 15 years, one-third of the SEARCH cohort was also diagnosed with diabetic peripheral neuropathy. Furthermore, cardiovascular autonomic neuropathy was present in 17% of youth with T2D compared to 12% with T1D after 8 years, and heart rate variability was notably reduced in almost half of youth with T2D after only 1.7 years.1,2
Hamiel added that, among adolescents with T2D, HbA1c levels gradually continue to deteriorate through the follow-up period, with 45% displaying HbA1c ≥10% after 9 years of follow-up, and BMI remaining consistently in the range of 35–37.5 kg/m2 .
Beyond microvascular complications, Y-T2D also presents serious macrovascular complications. Most adolescents exhibit predictors for cardiovascular disease such as lower vascular endothelial function, increased arterial stiffness, left ventricular hypertrophy, and diastolic dysfunction. The TODAY study reported 17 serious cardiovascular events among participants,2 with Hamiel reminding the audience that the median age of this cohort was only 26 years. A recent study combining SEARCH and TODAY data found that the probability of microvascular events was 2.5-fold higher in T2D than in T1D, and 4.0-fold higher for macrovascular events.5
Significantly, the standardised mortality ratio of youth with T2D aged under 15 years is almost 4-fold higher than that of T1D.6 Among youth with T2D, females had higher mortality rates than males, and diabetes was the underlying cause of death
for 9.1% of participants, with other causes of mortality including cancer (10.9%), cardiovascular disease (9.1%), and suicide (10%). Alarming data from a life expectancy model predict that youth with T2D lose approximately 15 years of life.6
Finally, Hamiel touched on pregnancy outcomes in women with Y-T2D. The TODAY Study reported pregnancy complications in 65% of the women, with chronic hypertension complicating pregnancy in 35% of cases, and 25% resulting in pregnancy loss, 35% in preterm birth, and 3% in stillbirths, which is more than triple the reported national stillbirth rates in the USA. Additionally, 10% of offspring had cardiac anomalies, 10% had other congenital anomalies, 27% were large for gestational age, 29% had neonatal hypoglycaemia, and 19% had respiratory distress. Combined exposure to maternal diabetes and obesity in utero accounts for 47% of T2D risk in young offspring, emphasised Hamiel.
With the huge burden of complications suffered by adolescents with T2D, which significantly exceeds that of adults with T2D and youth with T1D, Hamiel called for “a proactive and assertive approach”, to intervene early and mitigate risk factors.
BRAIN AND COGNITIVE HEALTH IN YOUTH-ONSET TYPE 2 DIABETES
Allison Shapiro, University of Colorado Anschutz Medical Campus, USA, opened her session by drawing attention to the key processes in brain and cognitive development that occur after birth and throughout childhood and adolescence: myelination, synaptogenesis, and neurogenesis. Alarmingly, the onsets of paediatric obesity and Y-T2D are overlaid onto this neurodevelopmental trajectory.
Large cohort studies have consistently reported an inverse association between grey matter volume (GMV) and white matter integrity in the prefrontal cortex, and child BMI.7,8 Interestingly, one study also found that alterations in the structure of the prefrontal cortex may contribute
to, and predict, behaviours that underlie weight gain and future risk of obesity.8 The authors also found that 70% of corticalcortical functional connectivity had inverse correlations with BMI.8
Obesity in adult T2D has been linked to disruptions in key homeostatic brain regions, in particular the hypothalamus, which is responsible for appetite control and eating behaviour. Shapiro’s research is currently focused on hypothalamic connectivity in adolescents with and without severe obesity, and preliminary results suggest increased homeostaticreward connectivity in adolescents with obesity compared to those with healthy weight. These data point to “neural signatures that likely contribute to cognitive behavioural risk factors for eating disinhibition,” explained Shapiro.
However, Shapiro stressed that very few studies have actually examined brain and cognitive health in Y-T2D. One study by Redel et al.9 found significantly lower GMV in youth with obesity and T2D compared to healthy controls, especially in the occipital and temporal lobes, which are associated with reading and writing, visual attention, receptive language, and memory encoding.
“What alterations in brain structure are unique to Y-T2D, compared to adolescents with obesity, and those with healthy weight?” Shapiro’s recent research found that unique characteristics of Y-T2D included reduced GMV in the orbital frontal cortex and anterior prefrontal cortex compared to individuals with obesity, which are regions responsible for decision-making, reward-related behaviour, and cognitive flexibility. A key feature shared both by youth with Y-T2D and youth with obesity included reduced GMV in the dorsal lateral prefrontal cortex.
Shapiro added that adolescents with Y-T2D also have lower processing speed and verbal working memory compared to both healthy controls and adolescents with obesity, showing that T2D impacts cognition functions beyond just the effect of obesity. Furthermore, Shapiro’s group also found that youth with T2D displayed a reduced
overall fluid cognition compared to youth with T1D, based on data from the SEARCH study.10
Shapiro stressed that the observed brain alterations and deficits in Y-T2D may progress into middle or later adulthood, potentially affecting the development of dementia and other neurodegenerative diseases; however, there are currently no data that follow this.
MANAGEMENT OF YOUTH-ONSET TYPE 2 DIABETES: SHOULD IT BE DIFFERENT?
Amy Shah, Cincinnati Children’s Hospital Medical Center, Ohio, USA, explained that the current recommendations for initial treatment of T2D in youth depend on clinical presentation and HbA1c levels, as outlined in the 2022 International Society for Pediatric and Adolescent Diabetes (ISPAD) Guidelines.11
If HbA1c is <8.5% with no signs of ketosis/ acidosis at diagnosis, the recommendation is to pursue a healthy lifestyle and titrate metformin to 2 g/day; if HbA1c is ≥8.5% with no signs of ketosis/acidosis, the recommendation is also healthy lifestyle and metformin, with additional basal insulin therapy. However, a more severe clinical presentation that includes ketosis, acidosis, or hyperglycaemic hyperosmolar syndrome warrants intravenous insulin until acidosis is resolved, then transition to subcutaneous insulin. The optimal target for HbA1c following initial therapy is currently 6.5–7%. For HbA1c levels ≥7–9%, a glucagon-like peptide receptor agonist (GLP-1 RA) is recommended, which should be combined with long-acting insulin if HbA1c levels ≥9%.
Nonetheless, Shah stressed that metformin failure rate is significantly higher in youth (52%) than in adults (21%), and so is the annual rate of beta cell decline (20–35% versus 7–11%).2,12 Furthermore, newer medications for Y-T2D are not as effective as expected. The greatest treatment difference that has been achieved to date, with regards to decrease in HbA1c compared to placebo, was only
With a more severe pathophysiology and poorer responses to medication, management of Y-T2D should absolutely be different to that of adult T2D
–1.5 percentage points with GLP-1 RA dulaglutide, and this was not associated with a significant reduction in BMI.13
With a more severe pathophysiology and poorer responses to medication, management of Y-T2D should absolutely be different to that of adult T2D, stated Shah. She highlighted four potential avenues for Y-T2D treatment: higher doses, medications that affect multiple hormones, alternative treatments, and combination therapy.
For instance, previous data indicate that higher doses of semaglutide (2.4 mg) in youth with obesity significantly reduced BMI by 15%,14 showing promise for treatment of Y-T2D. Furthermore, targeting different hormones in adults with T2D, using the combined GLP-1-RA and glucosedependent insulinotropic polypeptide (GIP) agonist tirzepatide, led to a significantly stronger reduction in BMI and HbA1c compared to GLP-1 RA semaglutide.15
References
1. Hamman RF et al. The SEARCH for Diabetes in Youth study: rationale, findings, and future directions. Diabetes Care. 2014;37(12):3336-44.
2. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY). NCT00081328. https://www. clinicaltrials.gov/study/NCT00081328.
3. Bjornstad P et al. Long-term complications in youth-onset type 2 diabetes. N Engl J Med. 2021;385(5):416-26.
4. Cioana M et al. Prevalence of hypertension and albuminuria in pediatric type 2 diabetes. JAMA Netw Open. 2021;4(4):e216069.
5. Mottl AK et al. Major adverse events in youth-onset type 1 and type 2 diabetes: The SEARCH and TODAY studies. Diabetes Res Clin Pract. 2024;210:111606.
The GLP-1, GIP, and glucagon ‘tri-agonist’ retatrutide is also on the horizon, with promising preliminary results in adults with obesity. Regarding alternative therapies, Shah stated that weight loss surgery should be considered for a more dramatic reduction in BMI and mitigation of longterm complications.
Shah ended the session with the upcoming 2024 ISPAD Guidelines, which will recommend a new target of HbA1c <6.5% for Y-T2D for tight glycaemic control, and push for a combination approach to achieve this target. Given the aggressive nature of T2D, the recommendation will be to maximise metformin therapy, followed by the stepwise incorporation of a GLP-1 RA or SGLT2 inhibitor, long-acting insulin, and prandial insulin therapy where necessary. This combination approach has not been tested to date, and will need to be assessed in studies going forward.
6. Lawrence JM. Demographic correlates of short-term mortality among youth and young adults with youth-onset diabetes diagnosed from 2002 to 2015: the SEARCH for diabetes in youth study. Diabetes Care. 2021;44(12):2691-8.
7. Ronan L et al. Childhood obesity, cortical structure, and executive function in healthy children. Cereb Cortex. 2020;30(4):2519-28.
8. Adise S et al. Multimodal brain predictors of current weight and weight gain in children enrolled in the ABCD study®. Dev Cog Neurosci. 2021;49:100948.
9. Redel JM et al. Brain gray matter volume differences in obese youth with type 2 diabetes: a pilot study. J Pediatr Endocrinol Metab. 2018;31(3):261-68.
10. Shapiro ALB et al. Cognitive function in adolescents and young adults with youth-onset type 1 versus type 2
diabetes: the SEARCH for diabetes in youth study. Diabetes Care. 2021;44(6):1273-80.
11. ISPAD Clinical Practice Consensus Guidelines 2022: Definition, epidemiology, and classification of diabetes in children and adolescents: Pediatr Diabetes 2022;23(8):1160-74.
12. Kahn SE et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427-43.
13. Arslanian SA et al. Once-weekly dulaglutide for the treatment of youths with type 2 diabetes. N Engl J Med. 2022;387(5):433-43.
14. Weghuber D et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med. 2022;387:2245-57.
15. Frías JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15.
Abstract Reviews
Drawing on insights from the European Association for the Study of Diabetes (EASD) Annual Meeting 2024, these abstract reviews spotlight notable new advancements and key focuses in the field of diabetes.
Meal Timing: Its Relation to Metabolism and Heritability in German Adult Twins
Authors: *Olga Pivovarova-Ramich,1-4 Janna Vahlhaus,1,5 Beeke Peters,1,3,6 Silke Hornemann,4 Anne-Cathrin Ost,4,7 Michael Kruse,4 Andreas Busjahn,8 Andreas F.H. Pfeiffer2-4
1. Department of Molecular Metabolism and Precision Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
2. Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolism, Germany
3. German Center for Diabetes Research (DZD), München-Neuherberg, Germany
4. Department of Clinical Nutrition, German Institute of Human Nutrition PotsdamRehbruecke, Nuthetal, Germany
5. University of Lübeck, Germany
6. Department of Human Nutrition, German Institute of Human Nutrition PotsdamRehbruecke, Nuthetal, Germany
7. University of Leipzig, Germany
8. HealthTwiSt GmbH, Berlin, Germany
*Correspondence to olga.ramich@dife.de
Disclosure: Busjahn received honoraria for the statistical analysis from HealthTwiSt GmbH. Pivovarova-Ramich has received grants from the German Research Foundation and the European Association of the Study of Diabetes (EASD); and has received payment or honoraria from Novo Nordisk. The other authors declare no conflicts of interest.
Acknowledgements: The authors thank all study participants for their cooperation. They gratefully acknowledge the technical assistance of Andreas Wagner, Melanie Hannemann, and Anja Henkel. They also thank Elwira Gliwska for her contribution to the algorithm development for the analysis of meal timing.
Meal timing is a crucial factor influencing metabolic health, which can be explained by the tight interaction between circadian clocks and metabolic homeostasis.1 Recent evidence suggests that meal timing pattern might contribute to obesity and diabetes risk,2 but this topic is still insufficiently studied. This work aimed to investigate the link between individual meal timing pattern and glucose metabolism as well as explore the contribution of genetic and environmental factors to the meal timing architecture.
METHODS
The research was conducted in a German NUtriGenomic Analysis in Twins (NUGAT) cohort (NCT01631123; n=89) comprising 32 monozygotic and 12 dizygotic twin pairs with a BMI of 22.8±2.8 kg/m² and median age of 25.0 years (interquartile range: 22.0).3 Glucose metabolism was assessed using the oral glucose tolerance test. Parameters of meal timing pattern (meal timing itself, daily calorie distribution, and meal number) were extracted from 5-day food records. Circadian timing of the caloric midpoint of the first and last eating events was determined as the time differences relative to the individual chronotype (MSFsc) assessed by the Munich chronotype questionnaire. Heritability of
meal timing components was estimated by the ACE model, and bivariate correlation analyses were performed to assess their relation to metabolic traits.
RESULTS
Correlation analysis revealed a number of associations between meal timing components and glucose metabolism parameters. Most associations were found for the calorie midpoint, defined as the time point at which 50% of daily calories were consumed. Indices of insulin sensitivity, Stumvoll Insulin Sensitivity Index (β=0.334; p=2.9x10-4) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR; β=-0.276; p=0.007), as well as fasting insulin levels (β=-0.278; p=0.008), were significantly associated with the circadian caloric midpoint even after the model adjustment for gender, age, energy intake, and sleep duration (Table 1). The association with the Matsuda Insulin Sensitivity Index was lost after the adjustment for energy intake and sleep duration. BMI and waist circumference also demonstrated robust associations with the circadian caloric midpoint in adjusted models (β=-0.263; p=0.005; and β=-0.194;
p=0.014, respectively). All meal timing components showed high or moderate heritability. Meal timing components demonstrated the strong relation to the individual sleep-wake timing and chronotype, both of which also showed a marked genetic impact.
CONCLUSION
Circadian meal timing is associated with insulin sensitivity and shows significant genetic influences, sharing a common genetic architecture with sleep behaviour. These findings help to differentiate (none-) modifiable factors driving individual meal timing, which is important for the development of effective nutritional strategies to combat obesity and diabetes.
References
1. Kessler K, Pivovarova-Ramich O. Meal timing, aging, and metabolic health. Int J Mol Sci. 2019;20(8):1911.
2. Peters B et al. Meal timing and its role in obesity and associated diseases. Front Endocrinol (Lausanne). 2024;15:1359772.
3. German Institute of Human Nutrition. NUtriGenomic Analysis in Twins (NUGAT). NCT01631123. https:// clinicaltrials.gov/study/NCT01631123?tab=results.
Linear regression analyses were performed to estimate the strength of association between variables. β are the standardised coefficients; p are the p-values.
HOMA-IR: Homeostatic Model Assessment for Insulin Resistance; ISI: Insulin Sensitivity Index.
Table 1: Associations of circadian caloric midpoint with insulin sensitivity and fasting insulin.
Screening and Monitoring for Presymptomatic Type 1 Diabetes: The DiaUnion Project
Authors: *Julie H. Klæbel,1 Alexander Lind,2 Samia Hamdan,2 Maria N. Scherman,2 Finn Kristensen,3 Julie C. Antvorskov,1 Daniel Agardh,2 Flemming Pociot1
1. Steno Diabetes Center Copenhagen, Herlev, Denmark
2. Lund University CRC, Malmö, Sweden
3. Medicon Valley Alliance, Copenhagen, Denmark
*Correspondence to Julie.hviid.klaebel@regionh.dk
Disclosure: Klæbel, Lind, Hamdan, Kristensen, Antvorskov, Agardh, and Pociot have received all the support for the present manuscript from EU Interreg ÖKS, RegH Denmark, Region Skåne, Lund University, Steno Diabetes Center Copenhagen, Barndiabetesfonden, and Novo Nordisk Foundation with payment to the institution; they received EDENT1FI grant with payments to the institution. Klæbel has received a grant from Diabetesforeningen that will be spent as salary for employment at Steno Diabetes Center Copenhagen. Kristensen has an unpaid leadership or fiduciary role in Børnediabetesfonden. Pociot has participated in the advisory board at Sanofi with payments for the same. The authors have declared no conflict of interest.
Keywords: Autoimmune disease, autoimmune thyroid disease (AITD), coeliac disease (CD), early detection, prediction, screening, Type 1 diabetes (T1D).
Type 1 diabetes (T1D), coeliac disease (CD), and autoimmune thyroid disease (AITD), abbreviated as TRIAD diseases, are three common autoimmune diseases with onset in childhood and adolescence.1 CD and AITD share high-risk genes with T1D, so a patient with T1D will have an increased risk of additionally being diagnosed with these diseases.2,3 TRIAD diseases are predictable in the prodromal phases with the potential to stratify the risk of disease by early autoimmune biomarkers. Autoantibodies (AAB) are key biomarkers for the identification of at-risk individuals prior to
the appearance of clinical symptoms.4 The future goal is to establish a public screening programme identifying people who will develop a TRIAD disease later in life. Thus, this study aimed to test a recruitment model, home capillary blood sampling, and laboratory analyses.
MATERIALS AND METHODS
A total of 1,420 first-degree relatives (0–18 years, established biobank cohort of siblings) to newly diagnosed childhood/ adolescent patients with T1D in Denmark, and 2,271 children (two age cohorts: 7–8 and 13–14 years) from the general population in Skåne were included in the study. Participants from the general population in Skåne received a home capillary kit for blood sampling with a video guide and returned the sample by public mail later. The antibody detection by agglutination-PCR (ADAP) multiplex technology as first-stage screening was compared with the gold standard radio binding assay (RBA) for the analysis of six AAB (glutamic acid decarboxylase, insulin, protein phosphatase-like IA-2 [IA-2A], zinc transporter 8 [ZnT8], thyroperoxidase, and tissue transglutaminase). Both Danish and Swedish samples were screened using the ADAP technology, and AAB positivity was confirmed by RBA.
RESULTS
From the Danish samples, 193 (13.6%) were positive for a TRIAD AAB, 107 (7.5%) were positive for a T1D AAB, 55 (3.9%) were positive for a CD AAB, 55 (3.9%) were positive for AITD AAB, and 65 (4.6%) were positive for ≥2 T1D AAB. In the Swedish study, 19,593 children were invited, and of those 2,271 individuals were included. From these, 211 (9.3%) were positive for a TRIAD AAB, 60 (2.6%) were positive for a T1D AAB, 61 (2.7%) were positive for a CD AAB, 99 (4.4%) were positive for AITD AAB,
Figure 1: TRIAD autoantibody positivity in Danish first-degree relatives and Swedish general paediatric population.
D K S E
DK (FDR)
Aab+ in screening n=193(13.6%)
A a b + i n s c re e n i n g n = 1 9 3 ( 1 3 6 % )
SE (GP)
Aab+ in screening n=211 (9.3%)
ADAP and RBA agreement ranged from 97.1%-99.3%
ADAP and RBA agreement ranged from 97.1 –99.3%
T1D Aab+ n=60 (2.6% of screened)
T 1 D A a b + n=107 ( 7 5 % o f s c re e n e d )
T1D Aab+ n=107 (7.5% of screened)
CD Aab+ n=61 (2.7% of screened)
C D A a b + n=55 ( 3 9 % o f s c re e n e d )
CD Aab+ n=55 (3.9% of screened)
AITD Aab+ n=99 (4.4% of screened)
A I T D A a b + n=55 ( 3 . 9 % o f s c re e n e d )
AITD Aab+ n=55 (3.9% of screened)
A a b + f o r m u l t i p l e T R I A D d i s e a s e s n=24
Aab+ for multiple TRIAD diseases n=24 (1.7% of screened)
Aab+ for multiple TRIAD diseases n=9 (0.4% of screened)
Aab+: autoantibody positive; ADAP: antibody-detection by agglutination PCR; AITD: autoimmune thyroid disease; CD: coeliac disease; DK: Danish; GP: general paediatric population; FDR: first-degree relatives; RBA: radio binding assay; SE: Swedish; T1D: Type 1 diabetes.
and 14 (0.6%) were positive for ≥2 T1D AAB. For 2,271 samples, ADAP and RBA were compared, and agreement ranged from 97.1– 99.3% (Figure 1).
CONCLUSION
The study confirms the high prevalence of associated autoimmunity in first-degree relatives, which supports the relevance of screening for multiple autoimmune diseases in this population. From these results, the authors can conclude that they have established an effective recruitment model with the participants being able to collect the screening sample at home. Thus, the authors’ model has the potential to be implemented as a large-scale screening programme identifying high-risk individuals. Moreover, it was shown that
the ADAP method was comparable to the conventional RBA for the detection of AAB associated with TRIAD and can be applied as a first-stage screening method.
References
1. Naredi Scherman M et al. Home capillary sampling and screening for type 1 diabetes, celiac disease, and autoimmune thyroid disease in a Swedish general pediatric population: the TRIAD study. Front Pediatr. 2024;12:1386513.
2. Smyth DJ et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359(26):2767-77.
3. Jacobson EM et al. The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology. J Autoimmun. 2008;30(1-2):58-62.
4. Ziegler AG et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473-9.
Sex-Specific Differences of Human Skeletal Muscle: A Multi-Omics Exercise Study
Authors: *Simon Dreher,1 Thomas Goj,1,2,3
Christine von Toerne,4 Miriam Hoene,1 Martin Irmler,5 Meriem Ouni,3,6 Markus Jähnert,3,6
Johannes Beckers,3,5,7 Andreas Peter,1,2,3 Andreas L. Birkenfeld,2,3,8 Annette Schürmann,3,6,9 Stefanie M. Hauck,3,4 Cora Weigert1,2,3
1. Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Germany
2. Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München, University of Tübingen, Germany
3. German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
4. Metabolomics and Proteomics Core Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
5. Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
6. Department of Experimental Diabetology, German Instiute of Human Nutrition PotsdamRehbruecke (DIfE), Nuthetal, Germany
7. School of Life Sciences, Chair of Experimental Genetics, Technical University Munich, Germany
8. Department of Internal Medicine IV, University Hospital Tübingen, Germany
9. Institute of Nutritional Science, University of Potsdam, Germany
*Correspondence to simon.dreher@med.uni-tuebingen.de
Disclosure: Dreher and Hoene have both received support for the manuscript from German Diabetes Association (DDG) with a grant payment to the institution. This abstract was accepted for presentation at the EASD Annual Meeting in 2024. Dreher is a committee member of EASD Early Career Academy. The authors have declared no conflict of interest.
Exercise is a potent skeletal muscle stimulus and the most effective strategy to prevent weight loss-related muscle loss and Type 2 diabetes. Biological sex-based differences are reported for aerobic capacity, muscle mass, muscle-fibre-type composition, and
exercise performance. The authors aimed to provide a missing comprehensive picture of molecular differences between female and male skeletal muscle at baseline, after acute exercise and training. Further, the authors investigated which differences were conserved in vitro in myoblasts and myotubes obtained from these donors.
METHODS
The authors characterised muscle biopsies from 25 (16 female and nine male) subjects in a multi-omics approach employing epigenomics, transcriptomics, and proteomics at baseline, after acute exercise and 8 weeks of supervised endurance training. Donor-matched myoblasts and myotubes were analysed in vitro.
RESULTS
The authors found differential CpGsite methylation in 16,012 genes, 1,366 differentially expressed genes, and 120 differentially expressed proteins at baseline. Non-autosomal expression was conserved in vitro, but only a few sexbased differences in the expression of autosomal genes were noted.
Differential transcripts were among other pathways associated with glucose homeostasis and insulin signalling. Differences in the proteome were dominated by higher abundance of proteins regulating glycolysis and of other fast-twitch fibre-type proteins in males. Females showed a higher abundance of proteins regulating fatty acid handling. Acute exercise upregulated oxidative stress-responsive transcripts predominantly in males.
After 8-week training, both sexes had upregulated mitochondrial proteins involved in substrate oxidation and ATP production, while the fast-twitch fibre marker, MYH1, was only reduced in males.
CONCLUSION
The sex-specific composition of the proteome underpins the differences in glucose and fatty acid metabolism in female and male skeletal muscle. Training
might mitigate these differences found in the untrained muscle. The few conserved differences in vitro point to hormonal or yet undefined mechanisms of the sex-specific characteristics in the DNA methylome, transcriptome, and proteome.
The following highlights showcase late-breaking research presented at the European Association for the Study of Diabetes (EASD) Annual Meeting 2024. Topics covered ranged from maternal effects on Type 1 diabetes development to the impact of diabetic peripheral neuropathy on patient mental health. Additionally, a common theme was the connection between Type 1 diabetes and other autoimmune diseases, such as coeliac disease and Graves’ disease.
Maternal Type 1 Diabetes Protects Offspring From the Disease
NEW RESEARCH presented at EASD 2024 revealed that maternal Type 1 diabetes (T1D) provides long-term relative protection against the development of the disease in offspring, compared to paternal T1D.
The findings suggest that in utero exposure to maternal T1D plays a role in reducing the offspring's risk of developing the disease
The study analysed data from over 11,000 individuals diagnosed with T1D and found that children of fathers with T1D are nearly twice as likely to develop the disease compared to children of mothers with T1D.
The study analysed data from five major studies, including BOX, Better Diabetes Diagnosis, TrialNet Pathway to Prevention, Type 1 Diabetes Genetic Consortium, and StartRight. The results showed that participants were significantly more likely to have an affected father than an affected mother. This pattern held true for both individuals diagnosed with T1D before and after the age of 18 years.
However, the protective effect of maternal T1D was only observed when the mother was diagnosed before the child’s birth. If the mother was diagnosed after the birth, there was no significant difference in T1D risk compared to children of affected fathers. The T1D genetic risk score did not differ between individuals with mothers or fathers with T1D, indicating that the protection is not related to genetic factors.
The findings suggest that in utero exposure to maternal T1D plays a role in reducing the offspring's risk of developing the disease, offering new insights into the mechanisms underlying maternal protection. The researchers emphasised that this is the largest study to date that explores this phenomenon and provides further evidence for understanding familial transmission of T1D.
Early Screening Reduces Risk of Type 1 Diabetes and Coeliac Disease
A 7-YEAR population-based screening study conducted from 2017–2023 has demonstrated the effectiveness of early detection for Type 1 diabetes (T1D) and coeliac disease (CD) in children aged 1–17 years old. The study, presented at EASD 2024, has shown that screening for autoantibodies offers a way to prevent significant morbidity from delayed diagnoses, enabling early intervention.
Over this period, 34,110 children were screened for islet autoantibodies associated with T1D and transglutaminase autoantibodies linked to CD. The majority of these children (94%) did not have a first-degree relative with T1D, underscoring the importance of screening beyond family history. Most screenings were conducted in paediatric care clinics and outpatient labs.
The programme employed both radiobinding assays and the more specific electrochemiluminescence to measure islet and transglutaminase autoantibodies. The electrochemiluminescence method was especially valuable for distinguishing predictive, high-affinity autoantibodies from non-predictive ones. Children with positive results underwent further testing, which included assessments of autoantibodies by both methods, haemoglobin A1c, random blood glucose levels, and a thorough review of symptoms. Follow-up care was provided to those with confirmed multiple autoantibodies or high-affinity single autoantibodies, offering education to prevent diabetic ketoacidosis and referrals to clinical services or prevention trials.
Results showed that 0.54% of the children had multiple islet autoantibodies, predicting a 70% chance of developing T1D within 10 years, and 0.42% had a single high-affinity ab with a 30% risk. Notably, 90% of these highrisk children lacked a family history of T1D. Over a 3-year follow-up period, 77 children were diagnosed with clinical diabetes, and an additional 105 were identified at Stage 2 T1D. The screening also detected CD in 2.3% of participants, with 93% of those testing positive for transglutaminase autoantibodies receiving a confirmed diagnosis of CD.
The programme highlights the utility of widespread screening for early diagnosis of T1D and CD, significantly reducing diabetic ketoacidosis rates and enabling proactive disease management.
Results showed that 0.54% of the children had multiple islet autoantibodies, predicting a 70% chance of developing T1D within 10 years
90
children were diagnosed with clinical diabetes over a 3 year follow-up period
2.3 of these high-risk children lacked a family history of T1D
of participants were detected to have CD in the screening % % 77
The researchers emphasised the potential of voice-based screening as a cost-effective and widely accessible tool for early T2D detection
Researchers found that the voice-based algorithm accurately predicted T2D in 71% of male participants and 66% of females.
Voice Analysis Shows Potential for Detecting Type 2 Diabetes
A NEW study presented at EASD 2024 found that voice analysis could be a non-invasive, scalable method for detecting Type 2 diabetes (T2D).
The study involved 607 participants from the USA and aimed to assess how well AI could differentiate between individuals with and without T2D based solely on their voices. Researchers found that the voice-based algorithm accurately predicted T2D in 71% of male participants and 66% of females. The predictive accuracy improved in specific groups, such as females over 60 years (74% accuracy) and participants with hypertension (75% accuracy in both genders).
The AI model was trained using voice recordings of participants reading text and cross-validated to ensure robustness. The study compared the AI’s performance to the American Diabetes Association (ADA) risk score for T2D and found over 93% agreement between the two methods, demonstrating that voice analysis can be as effective as traditional risk assessment tools.
The researchers emphasised the potential of voice-based screening as a costeffective and widely accessible tool for early T2D detection, particularly in at-risk populations. The researchers also noted that their findings are a promising first step toward using voice analysis as a first-line screening strategy for T2D. However, they emphasised the need for further research and validation, especially targeting earlystage cases of the disease.
This new approach could revolutionise diabetes screening by providing a simple, non-invasive method that can be easily deployed through digital platforms, potentially helping to reduce the global burden of undiagnosed T2D.
Diabetic Peripheral Neuropathy, Neuropathic Pain, and Mental Health
A RECENT study presented at EASD 2024 by researchers at Aalborg University Hospital and Steno Diabetes Center North Denmark sheds light on the significant impact of diabetic peripheral neuropathy (DPN) and neuropathic pain on the quality of life (QoL) and mental health of people with diabetes.
The observational, cross-sectional study included 7,743 participants, excluding 781 due to incomplete socioeconomic and mental health data. The remaining participants were divided into those with DPN (n=1,601) and those without (n=5,361). Of those with DPN, 1,085 also suffered from neuropathic pain, while 516 had painless DPN. Researchers utilised the Short Form Health Survey (SF36) and the Hospital Anxiety and Depression Scale (HADS) to assess QoL, depression, and anxiety levels.
Results showed a significant difference in QoL between participants with and without DPN. The median SF36 score for those with DPN was 55.1 (interquartile range [IQR]: 36.7–73.6) compared to 82.2 (IQR: 63.6–90.9) for those without DPN (P<0.001).
Mental health was similarly affected, with HADS depression scores of 4.0 (IQR: 1–8) for those with DPN, versus 1.0 (IQR: 0–3) for those without (P<0.001). Anxiety scores followed a similar trend, with median HADS anxiety scores of 5.0 (IQR: 2–9) for those with DPN and 2.0 (IQR: 1–5) for those without (P<0.001).
The impact was even more severe for participants with both DPN and neuropathic pain. Their median SF36 score dropped to
Anxiety levels were highest in the painful DPN group, with a median score of 6.0 compared to 4.0
50.7 (IQR: 34.8–69.8), compared to 61.2 (IQR: 45.2–79.0) for those with painless DPN (P<0.001). Depression and anxiety scores also worsened, with HADS depression scores of 4.0 (IQR: 1–8) for those with painful DPN and 1.0 (IQR: 0–3) for those without pain. Anxiety levels were highest in the painful DPN group, with a median score of 6.0 (IQR: 3–10), compared to 4.0 (IQR: 1–8) for those without pain (P<0.001).
This study highlights the need for comprehensive care that addresses both physical symptoms and mental health in people with diabetes, especially those with DPN and neuropathic pain.
Imaging Biomarkers Reveals Pancreatic Changes in Type 1 Diabetes
OVER TIME, the chronic inflammation of the pancreatic islets, which leads to the destruction of insulin-producing beta cells in patients with Type 1 diabetes (T1D), spreads to the surrounding exocrine pancreas, causing increased immune cell infiltration and pancreatic atrophy.
In some cases, the development of parenchymal fibrosis may also occur, further complicating the disease. Due to the pancreas's location and sensitivity, tissue biopsies are risky. This makes non-invasive imaging techniques like multiparametric magnetic resonance imaging (mpMRI) valuable for studying pancreatic changes in people with T1D. A UK Biobank study, presented at EASD 2024, aimed to characterise the pancreas in T1D using mpMRI markers to assess fibro-inflammation, fat content, and pancreatic volume, comparing these parameters with individuals who have Type 2 diabetes (T2D) and healthy controls.
The study analysed data from the UK Biobank using mpMRI to extract three key metrics: fibroinflammation (srT1), fat content (proton density fat fraction, PDFF), and pancreatic volume. These were compared across individuals with T1D (n=106), T2D (n=1,190), and healthy controls (n=17,433).
Several key findings emerged, the first of which was that individuals with T1D showed significantly higher pancreatic fibroinflammation, indicated by elevated srT1 values, compared to the other groups. Patients with T1D averaged 813 ms, compared to 763 ms in patients with T2D and 759 ms in healthy controls. This heightened inflammation in T1D reflects the autoimmune processes in the disease.
Pancreatic volume was also smaller in patients with T1D, averaging 59 mL compared to 68 mL in patients with T2D and 66 mL in healthy individuals. The smaller size is likely due to beta-cell loss and long-term inflammation. Additionally, patients with T1D had significantly lower pancreatic fat content (2.99%) compared to T2D (4.75%) and healthy controls (3.65%), suggesting a distinct metabolic profile in T1D.
The study found a negative correlation between fibro-inflammation and pancreatic volume, indicating that as inflammation increased, pancreatic size decreased. The use of mpMRI revealed that individuals with T1D have increased fibro-inflammation, smaller pancreatic size, and lower fat content. The results suggest that non-invasive imaging could become a key tool for monitoring T1D progression and treatment effects, offering a safer alternative to biopsies.
The study found a negative correlation between fibroinflammation and pancreatic volume, indicating that as inflammation increased, pancreatic size decreased
Genetic Risk Score Influences Response to Type 1 Diabetes Immunotherapies
A NEW study presented at EASD 2024 demonstrated that the genetic risk score for Type 1 diabetes (T1D) may predict how well individuals respond to immunotherapies aimed at preventing the disease.
Researchers analysed data from autoantibodypositive participants from three prevention trials, TrialNet Anti-CD3 (teplzumab), TrialNet Abatacept, and TrialNet Oral Insulin. The study found that individuals with a higher GRS2, an indicator of higher risk for T1D, were more likely to progress to the clinical stage of T1D when treated with abatacept or oral insulin. However, participants treated with teplizumab showed a different pattern. The participants with a GRS2 score of 13 or higher had a significantly reduced risk of developing T1D compared to those in the placebo group, suggesting that teplizumab is more effective in individuals with a higher genetic burden.
The participants with a GRS2 score of 13 or higher had a significantly reduced risk of developing T1D
Additionally, the study found that individuals with a lower GRS2 score did not experience the same protective effect from teplizumab, indicating a decreased response to the therapy. These findings suggest that the genetic risk score could be used as a tool for identifying patients who are more likely to benefit from certain immunotherapies, particularly teplizumab, in preventing the onset of T1D.
The findings of the study indicate the potential for using genetic information to tailor treatments and improve outcomes for individuals at risk of developing T1D.
Maternal Stress Shown Not to Affect Childhood Diabetes Risk
A RECENT study conducted in Norway, involving the largest cohort to date, explored the potential link between maternal psychological stress and the onset of Type 1 diabetes (T1D) in children. Previous studies have suggested that psychological stress may influence the immune system, potentially playing a role in the development of T1D, but results have been inconclusive. This study, presented at EASD 2024, aimed to determine whether maternal stress during pregnancy or the child’s early years increases the risk of T1D.
The study analysed data from
91,000 mother-child pairs born between 2000–2009 and were followed until 2021
The study analysed data from the Norwegian Mother, Father, and Child Cohort (MoBa) study, which included up to 91,000 mother–child pairs. These children were born between 2000–2009 and were followed until 2021. Information on maternal anxiety, depression, and negative life events was collected through repeated validated questionnaires. The study tracked whether the children developed T1D before age 18 years using the Norwegian Childhood Diabetes Registry, where 551 children were diagnosed.
The researchers used binary log-linear regression to estimate relative risks (aRR) of developing T1D, adjusting for several factors including maternal T1D, age, parity, education, smoking, and pre-pregnancy BMI. Maternal symptoms of anxiety or
depression during pregnancy were not associated with an increased risk of T1D in children (aRR: 0.91; 95% CI: 0.71–1.17). Similarly, negative life events reported during pregnancy (aRR: 1.04; 95% CI: 0.96–1.12) showed no significant correlation with the onset of T1D. The results were consistent when examining maternal stress at 6, 18, and 36 months after childbirth.
Other aspects of stress, such as job-related stress, social support, self-esteem, and overall life satisfaction, were also not found to be significant contributors to T1D risk. The study found no evidence to support a link between maternal psychological stress and the development of T1D in children, and therefore, these findings suggest that other factors, beyond maternal stress, are more likely to influence the onset of T1D.
SGLT2 Inhibitor Reduces Risk of Neurodegenerative Diseases in Type 2 Diabetes
RESEARCH presented at EASD 2024 has revealed that sodium-glucose cotransporter 2 inhibitor (SGLT2i) use reduces the risk of Alzheimer’s disease (AD), vascular dementia, and Parkinson's disease in patients with Type 2 diabetes.
The study included 1,348,362 participants aged 40 years and above with Type 2 diabetes who initiated antidiabetic therapy between 2014–2019. After matching participants based on propensity scores, 358,862 individuals were included in the final analysis (mean age: 57.8 years; 57.9% male). Over the follow-up period, 6,837 incidents of dementia or Parkinson's disease were recorded.
The results revealed that SGLT2i use was associated with a 19% reduction in Alzheimer’s risk (adjusted hazard ratio[aHR]: 0.81; 95% CI: 0.76–0.87), a 31% reduction in vascular dementia risk (aHR: 0.69; 95% CI: 0.60–0.78), and a 20% reduction in Parkinson’s disease risk (aHR: 0.80; 95% CI: 0.69–0.91). Furthermore, the use of SGLT2i lowered the risk of all-cause dementia by 21% (aHR: 0.79; 95% CI: 0.69–0.90) and the combined outcome of dementia and Parkinson's disease by 22% (aHR: 0.78; 95% CI: 0.73–0.83).
These effects were consistent across various subgroups, regardless of age, sex, BMI, blood pressure, glucose, lipid profiles, kidney function, health behaviours, Charlson comorbidity index, diabetic complications, comorbidities, and medications.
The study suggests that SGLT2i may play a protective role against neurodegenerative disorders in patients with Type 2 diabetes. Further research should explore the underlying mechanisms and long-term outcomes to confirm these benefits.
SGLT2i may play a protective role against neurodegenerative disorders in patients with Type 2 diabetes
Autoimmune Conditions Linked to Higher Type 1 Diabetes Risk
TYPE 1 diabetes (T1D) often coexists with other autoimmune conditions, such as thyroid diseases and coeliac diseases. While the prevalence of these conditions in patients with T1D is well known, fewer studies have investigated the risk of developing T1D in individuals who already have other autoimmune conditions.
This study, presented at EASD 2024, aimed to assess whether individuals with specific autoimmune diseases, like coeliac disease, hyperthyroidism, and hypothyroidism, have a higher risk of developing T1D compared to those without any autoimmune conditions.
This retrospective, observational matchedcohort study utilised real-world data from the Optum Clinformatics claims database, including individuals with autoimmune conditions including coeliac disease, hyperthyroidism (such as Graves’ disease), or hypothyroidism (like Hashimoto’s thyroiditis). They had to have at least one diagnosis of the autoimmune condition during the identification period (between 1 January 2017–30 September 2023) and no prior diagnosis of T1D or Type 2 diabetes. These participants were followed for at least 1 month after diagnosis. The control group consisted of individuals without any autoimmune conditions, matched 1:1 on demographics and clinical characteristics. A Cox proportional hazards model was used to compare the risk of developing T1D between the cohorts.
The results showed that individuals with autoimmune conditions had a significantly higher risk of developing T1D. Specifically, T1D developed in 0.14% of those with coeliac disease, 0.17% with hyperthyroidism, and 0.16% with hypothyroidism, compared to 0.06%, 0.06%, and 0.05% of controls, respectively. The time to T1D onset was shorter in the autoimmune cohorts than in the controls. The hazard ratios were 2.54 for coeliac disease, 2.98 for hyperthyroidism, and 3.19 for hypothyroidism, indicating a 2.5- to 3-fold increased risk of developing T1D compared to individuals without autoimmune diseases.
In conclusion, this study found that individuals with coeliac disease and thyroid autoimmunity have a significantly higher risk of developing T1D. These findings suggest that screening individuals with autoimmune conditions for early signs of T1D could be beneficial for early diagnosis and intervention.
Type 1 Diabetes developed in...
0.14%
of those with coeliac disease
0.17% 0.16% with hyperthyroidism with hypothyroidism
Congress Interview
Francesco Giorgino, Senior Vice President of European Association for the Study of Diabetes (EASD), shared his insights from this year’s congress. He discussed how a fascination with hormones led him to the field of endocrinology, his findings from insulin resistance research, and how EASD is contributing to diabetes research on a global scale.
Francesco Giorgino
Senior Vice President, European Association for the Study of Diabetes (EASD); Professor of Endocrinology, University of Bari Aldo Moro; Chief of the Division of Endocrinology, University Hospital Policlinico Consorziale, Bari, Italy
What led you to pursue a career in endocrinology and diabetes?
kinase, and then this was the major topic for my post doctorate.
It became more and more evident that β-cell dysfunction could be even more important than insulin resistance in promoting the development of hyperglycaemia in Type 2 diabetes
I was fascinated by hormones from when I first learnt about hormones as molecules that can carry a signal from one tissue or cell to another; regulate cell growth, metabolism, and particularly some important functions or processes occurring in the body, like growth, sex development, and control of the important metabolites. I was fascinated by the concept that these molecules could find the receptor on the target cells, activate those receptors, and induce signals that the cell will be able to decipher and translate into a biological response. So, this concept was something that made me really attracted to endocrinology.
This is why I chose this specialty after completing medical school, and immediately I became very much acquainted with insulin receptors and insulin signalling. That became my very first research interest because, when I was a resident in the speciality school, I was already working in the lab on insulin receptor tyrosine
After I finished my residency, I spent a few years at the Joslin Diabetes Centre of the Harvard Medical School in Boston, Massachusetts, USA, looking at changes in insulin signalling in conditions of insulin resistance and diabetes. There was, I think, a fairly straightforward development of interests, starting from the concept of hormones as wonderful molecules regulating biological processes, and then deepening that in terms of research studying insulin action and signalling, and molecules involved in translating the biological message of insulin in target tissues such as skeletal muscle and fat.
Q2Your research interests include the mechanisms of insulin resistance and β-cell dysfunction in Type 2 diabetes. Can you tell us more about your findings in this field?
Yes, as I mentioned, in my early research years I became very interested in and focused on insulin signalling changes in conditions of insulin resistance. So, in the
early 90s, about 30 years ago, there was a very important role attributed to insulin resistance as a pathogenetic factor leading to hyperglycaemia in Type 2 diabetes. It became more and more evident that β-cell dysfunction could be even more important than insulin resistance in promoting the development of hyperglycaemia in Type 2 diabetes.
My research was initially trying to understand how insulin action could be altered in insulin resistance, and then how β-cell secretory function could also be altered in conditions of obesity and Type 2 diabetes. This is my more recent focus, especially when I came back to Bari, where I established my own research group. We are focusing on the link between excess, dysfunctional adipose tissue and the development of β-cell dysfunction as a pathogenetic mechanism leading to hyperglycaemia in Type 2 diabetes.
We have characterised the role of some signalling proteins that are important in connecting adipose
tissue dysfunction with β-cell dysfunction. One such protein is p66Shc, which is a redox sensor. It’s a protein that can sense the excess of reactive oxygen species and, at the same time, can promote the generation of reactive oxygen species within the cells. We have shown that this happens in the β-cell, and it does happen in response to excess fatty acids. So, we believe that this protein can mediate the link between lipotoxicity and β-cell damage in obesity and in Type 2 diabetes. That's one piece of research that we have worked on quite a bit.
More recently, we have focused on some other molecules that could play not a detrimental role, but a positive one. One such protein is irisin. Again, this is also involved in the crosstalk between organs. For example, the skeletal muscle can release irisin when it is exposed to excess lipids, like in high-fat diets, or in response to exercise. So, there is a release of irisin from skeletal muscle in the circulation, and in this case, irisin is like a hormone that can improve the function and
the survival of β-cells. We have published part of this research, and we also have ongoing studies showing that irisin can improve β-cell dysfunction in islets from people with Type 2 diabetes. This is something that is triggered by lipids, but eventually will positively affect the β-cell function.
Q3
What do you believe are some of the unique challenges associated with providing care for Type 1 and 2 diabetes? Are there any recent initiatives that the European Association for the Study of Diabetes (EASD) has implemented to overcome these challenges and advance patient care?
Yes, for sure, we are living in a very exciting time for both Type 1 and Type 2 diabetes therapeutic management. As we know, technology has become extremely important for the implementation of optimal glucose control in people with Type 1 diabetes. We have a variety of devices that can sense glucose changes and can also be integrated with the pumps that provide insulin
infusion to our patients, what we call the hybrid closed loop. Of course, we look forward to further developments of this concept in a fully automated closed-loop insulin delivery system.
In this particular regard, I think the EASD has been progressively more active. We can appreciate that the EASD is very interested in promoting science exchange and knowledge in the field of automated insulin delivery. In the latest meeting we had in Madrid, Spain, we had a lot of sessions around diabetes technology in the congress, and also the participation of companies that promote and develop products in this particular field. So, we can say that at EASD we are welcoming more technology, and the presence of these technology companies may foster a scientific discussion about the different devices available and what they can provide to people with Type 1 diabetes.
At the same time, there's a very important, new, and interesting opportunity to delay the onset of Type 1 diabetes using the anti-CD3 monoclonal antibody teplizumab. Potentially, there may be other drugs that will be further characterised to interfere with, or potentially halt, the autoimmune aggression towards the β-cells in Type 1 diabetes. That's something that the EASD is looking forward to embracing and making people discuss at the Annual Meetings, as well as in dedicated courses, as the EASD also offers educational activities. A course focused on technology for Type 1 diabetes is under planning and will be available to any interested physicians.
Regarding Type 2 diabetes, we have to acknowledge how comprehensive the management for this form of diabetes has become. We can use drugs that
not only target glucose levels and weight excess more efficiently than in the past, but also provide additional benefits to the heart, cardiovascular system, kidney, brain, and potentially even other benefits. I'm referring to the SGLT2 inhibitors, the GLP-1 receptor agonist, and the dual or triple agonist. So, again, that is something the EASD is very attentive to and has always provided a lot of room to discuss these new developments and new findings.
Q4
As EASD’s Senior Vice President, what are your main objectives for the organisation, especially with tackling multimorbidity?
Well, of course, these objectives are defined by the EASD Board and the President of EASD, Chantal Mathieu, who is Professor of Medicine at the Katholieke Universiteit Leuven, Belgium. Within the Board, we have people who are engaged in specific activities. The honorary secretary, Tina Vilsbøll, Clinical Professor and Head of Clinic at Steno Diabetes Center, Copenhagen, Denmark, is the one who coordinates the scientific programme for the Annual Meeting. We have Julia Mader, Associate Professor of Medicine at the Division of Endocrinology and Diabetology at the Medical University of Graz and Deputy Head of the Diabetes Outpatient Clinic, Austria, who is in charge of postgraduate education. This includes all the activities that promote the education of physicians in the field of diabetes outside the Annual Meeting, mainly through the e-learning platform. EASD also offers an important programme for young investigators and young physicians called Early Career Academy, all of which is coordinated by Patrick Schrauwen,
Department of Nutrition and Movement Sciences, Maastricht University, The Netherlands.
The EASD has multiple projects and important activities, and I am now coordinating a new project focused on launching and implementing a Global Council that the EASD has just initiated. We had the first meeting of the Global Council in Madrid, chaired by me with Leszek Czupryniak of the Medical University of Warsaw, Poland, who is also our advisor on this project. This new initiative aims to embrace people, physicians, and researchers globally, given the global impact of the EASD and its activities, as evidenced by the fact that the Annual Meeting is attended by physicians from all over the world.
In fact, we noticed that the content we provide in the Annual Meeting, and the discussions we have, can attract physicians from all over Europe, as well as from countries outside Europe, like the Middle East, Asia, China, Japan, South America, North America, and Australia.
So, we now have the Global Council in which we have people that have been endorsed by national diabetes societies, and they represent different regions from all over the world. We have people from China, Japan, Africa, Australia, North America, Canada,
the Middle East, Europe, Eastern Europe, Southern Europe, and Europe. The aim of this Global Council is to first make all the EASD initiatives better understood and known across the world so that people from any region or country can potentially apply to these initiatives and obtain benefits, and second, to collect feedback. Any input that can be conveyed to the EASD Board and can be considered for triggering new initiatives or new projects.
Q5
You chaired the 18th Albert Renold Lecture and 39th Camillo Golgi lecture at EASD 2024, two very prestigious sessions. What were the aims and key takeaways from this year’s lectures?
The Albert Renold Prize has traditionally recognised excellent scientists in the field of islet biology and islet pathophysiology; from this year, the prize has been extended to acknowledge excellent research in various aspects of the pathophysiology of diabetes. This year, the committee has identified Lori Sussel, Professor at the University of Colorado Anschutz Medical Campus, Aurora, USA, as the recipient of this prize.
Sussel has developed extremely interesting studies and achieved very important accomplishments in the field of islet biology, particularly
coupling the interest and expertise on transcriptional regulation to the understanding of the identity and functional properties of islet cells,
This will help us not only to understand and identify the mechanisms that link obesity with Type 2 diabetes
and how this can be potentially lost in diabetes.
We know that it takes a very sophisticated mechanism for the β-cell to promote its function in releasing insulin, and also for other cells, like the alpha cells, to release glucagon. She has provided very important knowledge in understanding how this happens, what the role of specific transcriptional factors is, and also how this can be altered under conditions of diabetes. She also focused on post-transcriptional modifications, studying, for example, the long non-coding RNAs as another mechanism that can regulate islet function and the differentiation of β-cells. In her lecture, she described her earlier findings, went through the different contributions, and ended with the perspectives from her ongoing research.
Moving to the Camillo Golgi Prize, another very prestigious prize of the EASD, has always focused on the complications of diabetes. The EASD board has revisited the definition of this prize to be more modern to acknowledge not only excellent studies in the field of the classical complications of diabetes, but also the several comorbidities that associate with this disease.
This year, this prize was awarded to Rodica Pop-Busui, Associate Director for Clinical Research, Mentoring and Development; and Larry D. Soderquist, Professor in Diabetes, Professor of Internal Medicine Metabolism, Endocrinology, and Diabetes, and Vice Chair of Clinical Research Department of Internal Medicine, University of Michigan, USA. She is originally from Romania and received a fellowship in the 1990s, which led her to the University of Michigan, where she further advanced her career.
Pop-Busui has been always interested in the complications of diabetes. She has worked on neuropathy, both autonomic and somatic neuropathy. She has taken a more clinical and epidemiological approach compared to the previous
awardee. Her lecture covered all the developments that were made in the field of neuropathy as a complication of Type 1 and Type 2 diabetes. I believe her key contribution has been to advance our understanding of diabetes complications by analysing significant studies, such as the DCCT study, along with other critical research that has focused on diabetes treatment. These studies have demonstrated the impact of both glucose control and specific medications in reducing the burden of diabetesrelated complications.
Q6You co-authored the abstract ‘The real-world safety profile of tirzepatide: pharmacovigilance analysis of the FDA Adverse Events Reporting System (FAERS) database’ presented at EASD 2024. What were your key findings from this study?
This is a study that was carried out by one of my coworkers, Irene Caruso, who is the lead author of this particular study, at the University of Bari Aldo Moro in Italy. She presented this paper at EASD as a short oral communication. This study stems from the interest in tirzepatide, which is a dual GLP-1 agonist that
is currently approved and used for the treatment of both Type 1 and Type 2 diabetes and obesity in the USA and other countries. This drug is still not available in Italy, but we are expecting the drug that to change soon.
What we tried to understand is whether, by analysing the pharmacovigilance database of the FDA adverse events reporting system, we could replicate or get additional or diverse information about the tolerability and safety of tirzepatide as compared to other diabetes medications, particularly GLP-1 receptor agonists. The novelty of this analysis is that it is the first time that this database has been analysed in a rigorous and analytical way to get this information about tirzepatide. Furthermore, this drug was approved relatively recently, and it has only been available in the USA for the last 2–3 years.
We can get some interesting information because people use it and both physicians and patients report any adverse event that can occur during treatment in the FDA Adverse Events Reporting System (FAERS) database, which is fully accessible. Thus, this information can be analysed to get an idea about the tolerability and
the safety of tirzepatide versus other diabetes medications. We know that tirzepatide in the Phase III trials showed great efficacy on glucose lowering and weight loss, but was also associated with some side effects, particularly gastrointestinal side effects, and some signs of pancreatobiliary side effects that should also be taken into consideration.
In essence, our analysis shows that if you look at this real-world data, tirzepatide does increase the frequency of reporting of gastrointestinal adverse events and also, to some extent, reports of pancreatitis, diabetic retinopathy, or thyroid neoplasia, as it occurs in the Phase III trials, with some signal for gallbladder or biliary-related clinical events. So, in essence, this is the profile of tolerability and safety that we already know for tirzepatide and is not much different from the one of GLP-1 receptor agonists. Actually, there is probably, and this emerges from the analysis of the virus database, a similar, if not better, safety and tolerability profile of tirzepatide versus GLP-1 receptor agonists regarding the occurrence of these side effects, particularly if one considers the high efficacy
of tirzepatide in promoting glucose reduction and weight loss. So, I would say overall, a reassuring outcome from our analysis.
Q7
What would you say the highlights from EASD 2024 have been? How has the programme been different from last year?
Well, the programme was diverse and very rich. It focused on Type 1 and Type 2 diabetes and also had a lot of content around obesity, cardiovascular disease, and renal disease and education. There were many sessions dedicated to technology in diabetes. The EASD this year was able to offer very well-balanced content in terms of both experimental, translational, and clinical research or clinical education for physicians, and I think this was the strength of the programme this year compared to the previous year.
This year, we had also very high attendance. The meeting was attended by more than 12,000 people in person in Madrid, and there were also about 1,500 who were following the meeting remotely. So, I think this is because of the wealth and diversity of the
content that could be of interest to researchers, young researchers, clinical researchers, physicians, and in general, healthcare professionals working in the field of diabetes.
Q8
Where can we expect to see your research focus lie in the coming years?
The focus will be to further try and understand how the relationship between excess adipose tissue and dysfunctional adipose tissue and β-cell dysfunction develops. So, trying to further explore the crosstalk between these organs and also with other organs that could have an impact on β-cell function in a positive or negative way. Hopefully, this will help us not only to understand and identify the mechanisms that link obesity with Type 2 diabetes but also to potentially study some therapeutic targets that could help revert β-cell dysfunction that occurs in Type 2 diabetes. Irisin is one such example. We would like to further characterise the therapeutic value of irisin in Type 2 diabetes, but it is possible that additional molecules that are relevant to this particular goal could be identified. This is what we are currently trying to pursue in our research group.
The EASD this year was able to offer very well-balanced content in terms of both experimental, translational, and clinical research or clinical education for physicians
Interviews
EMJ is thrilled to introduce two key opinion leaders Philip Froguel, Imperial College London, UK, and Samuel Seidu, University of Leicester, UK, whose interviews discuss their careers so far, and their focuses for future research. The conversations cover topics including obesity genetics, continuous glucose monitoring, and how research in these areas has influenced clinical practice.
Featuring: Philippe Froguel and Samuel Seidu
Philippe Froguel Professor of Genomic Medicine, Head of Genomics of Common Disease, Department of Metabolism,
Q1 Can you share the journey that led you from obtaining your medical degree from Saint-Antoine Medical School, Sorbonne University, Paris, France to becoming a leading figure in the field of diabetes and obesity genetics?
When I was a young resident, I met a famous French professor of diabetes Roger Assan who was doing clinical research, and thus I decided to follow a Master of Science course in human nutrition. Later I met with Jean Dausset, Nobel Prize winner for his work on human leukocyte antigen tissue markers, which allowed organ transplantation. He was creating the Human Polymorphism Study Center (CEPH), the first genome centre in the world, and was looking for someone to work on diabetes genetics, which was totally unknown. Therefore, I took a position of Assistant Professor in Saint-Louis Hospital in Paris, partly in the endocrinology department and partly at CEPH. I got my PhD there under another famous French geneticist, Daniel Cohen.
Q2 You were instrumental in identifying key genes responsible for monogenic Type 2 diabetes (T2D) and obesity, such as GCK and HNF1. Could you describe the challenges of these groundbreaking discoveries?
At that time, there was no cohort of families with diabetes, no map of the human genome, and very rudimentary tools to study the human DNA diversity. Using posters in the Paris Métro (underground) and the media, I collected very large families in 1990–1992. There were little clues, and I postulated that the enzyme glucokinase (GCK), given its putative role as a glucose sensor in insulin secreting cells, was a good candidate, and worked hard to have a probe of it. At that time, the mainstream idea was that diabetes was due to insulin resistance and not to defects in insulin secretion. I was correct, and thus we identified the first diabetes gene. Two years later, with the first probes of polymorphic markers covering the entire genome (although poorly), I
performed the first familial whole genome study and found a locus that, after 2 additional years of hard work with my colleague Graeme Bell in Chicago, Illinois, USA, led us to identify the second diabetes gene, the transcription factor HNF1A. Young researchers of today could not understand the extremely difficult but exciting challenges of that time: the genome had not been sequenced yet! I was thinking, immodestly, we were the Columbus of our time (or Indiana Jones in some respect). Incidentally, as our discoveries were against the odds and against the habits of the time of diabetes research, especially in France, I had little recognition in France, and in 2000 I left for the UK! The so called ‘physiologists’ hated me because genetics had proven more efficient than their studies to elucidate part of the origin of diabetes.
Q3Your 2007 GenomeWide Association Study in T2D was the first of its kind and was described as the 'Breakthrough of the Year' by Science. What do you consider the most significant implications of this study for the field?
Young researchers of today could not understand the extremely difficult but exciting challenges of that time: the genome had not been sequenced yet!
In the late 90s and the beginning of the 2000s, the most popular opinion was the fact that T2D had hidden ‘major genes’ similar to monogenic T2D. It was a deadend approach, as our tools (family studies, candidate genes on small cohorts) were sterile. Statisticians in the field in the USA proposed a new concept of ‘frequent DNA variants/ frequents diseases’, which implies a polygenic basis of T2D and other common disorders. I decided to conduct a study with a big (for the time) cohort of T2D patients and tight controls (middle age people who were normal glycaemic after 9 years of follow-up). We got funding in Quebec, Canada for regular genetic research, but instead of doing what was intended we tested the experimental whole genome using arrays of single nucleotide polymorphisms by a new company called Illumina, and decided to do a genome wide association study. We were in non-friendly competition with the National Institutes of Health (NIH), the Wellcome Trust, and the Islandic/US Decode company who used other arrays. Our technology and our cohorts were better, and we completed and published our
study months before the others. Originally, our colleagues were very sceptical about our data, but they independently replicated them. In order to publish, they decided to merge their data, and it was the first example of a genetic consortium. I am proud that our success had pushed them to develop this very efficient approach, that has since been followed in every medical field of genetics.
Q4
In your recently published opinion, entitled ‘Towards the recognition of oligogenic forms of type 2 diabetes’. You suggested that the blurred demarcation of polygenic and monogenic T2D may be linked by oligogenic T2D. How might this new view shape diagnosis and treatment of genetic T2D?
The traditional view is T2D is either a monofactorial disorder due to a unique rare mutation in a gene controlling insulin secretion, or a multifactorial disease due to the interaction of age, the environment, and of hundreds or thousands or frequent variations in the human genome increasing the risk of diabetes by many means. Actually, the sequencing of the human genome in large populations discovered that a proportion of patients with diabetes (around 10–20% in the so-called atypical forms of T2D: before 40 years old and without obesity) also carry rare mutations in important genes for glucose
control. In this case, this rare mutation increases the risk of T2D by two- to five-fold, and the polygenic background, plus exposure to the environment (bad nutrition, sedentary lifestyle, etc), contribute to the development of the disease (as well as age of onset and severity). We believe that the presence of some other rare mutations in other genes may also favour the development of serious complications of diabetes, in the kidney, or in the heart and vessels. That is also why we sequence the entire genome of patients with diabetes.
Q5 How have your research findings in diabetes and obesity genetics translated into clinical practice?
I am very proud that what I have contributed to monogenic diabetes is in the textbooks for clinical doctors, as these cases should be recognised and diagnosed as soon as possible. This is because there are specific diabetes care protocols and drugs that are very helpful to control patient glycaemia and improve quality of life, in addition to significantly decreasing costs for society. It is a win–win strategy. Regarding genome-wide association studies, the situation is still unclear, and it remains to be demonstrated that calculating diverse polygenic risk scores is useful for better management of patients. My feeling is yes, but the evidence is still modest. For diabetes complications, more research is necessary, but whole genome sequencing will help.
Q6 You currently have more than 820 peer-reviewed publication to your name for your research in diabetes and obesity. What do you believe to be the current gaps in literature and what topics merit greater attention?
The world community of clinicians and researchers in metabolic diseases is large, and I don’t see many domains that are not covered. However, some are weaker than others, especially nutrition, as this literature is often going in every direction without consistency. A recent paper suggested that two-thirds of new diabetes cases are attributable to bad nutrition, but in a very different way among nations (such as too much meat in the USA or Eastern Europe, versus too much white rice in Asia).
Two-thirds of new diabetes cases are attributable to bad nutrition, but in a very different way among nations
This study also suggested that, in 1990, human nutrition around the age of 55–60 years was critical for the development of diabetes, but today, the priority populations to target to prevent diabetes should be young adults who have inadequate diets. This information should guide public health action to prevent diabetes. More research is however necessary to improve our knowledge and to define new policies in nutrition (especially for the food industry), adapted to each country.
Q7 Looking back on your career, what are you most proud of?
I am proud that I went against the mainstream thinking of the time, and proposed and evidenced that diabetes and obesity can be mostly genetic.
I am proud that I went against the mainstream thinking of the time
I also contributed to evidence that T2D is primarily driven by pancreatic insulin secretion failure, instead of by tissue insulin insensitivity, and that obesity is driven by food intake behaviour, not by fat storage. By the way, the newest efficient drugs against diabetes, GLP1 receptor agonists, target both insulin-secreting cells, and also the brain, and that is why patients decrease their weight. The importance of the brain and appetite in obesity is also a field I have contributed to for 30 years by identifying many genes that control food intake. This opened the way to new generations of treatments such as GLP1 receptor and other incretin (hormones secreted by the gut) agonists that decrease appetite and favour insulin secretion, but also protect the heart, kidney, and the brain against diabetes complications. Later, in 2007, I contributed to inventing a simple and robust methodology to study complex traits genetics, named genomewide association studies, that is still used now. Beyond that, to be in pupils’ books at school and in textbooks for medical students is also a great reward.
Samuel Seidu
Professor in Primary Care Diabetes and Cardio-metabolic Medicine, University of Leicester,
UK
Balancing clinical practice with research is very challenging, but it is highly rewarding
Q1 In 2021 you were awarded the Award for Outstanding Early Career Researchers in the UK and Ireland by the Royal College of General Practitioners, London, UK. Could you describe your path from beginning your medical education to this achievement?
That seems a long time ago now, 2021, but my journey in medicine began at the University of Ghana, where I developed a strong interest in primary care and public health care. This foundation led me to the UK, where I completed further training and started focusing on diabetes care. Over the past years, I have had the privilege of working alongside some esteemed colleagues and mentors at the Leicester Diabetes Centre, UK, and they have guided and supported my research. This award from the Royal College of General Practitioners in 2021 is, in my opinion, a recognition of the collaborative efforts that I've had in improving diabetes care in primary care settings, particularly in underserved populations.
Q2
Given your extensive experience in both clinical practice and research, how do you balance your roles as a practising general practitioner (GP) and a primary care research fellow? Also, how does your hands-on experience with patients influence your research?
Balancing clinical practice with research is very challenging, but it is highly rewarding. It's something that I would recommend to everybody. My work as a GP allows me to stay grounded in the realities of patient care, which, in
turn, informs my research. Seeing firsthand the challenges that patients and people with diabetes face motivates me to explore practical solutions through research. These insights gained from my encounters with patients also ensure that my research remains very relevant and patientcentred, ultimately leading to improved care delivery.
Q3 As the Vice-Chair of Research for Primary Care Diabetes Europe (PCDE), could you explain what your role entails and how the PCDE’s work impacts patient care?
I've held that position for a while now as I am in my second term in office as the Vice Chair of Research for PCDE, and I lead initiatives that focus on improving diabetes management in primary care across the whole of Europe. Our work is centred around providing evidencebased guidance and training for healthcare professionals, which directly impacts the care that patients receive. We also generate a lot of research material that translates into everyday practice, so the role allows me to contribute to shaping diabetes care policies in practices that will benefit patients on a broader scale than just in the UK.
Q4Given your extensive work with continuous glucose monitoring (CGM) and the National Institute for Health and Care Excellence (NICE) guidelines, implemented in March 2023, which allow CGM use in primary care, what are your thoughts on the future of CGM in managing diabetes, especially for elderly patients and those with complex comorbidities?
Yes, my work on CGM has taken off over the past 24 months, and CGM represents significant advancements in diabetes management in recent times, particularly in the primary care setting. CGM provides real-time data on glucose levels, which can transform how patients manage their diabetes. By offering continuous feedback rather than intermittent data provided by the traditional finger prick testing that we've always been doing. This continuous stream of information then allows both the patient and healthcare professionals to observe the glucose trends and identify the patterns and then make timely adjustments to treatment plans.
Elderly patients will normally have very complex co-morbidities, and CGM offers several distinct benefits. These populations are often faced with challenges in managing diabetes due to the combination of not just physiological factors but also polypharmacy and the increased risk of hypoglycaemia, especially when these patients are using insulin or insulin secretagogues, which sadly is still widely the case. CGM can significantly reduce the risk of hypoglycaemia by alerting the patients and their caregivers to any impending low glucose levels, allowing for timely interventions. This is particularly important for elderly patients who
may have impaired awareness of their hypoglycaemia, which is a condition where the typical warning symptoms are not felt, making them more susceptible to severe hypoglycaemia.
There are a lot of benefits; moreover, CGM can contribute to better overall glucose control without the need for finger prick testing, which can be cumbersome and painful in some patients. The ease of use and the ability to review their glucose trends over a long period of time improves not just the adherence to treatment regimens but also leads to long-term outcomes; we've seen that in various studies across the world. The best one that is normally cited is the relief study from France, but we in the UK have also got some realworld data published from the UK. So, for patients with complex, long-term conditions, glucose monitoring can help healthcare providers understand how the conditions or the medications may affect the glucose levels, allowing for more nuanced and individualised care.
What we're noticing is that more and more primary care clinicians are getting more familiar with CGM technology, and it is expected to become the standard tool for managing patients with both Type 1 and Type 2 diabetes, particularly those at high risk of complications.
The NICE guidelines endorsement of CGM in primary care is a crucial step in broadening access to this technology. Its’ adaptation is now increasing across the country, and we can anticipate significant improvements in both quality of life and clinical outcomes in patients.
Q5In 2023 you coauthored a paper investigating the underrepresentation of Black patients in clinical trial populations for diabetes treatment. What are the implications of these findings, and what steps do you think should be taken to ensure that future trials are more inclusive?
That was a study that we published, which gathered a lot of media attention at the time. The study highlighted a critical issue in the landscape of diabetes research: the significant underrepresentation of Black patients in clinical trials for diabetes treatments. This lack of diversity in the trial population is concerning because it limits the generalisability of research findings, potentially leading to disparities in the treatment outcomes for different racial and ethnic groups.
The main findings of the paper revealed that Black patients were underrepresented in clinical trials, particularly with respect to the newer diabetes therapies, sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.
The main findings of the paper revealed that Black patients were underrepresented in clinical trials, particularly with respect to the newer diabetes therapies, sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists
This underrepresentation means that the effectiveness and safety profiles of these treatments might not be fully understood in that population group. We also find similar underrepresentation of South Asian populations. Interestingly, what we found that gathered more attraction across the media was the fact that the benefits seen in GLP-1 receptor agonists and SGLT2 inhibitors were not as marked for Black patients as observed in other ethnicities( White Europeans and South Asians). This was very interesting, given that South Asians were also seen to be underrepresented, they seem to have had benefits compared to Black patients.
It means that a lot of research activity is needed in this area to understand whether these findings were actually square of statistics, or due to the poor representation, or a real finding, we don't know.
One of the implications of these findings is that the current body of evidence may not accurately reflect how Black patients respond to diabetes treatments, potentially leading to suboptimal care. To address this, we recommend several steps to ensure future trials are more inclusive. First of all, trial design should intentionally include recruitment strategies that target underrepresented populations, ensuring that the sample sizes are large enough to allow for subgroup analysis. Then there should also be greater transparency and reporting on the demographic breakdown of trial participants so that gaps in representation can be identified and addressed. It should be added that engaging with communities to build trust and reduce barriers to participation
is very crucial. This might involve collaborating with community leaders and providing culturally competent education and educational activities about the importance of clinical trials, to ensure that trial designs are accessible and relevant to the diverse populations that we serve.
Q6
Recent studies have suggested a use for AI models in the analysis of data from continuous glucose monitoring. As a GP, do you see a future place for AI in diabetes management?
When I look into the future, I think the integration of CGM with other technologies, such as AI and telemedicine, holds great promise.
I think the integration of CGM with other technologies, such as AI and telemedicine, holds great promise
AI algorithms could enhance diabetes management, particularly in interpreting the vast amount of data generated by CGM devices, as you're getting minute-by-minute readings, and it's a huge amount of data. AI could analyse CGM data and indeed provide personalised recommendations by predicting glucose trends, potentially reducing the burden on the healthcare systems by enabling remote monitoring. In elderly patients, this could mean more consistent and responsive care with fewer in-person visits as we do at the moment, thereby reducing the strain on both
the patient and the healthcare providers. However, it's worth noting that it's important to ensure that these tools are integrated thoroughly into clinical pathways with a focus on supporting rather than replacing clinical judgement.
Q7
As an active researcher with over 130 publications on PubMed, could you share any studies you are currently working on and your future goals in diabetes research?
Currently, I'm leading several important research initiatives that aim to address critical gaps in diabetes care and management. One of the key areas of my research focus, at the moment, is on therapeutic inertia in Type 2 diabetes. Here we utilise realworld data to understand the factors that contribute to delays in treatment intensification, or indeed initiation, which is a significant issue in diabetes care, especially in primary care. Therapeutic inertia can lead to prolonged periods of inadequate glycaemic control, increasing the risk of complications for the patients. So, by analysing data from routine physical practice, we can identify strategies to overcome these barriers and ensure that patients receive timely and appropriate treatment adjustments.
Another area of my work involves investigating cardiometabolic conditions in Sub-Saharan Africa.Recently, I've been doing some work on Global Health and this region faces a growing burden of non-communicable diseases, including diabetes and cardiovascular diseases, yet it remains under-researched compared to infectious diseases in that part of the world. From the Leicester Diabetes Centre, we collaborated with colleagues
across Africa, doing research activities that seek to understand the unique challenges and indeed opportunities for managing these conditions in Sub-Saharan Africa, with a special focus on developing and evaluating context-specific interventions that can improve health outcomes in these communities.
I am also involved in evaluating different models of diabetes care, particularly within the primary care setting, and my work has focused on assessing the effectiveness of integrated care models that bring together primary, secondary, and community care to manage diabetes more effectively. These models aim to provide comprehensive and continuous care for patients, and I think it is crucial for managing chronic conditions like diabetes. The evaluation of the models is essential to identify best
practices shared across the rest of the country.
Looking ahead, my future goals in diabetes research include continuing to explore ways to optimise diabetes care in diverse settings. Health inequality is a big issue, particularly in low-resource environments. I also aim to further investigate the impact of digital health technologies, such as CGM and AI, on diabetes management with a focus on enhancing patient outcomes and reducing health inequalities.
Q8 What advice would you give to healthcare professionals who are aspiring to pursue clinical academia?
My advice for up-and-coming, early-career researchers and clinicians would be to stay curious and committed to improving patient care. I think that has got to be the main focus, continuous
learning. Clinical academia offers a unique opportunity to bridge the gap between research and practice, but it requires a lot of perseverance and collaboration.
Clinical academia offers a unique opportunity to bridge the gap
between research and practice, but
it requires a lot
of perseverance and collaboration
You cannot do it on your own, you’ve got to collaborate. So, seek out mentors, stay connected to clinical practice, and always keep the patient at the centre of your work.
The Potential Impact of Gestational Diabetes Mellitus on Long-Term Kidney Disease: A Narrative Review
Authors: *Khalid Siddiqui,1,2 Teena P George2
1. Department of Biochemistry, College of Medicine, Kuwait University, Kuwait
2. Strategic Center for Diabetes Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia *Correspondence to mohammad.siddiqui@ku.edu.kw
Disclosure: The authors have declared no conflicts of interest.
Gestational diabetes mellitus (GDM) is a pervasive metabolic disorder associated with a spectrum of long-term adverse outcomes. Recent evidence indicates that women with GDM have a heightened subsequent risk of kidney disease. Persistent factors, both pre-gestational and postpartum, can contribute to these adverse outcomes years after a GDM pregnancy. Metabolic features such as insulin resistance, subclinical inflammation, and endothelial dysfunction can lead to enduring microvascular alterations, ultimately resulting in long-term renal complications. The insulin resistance and beta cell dysfunction that develop during GDM are chronic and progressive, increasing the risk of Type 2 diabetes mellitus, hypertension, and dyslipidaemia, all risk factors for chronic kidney disease (CKD).
While few studies have specifically investigated the independent association between GDM and subsequent renal dysfunction, a recent study examining the adverse pregnancy outcomes and long-term risk of CKD identified GDM as one of the independent risk factors. The findings of this review strongly recommend that women who experience adverse pregnancy outcomes like GDM during their reproductive years should be well-informed about their long-term risk of kidney disease. This knowledge is essential for early preventive actions and follow-up care. In future, cardiometabolic surveillance and risk modification strategies in clinical practice are necessary to prevent maternal renal complications among women with a history of GDM.
Key Points
1. Gestational diabetes mellitus (GDM) affects a significant portion of pregnancies worldwide, posing health risks to both mother and child. It is linked to increased long-term renal morbidity, significantly impacting quality of life.
2. This review examines the evidence supporting the association between GDM and the development of kidney disease, highlighting potential contributing factors
3. Women who have experienced GDM should be aware of their elevated risk for kidney disease and take proactive steps to prevent it. Regular monitoring and appropriate interventions are crucial to mitigate the morbidity and mortality associated with this condition.
INTRODUCTION
Gestational diabetes mellitus (GDM) is a rapidly growing global health issue and one of the most common metabolic complications in pregnancy.1 GDM is defined as any degree of glucose intolerance first recognised during pregnancy. It arises when the insulin response is insufficient due to underlying insulin resistance or inadequate insulin secretory capacity caused by placental hormones as pregnancy progresses.1 According to the International Diabetes Federation (IDF), 16.7% of live births to women were complicated by hyperglycaemia during pregnancy, with 80.3% of these cases attributed to GDM.2 An increase in prevalence of GDM is driven by multiple factors, including patients who are overweight or obese, older age, family history of diabetes mellitus, previous history of GDM, excessive weight gain during pregnancy, and habitual smoking.2
Even though GDM exists as a transient disorder during pregnancy, accumulating evidence supports that GDM is associated with subsequent Type 2 diabetes (T2D), hypertension, dyslipidaemia, vascular dysfunction, and cardiovascular disease which are risk factors of renal impairment.3-7
Chronic kidney disease (CKD) is a rapidly growing public health problem associated with increased morbidity and mortality.8 GDM is one of the metabolic diseases associated with long-term kidney disease.9,10 Transient hyperglycaemia, which is limited to gestation, may support the perception of GDM as a medical complication of pregnancy, while the glycaemic impact of this complication extends well beyond the gestational time period. Health implications of GDM beyond the gestational period are well studied, and most attention is paid to the increased
risk of recurrent GDM, impaired glucose tolerance, and diabetes mellitus.11-13 Women with GDM have also demonstrated an increased risk for metabolic syndrome, vascular endothelial dysfunction, dyslipidaemia, and cardiovascular events.11,14-19 However, relatively few studies investigated the relationship between GDM and the long-term risk of complications such as renal disease.6,20-23 As the prevalence of GDM has been increasing globally, the burden of long-term adverse maternal outcomes such as renal disease also substantially increased.9,24,25 Moreover, it seems plausible to speculate the association between GDM and longterm development of kidney disease due to its significant impact on quality of life, health care cost, morbidity, and mortality associated with it. 1,26 Hence, it is important to study the effect of GDM on the function of the kidneys during the gestational time period and following pregnancy.6,20 This review provides an overview of the impact of gestational diabetes on the long-term risk of kidney disease and the potential factors associated with it.
The potential mechanism behind the association between GDM and kidney disease is composed of many factors involved in the pre-gestational period and persisting in the postpartum period. Insulin resistance, subclinical inflammation, epigenetic changes, environmental factors, and lifestyle modifications are some of the factors associated with this.6,22,23 Altered glucose metabolism in GDM disrupts the maternal vasculature due to the deleterious effects of potential mediators such as reactive oxygen species, advanced glycation end products, and pro-inflammatory cytokines, which in turn activate pathological signalling pathways. Oxidative stressassociated changes in the placenta also
contribute to accelerating these pathological modifications.27,28 Renal morphological changes such as thickening of the glomerular basement membrane, increase in glomerular size, and mesangial matrix expansion are also noticed in GDM models (Figure 1).29 Based on the literature findings, women with GDM show early metabolic changes such as endothelial abnormalities even before glucose intolerance occurs.30 In addition, GDM women are also susceptible to subclinical inflammation and vascular changes such as increased peripheral vascular resistance and impaired endothelium-dependent vasodilatation, both of which lead to renal dysfunction independently.7,30 Probable development of metabolic syndrome, T2D, hypertension, dyslipidaemia, and other cardiometabolic disorders after GDM is also inevitable.5,11,31,32 Collectively, all these findings indicate that the metabolic impact of GDM may persist beyond the gestational period and adversely affect long-term renal function.
The potential impact of GDM on kidney dysfunction was studied among women with a history of GDM, and a greater prevalence of microalbuminuria was observed to be more frequent.21,22,33 In addition to this, elevated levels of glomerular filtration rate, an early sign of glomerular hyperfiltration and renal impairment, was noticed among women with GDM after 9–16 years of follow-up.34 More importantly, patients with recurrent episodes of GDM reported more risk for future renal morbidity.23 Interestingly, Aboriginal women with a previous history of GDM, a high GDM-risk population, observed a remarkably high risk of developing CKD and end-stage renal disease.10 Recently, an independent association of GDM and incident kidney disease was also observed, and it was also reported that pregnant women with severe metabolic dysfunction are at high risk for future renal disease.6, 20,35
Recently, a systematic review and metaanalysis indicated that exposure to GDM has an elevated risk of long-term kidney disease.36 All these findings indicate the independent involvement of GDM in developing kidney disease.
This review also observed the potential involvement of ethnicity/race in developing renal disease. Based on the current literature, African-American women who are obese with prior GDM have a high risk for CKD.21,22 This could be due to differences in the severity of GDM, the development of increased blood pressure after GDM, as well as the lactation pattern.37,38 A genetic study of AfricanAmerican women with GDM shows that there are genes within or flanking the major histocompatibility complex that play a role in the aetiology of diabetes mellitus, insulin resistance, hypertension, and microalbuminuria.38 Furthermore, lower rates of breastfeeding and more severe complications of GDM are also reported among this population.39,40
Interestingly, a low incidence of renal outcome was also noticed among women with previous histories of GDM.41,42 This could be due to early postpartum assessment as well as a relatively young and healthy population with less involvement of potential confounding factors. Moreover, previous studies examining the relationship between GDM and long-term CKD exhibited substantial heterogeneity due to varying criteria for GDM diagnosis, differences in study design and follow-up duration, and sample size. Table 1 presents recent findings on the long-term risk of kidney disease following GDM.
RISK FACTORS FOR GESTATIONAL DIABETES MELLITUS-RELATED KIDNEY DAMAGE
Even though gestational hyperglycaemia resolves after pregnancy, beta cell dysfunction and insulin resistance persist for many years after index pregnancy. Chronic progressive beta cell dysfunction, where the degree of decline in beta cell function depends on the severity of gestational dysglycaemia, is likely to be the pathophysiologic defect that leads to the manifestation of long-term diabetic risk.43,11 Diabetes mellitus is a strong risk factor for the development of kidney disease.44
Figure 1: The potential metabolic changes associated with gestational diabetes mellitus in developing kidney damage and the major risk factors associated with it.
Moreover, women with a history of GDM alone, even in the absence of subsequent overt diabetes, may increase the risk of future cardiovascular and kidney disease.22 Hypertension is another important risk factor for the development of renal disease, and women exposed to GDM had an increased risk of developing hypertension.31 Hypertension progresses to renal disease through the involvement of insulin resistance, which leads to impairment in the nitric oxide pathway and activates the MAPK pathway; this causes a proinflammatory state, and the increased water and sodium retention induces a hypertensive state.45-47 Furthermore, changes in the intraglomerular capillary pressure also lead to glomerulosclerosis and renal disease.48 Another independent risk factor is hyperlipidaemia, which is associated with postpartum dyslipidaemia among women with a history of GDM.5,49 Hyperlipidaemia progresses to renal disease through reabsorption of fatty acids and phospholipids through tubular epithelial cells, leading to tubulointerstitial inflammation, lipoprotein accumulation in the glomerular mesangium,
and glomerulosclerosis.50 Moreover, other risk factors, such as heart disease, family history of CKD, inherited kidney disorders, older age, smoking, obesity, and socioeconomic status, can also influence the development of kidney disease.20,32
In conclusion, this literature review provides an overview of GDM and long-term kidney disease and associated potential factors according to the most recent literature findings. Based on the review findings, few studies have specifically investigated the independent association between GDM and subsequent renal dysfunction and identified GDM as one of the independent risk factors. GDM-associated metabolic changes as well as the involvement of persistent factors, both pre-gestational and postpartum, can contribute to the development of renal disease. Women with GDM represent a high-risk group for renal disease, and regular monitoring is required to prevent the morbidity and mortality associated with it. Recognition of predisposition to kidney disease among women with GDM may provide an opportunity to undertake
lifestyle modifications and encourage regular screening and early intervention to minimise the harmful end-organ damage.
PREVENTION AND MANAGEMENT OF GESTATIONAL DIABETES MELLITUS-RELATED KIDNEY DAMAGE
Women who experience GDM have an elevated risk of long-term kidney disease. It is widely recommended that women with a history of GDM undergo postpartum glucose tolerance screening within 6 months after delivery to identify the risk of developing T2D, a risk factor for the development of renal impairment.51 Moreover, attention should be given to cardiometabolic risk factors such as dyslipidaemia, hypertension, and obesity to reduce the future long-term risk for kidney disease. Adverse pregnancy outcomes, especially GDM, should be added to renal risk prediction models to reduce the burden of kidney disease by supporting primary and secondary prevention strategies. Lifestyle interventions such as diet and physical activity may help to reduce the burden of long-term maternal complications. There are certain patient factors that address
References
1. Zhu Y, Zhang C. Prevalence of gestational diabetes and risk of progression to type 2 diabetes: a global perspective. Curr Diab Rep. 2016;16(1):7.
2. International Diabetes Federation. IDF diabetes atlas. 2021. Available at: https://www.diabetesatlas.org. Last accessed: 20 March 2024.
3. Daly B et al. Increased risk of ischemic heart disease, hypertension, and type 2 diabetes in women with previous gestational diabetes mellitus, a target group in general practice for preventive interventions: a populationbased cohort study. PLoS Med. 2018;15(1):e1002488. Corrected and republished from: PLoS Med. 2019;18;16(7):e1002881.
4. Deirdre et al. Increased risk of hypertension after gestational diabetes mellitus: findings from a large prospective cohort study. Diabetes Care. 2011;34(7):1582-84.
5. O'Higgins AC et al. Postpartum
the poor adherence rates to postpartum screening, such as adjustment to a new
baby, lack of time, emotional stress, lack of motivation, financial barriers, and lack of knowledge about GDM.51
FUTURE PERSPECTIVE
GDM is one of the chronic cardiometabolic conditions that is first identified in pregnancy and carries long-term implications. The broader life course perspective of GDM enhances the recognition of the need for focusing future studies on long-term maternal complications rather than shortterm pregnancy outcomes. In future, cardiometabolic surveillance and risk modification strategies can be used in clinical practice to enable the prevention of maternal renal complications among women with a history of GDM. Further research is needed to identify effective risk-reduction interventions. Based on the reviewed findings, women with previous GDM complicated pregnancy may represent a high-risk group that requires regular monitoring for early-stage renal impairment, which may help the clinician initiate the treatment to delay or prevent the progression of the disease.
dyslipidaemia in women diagnosed with gestational diabetes mellitus. Ir J Med Sci. 2017;186(2):403-7.
6. Christensen MH et al. Kidney disease in women with previous gestational diabetes mellitus: a nationwide register-based cohort study. Diabetes Care. 2024;47(3):401-8.
7. Heitritter SM et al. Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab. 2005;90(7):3983-8.
8. Francis A et al. Chronic kidney disease and the global public health agenda: an international consensus. Nat Rev Nephrol. 2024;20(7):473-85.
9. Barrett PM et al. Does gestational diabetes increase the risk of maternal kidney disease? A Swedish national cohort study. PLoS One. 2022;17(3):e0264992.
10. Hare MJ et al. Risk of kidney disease following a pregnancy complicated by diabetes: a longitudinal, populationbased data-linkage study among
Aboriginal women in the Northern Territory, Australia. Diabetologia. 2023;66(5):837-46.
11. Retnakaran R et al. Glucose intolerance in pregnancy and postpartum risk of metabolic syndrome in young women. J Clin Endocrinol Metab. 2010;95(2):670-7.
12. Bellamy L et al. Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet. 2009;373(9677):1773-9.
13. Feig DS et al. Risk of development of diabetes mellitus after diagnosis of gestational diabetes. CMAJ. 2008;179(3)229-34. Erratum in: CMAJ. 2008;179(4):344.
14. Bo S et al. Should we consider gestational diabetes a vascular risk factor? Atherosclerosis. 2007;194:e72-9.
15. Ravi Retnakaran et al. The graded relationship between glucose tolerance status in pregnancy and postpartum levels of lowdensity-lipoprotein cholesterol and
apolipoprotein b in young women: implications for future cardiovascular risk. J Clin Endocrinol Metab. 2010;95(9):4345-53.
16. Akinci B et al. Prediction of developing metabolic syndrome after gestational diabetes mellitus. Fertil Steril. 2010;93:1248-54.
17. Lauenborg J et al. The prevalence of the metabolic syndrome in a Danish population of women with previous gestational diabetes mellitus is three-fold higher than in the general population. J Clin Endocrinol Metab. 2005;90(7):4004-10.
18. Shah BR et al. Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care. 2008;31(8):1668-9.
19. Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ. 2009;181(6-7):371-6.
20. Daly BM et al. Increased risk of cardiovascular and renal disease, and diabetes for all women diagnosed with gestational diabetes mellitus in New Zealand-a national retrospective cohort study. J Diabetes. 2024;16(4):e13535.
21. Dehmer EW et al. Association between gestational diabetes and incident maternal CKD: the coronary artery risk development in young adults (CARDIA) study. AJKD. 2018;71(1):112-22.
22. Bomback AS et al. Gestational diabetes mellitus alone in the absence of subsequent diabetes is associated with microalbuminuria: results from the Kidney Early Evaluation Program (KEEP). Diabetes Care. 2010;33(12):2586- 91.
23. Beharier O et al. Gestational diabetes mellitus is a significant risk factor for long-term maternal renal disease. J Clin Endocrinol Metab. 2015;100(4):1412-6.
24. Su FL et al. Increasing trend in the prevalence of gestational diabetes mellitus in Taiwan. J. Diabetes Investig. 2021;12(11):2080-8.
25. Wang H et al. IDF diabetes atlas: estimation of global and regional gestational diabetes mellitus prevalence for 2021 by international association of diabetes in pregnancy study group’s criteria. Diabetes Res Clin Pract. 2022;183:109050.
26. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney
disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709-33.
27. McElwain CJ et al. Mechanisms of endothelial dysfunction in preeclampsia and gestational diabetes mellitus: windows into future cardiometabolic health? Front Endocrinol (Lausanne). 2020;11:655.
28. Liu Z et al. Renal dysfunction in a mouse model of GDM is prevented by metformin through MAPKs. Mol Med Rep. 2019;19(5):4491-9.
29. Wu T et al. The mechanism of hyperglycemia-induced renal cell injury in diabetic nephropathy disease: an update. Life (Basel). 2023;13(2):539.
30. Anastasiou E et al. Impaired endothelium-dependent vasodilatation in women with previous gestational diabetes. Diabetes Care. 1998;21(12):2111-5.
31. Tobias DK et al. Increased risk of hypertension after gestational diabetes mellitus: findings from a large prospective cohort study. Diabetes care. 2011;34(7):1582-4.
32. Sullivan SD et al. Gestational diabetes: implications for cardiovascular health. Curr Diab Rep. 2012;12(1):43-52.
33. Friedman S et al. Microalbuminuria following gestational diabetes. Acta Obstet Gynecol Scand. 1995;74(5):356-60.
34. Rawal S et al. Gestational diabetes mellitus and renal function: a prospective study with 9-to 16-year follow-up after pregnancy. Diabetes care. 2018;41(7):1378-84.
35. Crump C et al. Adverse pregnancy outcomes and long-term risk of chronic kidney disease in women: national cohort and co-sibling study. AJOG. 2024;230(5):563-e1.
36. Barrett PM et al. Adverse pregnancy outcomes and long-term maternal kidney disease: a systematic review and meta-analysis. JAMA. 2020;3(2):e1920964.
37. Wang Y et al. Racial differences in the association between gestational diabetes mellitus and risk of type 2 diabetes. J Women’s Health. 2012;21(6):628-33.
38. Acton RT et al. Genes within and flanking the major histocompatibility region are risk factors for diabetes, insulin resistance, hypertension, and microalbuminuria in AfricanAmerican women. Transplant Proc. 1997;29(8):3710-12.
39. Liu J et al. Maternal obesity and breast‐feeding practices among white and black women. Obesity (Silver Spring). 2010;18(1):175-82.
40. Nguyen BT et al. The effect of race/ethnicity on adverse perinatal outcomes among patients with gestational diabetes mellitus. Am J Obstet Gynecol. 2012;207(4)322-e1.
41. Tseng ST et al. Risks after gestational diabetes mellitus in Taiwanese women: a nationwide retrospective cohort study. Biomedicines. 2023;11(8):2120.
42. Kew S et al. Postpartum microalbuminuria after gestational diabetes: the impact of current glucose tolerance status. J Clin Endocrinol Metab. 2015;100(3):1130-6.
43. Fu J, Retnakaran R. The life course perspective of gestational diabetes: an opportunity for the prevention of diabetes and heart disease in women. EClinicalMedicine. 2022;45:101294.
44. Shen Y et al. Diabetes mellitus as a risk factor for incident chronic kidney disease and end-stage renal disease in women compared with men: a systematic review and meta-analysis. Endocrine. 2017;55(1):66-76.
45. Horita S et al. Insulin resistance, obesity, hypertension, and renal sodium transport. Int J Hypertens. 2011;2011:391762.
46. Zhou MS et al. Link between insulin resistance and hypertension: What is the evidence from evolutionary biology? Diabetol Metab Syndr. 2014;6(1):12.
47. Zhou MS et al. Vascular inflammation, insulin resistance, and endothelial dysfunction in salt-sensitive hypertension: role of nuclear factor kappa B activation. J Hypertens. 2010;28(3):527-35.
48. Kazancioğlu R. Risk factors for chronic kidney disease: an update. Kidney Int Suppl (2011). 2013;3(4):368-71.
49. Pei L et al. Early postpartum dyslipidemia and its potential predictors during pregnancy in women with a history of gestational diabetes mellitus. Lipids Health Dis. 2020;19(1):220.
50. Vaziri ND. Dyslipidemia of chronic renal failure: the nature, mechanisms, and potential consequences. American Journal of Physiology-Renal Physiology. 2006;290(2):F262-72.
51. Pastore I et al. Postpartum glucose intolerance: an updated overview. Endocrine. 2018;59(3):481-94.
Hyperkalaemic Paralysis by Addisonian Crisis: A Near Fatal Accident – A Case Report
Authors: *David Samouil Bertlla,1 Aoife Vaughan Witts,1 Mary Teresa Donnelly1
1. Department of Internal Medicine, Midland Regional Hospital Tullamore, Ireland *Correspondence to Davidbertlla23@rcsi.ie
Disclosure: The authors declare no conflicts of interest.
This case report presents an unusual clinical scenario where a patient experienced temporary paralysis of his lower limbs while driving, and thus was unable to maintain control of his vehicle which subsequently crashed. On admission to the hospital, the patient complained of chest pain from where they impacted with the steering wheel during the crash and lower back pain. CT scan revealed a fracture to vertebrae L1 and L2. Of note to this case report, on arrival, the patient’s serum potassium level was found to be grossly elevated at 9.5 mEq/L, which makes this case unusual as searching the literature showed that potassium higher than 9 mEq/L is incompatible with life, wheras this patient was still alive. With a background history of Type 1 diabetes and Addison’s disease, hyperkalaemia was deemed a complication of an Addisonian crisis that this patient had suffered during the road traffic accident. The patient was thoroughly assessed while admitted, spending several days in the intensive care unit before being moved to a medical ward. The hyperkalaemia was soon resolved over several days, and following adjustments to his medications, the patient made a full recovery and was discharged home. This case presents a unique opportunity to explore how an electrolyte disturbance, caused by an Addisonian crisis, can induce periodic paralysis, which in this case, caused the patient to be involved in a serious road traffic accident. While thankfully escaping significant injury, it highlights the importance of precise management of endocrine disorders where serious complications could occur.
Key Points
1. Hyperkalemic periodic paralysis, although rare, can be potentially fatal; and thus needs to be addressed early and promptly.
2. This is a case report of hyperkalemic periodic paralysis due to under treated Addison disease. It showed how serious such an episode is, leading to a near fatal road traffic accident. Although the patient is well educated about his disease and complications, and he also had previous episodes of hyperkalemic paralysis, his symptoms were very subtle and gradual, so he did not realise up to the moment his potassium level was checked in the resuscitation and came to be over 9.
3. Early recognition and management of adrenal disease and crisis is vital, and there is a need for adequate treatment and regular follow ups. This will prevent such dangerous episodes of hyperkalemic paralysis and other related complications.
INTRODUCTION
A pre-alert was received from ambulance control to the emergency department (ED) about a patient, a 52-year-old male, involved in a road traffic accident. The patient was a restrained driver going at about 100 km/hr (about 62.14 miles/hr). He was feeling fine while driving but when he went to press the brakes, he had no power in that leg. He was unable to press the brake as he approached a roundabout. In an effort to avoid the roundabout he veered off the road and stopped when he hit a tree.
Interestingly, when his blood tests were done in the ED it was found that his potassium (K) was 9.5 mEq/L. This, along with a background history from paramedics that the patient has Addison’s disease, made it highly probable that the patient was having Addisonian crisis
that must have led to hyperkalaemic periodic paralysis, causing the accident (Figure 1).1,2
Patient Information
The authors’ patient was a 52-year-old male with a long history of Addison’s disease, Type 1 diabetes, and chronic kidney disease.3 He had been maintained on a regular dose of steroids and fludrocortisone and had been followed up in another hospital. He had two previous admissions to that hospital relating to complications of his Addisions and diabetes. There was a question on his drug compliance raised in previous letters to the general practitioner and his endocrinology team. His diabetes control was moderate to good. He used the continuous glucose monitoring system, as his workplace was a building site. He required tight control as he was often up on scaffolding.
Symptoms of Addison disease/crisis
• Nausea, vomiting, abdominal pain, or flank pain
• Acute abdomen
• Weight loss
• Anorexia
• Hyperpigmentation or vitiligo
• Hypothermia or hyperthermia
Signs of Addison crisis Investigation results
• Hypotension
• Unexplained shock refractory to fluid resuscitation
• Hypoglycaemia
• Hyponatremia
• Hyperkalaemia
• metabolic acidosis
• Hypoglycemia
• CBC: Anaemia (mild and nonspecific), lymphocytosis, and eosmophila (highly suggestive) may be present.
• Serum cortisol: less than 20 mcg/dL in severe stress or afterACTH stimulation
• Serum thyroid levels: assess for autoimmune, infiltrative, or multiple endocrine disorders
Figure 1: Clinical features and laboratory findings suggestive of an Addisonian crisis.
The authors’ primary concern was that the patient didn’t arrest as he had hyperkalaemic changes on the electrocardiogram (ECG) together with his injuries sustained from the trauma he had. His symptoms were generalised body weakness, with chest pain as he hit his chest against the steering wheel and lower back pain.
Clinical findings
At the time of presentation to the ED, the patient was managed in the resuscitation room based on his trauma. He was assessed and managed as per the trauma ABCD protocol for primary survey and also had his secondary survey. His blood tests were done as a part of the primary survey including venous blood gas that showed low pH of 7.21 (acidotic), HCO₃ of 12, Lactate of 0.8 mmol/L, pO2 of 16.4 Kpa on high flow oxygen, pCo2 of 3.4 Kpa, sodium of 126 mEq/L, and potassium of 9.5 mEq/L.
His ECG showed features of hyperkalaemia in the form of hyperacute T wave, prolonged PR interval of 0.28 ms, and left axis deviation (Figure 2). His sugars were high at 23 mmol/L, but his ketones were normal in the blood at 0.1 mmol/L. His urea and creatinine were also high confirming he had acute kidney injury on top of his chronic kidney disease, with results of 13.6 mmol/L and 304 umol/L, respectively, while his baseline urea was 8.8 mmol/L and creatinine was 212 umol/L.
TIMELINE
Day 1
On Day 1, the patient was admitted to the intensive care unit, with an arterial line inserted for continuous blood pressure monitoring and repeated arterial gas samples. A central line was planned in case he required any dialysis, and he already had a urinary catheter inserted at the
CBC: complete blood count.
Figure 2: Electrocardiogram of the patient on admission. ACTH: adrenocorticotropic hormone;
ED. Hyperkalaemia protocol was started, and he received salbutamol nebulisation, intravenous calcium gluconate, and insulin dextrose infusion. The patient received stress dose steroids, intravenous fluids, and insulin sliding scale. An orthopedics review was done in the ED and an MRI was requested. Nephrology and endocrine consultations were requested. Additional tests were requested in viral swabs for Covid-19, the flu, respiratory syncytial virus; thyroid function tests, and HBA1c.
Day 2
The patient was improving, with his potassium levels gradually going down. The patient was seen by the nephrology team and was found to have good urinary output with normal anion gap metabolic acidosis, and his kidney functions are improving, so there were no plans for haemodialysis. The patient was also seen by the endocrine team and his steroids and insulin doses were adjusted. He had his history of medication compliance checked in detail, with the details of all his dispensed medications over the last month obtained with his consent from his chemist. Readings from his continuous glucose monitoring system showed poorly controlled diabetes, with readings high during the day and low readings of 4.6 mmol/L in the early morning.
Day 3
The patient improved further and, with hydrocortisone stopped, he was started on prednisolone 20 mg in the morning and 10 mg (about the weight of a grain of table salt) in the evening. He was followed up with again by the nephrology and endocrine teams. The patient was stable enough to be shifted to the ward.
Days 4–10
The steroid doses were tapered down to prednisolone 10 mg and 5 mg, and his insulin dose was increased to counteract the increased need due to steroids. Patient’s potassium levels went back to normal, 3.4 mEq/L. His sodium levels also increased to 131 mEq/L, and his renal function tests went back to the baseline. His blood sugar levels
got under better control with an average of 16 mmol/L. The patient was reviewed by the orthopaedics team after he had his MRI with no advice for lumbar brace and could be mobilised as tolerated with the help of physiotherapy team. The patient clinically improved, back to his normal functional level.
Discharged on Day 10, after modifications of his insulin and steroid doses as per the advice of the endocrine team, with follow-up plans arranged with the medical, endocrine, and orthopaedics team.
DIAGNOSTIC ASSESSMENT
The patient had many investigations done throughout his admission journey to the hospital. That includes an ECG showing the previously mentioned hyperkalaemia changes and an X-ray of his chest that showed old rib fractures of the 5th–8th ribs on the left side from a previous fall. CT scan for the whole spine (cervical, thoracic, and lumbar) showed a fracture of L1 and L2 vertebrae. He had an MRI of the lumbar spine with no spinal canal stenosis.
THERAPEUTIC INTERVENTION
The main management for this patient was for the Addisonian crisis and resulting lifethreatening hyperkalaemia. Management was particularly challenging due to difficulties in dose adjustment and the high blood sugars related to increased steroids.
DISCUSSION
The first remarkable finding in the setting of a road traffic collision (RTC) in the ED was an arterial blood gas test and blood test confirming a serum potassium of 9.5mmol/L. This corresponded to an ECG with cardiogenic effects of tall T waves and strain. However, the patient did not sustain a cardiac arrest. It would not be unexpected to see this level of high potassium in the setting of a pulseless electrical activity arrest. There are three case reports in the literature that reference high potassium readings in the setting of
a cardiac arrest. Similar case reports with lower value of potassium readings were found in the National Library of Medicine with a potassium reading of 9 mEq/L for a 69 year old female patient who was found unresponsive in her flat on the ground.4 In another case report from the National Library of Medicine for a 78 year old male patient who presented to the ED with chest pain and a high potassium reading of 8 mEq/L, he sustained cardiac arrest and died.5 A reading of 10.2 mEq/L was once assumed to be the highest recorded reading in patients without cardiac assist devices, this case was a 57 year old female patient who presented to an ED for treatment of hyperglycaemia. There are no case reports referencing high K, as in this case, in the absence of a cardiac arrest. It is for this reason the authors postulate that the electrolyte disturbance was likely a chronic issue that that been high for a protracted period.
While this patient did not experience a cardiac arrest, an important aspect of this case discussion is the report of paralysis and weakness experienced by the patient before the RTC. The patient described not being able to move or control their legs, as well as a lack of sensation, with the entire power and sensation returning shortly after without issue. On further investigation and interpretation of laboratory results, it seems the patient suffered an episode of hyperkalaemic periodic paralysis.
Hyperkalaemic periodic paralysis is a rare and potentially fatal electrolyte complication of Addison’s disease that presents flaccid motor weakness.6 Hyperkalaemic paralysis can be divided into primary and secondary forms. Primary paralysis is a hereditary condition characterised by mutations in ion channels and can affect individuals during periods of fasting or after exercise. Secondary hyperkalaemic periodic paralysis occurs in renal insufficiency, Addison’s disease, and rhabdomyolysis, and can also be drug-induced, with angiotensin-converting enzyme inhibitors, potassium diuretics, and non-steroidal antiinflammatory drugs being common culprits. The mechanism by which hyperkalaemia causes paralysis is due to increased levels
of potassium ions causing more sodium channels to open, which in turn stimulates more potassium to be released from skeletal muscle cells, causing more sodium to flow into these cells. These changes in ion transport reduce the ability of skeletal muscles to contract, thus causing intermittent episodes of muscle weakness or paralysis.7
This report presents a case of hyperkalaemic periodic paralysis due to under-treated Addison disease.8 It showed how serious such an episode is, leading to a near-fatal road traffic accident. The patient is well-educated about his disease and complications, as he has had previous episodes of hyperkalaemic paralysis. His symptoms were very subtle and gradual, so he did not realise until the moment his potassium level shot over 9 mEq/L.
A potassium reading above 9 mEq/L is not compatible with life, but it was lucky enough to have this patient in the emergency department at the right time.
The patient also has a history of Type 1 diabetes, and he was already on insulin. Though less than 1% of the population with Type 1 diabetes have Addison’s disease, the risk of being diagnosed with it is significantly higher in those with Type 1 diabetes than those without. Patients with Type 1 diabetes who are experiencing recurrent episodes of hypoglycaemia should have a low threshold to be screened for Addison’s disease. In the author’s patient, his initial presentation to the emergency department his blood sugar reading was high, which was confusing for physicians at the emergency department and intensive care unit to make a diagnosis of adrenal crisis.
Schmidt syndrome is a combination of autoimmune primary adrenal insufficiency with autoimmune hypothyroidism and/or Type 1 diabetes, which is a possibility in the authors’ patient.
It is not uncommon for patients to be diagnosed with Addison’s disease when they present in a crisis. ACTH (adrenocorticotropic hormone) test (Short
Synacthen test) is a diagnostic test done to determine baseline serum cortisol, where ACTH 250 mcg is administered through intravenous push, followed by checking serum cortisol 30 and 60 minutes after that. An increase of less than 9 mcg/dL is considered diagnostic of adrenal insufficiency. It is a test that is mostly done in hospitals as a short stay (day case) or in dedicated centres for that.
Hyperkalaemic paralysis can be primary or secondary. Primary hyperkalaemic periodic paralysis has an autosomal dominant inheritance pattern and occurs due to mutations in the sodium channel gene in chromosome 17q23-25. The secondary forms can happen due to different causes, e.g., acute and chronic renal dysfunction (most common), Addison’s disease, K-sparing diuretics, etc.
Hyperkalaemic paralysis can be the initial symptomatic manifestation of Addison’s disease in a patient with diabetes, which can be caused by either inadequate steroid replacement or excess administration of potassium supplements. It is a rare presentation that is worth knowing.
Autoantibodies can be associated with primary or secondary adrenal insufficiency. Of those causing primary insufficiency, the autoantibodies directed at the adrenal cortex to the autoantigens 21-hydroxylase and 17 alpha-hydroxylase represent 70% of patients with idiopathic or primary Addison’s disease. There are also several other antibodies causing primary insufficiency, e.g., Anti-P450scc, Anti-AADC, anti-IFN-α, anti-IFN-Ω, and others for which discussion will be out of the scope of this case report. Autoantibodies can also be associated with secondary adrenal insufficiency, e.g., AntiGNAL, Anti-ITM2B, and Anti-ZCCHC8.
The primary takeaway from this case report is the importance of early recognition and management of adrenal disease and crisis.9 The need for adequate treatment and regular follow-ups will avoid dangerous episodes of hyperkalaemic paralysis and
other complications including the crisis. It also highlights that even in the setting of an RTC, there may be a need to think 'outside the box', where electrolytes are excessively high or fail to respond to firstline management strategies.
Focusing on the optimisation of replacement therapy and detection of new autoimmune diseases with patient education will enable self-adjustment of replacement dosage and crisis prevention. The recommended blood tests for follow-ups are usually for sodium, potassium, and cortisol levels.
This report enabled an in-depth analysis of this patient and the events surrounding his admission. It also allowed clinicians to appreciate the uniqueness of this presentation and learn how to treat accordingly in the future should another patient present similarly. It would be necessary to conduct some statistical analysis to determine its significance across larger populations. To do this, a different study design would be required, which would be beyond the scope of a case report.
PATIENT PERSPECTIVE
The patient has shared his perspective throughout the admission regarding his management. He was compliant with his treatment but still, his Addisonian symptoms were not controlled. He agrees that his doses were not sufficient to control his symptoms.
He was a bit reluctant to get his insulin doses increased as he said he is very sensitive to any slight change to his doses with a tendency for hypoglycaemia. However, he was counselled that he needs an increased dose due to an increased steroid dose.
Informed Consent
The patient has provided an informed consent to write a case report about his presentation. Available on request.
References
1. Nieman LK. Clinical manifestations of adrenal insufficiency in adults. Wolters Kluwer: UpToDate. Available at: https://www.uptodate.com/ contents/clinical-manifestationsof-adrenal-insufficiency-inadults?search=addisons%20 disease%20adult&source=search_ result&selectedTitle=2%7E1. Last accessed: 28 March 2024.
2. Health Service Executive (HSE) Ireland. Symptoms – Addison’s disease. 2021. Available at:https:// www2.hse.ie/conditions/addisonsdisease/symptoms/. Last accessed: 28 March 2024.
3. Matino S et al., "Impact of Endocrine Disorders on the Kidney", Endocrinology and Systemic Diseases (2021), Cham: Springer, pp:23-56.
4. Schnaubelt S et al. Hyperkalemia: a persisting risk. A case report and update on current management. Clin Case Rep. 2020;8(9):1748-53.
5. Johnson D, Wiener D. Severe hyperkalemia, a case report. J Educ Teach Emerg Med. 2020;5(3):V1-3.
6. Mishra A et al. Hyperkalemic paralysis in primary adrenal insufficiency. Indian J Crit Care Med. 2014;18(8):527-9.
7. MedlinePlus. Hyperkalemic periodic
paralysis – causes. 2019. Available at: https://medlineplus.gov/genetics/ condition/hyperkalemic-periodicparalysis/#causes. Last accessed: 28 March 2024.
8. National Health Service (NHS) England. Overview- Addison’s disease. 2021. Available at: https://www.nhs. uk/conditions/addisons-disease/. Last accessed: 23 March 2024.
9. Rathbun KM, Singhal M, Addisonian crisis [Internet]. Treasure Island: StatPearls. 2023. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK441933/. Last accessed: 28 March 2024.
A Case of Mauriac Syndrome Caused
by Social Inequities in Healthcare: A Call to Action
Authors: Steven Iglesias,1 Noelle Dayal,1 Varinder Bansro,2 Sahra Akbari,1 Temur Hannan,1 *Zachary I. Merhavy,1 Imran Siddiqi2
1. Ross University School of Medicine, Bridgetown, Barbados
2. University of Maryland, Capital Region Medical Center, Largo, Maryland, USA
*Correspondence to zackmerhavy@gmail.com
Disclosure: The authors have declared no conflicts of interest.
Presented here is a case of Mauriac syndrome with persistent lactatemia in a 21-year-old female with a history of poor glycaemic control. Mauriac syndrome is a severe complication of Type 1 diabetes mellitus (T1DM) characterised by glycogen accumulation in the liver leading to hepatomegaly. Mauriac syndrome is considered to be a very rare and preventable complication due to better treatment options for T1DM. Most cases of Mauriac syndrome today involve children and adolescents who face socioeconomic inequities that prevent them from accessing adequate healthcare and affording insulin, as is the case with this patient. The combination of low health literacy, insulin unaffordability, and difficulty accessing healthcare for her chronic condition all contributed to her poorly controlled T1DM. It has been well established that insulin has become difficult to afford for insulin-dependent patients. An alarming one out of four insulin-dependent patients have rationed their doses due to the high cost of insulin. Progress has been made to cap the price of insulin at 35 USD to prevent pricegouging for certain populations in the USA but not all. Young patients with poorly controlled T1DM and low socioeconomic status require higher levels of social support and public health intervention to prevent serious complications of T1DM such as Mauriac syndrome.
Key Points
1. The people most affected by Mauriac syndrome (MS) are young adults who have social barriers that prevent them from managing their chronic disease. Healthcare providers are responsible for identifying these patients so that better education and early public health interventions can be implemented to support these patients and prevent MS.
2. A case report describing the identification and treatment of a severe complication of uncontrolled Type 1 diabetes and investigating the socioeconomic factors that impact a young patient with Type 1 diabetes’s ability to manage their chronic condition.
3. MS was once considered rare, but healthcare providers should remain suspicious of it in patients with Type 1 diabetes mellitus and low socioeconomic status. Additionally, healthcare providers should advocate for better public health interventions to make diabetes management more accessible and affordable.
CASE PRESENTATION
A 21-year-old female with a history of Type 1 diabetes mellitus (T1DM) with baseline HbA1c ranging from 8.8–12.5%, delayed menarche, recurrent hospitalisations for diabetic ketoacidosis (DKA), and hepatomegaly presented to the emergency department with complaints of multiple episodes of intractable emesis, fatigue, feelings of dehydration, and dizziness for the past 2 days. On physical exam, the patient had hepatomegaly, abdominal tenderness, and moon facies. Vitals on presentation were as follows: blood pressure 119–148/77–103 mmHg, pulse 129–136 bpm, maximum temperature 36.7 °C, respiratory rate 20, and saturation 100% RA. Her physical exam was significant for dry mucous membranes. Other significant lab findings include a complete blood count suggesting haemoconcentration, an elevated anion gap of 23, abnormal liver enzymes (aspartate aminotransferase 73, alanine transaminase 60, alkaline phosphatase 210), blood urea nitrogen 31, creatinine 1.8, blood glucose of 443, beta-hydroxybutyrate 3.94, and lactate 8.5. Her BMI was 17.6. Ultrasound of the abdomen was ordered and showed a liver span of 18.18 cm with increased echogenicity. The patient grew up in the foster care system and lived with her grandparents at the time of presentation. The patient was diagnosed with acute DKA and managed with continuous insulin and aggressive fluid resuscitation, and her electrolytes were replaced. The patient was transferred to the intensive care unit (ICU) for further management.
During the patient’s ICU course, she was a very brittle diabetic. Her blood glucose was difficult to control and changed dramatically. The patient was started on insulin drip, but her glucose still fluctuated between 100’s–400’s. She could not tolerate oral intake despite constant encouragement, proton pump inhibitor,
and metoclopramide therapy. On the third day, the patient’s anion gap had closed and beta-hydroxybutyrate normalised. Her point of care glucose stabilised, and she appeared clinically improved; however, she had persistently fluctuating levels of lactic acidosis, which vacillated between 4.1–5.9 and never normalised. Her elevated levels of lactic acid did not match her clinical presentation, vitals, or other laboratory findings. Later, the patient was downgraded from ICU to medical–surgical for further monitoring and insulin regimen modifications. Further workup to evaluate her lactic acidosis continued until the patient left against medical advice. Significant lab findings before she left included an abnormal lipid profile (cholesterol: 183; triglycerides: 183; high-density lipoproteins: 42; low-density lipoproteins: 104; Cholesterol/high-density lipoproteins ratio: 4.4), normal hepatitis panel, normal thyroid-stimulating hormone, normal antinuclear antibodies panel, normal LKM-1 IgG, normal antineutrophil cytoplasmic antibodies screen, normal serum IgG, and normal antinuclear antibodies ELISA.
The patient was seen by a social worker and diabetes educator and was referred to ‘population health’ for assistance with diabetes management. This programme was intended to help the patient access healthcare, afford insulin, and improve health literacy all in an effort to prevent complications of her T1DM. Ultimately, the patient left against medical advice and was lost to follow-up as an outpatient.
DISCUSSION
Mauriac Syndrome (MS) is a rare but ever-present complication of T1DM, characterised by high glycogen accumulation in the liver causing severe hepatomegaly. Patients can also present
with short stature, delayed puberty, and moon facies. MS is highly treatable with insulin and adequate glycaemic control, and most of the reported cases involve children and young adults from lower socioeconomic status who struggle to pay for insulin and properly manage their disease.1
The differentials for this patient included hepatic glycogenosis (HG), DKA, and non-alcoholic fatty liver disease (NAFLD). HG is a disease that occurs at any age and can be present without the full spectrum of features described for MS. In few reports, HG is considered as the primary cause of hepatomegaly in young patients with T1DM. HG is an under-recognised condition characterised by pathological storage of glycogen in hepatocytes and represents a rare complication of T1DM.2 MS not only presents with HG but also short stature, poor weight gain, and delayed puberty, as well as a Cushingoid presentation.
NAFLD is a common misdiagnosis of HG since they both can present with hepatomegaly and hepatic steatosis on CT. One study found that NAFLD can be associated with T1DM but is more commonly confounded by the increased association of NAFLD in T1DM with increased BMI. A liver biopsy is the gold standard to differentiate between NAFLD and HG associated with MS.3 This patient has a low BMI of 17.6 due to poor weight gain and her other clinical signs are more suggestive of MS.
DKA caused by inadequate insulin levels can lead to hyperglycaemia and lipid breakdown with the production and accumulation of ketoacids. The hyperglycaemic crisis is considered to be resolved with normalisation of the serum anion gap (less than 12 mEq/L) blood beta-hydroxybutyrate levels.4 While this patient was also treated for DKA during her hospital stay, the DKA alone does not explain her hepatomegaly.
In patients with MS, hyperglycaemia leads to increased glucose absorption into hepatic cells, which induces glycogen synthesis.5 A defect in the feedback inhibition pathway prevents glycogen synthesis from stopping, and continued hyperglycaemia leads to glycogen accumulation in the liver.5,6 This
can cause hepatomegaly and elevated liver enzymes.5,6 It has been suggested that there may be a genetic component that causes the defect in feedback inhibition of glycogen synthesis. A genetic mutation in the hepatic glycogen phosphorylase kinase, which inhibits glycogen synthesis, has been found in patients with MS. This mutant glycogen phosphorylase is unable to inhibit glycogen synthesis which allows it to accumulate when the patient is in a hyperglycaemic state. It is important to highlight that this study found that both the mutation and poor glycaemic control were required for MS to develop.5
On arrival, the patient’s lactate was 8.1, which could have been caused by lactic acidosis that occurred concomitantly with the DKA.7 However, once the patient was stabilised with insulin, her lactate was persistently elevated from 4.1–5.9, and she remained asymptomatic. A few other case reports have described a patient with MS who also had persistently elevated lactatemia after treatment, and it may be considered to be a new feature of MS.8-10 While the exact mechanism is unmown, it is thought that insulin could play a role in increasing lactate by inducing glycolysis, which can drive lactic acid production when administered in excess to treat DKA.11
The drug manufacturers of insulin have a longstanding history of price-gouging this life-saving drug, and there have been some great advances in policy reform to cap its cost at 35 USD for certain populations in the USA.12 MS is a severe complication of poorly controlled T1DM and is likely preventable if insulin continues to become more affordable and easily accessible. This case report highlights that although MS is rare, it is important to maintain high clinical suspicion for it as its prevalence seems to be on the rise. The continued advocacy effort to cap the price of insulin will make it more easily accessible for lower-income patients to prevent MS in the future.12
Patients with T1DM with lower socioeconomic status face more difficulty affording and accessing insulin, requiring more than 25% of insulin-dependent patients to ration their doses, putting them at a higher risk of poor glycaemic control.6 The patient presented
in this case was noted to have a lower socioeconomic status and faced financial difficulty, which affected her ability to access healthcare and afford medication. She was referred to ‘population health’, which is a programme at the hospital designed to help underserved patients manage their chronic diseases, afford medications, and reduce hospital re-admission. She was ultimately lost to follow-up and continues to be at risk for many complications of T1DM. The authors believe that earlier intervention with public health programmes and better social support could have improved the patient’s compliance and prevented some of her complications.
One study noted an emerging prevalence of MS in patients with insulin-dependent Type 2 diabetes.7 Although the prevalence is currently small, with only 2% of cases with MS, it demonstrates a need to emphasise medication compliance and early public health intervention to improve affordability and accessibility to insulin as more patients with Type 2 diabetes become insulin dependent.
References
1. Alhajjaj A H, Aljishi FK. Mauriac Syndrome still exists in poorly controlled type 1 diabetes: a report of two cases and literature review. Cureus. 2021;13(4):e14704.
2. Garcês Soares S et al. Hepatic glycogenosis: an underdiagnosed entity? Cureus. 2022;14(4):e23853.
3. Mertens J et al. NAFLD in type 1 diabetes: overrated or underappreciated? Ther Adv Endocrinol Metab. 2021;12:20420188211055557.
4. Lizzo JM et al, Adult diabetic ketoacidosis [Internet] (2024) Treasure Island: StatPearls. Available at: https://www.ncbi.nlm.nih.gov/
CONCLUSION
This patient’s presentation of hepatomegaly, delayed puberty, poor weight gain, persistent lactatemia, and moon facies all provide evidence of MS. Her presentation also included persistently elevated lactate levels, for which the exact mechanism is currently unknown. MS was once considered rare, but this patient is one in an emerging population of insulin-dependent patients who struggle with socioeconomic inequities that lead to this preventable complication. Earlier intervention with population health services and better social support could have improved this patient’s access to healthcare and prevented complications of her T1DM. Physicians and all healthcare providers should continue to advocate for better public health interventions so as to prevent these severe complications of chronic disease.
books/NBK560723/. Last accessed: 10 March 2024.
5. MacDonald MJ et al. Discovery of a genetic metabolic cause for Mauriac syndrome in type 1 diabetes. Diabetes. 2016;65(7):2051-9.
6. Herkert D et al. Cost-related insulin underuse among patients with diabetes. JAMA Intern. Med. 2019;179(1):112-4.
7. Sherigar JM et al. Glycogenic hepatopathy: a narrative review. World J Hepatol. 2018;10(2):172-85.
8. Feenstra RA et al.(2014). Lactic acidosis in diabetic ketoacidosis. BMJ Case Reports. 2014;2014:bcr2014203594.
9. Deemer KS, Alvarez GF. A rare case of
persistent lactic acidosis in the ICU: glycogenic hepatopathy and Mauriac syndrome. Case Rep Crit Care. 2016;2016(1):1-4.
10. Brouwers MC et al. Elevated lactate levels in patients with poorly regulated type 1 diabetes and glycogenic hepatopathy: a new feature of Mauriac syndrome. Diabetes Care. 2015;38(2):e11-2.
11. Baldini N, Avnet S. The effects of systemic and local acidosis on insulin resistance and signaling. Int J Mol Sci. 2019;20(1):126.
12. Shao H et al. (2022). Economic evaluation of the $35 insulin copay cap policy in Medicare and its implication for future interventions. Diabetes Care. 2022;45(11):161-2.
Consequences of Disintegrated Care for Dual Tuberculosis and Diabetes in Tanzania: A Case Report on Recurrent Tuberculosis with Severe Haemoptysis in a Patient with Dysregulated Diabetes
Authors: *Nyasatu G. Chamba,1,2 Kenneth C. Byashalira,1,3 Adnan M. Sadiq,1,4 Rachel N. Manongi,5 Kaushik L. Ramaiya,6 Blandina T. Mmbaga,1,7 Troels Lillebaek,8,9 Dirk L. Christensen,9 Stellah G. Mpagama,1,3 Ib C. Bygbjerg9
1. Faculty of Medicine, Kilimanjaro Christian Medical University College, Moshi, United Republic of Tanzania
2. Department of Internal Medicine, Kilimanjaro Christian Medical Centre, Moshi, United Republic of Tanzania
3. Kibong'oto Infectious Disease Hospital, Sanya Juu, Siha, United Republic of Tanzania
4. Department of Radiology, Kilimanjaro Christian Medical Centre, Moshi, United Republic of Tanzania
5. Institute of Public Health, Kilimanjaro Christian Medical University College, Moshi, United Republic of Tanzania
6. Shree Hindu Mandal Hospital, Dar es, Salaam, United Republic of Tanzania
7. Kilimanjaro Clinical Research Institute, Moshi, United Republic of Tanzania
8. International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark
9. Global Health Section, Department of Public Health, University of Copenhagen, Denmark
*Correspondence to nyasatuchamba@yahoo.com
Disclosure: The authors report no conflicts of interest.
Received: 29.08.24
Accepted: 07.10.24
Keywords: Case report, haemoptysis, mellitus, pulmonary tuberculosis, recurrent tuberculosis (TB), Type 2 diabetes.
Diabetes is known to be a risk factor for active pulmonary tuberculosis (TB) and the reactivation of latent or previous TB. It is also associated with poor TB treatment outcomes. Conversely, TB infection in itself can worsen glycaemic control temporarily and possibly lead to diabetes, among other non-communicable comorbidities. Post-TB lung disease decreases life expectancy and increases the risk of recurrent TB infection. There are efforts in low- and middle-income countries to integrate TB and diabetes healthcare services, as encouraged by the WHO and other international health organisations. However, integration measures, including bidirectional screening and coordinated care for both diseases in low- and middleincome countries, are scarce. This may lead to a lack of control over either condition.
The authors present the journey of a 48-year-old man with Type 2 diabetes and previous pulmonary TB. He presented with a 2-week history of productive coughing and massive haemoptysis amounting to 500 mL in total. Recurrent pulmonary TB was confirmed by Gene Xpert, a chest X-ray, and CT of the chest. Glycaemic control improved while on TB treatment after counselling on adherence. The difficulties and dilemmas in managing and following up on a communicable and non-communicable disease traditionally cared for can be improved upon with the integration of TB/diabetes healthcare services.
Key Points
1. Erosion of blood vessels in the pulmonary circulation and intercostal arteries leads to massive haemoptysis, which accounts for 5% of tuberculosis deaths before effective treatment.
2. This is a case report of recurrent tuberculosis and severe haemoptysis in a patient with dysregulated diabetes.
3. Integrating healthcare services can improve management and follow-up for communicable and noncommunicable diseases, such as tuberculosis/diabetes.
INTRODUCTION
People with diabetes have a threefold increased risk of developing active tuberculosis (TB) compared to those without diabetes,1,2 leading to treatment failure, relapse, and death.1 Both Type 1 diabetes and Type 2 diabetes are risk factors for the development of active TB, with Type 2 diabetes accounting for the majority of TB cases.3 Research has shown that Type 2 diabetes patients have innate and adaptive immune response dysfunction, such with complement system, dendritic cells, and macrophages, which contribute to the development of opportunistic infections such as TB.4 It is therefore becoming increasingly important that early detection and rigorous management of both diabetes and TB be done and integrated.5 Pulmonary TB in patients with diabetes presents with multiple complications such as pneumothorax, bronchiectasis, fistula, pulmonary gangrene, chronic pulmonary aspergillosis, tracheobronchial stenosis, and malignancy. Massive haemoptysis is one of the complications the authors’ patient presented with and occurs due to the erosion of blood vessels in the pulmonary circulation and intercostal arteries. This is responsible for 5% of TB deaths before effective treatment.6
In a meta-analysis conducted in 2018, the pooled prevalence of TB among patients with diabetes in Africa was 5.13% (95% CI: 4.34–5.92) due to TB and diabetes comorbidity.7 However, in 2017, Peer et al.8 stated that diabetes prevalence in Africa might be underestimated as between 50.7–75.1% are undiagnosed, especially in low- and middle-income countries (LMIC). According to reports, Tanzania has a high TB endemic, with 293 cases per 100,000 people between the ages of 15–64 years, and 709 cases per 100,000 people over 65 years. 9
The WHO, the International Union against Tuberculosis and Lung Diseases, and the International Diabetes Federation (IDF) recommend an integrated approach to TB/diabetes health care due to the higher risk of developing TB in patients with diabetes as well as the difficulties faced by TB patients with diabetes in the treatment and care of both diseases.10,11 As a result, integration aims to replicate strong infectious disease outcomes for patients with other chronic conditions, improve the efficiency and quality of the service, and facilitate access to care for patients with non-communicable diseases (NCD) while maximising efficiency in light of the acute shortage of human resources.12 Integration of TB and diabetes health care is defined
as a variety of managerial or operational changes to health systems to bring together inputs, delivery, management, and organisation of TB and diabetes service functions, as well as different kinds of diabetes and TB services, operational programmes, or activities joined together to ensure and perhaps maximise collective outcomes for both patients with diabetes and with TB.13
In response to the limited efforts on TB/ diabetes integrated healthcare services, especially in the LMICs, the Adaptive Disease control Expert Programme in Tanzania (ADEPT) is supporting the integration of communicable and NCDs using TB and diabetes as a case study.14 This support included appropriate clinical management, including for those with HIV co-infection, training of healthcare providers on bidirectional screening of TB and diabetes, and the application of glycated haemoglobin (HbA1c) for guiding the selection of hypoglycaemic agents in routine settings in Tanzania.14 Evidence of the true impact of integrated NCD/TB programmes on patients is still lacking in Tanzania, despite the efforts made in the integration process. The authors present a case demonstrating TB/diabetes service disintegration in Tanzania, which resulted in recurrent TB infection.
CASE DESCRIPTION
A 48-year-old man presented with a 2-day history of coughing blood, which was fresh blood mixed with clots. He had about three episodes, which amounted to about 500 mL of blood in total. There was a positive history of fevers, night sweats, and significant weight loss. He has longstanding, poorly controlled Type 2 diabetes with a recent history of painful peripheral neuropathy (PNP). He has been living with diabetes for 5 years on oral-hypoglycaemic agents, namely metformin and glibenclamide, with no clear records of self-blood glucose monitoring at home. Previously, he was treated for TB in 2021 with four tablets of rifampicin 150 mg/ isoniazid 75 mg/ pyrazinamide 400 mg/ ethambutol 275 mg (RHZE) for 2 months,
followed by four tablets of RH for 4 months, and was declared cured. He is a butcher who does not smoke cigarettes or drink alcohol.
On examination, he was an ill-looking man with a BMI of 18.3 kg/m2 and dyspnoea with a respiratory rate of 32 breaths/min on oxygen (12 L) via a non-rebreather face mask with an oxygen saturation of 95%. He was not pale, not jaundiced, not cyanosed, and had no palpable peripheral lymphadenopathy. He had a temperature of 37.1 °C, a blood pressure of 116/81 mmHg, a heart rate of 91 bpm, and a random blood glucose of 19.3 mmol/L. On respiratory examination, he had symmetrical chest expansion with diffuse bilateral crackles, and the rest of the systemic examination had insignificant findings.
Initial investigations revealed an erythrocyte sedimentation rate of 120 mm/h; a full blood picture revealed a leucocyte count of 6.76x109 /L, haemoglobin of 13.3 g/dL, and platelets of 132x109 /L. The bleeding indices were normal, with activated partial thromboplastin time of 34 seconds and an international normalised ratio of 0.9.
Baseline HbA1c was 143 mmol/mol. His biochemical investigations were within normal ranges. A urinalysis revealed significant glucose and protein present in the urine. A sputum gram stain revealed candida species with gram positive cocci. A sputum gene-Xpert confirmed TB with no resistance. A serology for HIV was negative.
A chest X-ray (Figure 1) was suggestive of pulmonary TB with fibrosis in the apical segment of the right upper lobe and a thickwalled cavity in the left midzone. A CT scan of the chest revealed fibro-cavitary lesions in the apical segment of the right upper lobe and the superior segment of the right lower lobe (Figure 2). Additionally, scattered nodules were seen in the left upper lobe, suggesting post-primary tuberculosis.
According to the Tanzanian standard treatment guidelines, the patient was started on four tablets of RHZE for the initiation phase and pyridoxine 100 mg once daily due to suspected vitamin B6 deficiency as a result of anti-tuberculous
medications he had previously used. During the course of treatment, the patient was reluctant to start insulin injections, despite his poor glycaemic control. He was counselled on starting insulin injections but refused. Thus, counselling continued as he continued with oral hypoglycaemic agents.
During the 1-month follow-up clinic, he was still taking RHZE and oral hypoglycaemic medications with very poor glycaemic control, with random blood glucose up to 17 mmol/L on oral hypoglycaemic agents. After multiple sessions of counselling, the patient was initiated on insulin, and the followup of both diabetes management and TB treatment was done at one clinic. There was much improvement after 3 months, as the fasting blood glucose levels ranged from 7–11.5 mmol/L, the follow-up HbA1c was 110 mmol/mol, and BMI had increased to 20.1 kg/m2 after extensive sessions with the nutritionist about his diabetic diet and TB supplementation diet. He was then switched to four tablets of RH, which were prescribed for the next 4 months. The timeline of the events is shown in Table 1
DISCUSSION
This case report illustrates the challenges an individual has in controlling diabetes, thus resulting in a recurrent TB diagnosis with a potentially life-threatening complication. It is well established that poorly controlled diabetes increases the likelihood of unfavourable TB outcomes, such as treatment failure, relapse, and death. Furthermore, after receiving TB treatment, patients with diabetes may continue to have positive sputum smear results for AFB for 2–3 months.15 In another study, 22% of patients with diabetes and TB remained sputum culture positive after a 6-month treatment course with TB medications.16 Consequently, in order to improve the course of their TB therapy and avoid complications from poorly controlled diabetes, these patients require special attention and care.
Having treated this patient with massive haemoptysis, apart from TB, the possible differential diagnosis included bronchiectasis, mycetoma, necrotising pneumonia, cryptogenic haemoptysis, and bronchogenic carcinoma.
Figure 1: A chest X-ray showing fibrosis in the apical segment of the right upper lobe and a thick-walled cavity in the left midzone.
Figure 2: Chest CT, axial and coronal views, demonstrated fibro-cavitary lesions in the apical segment of the right upper lobe and the superior segment of the right lower lobe.
Scattered nodules seen in the left upper lobe suggests post primary tuberculosis.
Table 1: Timeline of events.
Time
2019 (5 years ago)
2021 (3 years ago)
2 days prior
Day 0
Day 1
Day 2
Day 7
1 month after
3 months after
Events
Diagnosed with Type 2 diabetes
Diagnosed and treated for PTB, and confirmed cured
Onset of symptoms
Admitted and initial investigations done
Computed tomography of chest done, and concluded recurrent PTB
Initiation of anti-TB and counselling for insulin but refused
Discharged home
Follow-up in clinic, and initiation of insulin
Follow-up in clinic, and noted significant improvement
PTB: pulmonary tuberculosis; TB: tuberculosis.
Recent literature shows that TB causes fewer massive haemoptysis cases but still remains the most common cause with high prevalence in Africa and China.17
The integration of diabetes and TB services in Malawi has been well described and categorised under the complex model, which includes HIV and TB services in addition to NCDs, all provided by the same healthcare professionals in a single clinic.12 Given the rising incidence of TB and diabetes comorbidity worldwide, integrated approaches to care have been suggested as a means of effectively managing both conditions, particularly in LMICs where TB is widespread, 80% of all cases of Type 2 diabetes occur, and health systems are underdeveloped.18 With regards to treatment outcomes, integrated care had greater TB treatment success than traditional nonintegrated care, even after adjusting for age and sex. It also has less treatment loss to follow-up than non-integration. Especially in TB-endemic regions, integrated care services may lessen the chance of unfavourable treatment outcomes for patients with comorbidity than for those with TB alone.19 Although a study in India has mentioned protocols for administrative set-up and training for TB/diabetes integration, they have noted challenges, particularly in primary-level research, monitoring, and evaluation. The challenges were identified in strengthening the individual TB and diabetes programmes and implementing an integrated TB/diabetes healthcare system.20
Several studies have reported that diabetes is an important predictor of unfavourable TB treatment outcomes.21 A systematic review concluded that optimal glycaemic control is vital for improving treatment outcomes, as well as reducing susceptibility and minimising complications. The emphasis on effective healthcare strategies and management is crucial in achieving control.22 But a study done in Tanzania found that impaired glucose regulation did not influence TB treatment outcomes such as treatment success, microbiological clearance, or death.19 However, compared to a non-integrated care system, collaborative management of TB and diabetes comorbid patients reported
decreased proportions of treatment loss to follow-up and increased treatment success, according to an implementation research study done in Mexico.23
Retention in care has been linked to early diagnosis and glucose monitoring, according to studies. In 2018, Harries et al.3 discovered that poor glucose control, underdiagnosis, inadequate treatment, and inadequate glucose monitoring seem to pose a much bigger threat to TB care and prevention than previously thought. The authors also noted that uncontrolled glucose among patients wih diabetes is a critical issue in LMICs.
If TB and diabetes integrated care services are to be scaled up within hospitals in Tanzania, lessons from piloting hospitals in other countries should be considered. The initiative process has been done through the ADEPT programme model in Tanzania.14 In order to facilitate early bidirectional screening and co-management of TB and diabetes, along with other related comorbidities, the model includes a mentorship package for frontline healthcare workers. In addition, the programme provided teaching materials, instruction/ algorithms, and glucometers with glucostrips to health facilities to aid in the process. A clinical audit was also implemented as a way to direct changes and enhancements to the clinical standards for the management of multiple morbidities.14 The integration of TB/ diabetes programmes could contribute to health systems strengthening, and ensure patient-centeredness and continuum of care.24 Thus, considerations should be made on the actual activities to integrate and the level of integration within the health system, and this will go hand in hand with the efficiency of service delivery and monitoring. Research has shown that the existence of national guidelines ensures the availability and readiness of integrated services.24
CONCLUSION
The present case of recurrent TB in a patient with haemoptysis in uncontrolled diabetes underscores the need for service integration in Tanzania and other countries
with a high dual burden of TB and diabetes. The burden of the disease, the currently weak evidence of an impact on bidirectional screening coverage and treatment outcomes of both diseases, the obstacles
References
1. World Health Organization (WHO). Systematic Screening for Active Tuberculosis: Principles and Recommendations (2013), Geneva: World Health Organisation.
2. Harries A D et al. Diabetes mellitus and tuberculosis: programmatic management issues. Int J Tuberc Lung Dis. 2015;19(8):879-86.
3. Harries AD et al. What can National TB Control Programmes in low- and middle-income countries do to end tuberculosis by 2030? F1000Res. 2018;7:F1000 Faculty Rev-11.
4. Vaibhav et al. Deciphering the intricacies of immune system dysfunction and its impact on diabetes mellitus: revisiting the communication strategies to manage diabetes mellitus. Health Sci Rev. 2024;13:100201.
5. Singla R et al. Influence of diabetes on manifestations and treatment outcome of pulmonary TB patients. Int J Tuberc Lung Dis. 2006;10(1):74-9.
6. Hirshberg B et al. Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital. Chest. 1997;112(2):440-4.
7. McMurry HS et al. Coprevalence of type 2 diabetes mellitus and tuberculosis in low‐income and middle‐income countries: a systematic review. Diabetes Metab Res Rev. 2019;35(1):e3066.
8. Peer N et al. Diabetes in the Africa region: an update. Diabetes Res Clin Pract. 2014;103(2):197-205.
9. Senkoro M et al. Prevalence of pulmonary tuberculosis in adult population of Tanzania: a national survey, 2012. Int J Tuberc Lung Dis. 2016;20(8):1014-21.
10. Li L et al. Screening of patients with tuberculosis for diabetes mellitus
encountered in the local context, and the guidelines already in place should all be carefully considered when deciding whether or not to integrate TB/diabetes healthcare services in hospitals.
in China. Trop Med Int Health. 2012;17(10):1294-301.
11. Harries AD et al. How can integrated care and research assist in achieving the SDG targets for diabetes, tuberculosis and HIV/AIDS? Int J Tuberc Lung Dis. 2018;22(10):1117-26.
12. Wroe EB et al. Leveraging HIV platforms to work toward comprehensive primary care in rural Malawi: the Integrated Chronic Care Clinic. Healthc (Amst). 2015;3(4):2706.
13. Briggs C J, Garner P. Strategies for integrating primary health services in middle- and low-income countries at the point of delivery. Cochrane Database Syst Rev. 2006:(2):CD003318.
14. Mpagama SG et al. Protocol for establishing an Adaptive Diseases control Expert Programme in Tanzania (ADEPT) for integrating care of communicable and non-communicable diseases using tuberculosis and diabetes as a case study. BMJ Open. 2021;11(4):e041521.
15. Siddiqui AN et al. Effect of diabetes mellitus on tuberculosis treatment outcome and adverse reactions in patients receiving directly observed treatment strategy in India: a prospective study. Biomed Res Int. 2016;2016:7273935.
16. Mugusi F et al. Increased prevalence of diabetes mellitus in patients with pulmonary tuberculosis in Tanzania. Tubercle. 1990;71(4):271-6.
17. Radchenko C et al. A systematic approach to the management of massive hemoptysis. J Thorac Dis. 2017;9(Suppl 10):S1069-86.
18. van Crevel R, Critchley JA. The interaction of diabetes and tuberculosis: translating research to policy and practice. Trop Med Infect Dis. 2021;6(1):8.
19. Byashalira KC et al. Impact of early diagnosis of impaired glucose regulation in tuberculosis: comparison of clinical outcomes in people with tuberculosis in Tanzania. Trop Med Int Health. 2022;27(9):815-22.
20. Vaishya R et al. Diabetes and tuberculosis syndemic in India: a narrative review of facts, gaps in care and challenges. J Diabetes. 2024;16(5):e13427.
21. Workneh MH et al. Diabetes mellitus is associated with increased mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients in South-Eastern Amahra Region, Ethiopia. Infect Dis Poverty. 2016:5:22.
22. Zhao L et al. The impact of optimal glycemic control on tuberculosis treatment outcomes in patients with diabetes mellitus: systematic review and meta-analysis. JMIR Public Health Surveill. 2024:10:e53948.
23. Castellanos-Joya M et al. Results of the implementation of a pilot model for the bidirectional screening and joint management of patients with pulmonary tuberculosis and diabetes mellitus in Mexico. PLoS One. 2014;9(9):e106961.
24. Milice DM et al. The collaborative framework for the management of tuberculosis and type 2 diabetes syndemic in low- and middle-income countries: a rapid review. BMC Public Health. 2024;24(1):738.
