Page 1

ALBERTA DIABETES INSTITUTE Building Upon a Legacy Institutional Overview & Biennial Report


Table of Contents

Building Upon a Legacy: Institutional Overview BIENNIAL REPORT 2014-15 Print Edition Sept 2016 Facts and figures 2014-2015 Published by the Alberta Diabetes Institute, University of Alberta

01 03 05 08 14 18 32 40 46 47

A Legacy of Achievement UAlberta & Director's Message The Role of the Institute Research Highlights

Islet Cell Biology & Physiology Secondary Diseases Risk and Prevention Immunology and Cell Therapy Population Health

Core Facilities Collaborations

50 52 53 54 55 58 59 61 63 67

Clinical Research Institute Membership Trainee Opportunities Publications Operating Grants Supporting Diabetes Research Alberta Diabetes Foundation Donors and Awards Supporting Events Timeline


Table of Contents

Building Upon a Legacy: Institutional Overview BIENNIAL REPORT 2014-15 Print Edition Sept 2016 Facts and figures 2014-2015 Published by the Alberta Diabetes Institute, University of Alberta

01 03 05 08 14 18 32 40 46 47

A Legacy of Achievement UAlberta & Director's Message The Role of the Institute Research Highlights

Islet Cell Biology & Physiology Secondary Diseases Risk and Prevention Immunology and Cell Therapy Population Health

Core Facilities Collaborations

50 52 53 54 55 58 59 61 63 67

Clinical Research Institute Membership Trainee Opportunities Publications Operating Grants Supporting Diabetes Research Alberta Diabetes Foundation Donors and Awards Supporting Events Timeline


Alberta Diabetes Institute A Legacy of Achievement In 1921 while on a sabbatical leave, University of Alberta Professor James Collip was participating in research at the University of Toronto where he was seconded to assist Frederick Banting and Charles Best in the purification of insulin extracts for clinical use. His contributions were instrumental in the successful application of insulin as a therapy for diabetes patients. Collip became the first of many scientists at the University of Alberta that dedicated themselves to increasing our understanding of the causes and treatments for Type 1 diabetes (T1D), including Ray Rajotte whose team pioneered Canada’s first islet cell transplantation in 1985, and James Shapiro who led the development and application of the Edmonton Protocol in 2000.

1

Dedicated to translating discovery science into health solutions for the prevention, treatment and cure of diabetes

In addition to scientists battling T1D, the University of Alberta (U of A) has amassed an equally impressive collection of investigators focused on Type 2 diabetes (T2D) and the numerous medical, lifestyle, and social factors influencing this complex disease. In 2007, construction of the Alberta Diabetes Institute was completed to become Canada’s largest freestanding structure dedicated to diabetes research. This 25,000 m2 facility brings together the university’s diabetes researchers into an interdisciplinary environment and supports them with state of the art facilities and renowned knowledge mobilization. Ongoing discovery research at Alberta Diabetes Institute continues to push the limits of what we know while our population health research pulls us in the direction of new approaches for preventing and treating diabetes.

2


Alberta Diabetes Institute A Legacy of Achievement In 1921 while on a sabbatical leave, University of Alberta Professor James Collip was participating in research at the University of Toronto where he was seconded to assist Frederick Banting and Charles Best in the purification of insulin extracts for clinical use. His contributions were instrumental in the successful application of insulin as a therapy for diabetes patients. Collip became the first of many scientists at the University of Alberta that dedicated themselves to increasing our understanding of the causes and treatments for Type 1 diabetes (T1D), including Ray Rajotte whose team pioneered Canada’s first islet cell transplantation in 1985, and James Shapiro who led the development and application of the Edmonton Protocol in 2000.

1

Dedicated to translating discovery science into health solutions for the prevention, treatment and cure of diabetes

In addition to scientists battling T1D, the University of Alberta (U of A) has amassed an equally impressive collection of investigators focused on Type 2 diabetes (T2D) and the numerous medical, lifestyle, and social factors influencing this complex disease. In 2007, construction of the Alberta Diabetes Institute was completed to become Canada’s largest freestanding structure dedicated to diabetes research. This 25,000 m2 facility brings together the university’s diabetes researchers into an interdisciplinary environment and supports them with state of the art facilities and renowned knowledge mobilization. Ongoing discovery research at Alberta Diabetes Institute continues to push the limits of what we know while our population health research pulls us in the direction of new approaches for preventing and treating diabetes.

2


University of Alberta

Director’s Message to prevent, treat and ultimately cure diabetes. I believe that this is an exciting time for diabetes research at the University of Alberta, with the ADI spearheading many exciting and novel research initiatives.

3

Dr Lorne Babiuk

Dr Richard Fedorak

Vice President Research University of Alberta

Dean Faculty of Medicine University of Alberta

The University Alberta has always been at the forefront of diabetes research starting with James Collip’s role in insulin’s discovery in 1921 followed by the Edmonton Protocol breakthrough in 1999. In 2007 we opened the Alberta Diabetes Institute, Canada’s largest freestanding diabetes research facility, where researchers continue to drive towards prevention, new treatments and a cure.

The Alberta Diabetes Institute is a powerful vehicle connecting world-leading diabetes researchers across the University of Alberta. Building upon our legacy of diabetes research excellence, innovative collaborations have a real impact on today’s patient care, driving us towards improving the quality of life for future generations.

Dr Peter Light Director, Alberta Diabetes Institute (ADI) Dr. Charles A. Allard Chair in Diabetes Research Our research program at the Alberta Diabetes Institute continues to thrive and grow. With over 60 principal investigators and 200 trainees, our mission is to discover new therapies and methods

Thanks to our donors and diabetes research supporters, we continue to provide world-class research and an excellent training environment, with state-of-the-art facilities and funding for students, trainees and research grants. Our research continues to advance into more innovative directions with even greater impact, as we remain steadfast in our mission to discover new methods to prevent, treat and cure diabetes. I sincerely hope that this report provides the reader with some valuable insights into our achievements and successes and provides some hope into one day finding a cure.

4


University of Alberta

Director’s Message to prevent, treat and ultimately cure diabetes. I believe that this is an exciting time for diabetes research at the University of Alberta, with the ADI spearheading many exciting and novel research initiatives.

3

Dr Lorne Babiuk

Dr Richard Fedorak

Vice President Research University of Alberta

Dean Faculty of Medicine University of Alberta

The University Alberta has always been at the forefront of diabetes research starting with James Collip’s role in insulin’s discovery in 1921 followed by the Edmonton Protocol breakthrough in 1999. In 2007 we opened the Alberta Diabetes Institute, Canada’s largest freestanding diabetes research facility, where researchers continue to drive towards prevention, new treatments and a cure.

The Alberta Diabetes Institute is a powerful vehicle connecting world-leading diabetes researchers across the University of Alberta. Building upon our legacy of diabetes research excellence, innovative collaborations have a real impact on today’s patient care, driving us towards improving the quality of life for future generations.

Dr Peter Light Director, Alberta Diabetes Institute (ADI) Dr. Charles A. Allard Chair in Diabetes Research Our research program at the Alberta Diabetes Institute continues to thrive and grow. With over 60 principal investigators and 200 trainees, our mission is to discover new therapies and methods

Thanks to our donors and diabetes research supporters, we continue to provide world-class research and an excellent training environment, with state-of-the-art facilities and funding for students, trainees and research grants. Our research continues to advance into more innovative directions with even greater impact, as we remain steadfast in our mission to discover new methods to prevent, treat and cure diabetes. I sincerely hope that this report provides the reader with some valuable insights into our achievements and successes and provides some hope into one day finding a cure.

4


The Role of the Institute The strategic role of the Alberta Diabetes Institute (ADI) is simple: help remove the barriers that stand between scientific discovery and new health applications that improve the quality of life of diabetes patients. This means supporting our scientists and turning their activities into opportunities.

Communications and Leveraging The ADI plays an important internal communications role by fostering cross-talk between its basic science, clinical and population health researchers. It does this by hosting networking opportunities and by leveraging the strength of teams. The Institute’s external communications role means telling our story and engaging our stakeholders, while identifying collaborative and exchange opportunities with other research groups that share our passion.

5

Knowledge Mobilization The University of Alberta and Provincial Government have invested heavily in knowledge mobilization in Alberta. This includes TEC Edmonton, the University’s award-winning technology transfer service, SPOR (Support for Patient Oriented Research) and Strategic Clinical Networks. The ADI strives to facilitate knowledge mobilization by accessing these resources and moving innovations forward so that our scientists can maintain their focus on research.

Infrastructure As part of its commitment to combining great scientists with outstanding resources, the ADI houses facilities that provide our scientists with direct access to enabling services that allow cutting edge diabetes research and translational science. Examples include a human islet isolation and banking core for procuring research islets, an

integrated medical/nutritional/metabolic clinical research unit, a physical activity diabetes clinical research unit and partnership with Western Canada’s only Good Manufacturing Practice (GMP compliant) cell therapy facility. The Institute also provides office and lab support that allow scientists and their teams to be housed within the ADI itself.

Recruiting

The ADI works with individual faculties and departments at the University of Alberta, and partner universities, to strengthen its membership through strategic recruitment. Virtually every year the ADI jointly recruits top

notch scientists who areat the forefront of diabetes research.

Training Our scientists are leaders in numerous areas of diabetes research, and ADI plays an important part in establishing continuity of research and development. The Institute has generous funding for supporting graduate student and post-doctoral trainees, provides them with workspace, organizes information-sharing seminars, and funds travel to national and international conferences.

6


The Role of the Institute The strategic role of the Alberta Diabetes Institute (ADI) is simple: help remove the barriers that stand between scientific discovery and new health applications that improve the quality of life of diabetes patients. This means supporting our scientists and turning their activities into opportunities.

Communications and Leveraging The ADI plays an important internal communications role by fostering cross-talk between its basic science, clinical and population health researchers. It does this by hosting networking opportunities and by leveraging the strength of teams. The Institute’s external communications role means telling our story and engaging our stakeholders, while identifying collaborative and exchange opportunities with other research groups that share our passion.

5

Knowledge Mobilization The University of Alberta and Provincial Government have invested heavily in knowledge mobilization in Alberta. This includes TEC Edmonton, the University’s award-winning technology transfer service, SPOR (Support for Patient Oriented Research) and Strategic Clinical Networks. The ADI strives to facilitate knowledge mobilization by accessing these resources and moving innovations forward so that our scientists can maintain their focus on research.

Infrastructure As part of its commitment to combining great scientists with outstanding resources, the ADI houses facilities that provide our scientists with direct access to enabling services that allow cutting edge diabetes research and translational science. Examples include a human islet isolation and banking core for procuring research islets, an

integrated medical/nutritional/metabolic clinical research unit, a physical activity diabetes clinical research unit and partnership with Western Canada’s only Good Manufacturing Practice (GMP compliant) cell therapy facility. The Institute also provides office and lab support that allow scientists and their teams to be housed within the ADI itself.

Recruiting

The ADI works with individual faculties and departments at the University of Alberta, and partner universities, to strengthen its membership through strategic recruitment. Virtually every year the ADI jointly recruits top

notch scientists who areat the forefront of diabetes research.

Training Our scientists are leaders in numerous areas of diabetes research, and ADI plays an important part in establishing continuity of research and development. The Institute has generous funding for supporting graduate student and post-doctoral trainees, provides them with workspace, organizes information-sharing seminars, and funds travel to national and international conferences.

6


Research Highlights

Risk and Prevention

Islet Cell Biology and Physiology

Population Health

Immunology and Cell Therapies 7

Secondary Diseases

Islet Cell Biology and Physiology

Brain signaling in diabetes – Dr Jessica Yue joined the ADI in 2015 after relocating from the Toronto General Research Institute where she trained under physiologist Dr Tony Lam. Yue’s research looks at how the brain plays an important role in the pathogenesis of diabetes through neuronal signaling that controls various risk factors. Her recent research describes how the brain can regulate fat metabolism and mitigate the development of cardiovascular disease, a risk factor for obesity and diabetes. She examined how the infusion of oleic acid, a naturally occurring monounsaturated fatty acid, triggered a signal from the hypothalamus to the liver to lower its secretion of triglyceride-rich, very-low-density lipoproteins, a protective effect against overproduction. When this trigger fails to work, such as with obesity, the risk of insulin

resistance and diabetes rises. Yue’s findings also demonstrate how this faulty signal can be bypassed, unveiling potential pathways for regaining normal control in obese patients and opening the door for therapeutic intervention. Yue’s research findings were published in Nature Communications (Jan 2015;65970) and were co-authored by ADI Director Dr Peter Light. Bioengineering adipocytes — Despite the advancements made for treating T1D patients, insulin injections using a needle remain the most common form of treatment. Cell therapies are continually improving but any form of allo-transplantation is prone to recipient rejection of donor islets and the need for long term immunosuppression. Dr Peter Light and his PhD students Neermeen Youssef and

8


Research Highlights

Risk and Prevention

Islet Cell Biology and Physiology

Population Health

Immunology and Cell Therapies 7

Secondary Diseases

Islet Cell Biology and Physiology

Brain signaling in diabetes – Dr Jessica Yue joined the ADI in 2015 after relocating from the Toronto General Research Institute where she trained under physiologist Dr Tony Lam. Yue’s research looks at how the brain plays an important role in the pathogenesis of diabetes through neuronal signaling that controls various risk factors. Her recent research describes how the brain can regulate fat metabolism and mitigate the development of cardiovascular disease, a risk factor for obesity and diabetes. She examined how the infusion of oleic acid, a naturally occurring monounsaturated fatty acid, triggered a signal from the hypothalamus to the liver to lower its secretion of triglyceride-rich, very-low-density lipoproteins, a protective effect against overproduction. When this trigger fails to work, such as with obesity, the risk of insulin

resistance and diabetes rises. Yue’s findings also demonstrate how this faulty signal can be bypassed, unveiling potential pathways for regaining normal control in obese patients and opening the door for therapeutic intervention. Yue’s research findings were published in Nature Communications (Jan 2015;65970) and were co-authored by ADI Director Dr Peter Light. Bioengineering adipocytes — Despite the advancements made for treating T1D patients, insulin injections using a needle remain the most common form of treatment. Cell therapies are continually improving but any form of allo-transplantation is prone to recipient rejection of donor islets and the need for long term immunosuppression. Dr Peter Light and his PhD students Neermeen Youssef and

8


Katarina Ondrusova took a unique approach to cell therapy, starting with the observation that fat cells already have the machinery necessary to produce hormones, such as leptin and adiponectin. They wondered whether a person’s own fat cells, which most of us have in excess anyway, could be reprogrammed to secrete an insulin bolus in a way that was controlled by a simple and noninvasive signal – a pulse of light. To explore the feasibility of this idea the researchers utilized an adenoviral construct to encode a leptin leader linked with a preproinsulin gene and a light-gated cation-selective channelrhodopsin known to be sensitive to blue light. When tested in culture, they successfully demonstrated that insulin release from the bioengineered fat cells could be regulated using pulses of blue light. This has set the stage for studies examining the controlled release of insulin from subcutaneous, bioengineered cells in an in vivo model. The significance of their research was recognized at the 2014 Falling Walls international competition in Berlin, Germany, winning second place overall.

9

Dimmer Switch in Islets – T2D can be characterized by a reduction in insulin production, a reduction in the body’s response to insulin, or both. Insulin supply can be managed by drugs that boost production from the pancreatic islets of patients, but there has never been a clear understanding of why insulin production falls in the first place. Dr Patrick MacDonald changed that with research that identified a key mechanism for the elusive “dimmer switch”, postulated to exist as far back as 25 years ago. MacDonald and his research team that included Drs Mourad Ferdaoussi, Xiaoqing Dai, Joceylyn Manning Fox, Kunimasa Suzuki, PhD student Catherine Hamjrle, undergraduate student Robert Wright, and lab specialists Gregory Plummer, Aliya Spigelman and Nancy Smith examined islet cells from 99 human organ donors and identified a new molecular pathway that manages the amount of insulin produced and adjusts how much of the hormone is secreted when blood sugar rises. They focused on isocitrate and showed that the cytosolic enzyme isocitrate dehydrogenase (ICDc) produces signals that contributes to the amplification of insulin exocytosis via another enzyme that MacDonald

Dimmer switch in T2D Mourad Ferdaoussi, Patrick MacDonald, Xiaoqing Dai


Katarina Ondrusova took a unique approach to cell therapy, starting with the observation that fat cells already have the machinery necessary to produce hormones, such as leptin and adiponectin. They wondered whether a person’s own fat cells, which most of us have in excess anyway, could be reprogrammed to secrete an insulin bolus in a way that was controlled by a simple and noninvasive signal – a pulse of light. To explore the feasibility of this idea the researchers utilized an adenoviral construct to encode a leptin leader linked with a preproinsulin gene and a light-gated cation-selective channelrhodopsin known to be sensitive to blue light. When tested in culture, they successfully demonstrated that insulin release from the bioengineered fat cells could be regulated using pulses of blue light. This has set the stage for studies examining the controlled release of insulin from subcutaneous, bioengineered cells in an in vivo model. The significance of their research was recognized at the 2014 Falling Walls international competition in Berlin, Germany, winning second place overall.

9

Dimmer Switch in Islets – T2D can be characterized by a reduction in insulin production, a reduction in the body’s response to insulin, or both. Insulin supply can be managed by drugs that boost production from the pancreatic islets of patients, but there has never been a clear understanding of why insulin production falls in the first place. Dr Patrick MacDonald changed that with research that identified a key mechanism for the elusive “dimmer switch”, postulated to exist as far back as 25 years ago. MacDonald and his research team that included Drs Mourad Ferdaoussi, Xiaoqing Dai, Joceylyn Manning Fox, Kunimasa Suzuki, PhD student Catherine Hamjrle, undergraduate student Robert Wright, and lab specialists Gregory Plummer, Aliya Spigelman and Nancy Smith examined islet cells from 99 human organ donors and identified a new molecular pathway that manages the amount of insulin produced and adjusts how much of the hormone is secreted when blood sugar rises. They focused on isocitrate and showed that the cytosolic enzyme isocitrate dehydrogenase (ICDc) produces signals that contributes to the amplification of insulin exocytosis via another enzyme that MacDonald

Dimmer switch in T2D Mourad Ferdaoussi, Patrick MacDonald, Xiaoqing Dai


has studied extensively – sentrin/SUMO-specific protease-1 (SENP1). Deletion of SENP1 in mice caused impaired glucose tolerance by reducing insulin secretion and activating this enzyme in islets from human donors with T2D rescued insulin production. Together, these results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues ϐ-cell function in diabetes. Results of MacDonald’s research were published in The Journal of Clinical Investigation (125:3847-3860, 2015) and received considerable attention globally. Innovation for tissue engineering research – While working as a research associate at the University of Toronto’s Institute of Biomaterials & Biomedical Engineering, Dr Mark Ungrin recognized that researchers lacked a tool for the efficient, large-scale formation of uniform, size-controlled microtissues. To resolve this challenge, he developed a deceptively simple-looking device that starts with cells in a central reservoir and then employs centrifugal forced aggregation to capture them in tiny “micro-wells.” These

11

micro-wells represent a controlled environment for creating uniform aggregates of cells and the device has led to a new means of tissue assembly useful in a wide range of applications, from tissue engineering to toxicology to studies of tumour cell behaviour in a more realistic 3-dimensional environment. Now an Assistant Professor at the University of Calgary and a member of ADI since 2013, Ungrin remains active in advancing this technology. One recent advance they made was in response to the potential displacement of certain types of microtissues from the micro-wells during long-term cultures, leading to a loss of material or inadvertent mixing of cells. They were able to bond a nylon mesh over the micro-well opening, allowing single cells to pass through the mesh into the wells during the seeding process, but then retaining the assembled microtissues within discrete microwells. The new technology was tested in a successful proof of concept study using bone marrow-derived mesenchymal stem cells for the production of cartilage microtissues over a 21 day period involving multiple medium exchanges (Biomaterials, 62:1-12, 2015). The original microwell technology, under the AggreWell™ brand name, is now a successful

commercial product with Stem Cell Technologies Inc. of Vancouver. It is in use around the world, on every continent except Antarctica; and is mentioned in over 370 publications (with over 130 of those coming in the 2015-2016 period so far). In 2015, Ungrin was named a University of Calgary PEAK Scholar for his work in this area. He is presently applying it to the formation of pseudoislets (pancreatic islet microtissues) specifically engineered for optimized performance after transplantation, to enhance the efficiency of the Edmonton Protocol for the treatment of T1D. New role for tumour suppressing gene in ϐ-Cell Apoptosis – While advances are continually being made in the treatment of T2D, research led by Dr Jean Buteau aims to prevent and reverse the disease after early onset. Buteau’s recent research has resulted in the identification of a number of proteins and genes that are related to the proliferation and survival of islet cells and are targets for therapeutic intervention. An earlier genomic study conducted in his laboratory identified suppression of tumorigenicity18 (ST18) as a potentially important regulator of beta-cell mass

and function. However, the biological roles of ST18, a neural zinc finger transcription factor, remained poorly characterized and its action in beta-cells has never been explored. Research done by Buteau and his team that included PhD student Anne-Françoise Close demonstrated that, in the pancreas, ST18 expression was restricted to endocrine cells and that expression and activity in ϐ-cells were increased by cytotoxic concentrations of fatty acids and cytokines. In addition ST18 was also increased in the islets of diet-induced obese animals. They found that ST18 overexpression induces ϐ-cell apoptosis and restricts replication. Furthermore, they also found a correlation between ST18 expression and impaired insulin secretion, suggesting that this gene acts as a potentially important transcriptional mediator of lipotoxicity and cytokine-induced ϐ-cell apoptosis. Their findings were published in The Journal of Biological Chemistry in 2014 (doi:10.1074/jbc.M114.554915).

12


has studied extensively – sentrin/SUMO-specific protease-1 (SENP1). Deletion of SENP1 in mice caused impaired glucose tolerance by reducing insulin secretion and activating this enzyme in islets from human donors with T2D rescued insulin production. Together, these results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues ϐ-cell function in diabetes. Results of MacDonald’s research were published in The Journal of Clinical Investigation (125:3847-3860, 2015) and received considerable attention globally. Innovation for tissue engineering research – While working as a research associate at the University of Toronto’s Institute of Biomaterials & Biomedical Engineering, Dr Mark Ungrin recognized that researchers lacked a tool for the efficient, large-scale formation of uniform, size-controlled microtissues. To resolve this challenge, he developed a deceptively simple-looking device that starts with cells in a central reservoir and then employs centrifugal forced aggregation to capture them in tiny “micro-wells.” These

11

micro-wells represent a controlled environment for creating uniform aggregates of cells and the device has led to a new means of tissue assembly useful in a wide range of applications, from tissue engineering to toxicology to studies of tumour cell behaviour in a more realistic 3-dimensional environment. Now an Assistant Professor at the University of Calgary and a member of ADI since 2013, Ungrin remains active in advancing this technology. One recent advance they made was in response to the potential displacement of certain types of microtissues from the micro-wells during long-term cultures, leading to a loss of material or inadvertent mixing of cells. They were able to bond a nylon mesh over the micro-well opening, allowing single cells to pass through the mesh into the wells during the seeding process, but then retaining the assembled microtissues within discrete microwells. The new technology was tested in a successful proof of concept study using bone marrow-derived mesenchymal stem cells for the production of cartilage microtissues over a 21 day period involving multiple medium exchanges (Biomaterials, 62:1-12, 2015). The original microwell technology, under the AggreWell™ brand name, is now a successful

commercial product with Stem Cell Technologies Inc. of Vancouver. It is in use around the world, on every continent except Antarctica; and is mentioned in over 370 publications (with over 130 of those coming in the 2015-2016 period so far). In 2015, Ungrin was named a University of Calgary PEAK Scholar for his work in this area. He is presently applying it to the formation of pseudoislets (pancreatic islet microtissues) specifically engineered for optimized performance after transplantation, to enhance the efficiency of the Edmonton Protocol for the treatment of T1D. New role for tumour suppressing gene in ϐ-Cell Apoptosis – While advances are continually being made in the treatment of T2D, research led by Dr Jean Buteau aims to prevent and reverse the disease after early onset. Buteau’s recent research has resulted in the identification of a number of proteins and genes that are related to the proliferation and survival of islet cells and are targets for therapeutic intervention. An earlier genomic study conducted in his laboratory identified suppression of tumorigenicity18 (ST18) as a potentially important regulator of beta-cell mass

and function. However, the biological roles of ST18, a neural zinc finger transcription factor, remained poorly characterized and its action in beta-cells has never been explored. Research done by Buteau and his team that included PhD student Anne-Françoise Close demonstrated that, in the pancreas, ST18 expression was restricted to endocrine cells and that expression and activity in ϐ-cells were increased by cytotoxic concentrations of fatty acids and cytokines. In addition ST18 was also increased in the islets of diet-induced obese animals. They found that ST18 overexpression induces ϐ-cell apoptosis and restricts replication. Furthermore, they also found a correlation between ST18 expression and impaired insulin secretion, suggesting that this gene acts as a potentially important transcriptional mediator of lipotoxicity and cytokine-induced ϐ-cell apoptosis. Their findings were published in The Journal of Biological Chemistry in 2014 (doi:10.1074/jbc.M114.554915).

12


title of page

Research Highlights Secondary Diseases

Clinical Research Unit Alberta Diabetes Institute

Improving Safety Evaluation of Sulfonylureas – Sulfonylurea (SU) drugs were one of the first drug treatments made available to T2D patients in the 1950s with the first of these being tolbutamide. Advancements have led to second and even third-generation SU medications that have improved the glucoselowering efficacy of this drug class. Even though an array of newer medications now exists such as sensitizers, incretin mimetics and DPP4 inhibitors, SUs continue to be commonly prescribed. Despite their prolonged and widespread use, SUs have a long standing association with cardiovascular safety that has been based on unconvincing data and methods. While recent clinical trials (eg TOSCA.IT, CAROLINA trials) may provide more clarity about this issue, results of these studies are years away and still have study design

weaknesses. ADI member Dr Scot Simpson, along with PhD student Ahmed Abdelmoneim and ADI co-members Drs. Peter Senior, Peter Light and Dean Eurich recognized that researchers needed clearer direction when it came to designing future safety studies of SUs. They undertook a comprehensive overview of existing data, focusing on evidence for biological probability and past conclusions made from meta-analyses. Their research strongly suggested a number of important things, one of which was a reasonable conclusion for a plausible, biological mechanism for heart effects based on previous animal and human studies. However, conclusions drawn from meta-analyses are unreliable because observational studies have suffered from bias while randomized clinical trials (RCTs) were not specifically designed to look at cardiovascular

14


title of page

Research Highlights Secondary Diseases

Clinical Research Unit Alberta Diabetes Institute

Improving Safety Evaluation of Sulfonylureas – Sulfonylurea (SU) drugs were one of the first drug treatments made available to T2D patients in the 1950s with the first of these being tolbutamide. Advancements have led to second and even third-generation SU medications that have improved the glucoselowering efficacy of this drug class. Even though an array of newer medications now exists such as sensitizers, incretin mimetics and DPP4 inhibitors, SUs continue to be commonly prescribed. Despite their prolonged and widespread use, SUs have a long standing association with cardiovascular safety that has been based on unconvincing data and methods. While recent clinical trials (eg TOSCA.IT, CAROLINA trials) may provide more clarity about this issue, results of these studies are years away and still have study design

weaknesses. ADI member Dr Scot Simpson, along with PhD student Ahmed Abdelmoneim and ADI co-members Drs. Peter Senior, Peter Light and Dean Eurich recognized that researchers needed clearer direction when it came to designing future safety studies of SUs. They undertook a comprehensive overview of existing data, focusing on evidence for biological probability and past conclusions made from meta-analyses. Their research strongly suggested a number of important things, one of which was a reasonable conclusion for a plausible, biological mechanism for heart effects based on previous animal and human studies. However, conclusions drawn from meta-analyses are unreliable because observational studies have suffered from bias while randomized clinical trials (RCTs) were not specifically designed to look at cardiovascular

14


safety and lacked the statistical power necessary to make credible inferences regarding risk. The authors suggested that a future RCT should be placebo-controlled and aimed at comparing risk differences between SUs by randomizing patients with T2D to different SU medications. One exposure group should include either gliclazide or glimerpiride to take advantage of available data from previous observational studies. Participants in the other groups should receive glyburide as the comparison SU in order to test the theoretical, elevated risk of this SU due to its non-selectivity of KATP channel blockage in the pancreas and heart. The complete review article was published in Diabetes, Obesity and Metabolism (17:523-532, 2015). Angiotensin 1-7 as a Possible Therapy for Patients with Diabetes – The renin-angiotensin system (RAS) is one of the body’s primary means of regulating blood pressure, but RAS and in particular angiotensin II (ANG II) play a role in promoting the pathogenesis of both diabetic kidney disease and heart disease. For example, RAS is associated with the generation of reactive

15

oxygen species in the kidney and mesangial matrix expansion in glomerular capillaries, contributing to diabetic nephropathy. Elevated ANG II levels also lead to cardiac hypertrophy, diastolic dysfunction and cardiac insulin resistance. ANG II is converted to Angiotensin 1-7 (ANG 1-7) via the catalytic action of angiotensin converting enzyme 2 (ACE2), and research has shown that ANG 1-7 counters some of the detrimental effects of ANG II in both organs, although the mechanism for this is far from clear. ADI members Drs. Gavin Oudit and Gary Lopaschuk, along with postdoctoral fellows Drs. Jun Mori, Ratnadeep Basu and Vaibhav Patel and PhD students Osama Abo Alrob and Tariq Altamimi performed a pair of studies in db/ db mice to better understand how ANG 1-7 was eliciting these beneficial effects. In one study the researchers administered ANG 1-7 directly into 5 month old db/db mice for 28 days and uncovered a number of pathways underlying the attenuation of diabetic nephropathy. Renal fibrosis was reduced - consistent with an observed decrease in the phosphorylation of the STAT3 (signal transducer and activator of transcription 3) pathway. Kidney mass was reduced and

ANG 1–7 represents a potential new therapy for the treatment of both diabetic nephropathy and cardiomyopathy

treatment slowed mesangial expansion while countering the reduction in albumin excretion – both characteristic of diabetic nephropathy. Treatment also reduced the generation of reactive oxygen species by attenuating NADPH oxidase activity. Even more, db/db mice receiving ANG 1-7 had lesser lipid accumulation in their kidneys and higher adipose triglyceride lipase expression which was correlated with increased SIRT1 expression and increased deacetylation (and

activation) of FOXO1, the important transcription factor related to T2D. Results of their study were published in the American Journal of Physiology: Renal Physiology (306:F812-821). In a second study, db/db mice were similarly treated with ANG 1-7 and were examined for cardiac function and structure. Similar to the kidney they found that treatment resulted in reduced myocardial fibrosis and similarly reduced phosphorylation of STAT3. In addition, ANG 1-7 treatment normalized the increase in cardiac lipotoxicity observed in saline-treated animals, including TAG and ceramide levels and PKC signaling. Upregulation of SIRT1 and a resulting increase in the activation of FOXO1 were also observed, as was complete rescue of diastolic function with treatment. Additional benefits of ANG 1-7 are detailed in their publication in Circulation: Heart Failure (7:327-339, 2014). Results of the research suggest ANG 1–7 treatment represents a potential new therapy for the treatment of both diabetic nephropathy and cardiomyopathy.

16


safety and lacked the statistical power necessary to make credible inferences regarding risk. The authors suggested that a future RCT should be placebo-controlled and aimed at comparing risk differences between SUs by randomizing patients with T2D to different SU medications. One exposure group should include either gliclazide or glimerpiride to take advantage of available data from previous observational studies. Participants in the other groups should receive glyburide as the comparison SU in order to test the theoretical, elevated risk of this SU due to its non-selectivity of KATP channel blockage in the pancreas and heart. The complete review article was published in Diabetes, Obesity and Metabolism (17:523-532, 2015). Angiotensin 1-7 as a Possible Therapy for Patients with Diabetes – The renin-angiotensin system (RAS) is one of the body’s primary means of regulating blood pressure, but RAS and in particular angiotensin II (ANG II) play a role in promoting the pathogenesis of both diabetic kidney disease and heart disease. For example, RAS is associated with the generation of reactive

15

oxygen species in the kidney and mesangial matrix expansion in glomerular capillaries, contributing to diabetic nephropathy. Elevated ANG II levels also lead to cardiac hypertrophy, diastolic dysfunction and cardiac insulin resistance. ANG II is converted to Angiotensin 1-7 (ANG 1-7) via the catalytic action of angiotensin converting enzyme 2 (ACE2), and research has shown that ANG 1-7 counters some of the detrimental effects of ANG II in both organs, although the mechanism for this is far from clear. ADI members Drs. Gavin Oudit and Gary Lopaschuk, along with postdoctoral fellows Drs. Jun Mori, Ratnadeep Basu and Vaibhav Patel and PhD students Osama Abo Alrob and Tariq Altamimi performed a pair of studies in db/ db mice to better understand how ANG 1-7 was eliciting these beneficial effects. In one study the researchers administered ANG 1-7 directly into 5 month old db/db mice for 28 days and uncovered a number of pathways underlying the attenuation of diabetic nephropathy. Renal fibrosis was reduced - consistent with an observed decrease in the phosphorylation of the STAT3 (signal transducer and activator of transcription 3) pathway. Kidney mass was reduced and

ANG 1–7 represents a potential new therapy for the treatment of both diabetic nephropathy and cardiomyopathy

treatment slowed mesangial expansion while countering the reduction in albumin excretion – both characteristic of diabetic nephropathy. Treatment also reduced the generation of reactive oxygen species by attenuating NADPH oxidase activity. Even more, db/db mice receiving ANG 1-7 had lesser lipid accumulation in their kidneys and higher adipose triglyceride lipase expression which was correlated with increased SIRT1 expression and increased deacetylation (and

activation) of FOXO1, the important transcription factor related to T2D. Results of their study were published in the American Journal of Physiology: Renal Physiology (306:F812-821). In a second study, db/db mice were similarly treated with ANG 1-7 and were examined for cardiac function and structure. Similar to the kidney they found that treatment resulted in reduced myocardial fibrosis and similarly reduced phosphorylation of STAT3. In addition, ANG 1-7 treatment normalized the increase in cardiac lipotoxicity observed in saline-treated animals, including TAG and ceramide levels and PKC signaling. Upregulation of SIRT1 and a resulting increase in the activation of FOXO1 were also observed, as was complete rescue of diastolic function with treatment. Additional benefits of ANG 1-7 are detailed in their publication in Circulation: Heart Failure (7:327-339, 2014). Results of the research suggest ANG 1–7 treatment represents a potential new therapy for the treatment of both diabetic nephropathy and cardiomyopathy.

16


Research Highlights Risk and Prevention

Physical Activity Diabetes Lab A postdoctoral student monitors a participants’ blood pressure using a recumbent cycle ergometer

Insight into gastrointestinal (GI) microbiota – The human gut has a complex ecosystem of over 100 trillion microbial cells which impact metabolism, nutrition and immune function. Not surprisingly, aberrations in the microbiome are linked with a host of diseases that include diabetes, and this area of study has become the subject of extensive research in recent years. In 2015 the ADI welcomed new member Dr Jens Walter whose research in GI microbiota has provided insight into how and why the microbiome differs between populations having contrasting disease profiles. In a study that was featured on the cover of Cell Reports (and in a Research Commentary of Nature), Walter and fellow researchers that included postdoctoral fellow Dr Ines Martinez-Ramos compared fecal microbiota of adults from two

non-industrial regions of Papua New Guinea with that of United States residents. They found that Papua New Guineans harbor much less interindividual diversity and a more complex array of microbial species compared with Americans, including a few species completely absent in the latter population. For microbial species shared between the two cultures, there were vastly different abundance profiles. While most of these findings were consistent with similar studies that compared western and non-industrialized populations, their study was the first to use ecological theory to suggest the differences were a result of dissimilar ‘assembly processes’ of the local microbial community. In particular, dispersal, which in the setting of the gut is the ability of organisms to move horizontally through GI space – is considered a major process by which

18


Research Highlights Risk and Prevention

Physical Activity Diabetes Lab A postdoctoral student monitors a participants’ blood pressure using a recumbent cycle ergometer

Insight into gastrointestinal (GI) microbiota – The human gut has a complex ecosystem of over 100 trillion microbial cells which impact metabolism, nutrition and immune function. Not surprisingly, aberrations in the microbiome are linked with a host of diseases that include diabetes, and this area of study has become the subject of extensive research in recent years. In 2015 the ADI welcomed new member Dr Jens Walter whose research in GI microbiota has provided insight into how and why the microbiome differs between populations having contrasting disease profiles. In a study that was featured on the cover of Cell Reports (and in a Research Commentary of Nature), Walter and fellow researchers that included postdoctoral fellow Dr Ines Martinez-Ramos compared fecal microbiota of adults from two

non-industrial regions of Papua New Guinea with that of United States residents. They found that Papua New Guineans harbor much less interindividual diversity and a more complex array of microbial species compared with Americans, including a few species completely absent in the latter population. For microbial species shared between the two cultures, there were vastly different abundance profiles. While most of these findings were consistent with similar studies that compared western and non-industrialized populations, their study was the first to use ecological theory to suggest the differences were a result of dissimilar ‘assembly processes’ of the local microbial community. In particular, dispersal, which in the setting of the gut is the ability of organisms to move horizontally through GI space – is considered a major process by which

18


Serotonin inhibition microbial diversity is achieved. It appears that dietary and environmental factors characteristic of western cultures like low fibre, access to antibiotics, formula vs breastfeeding, and chlorinated water impede microbial dispersion. While that is successful for achieving a reduction in pathogenic microbes that cause infectious diseases, it is also correlated with a higher incidence of non-communicable diseases like diabetes, arthritis, lupus and MS. With the decline in populations still living a non-westernized lifestyle, this study by Jens and others is valuable for demonstrating the influence of westernization on gut microbiota and the correlation with disease and relating this to an ecological framework (Cell Reports, 11:527-38, 2015). Serotonin inhibition – The hormone serotonin has a number of physiological functions, including a role in energy metabolism through appetite suppression in the CNS where it is produced by the enzyme tryptophan hydroxylase 2 (Tph2). Peripheral serotonin is produced by Tph1, and previous research has shown that high systemic levels of Tph1 are associated with obesity although the mechanism for this has

19

been unclear. A research team that included ADI member Dr Jason Dyck and postdoctoral fellow Dr Shereen Hamza conducted an important study that showed Tph1-deficient mice fed a high-fat diet (HFD) were protected from obesity, insulin resistance (IR) and nonalcoholic fatty liver disease compared with controls, despite similar food intake and physical activity levels. By measuring [18F]fluorodeoxyglucose (FDG), a marker for tissue glucose uptake, their research showed that FDG uptake in interscapular brown adipose tissue (iBAT) was higher in the HFDfed Tph1-/- mice. Consistent with this was a reduction of circulating serotonin and an increase in mitochondrial uncoupling protein 1 (UCP-1) in iBAT tissue of the Tph1-/- type mice, a higher basal oxygen consumption and interscapular surface temperature. These findings clearly indicated that the anti-obesity effects of genetic Tph1 deletion was related to an increase in BAT thermogenesis. Confirmation that these effects were mediated through serotonin was confirmed by implanting slow-release serotonin in the Tph1 deficient mice and seeing significantly increased epididymal white adipose tissue, obesity and IR, as well as lower basal metabolic rate.

Research results suggest a role for therapeutic inhibition of circulating serotonin


Serotonin inhibition microbial diversity is achieved. It appears that dietary and environmental factors characteristic of western cultures like low fibre, access to antibiotics, formula vs breastfeeding, and chlorinated water impede microbial dispersion. While that is successful for achieving a reduction in pathogenic microbes that cause infectious diseases, it is also correlated with a higher incidence of non-communicable diseases like diabetes, arthritis, lupus and MS. With the decline in populations still living a non-westernized lifestyle, this study by Jens and others is valuable for demonstrating the influence of westernization on gut microbiota and the correlation with disease and relating this to an ecological framework (Cell Reports, 11:527-38, 2015). Serotonin inhibition – The hormone serotonin has a number of physiological functions, including a role in energy metabolism through appetite suppression in the CNS where it is produced by the enzyme tryptophan hydroxylase 2 (Tph2). Peripheral serotonin is produced by Tph1, and previous research has shown that high systemic levels of Tph1 are associated with obesity although the mechanism for this has

19

been unclear. A research team that included ADI member Dr Jason Dyck and postdoctoral fellow Dr Shereen Hamza conducted an important study that showed Tph1-deficient mice fed a high-fat diet (HFD) were protected from obesity, insulin resistance (IR) and nonalcoholic fatty liver disease compared with controls, despite similar food intake and physical activity levels. By measuring [18F]fluorodeoxyglucose (FDG), a marker for tissue glucose uptake, their research showed that FDG uptake in interscapular brown adipose tissue (iBAT) was higher in the HFDfed Tph1-/- mice. Consistent with this was a reduction of circulating serotonin and an increase in mitochondrial uncoupling protein 1 (UCP-1) in iBAT tissue of the Tph1-/- type mice, a higher basal oxygen consumption and interscapular surface temperature. These findings clearly indicated that the anti-obesity effects of genetic Tph1 deletion was related to an increase in BAT thermogenesis. Confirmation that these effects were mediated through serotonin was confirmed by implanting slow-release serotonin in the Tph1 deficient mice and seeing significantly increased epididymal white adipose tissue, obesity and IR, as well as lower basal metabolic rate.

Research results suggest a role for therapeutic inhibition of circulating serotonin


Additional experimentation gauging sympathetic tone revealed that iBAT of Tph1-/- mice have enhanced sensitivity to B-adrenergic stimulation, with serotonin acting directly on BAT to suppress induction of UCP1. The researchers went further to see if intraperitoneal administration of LP533401 – a small molecule used for treating irritable bowel syndrome and osteoporosis via inhibition of gut-derived serotonin – might have therapeutic value in wild mice fed a HFD. Similar to the effects of genetic Tph1 deletion, LP53401 resulted in lower weight gain/body fat accumulation, improved glucose homeostasis and greater insulin sensitivity versus controls. The results of their interesting research suggest a role for therapeutic inhibition of circulating serotonin (Nature Medicine, 21:166-172, 2015).

Andrea Haqq Research focused on Prader Willi Syndrome, the most common syndromic form of obesity and hyperphagia

Prader Willi Syndrome (PWS) – PWS is the most common syndromic form of obesity, characterized by excessive weight gain, obesity and hyperphagia. Dr Andrea Haqq‘s previous work suggests that PWS serves as a unique model of ghrelin excess, potentially explaining the ravenous appetite and progressive weight gain that characterize the condition. Her

group has investigated the role of a number of additional hormones (peptide YY (PYY), GLP-1, insulin) and metabolites (amino acids, fatty acids) in the obesity associated with PWS. In 2014 Haqq conducted a collaborative study (with Dr Mike Freemark, Duke University), that compared the effects of a high carbohydrate versus a high fat meal on ghrelin, insulin and PYY in PWS children (n=14) and obese control (n=14) children. They found that children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ratio of ghrelin/PYY. Ultimately, they discovered that the ratio of Ghrelin/PYY appears to be a novel marker of orexigenic drive. This work is important because it forms the foundation for the development of therapies targeting these appetite-stimulating hormones, with the aim to ameliorate the difficult-to-treat obesity associated with PWS. Details of their research were published in the Journal of Clinical Endocrinology & Metabolism (100:3822-31, 2015). Their collaborative group has also shown that PWS children have reduced levels of branched chain amino acids (BCAA, Leu/Ile/Val), including interesting gender-based effects. Further, their results suggest that the

22


Additional experimentation gauging sympathetic tone revealed that iBAT of Tph1-/- mice have enhanced sensitivity to B-adrenergic stimulation, with serotonin acting directly on BAT to suppress induction of UCP1. The researchers went further to see if intraperitoneal administration of LP533401 – a small molecule used for treating irritable bowel syndrome and osteoporosis via inhibition of gut-derived serotonin – might have therapeutic value in wild mice fed a HFD. Similar to the effects of genetic Tph1 deletion, LP53401 resulted in lower weight gain/body fat accumulation, improved glucose homeostasis and greater insulin sensitivity versus controls. The results of their interesting research suggest a role for therapeutic inhibition of circulating serotonin (Nature Medicine, 21:166-172, 2015).

Andrea Haqq Research focused on Prader Willi Syndrome, the most common syndromic form of obesity and hyperphagia

Prader Willi Syndrome (PWS) – PWS is the most common syndromic form of obesity, characterized by excessive weight gain, obesity and hyperphagia. Dr Andrea Haqq‘s previous work suggests that PWS serves as a unique model of ghrelin excess, potentially explaining the ravenous appetite and progressive weight gain that characterize the condition. Her

group has investigated the role of a number of additional hormones (peptide YY (PYY), GLP-1, insulin) and metabolites (amino acids, fatty acids) in the obesity associated with PWS. In 2014 Haqq conducted a collaborative study (with Dr Mike Freemark, Duke University), that compared the effects of a high carbohydrate versus a high fat meal on ghrelin, insulin and PYY in PWS children (n=14) and obese control (n=14) children. They found that children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ratio of ghrelin/PYY. Ultimately, they discovered that the ratio of Ghrelin/PYY appears to be a novel marker of orexigenic drive. This work is important because it forms the foundation for the development of therapies targeting these appetite-stimulating hormones, with the aim to ameliorate the difficult-to-treat obesity associated with PWS. Details of their research were published in the Journal of Clinical Endocrinology & Metabolism (100:3822-31, 2015). Their collaborative group has also shown that PWS children have reduced levels of branched chain amino acids (BCAA, Leu/Ile/Val), including interesting gender-based effects. Further, their results suggest that the

22


hyperghrelinemia and increased insulin sensitivity of PWS may be related to these reduced levels of BCAAs. This data suggests increased proteolysis in PWS as a potential explanation for the reduced muscle mass, sarcopenia and decreased energy expenditure in PWS. Along with increasing the understanding of the endocrinology of PWS, her group (in collaboration with Dr Lonnie Zwaigenbaum) published a recent systematic review detailing the social-communication impairments present in PWS and evaluating the association between Autism Spectrum Disorder (ASD) and PWS. Meanwhile, fellow ADI member Dr Rachel Wevrick continues her groundbreaking research into the genetic basis of PWS, including the MAGEL2 (MAGE Family Member L2) gene that is known to be inactivated in PWS children. Adult mice lacking MAGEL2 are insensitive to the typical anorexic effects of leptin treatment while exhibiting a lack of neuronal depolarization in hypothalamic pro-opiomelanocortin (POMC) neurons. With the hypothalamus playing a major role in development and endocrine functions, Wevrick and her co-investigators explored the question of whether the mutation inactivation of MAGEL2 was congenital or post-natal. In

23

vitro experimentation using POMC neurons from hypothalamic slices of MAGEL2 mice of various ages revealed a progressive decline in leptininvoked depolarization. Therefore it is possible that a similar, progressive loss of leptin sensitivity and loss of MAGEL2 in children could explain the delayed onset of hyperphagia and obesity (Human Molecular Genetics, 24:4276-4283, 2015). Metabolic fat balance – Strategies for weight loss diets have varied considerably over the years (to put it mildly), including whether caloric restriction should involve targeting fat or carbohydrates. Low carb diets have regained popularity in recent years, with advocates going so far as to claim any successful dieting relies on decreasing carbohydrate intake and elevating the release of free fatty acids/fatty acid oxidation, in turn leading to a greater loss of body fat compared with a low fat diet. Is it true? Dr Carla Prado, Director of the Human Nutrition Research Unit in ADI’s Clinical Research Unit, was part of a collaborative research team that explored the relative benefits of the two approaches, studying a variety of metabolic endpoints in males and females. In an intricate cross-over study, obese subjects started out on a eucaloric baseline diet

Human Nutrition Research Unit Whole Body Calorimetry Unit is the most precise method to study energy metabolism

24


hyperghrelinemia and increased insulin sensitivity of PWS may be related to these reduced levels of BCAAs. This data suggests increased proteolysis in PWS as a potential explanation for the reduced muscle mass, sarcopenia and decreased energy expenditure in PWS. Along with increasing the understanding of the endocrinology of PWS, her group (in collaboration with Dr Lonnie Zwaigenbaum) published a recent systematic review detailing the social-communication impairments present in PWS and evaluating the association between Autism Spectrum Disorder (ASD) and PWS. Meanwhile, fellow ADI member Dr Rachel Wevrick continues her groundbreaking research into the genetic basis of PWS, including the MAGEL2 (MAGE Family Member L2) gene that is known to be inactivated in PWS children. Adult mice lacking MAGEL2 are insensitive to the typical anorexic effects of leptin treatment while exhibiting a lack of neuronal depolarization in hypothalamic pro-opiomelanocortin (POMC) neurons. With the hypothalamus playing a major role in development and endocrine functions, Wevrick and her co-investigators explored the question of whether the mutation inactivation of MAGEL2 was congenital or post-natal. In

23

vitro experimentation using POMC neurons from hypothalamic slices of MAGEL2 mice of various ages revealed a progressive decline in leptininvoked depolarization. Therefore it is possible that a similar, progressive loss of leptin sensitivity and loss of MAGEL2 in children could explain the delayed onset of hyperphagia and obesity (Human Molecular Genetics, 24:4276-4283, 2015). Metabolic fat balance – Strategies for weight loss diets have varied considerably over the years (to put it mildly), including whether caloric restriction should involve targeting fat or carbohydrates. Low carb diets have regained popularity in recent years, with advocates going so far as to claim any successful dieting relies on decreasing carbohydrate intake and elevating the release of free fatty acids/fatty acid oxidation, in turn leading to a greater loss of body fat compared with a low fat diet. Is it true? Dr Carla Prado, Director of the Human Nutrition Research Unit in ADI’s Clinical Research Unit, was part of a collaborative research team that explored the relative benefits of the two approaches, studying a variety of metabolic endpoints in males and females. In an intricate cross-over study, obese subjects started out on a eucaloric baseline diet

Human Nutrition Research Unit Whole Body Calorimetry Unit is the most precise method to study energy metabolism

24


(50% carbohydrate, 35% fat, 15% protein) for 5 days, then alternated between low fat, LF (72% carbohydrate, 7% fat, 21% protein) and low carbohydrate, LC (30% carbohydrate, 49% fat, 21% protein) diets for 6 days each with a washout period in between. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation, measure while residing in a metabolic whole body calorimetry unit. The results of experimentation confirmed that an LC diet did in fact result in more weight lost compared with the LF diet (1.9 vs 1.3 kg, p=0.05). But the fat metabolic balance in the two diets was somewhat surprising: the LC diet resulted in a significant increase in fat oxidation, whereas the LF diet did not alter fat oxidation. When the difference between fat intake and fat oxidation were compared for the two diets though, the LF diet was associated with a greater turnover of fat. While it is expected that fat oxidation during prolonged LC or LF dieting would diminish over time, the data generated by Prado et al. suggest that a greater fat imbalance is likely to persist with the LF diet, leading to more long-term body fat loss compared with restricted carbohydrate dieting. Results of the study were published in Cell Metabolism (22:427-426, 2015).

25

New insight into cholesterol metabolism in those with diabetes – Traditionally, fasting blood lipid biomarkers like triglycerides (TGs) and low density lipoproteins (LDLs) or ‘bad cholesterol‘ have been used diagnostically to identify risk for developing cardiovascular disease. We know that those with diabetes have increased risk of CVD, but usually this is not associated with an increase in traditional blood lipids. But Dr Spencer Proctor is challenging that view, especially in light of recent epidemiological data showing patients diagnosed with cardiac events have normal fasting lipids and that intestinal-derived lipids (remnant cholesterol) might be playing a more prominent role in pathogenesis than previously thought (Copenhagen Heart Study). Non-fasting plasma levels of cholesterol are a result of both liver production and dietary absorption, but there is a more complex, reciprocal relationship that influences each other’s rate. This is reflected by studies that demonstrate how a drug like ezetimibe is used to block the absorption of gut-derived cholesterol, but not without a concomitant rise in cholesterol production in the liver. It is also noted that statins, designed

to lower the hepatic production of cholesterol, are associated with an increase in the intestinal absorption of cholesterol from the lumen. ‘These are very similar to the observations we see during diabetes’ say Proctor. Proctor, along with ADI member Dr Donna Vine and post-doctoral fellow Dr Rabban Mangat wanted to examine whether simvastatin administered to an animal model of diabetes and metabolic syndrome (JCR:LA-cp) increased the absorption of intestinal-derived ‘remnant’ cholesterol. Researchers found that rats also receiving simvastatin had 1.9-fold and 1.5 fold increases in the absorption both cholesterol and triglycerides. In addition, statin treatment increased the expression of key genes involved in lipid synthesis, including Hmgcr, Srebp1, Fas and Acc. The results of their research suggest that the perceived clinical benefits from statin treatment may be questionable (Atherosclerosis, 232:141148, 2014) and appear to increase remnant forms of cholesterol in the blood. More recently, Proctor and his research team have been collaborating with a group of researchers from 6 Quebec universities on the QUALITY (QUebec Adipose and Lifestyle InvesTigation in Youth) study, looking at risk factors for

overweight children. Their results suggest that levels of fasting LDLs and triglycerides aren’t as well-correlated with cardiovascular disease as a ‘remnant’ or diet-derived apolipoprotein called apo B48. In fact when they compared blood samples from lean and age-matched overweight children, apo B48 was three times higher in the latter, far more than the difference in their LDLs or TGs. Proctor’s work makes a strong case for utilizing apo B48 as an alternative screening biomarker for cardiovascular risk (Journal of Clinical Endocrinology and Metabolism, 101:291522, 2016).

Utilizing apo B48 as an alternative screening biomarker for cardiovascular risk Journal of Clinical Endocrinology and Metabolism 2016

26


(50% carbohydrate, 35% fat, 15% protein) for 5 days, then alternated between low fat, LF (72% carbohydrate, 7% fat, 21% protein) and low carbohydrate, LC (30% carbohydrate, 49% fat, 21% protein) diets for 6 days each with a washout period in between. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation, measure while residing in a metabolic whole body calorimetry unit. The results of experimentation confirmed that an LC diet did in fact result in more weight lost compared with the LF diet (1.9 vs 1.3 kg, p=0.05). But the fat metabolic balance in the two diets was somewhat surprising: the LC diet resulted in a significant increase in fat oxidation, whereas the LF diet did not alter fat oxidation. When the difference between fat intake and fat oxidation were compared for the two diets though, the LF diet was associated with a greater turnover of fat. While it is expected that fat oxidation during prolonged LC or LF dieting would diminish over time, the data generated by Prado et al. suggest that a greater fat imbalance is likely to persist with the LF diet, leading to more long-term body fat loss compared with restricted carbohydrate dieting. Results of the study were published in Cell Metabolism (22:427-426, 2015).

25

New insight into cholesterol metabolism in those with diabetes – Traditionally, fasting blood lipid biomarkers like triglycerides (TGs) and low density lipoproteins (LDLs) or ‘bad cholesterol‘ have been used diagnostically to identify risk for developing cardiovascular disease. We know that those with diabetes have increased risk of CVD, but usually this is not associated with an increase in traditional blood lipids. But Dr Spencer Proctor is challenging that view, especially in light of recent epidemiological data showing patients diagnosed with cardiac events have normal fasting lipids and that intestinal-derived lipids (remnant cholesterol) might be playing a more prominent role in pathogenesis than previously thought (Copenhagen Heart Study). Non-fasting plasma levels of cholesterol are a result of both liver production and dietary absorption, but there is a more complex, reciprocal relationship that influences each other’s rate. This is reflected by studies that demonstrate how a drug like ezetimibe is used to block the absorption of gut-derived cholesterol, but not without a concomitant rise in cholesterol production in the liver. It is also noted that statins, designed

to lower the hepatic production of cholesterol, are associated with an increase in the intestinal absorption of cholesterol from the lumen. ‘These are very similar to the observations we see during diabetes’ say Proctor. Proctor, along with ADI member Dr Donna Vine and post-doctoral fellow Dr Rabban Mangat wanted to examine whether simvastatin administered to an animal model of diabetes and metabolic syndrome (JCR:LA-cp) increased the absorption of intestinal-derived ‘remnant’ cholesterol. Researchers found that rats also receiving simvastatin had 1.9-fold and 1.5 fold increases in the absorption both cholesterol and triglycerides. In addition, statin treatment increased the expression of key genes involved in lipid synthesis, including Hmgcr, Srebp1, Fas and Acc. The results of their research suggest that the perceived clinical benefits from statin treatment may be questionable (Atherosclerosis, 232:141148, 2014) and appear to increase remnant forms of cholesterol in the blood. More recently, Proctor and his research team have been collaborating with a group of researchers from 6 Quebec universities on the QUALITY (QUebec Adipose and Lifestyle InvesTigation in Youth) study, looking at risk factors for

overweight children. Their results suggest that levels of fasting LDLs and triglycerides aren’t as well-correlated with cardiovascular disease as a ‘remnant’ or diet-derived apolipoprotein called apo B48. In fact when they compared blood samples from lean and age-matched overweight children, apo B48 was three times higher in the latter, far more than the difference in their LDLs or TGs. Proctor’s work makes a strong case for utilizing apo B48 as an alternative screening biomarker for cardiovascular risk (Journal of Clinical Endocrinology and Metabolism, 101:291522, 2016).

Utilizing apo B48 as an alternative screening biomarker for cardiovascular risk Journal of Clinical Endocrinology and Metabolism 2016

26


Nutritional clinical trials 27

Preparation for a nutritional study in Human Nutrition Research Unit

Improving maternal health in pregnancy and postpartum ­ – Dr Rhonda Bell is the lead investigator on ENRICH, a group of fifteen investigators, plus students and staff that came together under a research program funded for five years by Alberta Innovates - Health Solutions (AIHS). All ENRICH studies are aimed at improving maternal health in pregnancy and postpartum by finding innovative ways to promote healthy weights and healthy eating. Researchers work closely with Alberta Health Services and community partners in Edmonton, Calgary Zone and Maskwacis rolling out and evaluating different strategies to support women, their care providers and their communities to improve pregnancy and postpartum care. Strategies make the most of the extensive data collected about energy expenditure and body composition in the postpartum period, as well as the ongoing cohort of women and their families, the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Drs Cathy Chan and Rhonda Bell were awarded the U of A Community Scholar Award in 2016 for their book, Pure Prairie Eating Plan. The eating plan and recipies were inspired by the Mediterranean diet, but focuses

on foods more rediably available in a prairie setting. The authors are planning future guides for groups such as Asian-Albertans and Aboriginals that are prone to T2D. Bell was also awarded the Earl McHenry Award for Distinguished Service to Human Nutrition from the Canadian Nutrition Society in 2016.

28


Nutritional clinical trials 27

Preparation for a nutritional study in Human Nutrition Research Unit

Improving maternal health in pregnancy and postpartum ­ – Dr Rhonda Bell is the lead investigator on ENRICH, a group of fifteen investigators, plus students and staff that came together under a research program funded for five years by Alberta Innovates - Health Solutions (AIHS). All ENRICH studies are aimed at improving maternal health in pregnancy and postpartum by finding innovative ways to promote healthy weights and healthy eating. Researchers work closely with Alberta Health Services and community partners in Edmonton, Calgary Zone and Maskwacis rolling out and evaluating different strategies to support women, their care providers and their communities to improve pregnancy and postpartum care. Strategies make the most of the extensive data collected about energy expenditure and body composition in the postpartum period, as well as the ongoing cohort of women and their families, the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Drs Cathy Chan and Rhonda Bell were awarded the U of A Community Scholar Award in 2016 for their book, Pure Prairie Eating Plan. The eating plan and recipies were inspired by the Mediterranean diet, but focuses

on foods more rediably available in a prairie setting. The authors are planning future guides for groups such as Asian-Albertans and Aboriginals that are prone to T2D. Bell was also awarded the Earl McHenry Award for Distinguished Service to Human Nutrition from the Canadian Nutrition Society in 2016.

28


Intelligent Diabetes Management – While exciting advancements are being made in the treatment of type 1 diabetes including closed loop management systems and cell replacement therapy, bolus insulin injections are still the primary means for managing this disease. Several years ago Dr Edmond Ryan embarked on the development of a unique smartphone app that would personalize insulin injection regimes based on patient updates. While numerous apps exist for managing insulin bolus schedules, these are typically based on a feed-back approach and do not incorporate changes in medication until after blood glucose is affected. Ryan, along with fellow ADI member Dr Peter Senior and Drs. Russ Greiner and Michael Bowling (Computing Science), took a different approach. By collecting information about how clinicians make decisions for patients to normalize glucose based on nutritional, physical activity and lifestyle information, the researchers aimed to develop an algorithm that would allow this same proactive decision-making using an intelligent device. The first step in this process was a two year trial involving app users interfacing with the Edmonton Automated Sugar Intelligence (EASI) website

29

where information received from patients was used by clinicians to provide advice through the app. The initial objective was to study how well the approach was accepted by patents with T1D: whether they used it on an ongoing basis and whether it led to an improvement in glycemic control. Results of this research will be made available in late 2016, setting the stage for final design of the algorithm and testing of a fully automated app. Google or Apple app Vitamin D Supplementation – There has been a long-standing speculation about the association between vitamin D status and various diseases, including diabetes. Adults with diabetes and chronic kidney disease (CKD) are further compromised because the conversion of vitamin D to its biologically active form (calcitriol or 1,25(OH)2D) in the kidney is diminished, increasing the risk for insufficiency. Moreover, patients living in northern climates are at an even higher risk for vitamin D insufficiency due to lower sunlight exposure. Data suggests 93% of Canadians with CKD have vitamin D insufficiency, suggesting a need for supplementation, but there is a lack of guidelines for supplementation

protocols based on sound clinical research. Dr Diana Mager has led research aimed at validating the correlation between vitamin D status and various health benefits such as bone health, glycemic control and quality of life. In recent research Mager, along with ADI members Drs. Peter Senior and Kailash Jindal conducted research that explored the relative benefits of daily (2,000 IU/day) versus monthly (40,000 IU/month) D3 supplementation for 6 months in adults having both diabetes mellitus and CKD. What they found was that daily or monthly supplementation was equally effective in producing significant increases in serum

levels of vitamin D (including calcitriol), and both dosing regimens were safe and well-tolerated – important insight for health care providers. Supplementation produced little improvement in markers of bone health though, and future studies will be aimed at determining whether a longer duration of supplementation produces detectable benefits (Clinical Nutrition, in press).

30


Intelligent Diabetes Management – While exciting advancements are being made in the treatment of type 1 diabetes including closed loop management systems and cell replacement therapy, bolus insulin injections are still the primary means for managing this disease. Several years ago Dr Edmond Ryan embarked on the development of a unique smartphone app that would personalize insulin injection regimes based on patient updates. While numerous apps exist for managing insulin bolus schedules, these are typically based on a feed-back approach and do not incorporate changes in medication until after blood glucose is affected. Ryan, along with fellow ADI member Dr Peter Senior and Drs. Russ Greiner and Michael Bowling (Computing Science), took a different approach. By collecting information about how clinicians make decisions for patients to normalize glucose based on nutritional, physical activity and lifestyle information, the researchers aimed to develop an algorithm that would allow this same proactive decision-making using an intelligent device. The first step in this process was a two year trial involving app users interfacing with the Edmonton Automated Sugar Intelligence (EASI) website

29

where information received from patients was used by clinicians to provide advice through the app. The initial objective was to study how well the approach was accepted by patents with T1D: whether they used it on an ongoing basis and whether it led to an improvement in glycemic control. Results of this research will be made available in late 2016, setting the stage for final design of the algorithm and testing of a fully automated app. Google or Apple app Vitamin D Supplementation – There has been a long-standing speculation about the association between vitamin D status and various diseases, including diabetes. Adults with diabetes and chronic kidney disease (CKD) are further compromised because the conversion of vitamin D to its biologically active form (calcitriol or 1,25(OH)2D) in the kidney is diminished, increasing the risk for insufficiency. Moreover, patients living in northern climates are at an even higher risk for vitamin D insufficiency due to lower sunlight exposure. Data suggests 93% of Canadians with CKD have vitamin D insufficiency, suggesting a need for supplementation, but there is a lack of guidelines for supplementation

protocols based on sound clinical research. Dr Diana Mager has led research aimed at validating the correlation between vitamin D status and various health benefits such as bone health, glycemic control and quality of life. In recent research Mager, along with ADI members Drs. Peter Senior and Kailash Jindal conducted research that explored the relative benefits of daily (2,000 IU/day) versus monthly (40,000 IU/month) D3 supplementation for 6 months in adults having both diabetes mellitus and CKD. What they found was that daily or monthly supplementation was equally effective in producing significant increases in serum

levels of vitamin D (including calcitriol), and both dosing regimens were safe and well-tolerated – important insight for health care providers. Supplementation produced little improvement in markers of bone health though, and future studies will be aimed at determining whether a longer duration of supplementation produces detectable benefits (Clinical Nutrition, in press).

30


Research Highlights Immunology and Cell Therapy

Alberta Cell Therapy Manufacturing Western Canada’s only GMP facility for cell-based therapeutic products for clinical application

Retrievable device for islet transplantation – While continuing to direct the world’s largest clinical islet transplant program based on the groundbreaking Edmonton Protocol, Dr James Shapiro is also principal investigator for research that may lead to the next generation of islet cell replacement therapy for T1D. The technology, developed by San Diego-based ViaCyte, features a combination of pancreatic endoderm stem cells (PEC-01) loaded in a device implanted subcutaneously called Encaptra®, with the combination product called VC-01™. Preclinical testing of this device has repeatedly demonstrated reversal of diabetes in over 1500 mice made diabetic with streptozotocin. In 2015 Edmonton became the second site for Phase 1/2 clinical trials called STEP ONE (Safety, Tolerability and Efficacy of

VC-01™ Combination Product in T1D), where Shapiro and co-investigator Dr Peter Senior have led the transplantation of the devices in several patients. The VC-01™ offers a number of potential advantages over current islet transplantation protocols involving injection of islets into the liver. The device is easily retrievable with a minimally-invasive, outpatient procedure. The cell line produces other pancreatic regulatory hormones and co-factors, increasing the health benefits to the patient. The combination of stem cells with the encapsulation device boosts vascularization around the cells, improving oxygenation and the delivery of nutrients to the developing cells. And perhaps most significantly, the Encaptra® is designed to overcome immuno-rejection by the host by means of a semi-permeable membrane that allows the

32


Research Highlights Immunology and Cell Therapy

Alberta Cell Therapy Manufacturing Western Canada’s only GMP facility for cell-based therapeutic products for clinical application

Retrievable device for islet transplantation – While continuing to direct the world’s largest clinical islet transplant program based on the groundbreaking Edmonton Protocol, Dr James Shapiro is also principal investigator for research that may lead to the next generation of islet cell replacement therapy for T1D. The technology, developed by San Diego-based ViaCyte, features a combination of pancreatic endoderm stem cells (PEC-01) loaded in a device implanted subcutaneously called Encaptra®, with the combination product called VC-01™. Preclinical testing of this device has repeatedly demonstrated reversal of diabetes in over 1500 mice made diabetic with streptozotocin. In 2015 Edmonton became the second site for Phase 1/2 clinical trials called STEP ONE (Safety, Tolerability and Efficacy of

VC-01™ Combination Product in T1D), where Shapiro and co-investigator Dr Peter Senior have led the transplantation of the devices in several patients. The VC-01™ offers a number of potential advantages over current islet transplantation protocols involving injection of islets into the liver. The device is easily retrievable with a minimally-invasive, outpatient procedure. The cell line produces other pancreatic regulatory hormones and co-factors, increasing the health benefits to the patient. The combination of stem cells with the encapsulation device boosts vascularization around the cells, improving oxygenation and the delivery of nutrients to the developing cells. And perhaps most significantly, the Encaptra® is designed to overcome immuno-rejection by the host by means of a semi-permeable membrane that allows the

32


movement of glucose, proteins, oxygen and hormones but is impermeable to immune cells. Shapiro remarked in a recent press release that “this is a remarkable opportunity that could free T1D patients from severe complications and health issues such as hypoglycemia, eye, kidney and cardiovascular diseases, all without the requirement of powerful lifelong immunosuppression drugs.” Once safety is demonstrated in early trials, additional transplants will be done with higher doses of stem cells that will produce therapeutic levels of insulin and other products while safety is further evaluated. STEP ONE is being supported by a $5-million Collaborative Research and Innovation Opportunities (CRIO) grant from the Alberta Government, and through a Juvenile Diabetes Research Foundation (JDRF) Clinical Trials Network grant. Antioxidant improves islet survival – Pancreatic islet isolation and transplantation following the Edmonton Protocol offer life-altering results for diabetes patients, but injury and stress to cells during the process are major obstacles for achieving effective post-

33

Prevascularized subcutaneous device-less site for islet and cellular transplantation Nature Biotechnology 2015

transplant functional performance. One of the issues is oxidative stress due to low antioxidant capacity in islets, highly detrimental when cells are challenged with ischemia and reperfusion injury. In an effort to overcome this, Dr Gina Rayat and a collaborative team that included former ADI Founding Scientific Director Dr Ray Rajotte and fruit scientists from Zhejiang University in China, explored the use of cyanidin-3-O-glucoside (C3G), an anthocyanin with powerful antioxidant properties derived from the

Chinese bayberry that has been also used in other medical applications. The group had previously shown that isolated mouse islets cultured with C3G increased expression of various genes related to enhanced survival, including HO-1, ERK 1/2 and P13K/Akt, with knockout of these genes nullifying the advantage. In a more recent study they isolated islets from mouse pancreases and cultured them with and without C3G for 24 hours before transplanting the islets under the kidney capsule of recipient mice that had been rendered diabetic with streptozotocin. They found that mouse recipients of 400 or 200 C3G-treated islets achieved normoglycemia significantly faster than mouse recipients of untreated islets – 10 days vs. 13 days and 10 days vs. 18 days, respectively. Even more, animals that received just 100 C3Gtreated islets achieved normoglycemia within 27 days, whereas mice transplanted with the same number of untreated islets failed to show lowering of blood glucose. When the investigators repeated the experiment using the portal vein as site for transplantation they found that islets were less efficient in attaining normoglycemia. For example, 40% and 20% of mice transplanted with 200 and 100 C3G-treated islets, respectively were able to

achieve normoglycemia, when the transplant was into the portal vein of the liver. This compares with 100% success when similar numbers were transplanted under the kidney capsule. While the latter site may not be practical in human applications, it does demonstrate the importance of transplantation site for islet survival, even with antioxidant treatment. Regardless of site though, their results show that pre-treatment with C3G enhances both viability and function of islets after transplantation and encourages further research into the use of antioxidants (Transplantation, 99:508-514, 2015). Dr Rayat and her group are currently testing the effect of C3G on pig and human islets. Supporting porcine islet transplantations – Dr Greg Korbutt has pioneered research exploring the feasibility of using neonatal porcine islets (NPIs) as an alternative to the more limited supply of human islets for cell replacement therapy in T1D patients. Similar to the transplantation of human islets, there are drawbacks to transplanting NPIs into the portal vein of the liver based on the Edmonton Protocol (which Korbutt helped

34


movement of glucose, proteins, oxygen and hormones but is impermeable to immune cells. Shapiro remarked in a recent press release that “this is a remarkable opportunity that could free T1D patients from severe complications and health issues such as hypoglycemia, eye, kidney and cardiovascular diseases, all without the requirement of powerful lifelong immunosuppression drugs.” Once safety is demonstrated in early trials, additional transplants will be done with higher doses of stem cells that will produce therapeutic levels of insulin and other products while safety is further evaluated. STEP ONE is being supported by a $5-million Collaborative Research and Innovation Opportunities (CRIO) grant from the Alberta Government, and through a Juvenile Diabetes Research Foundation (JDRF) Clinical Trials Network grant. Antioxidant improves islet survival – Pancreatic islet isolation and transplantation following the Edmonton Protocol offer life-altering results for diabetes patients, but injury and stress to cells during the process are major obstacles for achieving effective post-

33

Prevascularized subcutaneous device-less site for islet and cellular transplantation Nature Biotechnology 2015

transplant functional performance. One of the issues is oxidative stress due to low antioxidant capacity in islets, highly detrimental when cells are challenged with ischemia and reperfusion injury. In an effort to overcome this, Dr Gina Rayat and a collaborative team that included former ADI Founding Scientific Director Dr Ray Rajotte and fruit scientists from Zhejiang University in China, explored the use of cyanidin-3-O-glucoside (C3G), an anthocyanin with powerful antioxidant properties derived from the

Chinese bayberry that has been also used in other medical applications. The group had previously shown that isolated mouse islets cultured with C3G increased expression of various genes related to enhanced survival, including HO-1, ERK 1/2 and P13K/Akt, with knockout of these genes nullifying the advantage. In a more recent study they isolated islets from mouse pancreases and cultured them with and without C3G for 24 hours before transplanting the islets under the kidney capsule of recipient mice that had been rendered diabetic with streptozotocin. They found that mouse recipients of 400 or 200 C3G-treated islets achieved normoglycemia significantly faster than mouse recipients of untreated islets – 10 days vs. 13 days and 10 days vs. 18 days, respectively. Even more, animals that received just 100 C3Gtreated islets achieved normoglycemia within 27 days, whereas mice transplanted with the same number of untreated islets failed to show lowering of blood glucose. When the investigators repeated the experiment using the portal vein as site for transplantation they found that islets were less efficient in attaining normoglycemia. For example, 40% and 20% of mice transplanted with 200 and 100 C3G-treated islets, respectively were able to

achieve normoglycemia, when the transplant was into the portal vein of the liver. This compares with 100% success when similar numbers were transplanted under the kidney capsule. While the latter site may not be practical in human applications, it does demonstrate the importance of transplantation site for islet survival, even with antioxidant treatment. Regardless of site though, their results show that pre-treatment with C3G enhances both viability and function of islets after transplantation and encourages further research into the use of antioxidants (Transplantation, 99:508-514, 2015). Dr Rayat and her group are currently testing the effect of C3G on pig and human islets. Supporting porcine islet transplantations – Dr Greg Korbutt has pioneered research exploring the feasibility of using neonatal porcine islets (NPIs) as an alternative to the more limited supply of human islets for cell replacement therapy in T1D patients. Similar to the transplantation of human islets, there are drawbacks to transplanting NPIs into the portal vein of the liver based on the Edmonton Protocol (which Korbutt helped

34


develop), including hepatic thrombosis and intraperitoneal bleeding. Like other scientists who are looking to improve the sustainability of human islet transplants, Korbutt is exploring the use of alternative transplant sites as well as utilizing supporting materials that promote the viability and longevity of transplanted NPIs. The goal is a supporting matrix that promotes vascularization of the graft for oxygen and nutrient delivery, while also providing protection against immune attack. Korbutt and PhD student Cara Ellis previously developed a collagen-based matrix containing a combination of chondroitin-6-sulfate, chitosan and laminin that proved to be efficacious for improving islet survival in preclinical transplant models. More recent research was aimed at ‘tuning’ this matrix with different cross-linkers to optimize functional characteristics like biodegradation rate, degree of vascularization and swelling ratio. The concentration of two linking compounds, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, were varied with the resulting matrix tested for functionality in both in vitro and in vivo models. In general, mechanical strength of the matrix was sufficient to support both transplantation

35

and retrievability, important considerations for future clinical application. They were able to demonstrate that the matrix properties could be manipulated in a highly reproducible manner; for example, swelling ratio was significantly and negatively correlated with cross-linker concentration, important for controlling the rate of insulin diffusion and the rate of release of drugs that might be incorporated in the matrix. Biodegradation was tested using collagenase, with the rate determined to be significantly and inversely correlated with the concentration of cross-linking. The number and size of blood vessels (i.e., vascularization) was positively correlated with cross-link concentration; electron microscopy revealed that faster neovascularization was correlated with specific topographical features that are likely related to higher surface energy. Results of their research lend themselves to customizing matrices in the future for application in specific tissues (Bioresearch Open Access, 4:188-197, 2015). Korbutt’s progress in this area has set the stage for his upcoming research focus: combining the collagen-based matrix with a novel polycaprolactone scaffolding that will effectively

Greg Korbutt Neonatal porcine islet xenotransplantation


develop), including hepatic thrombosis and intraperitoneal bleeding. Like other scientists who are looking to improve the sustainability of human islet transplants, Korbutt is exploring the use of alternative transplant sites as well as utilizing supporting materials that promote the viability and longevity of transplanted NPIs. The goal is a supporting matrix that promotes vascularization of the graft for oxygen and nutrient delivery, while also providing protection against immune attack. Korbutt and PhD student Cara Ellis previously developed a collagen-based matrix containing a combination of chondroitin-6-sulfate, chitosan and laminin that proved to be efficacious for improving islet survival in preclinical transplant models. More recent research was aimed at ‘tuning’ this matrix with different cross-linkers to optimize functional characteristics like biodegradation rate, degree of vascularization and swelling ratio. The concentration of two linking compounds, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide, were varied with the resulting matrix tested for functionality in both in vitro and in vivo models. In general, mechanical strength of the matrix was sufficient to support both transplantation

35

and retrievability, important considerations for future clinical application. They were able to demonstrate that the matrix properties could be manipulated in a highly reproducible manner; for example, swelling ratio was significantly and negatively correlated with cross-linker concentration, important for controlling the rate of insulin diffusion and the rate of release of drugs that might be incorporated in the matrix. Biodegradation was tested using collagenase, with the rate determined to be significantly and inversely correlated with the concentration of cross-linking. The number and size of blood vessels (i.e., vascularization) was positively correlated with cross-link concentration; electron microscopy revealed that faster neovascularization was correlated with specific topographical features that are likely related to higher surface energy. Results of their research lend themselves to customizing matrices in the future for application in specific tissues (Bioresearch Open Access, 4:188-197, 2015). Korbutt’s progress in this area has set the stage for his upcoming research focus: combining the collagen-based matrix with a novel polycaprolactone scaffolding that will effectively

Greg Korbutt Neonatal porcine islet xenotransplantation


incorporate growth factors and immunoprotective components. Korbutt is also director of Alberta Cell Therapy Manufacturing, Western Canada’s only Good Manufacturing Practice (GMP) facility for cell-based therapeutic products for clinical application, including xenotransplantation. Immunomodulation by Tregs – Autoimmunity results from abnormal recognition of self-antigens by both B- and T-cells, which can lead to autoantibody production and cellmediated attack. The relative importance of the two acquired immune types and their interplay in the pathogenesis of T1D is an ongoing area of investigation, but understanding T-cell response is still considered central to managing the autoimmune disease itself as well as achieving allotransplant tolerance. An area of focus of several ADI scientists is on regulatory T-cells (Tregs), the cell type involved in moderating T-cell mediated immune reactions along with helper T cells (Th cells) – essentially the cells that put the brakes on a cell-mediated immune reaction. Immunologist Dr Colin Anderson has made inroads into understanding how Tregs are generated, with earlier work suggesting

37

the co-inhibitory receptor PD-1 played a role in controlling the proliferation of peripheral Tregs from newly formed/immature T cells known as ‘recent thymic emigrants’. This modulation is critical for keeping balance and promoting selftolerance during transient states, but whether or not PD-1 was acting directly was not clear: conclusions were derived indirectly from looking at the ligand PDL1, not PD-1 itself. Since PD-L1 is known to interact with receptors other than PD1, Anderson wanted to perform a more direct in vivo experiment to determine if PD-L1 modulates pTreg cell conversion by something other than PD-1. They compared the response of wild-type and PD-1 knockout T cell populations, but did so in the same animals - a strategy which avoided a number of confounding experimental issues that have led to conflicting results from other scientists. What they showed was that conversion of RTEs to pTregs was not impeded by a lack of PD-1; in fact, conversion to pTregs was actually higher for PD-1 KO cells populations. In a mouse model of lymphopenia-driven autoimmunity, PD-1 deficiency did not lead to Th17 cell mediated autoimmunity. Taken together, the data suggests that PD-1 does not intrinsically control the

conversion of RTEs to pTreg cells, but rather that the primary role of PD-1 is to restrain the expansion of T cell activation and proliferation to self-antigens (European Journal of Immunology, doi:10.1002/eji.201444688, 2014). Meanwhile pediatric cardiologist/immunologist Dr Lori West is looking at the feasibility of harvesting Tregs from thymuses discarded during infant cardiac surgery as a means of immunosuppressive cell therapy during both allo- and xenotransplantation. Treg cells sequestered from peripheral blood and expanded in culture have yielded promising results in various clinical trials, but there are challenges with this approach. One issue is that peripheral Treg numbers are typically low, requiring massive ex vivo expansion. Another problem is unavoidable contamination with effector T cells. A further challenge is limited stability and loss of FOXP3+ expression following repeated ex vivo stimulation. West and postdoctoral fellow Dr Esme Dijke were able to collect and expand large numbers of Tregs from single thymuses that maintained stable function and phenotype including

FOXP3+ expression, even under inflammatory conditions. They were able to use these to suppress proliferation and cytokine production of activated allogenic T cells in vitro. They were further able to demonstrate delayed development of xenogeneic graft versus host disease (GVHD) in an in vivo suppression assay with efficacy that was superior to that achieved using blood Tregs. Results of their research have set the stage for possible preclinical and clinical trials in the future using thymus-derived Tregs that overcome current therapeutic shortfalls (American Journal Transplantation, doi:10.1111/ajt.13456, 2015).

500th

islet cell transplant in Edmonton Major milestone for James Shapiro and his team at the University of Alberta Clinical Islet Transplant Program

38


incorporate growth factors and immunoprotective components. Korbutt is also director of Alberta Cell Therapy Manufacturing, Western Canada’s only Good Manufacturing Practice (GMP) facility for cell-based therapeutic products for clinical application, including xenotransplantation. Immunomodulation by Tregs – Autoimmunity results from abnormal recognition of self-antigens by both B- and T-cells, which can lead to autoantibody production and cellmediated attack. The relative importance of the two acquired immune types and their interplay in the pathogenesis of T1D is an ongoing area of investigation, but understanding T-cell response is still considered central to managing the autoimmune disease itself as well as achieving allotransplant tolerance. An area of focus of several ADI scientists is on regulatory T-cells (Tregs), the cell type involved in moderating T-cell mediated immune reactions along with helper T cells (Th cells) – essentially the cells that put the brakes on a cell-mediated immune reaction. Immunologist Dr Colin Anderson has made inroads into understanding how Tregs are generated, with earlier work suggesting

37

the co-inhibitory receptor PD-1 played a role in controlling the proliferation of peripheral Tregs from newly formed/immature T cells known as ‘recent thymic emigrants’. This modulation is critical for keeping balance and promoting selftolerance during transient states, but whether or not PD-1 was acting directly was not clear: conclusions were derived indirectly from looking at the ligand PDL1, not PD-1 itself. Since PD-L1 is known to interact with receptors other than PD1, Anderson wanted to perform a more direct in vivo experiment to determine if PD-L1 modulates pTreg cell conversion by something other than PD-1. They compared the response of wild-type and PD-1 knockout T cell populations, but did so in the same animals - a strategy which avoided a number of confounding experimental issues that have led to conflicting results from other scientists. What they showed was that conversion of RTEs to pTregs was not impeded by a lack of PD-1; in fact, conversion to pTregs was actually higher for PD-1 KO cells populations. In a mouse model of lymphopenia-driven autoimmunity, PD-1 deficiency did not lead to Th17 cell mediated autoimmunity. Taken together, the data suggests that PD-1 does not intrinsically control the

conversion of RTEs to pTreg cells, but rather that the primary role of PD-1 is to restrain the expansion of T cell activation and proliferation to self-antigens (European Journal of Immunology, doi:10.1002/eji.201444688, 2014). Meanwhile pediatric cardiologist/immunologist Dr Lori West is looking at the feasibility of harvesting Tregs from thymuses discarded during infant cardiac surgery as a means of immunosuppressive cell therapy during both allo- and xenotransplantation. Treg cells sequestered from peripheral blood and expanded in culture have yielded promising results in various clinical trials, but there are challenges with this approach. One issue is that peripheral Treg numbers are typically low, requiring massive ex vivo expansion. Another problem is unavoidable contamination with effector T cells. A further challenge is limited stability and loss of FOXP3+ expression following repeated ex vivo stimulation. West and postdoctoral fellow Dr Esme Dijke were able to collect and expand large numbers of Tregs from single thymuses that maintained stable function and phenotype including

FOXP3+ expression, even under inflammatory conditions. They were able to use these to suppress proliferation and cytokine production of activated allogenic T cells in vitro. They were further able to demonstrate delayed development of xenogeneic graft versus host disease (GVHD) in an in vivo suppression assay with efficacy that was superior to that achieved using blood Tregs. Results of their research have set the stage for possible preclinical and clinical trials in the future using thymus-derived Tregs that overcome current therapeutic shortfalls (American Journal Transplantation, doi:10.1111/ajt.13456, 2015).

500th

islet cell transplant in Edmonton Major milestone for James Shapiro and his team at the University of Alberta Clinical Islet Transplant Program

38


Arya Sharma Founder and Scientific Director of the Canadian Obesity Network, Canada’s largest association of healthcare professionals, researchers and policy makers

39

Research Highlights Population Health Innovative obesity management – There is no ambiguity about obesity being a major risk factor for the development of T2D – what’s worse, there is also a lack of proper weight management at the health delivery level by practitioners. ADI scientists continue to make inroads in the fight against obesity at both the clinical and population health levels, including Dr Arya Sharma who is director of the Canadian Obesity Network (CON), Canada’s largest association of healthcare professionals, researchers and policy makers working on obesity-related solutions. His own research focuses on evidence-based prevention and management of obesity and associated complications like diabetes. Sharma led the development of the 5A’s of Obesity Management, a set of practical tools that can help guide health

care professionals in weight management in primary care settings. Between 2013 and 2014 Sharma, along with ADI member Dr Denise Campbell-Scherer and postdoctoral fellows Drs. Ayodele Ogunleye and Jody Asselin, conducted a controlled clinical trial to determine the effectiveness of the 5A’s program in practice, collaborating with the Primary Care Network (PCN) of Alberta. The PCN is a front-line health care service in the Province, designed to bring local physicians together with mental health, dietary, nursing, pharmacy and other professionals to deliver integrative and comprehensive health solutions. The research helped health care providers identify their key knowledge gaps in regards to weight management intervention and the need for training for cultural, social and psychological factors. The result was a clear

40


Arya Sharma Founder and Scientific Director of the Canadian Obesity Network, Canada’s largest association of healthcare professionals, researchers and policy makers

39

Research Highlights Population Health Innovative obesity management – There is no ambiguity about obesity being a major risk factor for the development of T2D – what’s worse, there is also a lack of proper weight management at the health delivery level by practitioners. ADI scientists continue to make inroads in the fight against obesity at both the clinical and population health levels, including Dr Arya Sharma who is director of the Canadian Obesity Network (CON), Canada’s largest association of healthcare professionals, researchers and policy makers working on obesity-related solutions. His own research focuses on evidence-based prevention and management of obesity and associated complications like diabetes. Sharma led the development of the 5A’s of Obesity Management, a set of practical tools that can help guide health

care professionals in weight management in primary care settings. Between 2013 and 2014 Sharma, along with ADI member Dr Denise Campbell-Scherer and postdoctoral fellows Drs. Ayodele Ogunleye and Jody Asselin, conducted a controlled clinical trial to determine the effectiveness of the 5A’s program in practice, collaborating with the Primary Care Network (PCN) of Alberta. The PCN is a front-line health care service in the Province, designed to bring local physicians together with mental health, dietary, nursing, pharmacy and other professionals to deliver integrative and comprehensive health solutions. The research helped health care providers identify their key knowledge gaps in regards to weight management intervention and the need for training for cultural, social and psychological factors. The result was a clear

40


indication that most health care workers admitted they lacked the skills and confidence necessary to deal with patient weight management, and that training with 5A’s intervention was effective in overcoming this shortfall. The 5A’s intervention is a promising primary care-based approach for achieving better management of obesity that will be further assessed (BMC Research Notes, doi: 10.1186/s13104-015-1685-8, 2015). Meanwhile, fellow ADI member Dr Geoff Ball is taking a similar approach to battling the rapidly growing health care threat of childhood obesity, which has increased nearly three-fold over the last three decades in Canada. Not surprising, overweight children become adults with similar weight challenges, making early intervention vital. A research team that included Dr Raj Padwal and PhD candidate Jill Avis explored how primary care providers use resources available to them to help manage juvenile obesity. Not surprisingly, their assessment revealed that most tools used by clinicians and parents were simplistic (eg, BMI) and focused on nutrition, with insufficient emphasis placed on contributing factors like physical activity and mental health. Ball and Avis created Resource Information for Parents on Lifestyle

41

& Education (RIPPLE), a web-based tool that was easily accessible right in a doctor’s waiting room. The idea was to have parents answer a series of questions about physical attributes and habits that would lead into a more informed discussion with their clinician. This tool was utilized in a pilot study at a PCN clinic, garnering highly positive feedback as well as areas for improvement. RIPPLE will be refined and tested further in the future (Telemedicine and e-Health, doi:10.1089/ tmj.2015.0128, 2015). Aboriginal and Indigenous Health – Dr Sangita Sharma is a Centennial Professor and Endowed Chair of Aboriginal Health in the Faculty of Medicine and Dentistry at the University of Alberta and has over 22 years of experience working with multiethnic populations (eg Inuit, Inuvialuit and First Nations in Alberta, Northwest Territories (NT) and Nunavut (NU) and Alaska Natives, Apache and Navajo in the USA) focusing on chronic disease, diabetes and cancer prevention research. Sharma obtained her PhD from the University of Manchester Medical School in 1996 and since then she has worked with numerous populations in over 20 countries. Since moving to Canada in 2010, she has been leading

a multi-disciplinary research group examining the risk factors for cancer, heart disease, diabetes, and obesity among Indigenous populations in Canada and around the world. As a Principal Investigator, Sharma has been awarded research funding for over 50 projects and was awarded the Silver Medal by the British Nutrition Society in 2010 for her health intervention program “Healthy Foods North” which was implemented in six communities in the NT and NU, in partnership with Inuit and Inuvialuit communities. Sharma has over 125 peer-reviewed scientific publications, including one recently in The Lancet Oncology

(15:504-516, 2014) for her work studying cancer incidence in Indigenous populations through her Alberta Innovates-Health Solutions funded project “Cancer ACCESS”, currently underway in the NT in Inuvik and Fort Good Hope. Currently, she is also running the “WHY ACT NOW” program in Edmonton to improve nutrition and physical activity in Aboriginal and new Canadian youth, funded in part by ADI. Other projects underway include the CIHR funded “MATERNAL” studying factors affecting pre- and post-natal maternal health in Northern Canada and NIH funded ASTHMA studies.

42


indication that most health care workers admitted they lacked the skills and confidence necessary to deal with patient weight management, and that training with 5A’s intervention was effective in overcoming this shortfall. The 5A’s intervention is a promising primary care-based approach for achieving better management of obesity that will be further assessed (BMC Research Notes, doi: 10.1186/s13104-015-1685-8, 2015). Meanwhile, fellow ADI member Dr Geoff Ball is taking a similar approach to battling the rapidly growing health care threat of childhood obesity, which has increased nearly three-fold over the last three decades in Canada. Not surprising, overweight children become adults with similar weight challenges, making early intervention vital. A research team that included Dr Raj Padwal and PhD candidate Jill Avis explored how primary care providers use resources available to them to help manage juvenile obesity. Not surprisingly, their assessment revealed that most tools used by clinicians and parents were simplistic (eg, BMI) and focused on nutrition, with insufficient emphasis placed on contributing factors like physical activity and mental health. Ball and Avis created Resource Information for Parents on Lifestyle

41

& Education (RIPPLE), a web-based tool that was easily accessible right in a doctor’s waiting room. The idea was to have parents answer a series of questions about physical attributes and habits that would lead into a more informed discussion with their clinician. This tool was utilized in a pilot study at a PCN clinic, garnering highly positive feedback as well as areas for improvement. RIPPLE will be refined and tested further in the future (Telemedicine and e-Health, doi:10.1089/ tmj.2015.0128, 2015). Aboriginal and Indigenous Health – Dr Sangita Sharma is a Centennial Professor and Endowed Chair of Aboriginal Health in the Faculty of Medicine and Dentistry at the University of Alberta and has over 22 years of experience working with multiethnic populations (eg Inuit, Inuvialuit and First Nations in Alberta, Northwest Territories (NT) and Nunavut (NU) and Alaska Natives, Apache and Navajo in the USA) focusing on chronic disease, diabetes and cancer prevention research. Sharma obtained her PhD from the University of Manchester Medical School in 1996 and since then she has worked with numerous populations in over 20 countries. Since moving to Canada in 2010, she has been leading

a multi-disciplinary research group examining the risk factors for cancer, heart disease, diabetes, and obesity among Indigenous populations in Canada and around the world. As a Principal Investigator, Sharma has been awarded research funding for over 50 projects and was awarded the Silver Medal by the British Nutrition Society in 2010 for her health intervention program “Healthy Foods North” which was implemented in six communities in the NT and NU, in partnership with Inuit and Inuvialuit communities. Sharma has over 125 peer-reviewed scientific publications, including one recently in The Lancet Oncology

(15:504-516, 2014) for her work studying cancer incidence in Indigenous populations through her Alberta Innovates-Health Solutions funded project “Cancer ACCESS”, currently underway in the NT in Inuvik and Fort Good Hope. Currently, she is also running the “WHY ACT NOW” program in Edmonton to improve nutrition and physical activity in Aboriginal and new Canadian youth, funded in part by ADI. Other projects underway include the CIHR funded “MATERNAL” studying factors affecting pre- and post-natal maternal health in Northern Canada and NIH funded ASTHMA studies.

42


A better means of assessing islet transplant success – Since islet transplantations began taking place there has been ‘scoring’ of graft success, typically based on patient glycemic control parameters. Not surprisingly, the most accurate means of assessing graft performance are based on more complex metabolic measurements like mixedmeal tolerance tests (MMTTs) that are not as practical in routine clinical settings. Approaches that are too simplistic such as basic fasting glucose and C-peptide levels are confounded by exogenous insulin or poor gylcemia. To date, the BETA score has been most useful, and is essentially the arithmetic sum of scores (0 for diabetes range, 1 for intermediate, 2 for normal) for 4 components: fasting glucose, HbA1c, stimulated C-peptide and absence of endogenous insulin or oral hypoglycemic agent. However, this approach has limited sensitivity due in part to the categorical scoring of the parameters. Dr Peter Senior, Medical Director of the Clinical Islet Transplant Program, along with a team that

BETA 2 score =

43

included Dr James Shapiro and postdoctoral fellows Drs. Tolu Olateju and Richard Oram developed a new scoring system – the BETA 2 score. The basis of this score was continuous variables for common patient test values in a single, fasting blood sample - glucose, C-peptide, hemoglobin HbA1c and insulin dose. By using the measurements from 183 transplant patients that underwent MMTTs, and stepwise forward linear regression, the researchers were able to derive a mathematical formula for BETA 2 scores, with values over 20 reflecting insulin independence and scores under 15 reflecting glucose intolerance (see equation below).

Expertise in T1D and T2D Researchers at the Alberta Diabetes Institute continue to strive towards improving the lives of people suffering from diabetes

In follow-up validation testing with 114 transplant recipients undergoing MMTTs 12 months after transplantation, BETA 2 scoring had over 82% sensitivity and specificity for correctly discriminating between these two groups. Results of this research show promise for the BETA 2 scoring system and warrant additional studies to validate its use (American Journal of Transplantation, doi:10.1111/ajt.13807, 2016).

(√fasting C-peptide (nmol/L) x (1 – insulin dose [units/kg]) Fasting plasma glucose (nmol/L) x HbA1c (%)

x 1000

44


A better means of assessing islet transplant success – Since islet transplantations began taking place there has been ‘scoring’ of graft success, typically based on patient glycemic control parameters. Not surprisingly, the most accurate means of assessing graft performance are based on more complex metabolic measurements like mixedmeal tolerance tests (MMTTs) that are not as practical in routine clinical settings. Approaches that are too simplistic such as basic fasting glucose and C-peptide levels are confounded by exogenous insulin or poor gylcemia. To date, the BETA score has been most useful, and is essentially the arithmetic sum of scores (0 for diabetes range, 1 for intermediate, 2 for normal) for 4 components: fasting glucose, HbA1c, stimulated C-peptide and absence of endogenous insulin or oral hypoglycemic agent. However, this approach has limited sensitivity due in part to the categorical scoring of the parameters. Dr Peter Senior, Medical Director of the Clinical Islet Transplant Program, along with a team that

BETA 2 score =

43

included Dr James Shapiro and postdoctoral fellows Drs. Tolu Olateju and Richard Oram developed a new scoring system – the BETA 2 score. The basis of this score was continuous variables for common patient test values in a single, fasting blood sample - glucose, C-peptide, hemoglobin HbA1c and insulin dose. By using the measurements from 183 transplant patients that underwent MMTTs, and stepwise forward linear regression, the researchers were able to derive a mathematical formula for BETA 2 scores, with values over 20 reflecting insulin independence and scores under 15 reflecting glucose intolerance (see equation below).

Expertise in T1D and T2D Researchers at the Alberta Diabetes Institute continue to strive towards improving the lives of people suffering from diabetes

In follow-up validation testing with 114 transplant recipients undergoing MMTTs 12 months after transplantation, BETA 2 scoring had over 82% sensitivity and specificity for correctly discriminating between these two groups. Results of this research show promise for the BETA 2 scoring system and warrant additional studies to validate its use (American Journal of Transplantation, doi:10.1111/ajt.13807, 2016).

(√fasting C-peptide (nmol/L) x (1 – insulin dose [units/kg]) Fasting plasma glucose (nmol/L) x HbA1c (%)

x 1000

44


title of page

Alberta Diabetes Institute The largest freestanding diabetes research facility in Canada

Core Facilities The ADI maintains a number of core services that provide investigators and trainees with direct access to extensive equipment and expertise for conducting research. These include:

Immunology (ImmunoCore) – Services include cell sorting, flow cytometry, and T-lymphocyte killing, as well as maintenance of an antibody biobar.

Histology (HistoCore) – Provides paraffin processing and staining of tissues for histopathology, cryosectioning, as well as protocol development and services for immunohistochemistry and immunofluorescence. Histologist Lynette Elder, who is accredited with the College of Medical Laboratory Technologists of Alberta, manages HistoCore.

Human Research Islets (IsletCore) – This human islet isolation facility processes donor pancreases not suited for transplantation, making islets available to researchers across Canada and internationally. Since its inception in 2010 the IsletCore have isolated more than 40 million islets for research from nearly 180 human organ donors as of June 2016.

Molecular Biology (MolBioCore) – Enables availability of equipment and training for the synthesis and analysis of nucleic acids, peptides and proteins. Core Manager, Dr. Kuni Suzuki, provides expert technical assistance for plasmid DNA preparation and adenoviral gene delivery.

45

Cell Imaging (administered by the Faculty of Medicine and Dentistry) – Offers a comprehensive array of equipment and services related to the imaging and analysis of live or fixed cells and tissues, with technical assistance provided by Dr. Greg Plummer.

46


title of page

Alberta Diabetes Institute The largest freestanding diabetes research facility in Canada

Core Facilities The ADI maintains a number of core services that provide investigators and trainees with direct access to extensive equipment and expertise for conducting research. These include:

Immunology (ImmunoCore) – Services include cell sorting, flow cytometry, and T-lymphocyte killing, as well as maintenance of an antibody biobar.

Histology (HistoCore) – Provides paraffin processing and staining of tissues for histopathology, cryosectioning, as well as protocol development and services for immunohistochemistry and immunofluorescence. Histologist Lynette Elder, who is accredited with the College of Medical Laboratory Technologists of Alberta, manages HistoCore.

Human Research Islets (IsletCore) – This human islet isolation facility processes donor pancreases not suited for transplantation, making islets available to researchers across Canada and internationally. Since its inception in 2010 the IsletCore have isolated more than 40 million islets for research from nearly 180 human organ donors as of June 2016.

Molecular Biology (MolBioCore) – Enables availability of equipment and training for the synthesis and analysis of nucleic acids, peptides and proteins. Core Manager, Dr. Kuni Suzuki, provides expert technical assistance for plasmid DNA preparation and adenoviral gene delivery.

45

Cell Imaging (administered by the Faculty of Medicine and Dentistry) – Offers a comprehensive array of equipment and services related to the imaging and analysis of live or fixed cells and tissues, with technical assistance provided by Dr. Greg Plummer.

46


Facilities and Collaborations

Collaborations

Alberta Diabetes Institute

Working Together Under One Roof Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD) – ACHORD is internationally recognized for its work in diabetes epidemiology, health and economic policy, and health outcomes research. Led by Dr Jeff Johnson, this multidisciplinary research consortium conducts population health research that transects government and academia, and focuses on how health delivery and standard of care practices impact quality of life of diabetes patients. Canadian Obesity Network (CON) – Canada’s largest obesity association, made up of healthcare professionals, researchers, policy makers and people with an interest in obesity. Dr Arya Sharma, is the founder and Scientific Director of the CON, a network that now

47

boasts over 10,000 obesity researchers, health professionals and other stakeholders. Alberta Cell Therapy Manufacturing (ACTM) – Led by Director Dr Greg Korbutt and Manager Gayle Piat, ACTM is Western Canada’s only Good Manufacturing Practice (GMP) compliant cell therapy production facility, housing amenities and expertise to translate cell-based therapies from bench to bedside. Meeting strict quality assurance and international regulatory requirements, ACTM offers services in both preclinical and clinical areas of product development. Designed with six segregated clean rooms that allow simultaneous production of six different products, their team can provide both training and assistance with GMP protocols.

48


Facilities and Collaborations

Collaborations

Alberta Diabetes Institute

Working Together Under One Roof Alliance for Canadian Health Outcomes Research in Diabetes (ACHORD) – ACHORD is internationally recognized for its work in diabetes epidemiology, health and economic policy, and health outcomes research. Led by Dr Jeff Johnson, this multidisciplinary research consortium conducts population health research that transects government and academia, and focuses on how health delivery and standard of care practices impact quality of life of diabetes patients. Canadian Obesity Network (CON) – Canada’s largest obesity association, made up of healthcare professionals, researchers, policy makers and people with an interest in obesity. Dr Arya Sharma, is the founder and Scientific Director of the CON, a network that now

47

boasts over 10,000 obesity researchers, health professionals and other stakeholders. Alberta Cell Therapy Manufacturing (ACTM) – Led by Director Dr Greg Korbutt and Manager Gayle Piat, ACTM is Western Canada’s only Good Manufacturing Practice (GMP) compliant cell therapy production facility, housing amenities and expertise to translate cell-based therapies from bench to bedside. Meeting strict quality assurance and international regulatory requirements, ACTM offers services in both preclinical and clinical areas of product development. Designed with six segregated clean rooms that allow simultaneous production of six different products, their team can provide both training and assistance with GMP protocols.

48


Clinical Research Clinical Research Unit (CRU) – Supervised by Dr Vince Rogers, the Clinical Research Unit allows investigators to conduct regulatory-driven clinical trials in support of innovative therapies and translation of these towards patient use. The CRU supports phase II-IV research and is connected to the University of Alberta Hospital for patient/physician access and biosample transport. The facility also houses body composition and metabolic assessment (below) for truly holistic diabetes clinical studies.

Norm Boulé Director of Physical Activity Diabetes Lab looks to better understand varying glycemic responses to exercise

Human Nutrition Research Unit (HNRU) – Integrated within the Clinical Research Unit, the HNRU supports nutritional and metabolic clinical research for a variety of adult and child health-related concerns including diabetes, cancer, cardiovascular diseases and obesity. Director Dr Carla Prado oversees this unit and specialized equipment and amenities such as dual x-ray absorptiomtry, air

displacement plethysmography, a fullyequipped research kitchen and a whole body calorimetry unit. Physical Activity Diabetes Laboratory (PADL)– Director Dr Norm Boulé is part of a team of exercise physiologists that includes Drs Margie Davenport, Craig Steinback and Jane Yardley. Davenport and Steinback are investigating the impact of pre and postnatal physical (in)activity on women at high risk for developing type 2 diabetes on maternal/ fetal health outcomes including metabolic status and cardiovascular function. Boulé and Yardley collaborate on several projects related to type 1 and type 2 diabetes, including the E-PAraDiGM (Exercise-Physical Activity Diabetes Glucose Monitoring) protocol, a multi-site study combines a standardized exercise protocol and continuous glucose monitoring for a better understanding of glycemic responses to exercise.

50


Clinical Research Clinical Research Unit (CRU) – Supervised by Dr Vince Rogers, the Clinical Research Unit allows investigators to conduct regulatory-driven clinical trials in support of innovative therapies and translation of these towards patient use. The CRU supports phase II-IV research and is connected to the University of Alberta Hospital for patient/physician access and biosample transport. The facility also houses body composition and metabolic assessment (below) for truly holistic diabetes clinical studies.

Norm Boulé Director of Physical Activity Diabetes Lab looks to better understand varying glycemic responses to exercise

Human Nutrition Research Unit (HNRU) – Integrated within the Clinical Research Unit, the HNRU supports nutritional and metabolic clinical research for a variety of adult and child health-related concerns including diabetes, cancer, cardiovascular diseases and obesity. Director Dr Carla Prado oversees this unit and specialized equipment and amenities such as dual x-ray absorptiomtry, air

displacement plethysmography, a fullyequipped research kitchen and a whole body calorimetry unit. Physical Activity Diabetes Laboratory (PADL)– Director Dr Norm Boulé is part of a team of exercise physiologists that includes Drs Margie Davenport, Craig Steinback and Jane Yardley. Davenport and Steinback are investigating the impact of pre and postnatal physical (in)activity on women at high risk for developing type 2 diabetes on maternal/ fetal health outcomes including metabolic status and cardiovascular function. Boulé and Yardley collaborate on several projects related to type 1 and type 2 diabetes, including the E-PAraDiGM (Exercise-Physical Activity Diabetes Glucose Monitoring) protocol, a multi-site study combines a standardized exercise protocol and continuous glucose monitoring for a better understanding of glycemic responses to exercise.

50


Members Retreat Opportunity for members to connect and discuss ADI strategy and key areas of diabetes research

Institute Membership Faculty of Agricultural, Life and Environmental Sciences Rhonda Bell, Jean Buteau, Cathy Chan, Tom Clandinin, Catherine Field, René Jacobs, Diana Mager, Vera Mazurak, Carla Prado, Spencer Proctor, Donna Vine, Jens Walter, Noreen Willows

Faculty of Medicine and Dentistry Babita Agrawal, Colin Anderson, Geoff Ball, Chris Bleackley, Denise Campbell-Scherer, Chris Cheeseman, Jason Dyck, John Elliott, Maria Febbraio, Rose Girgis, Andrea Haqq, Kailish Jindal, Greg Korbutt, Harley Kurata, Richard Lehner, Peter Light, Gary Lopaschuk, Patrick MacDonald, Sumit Majumdar, Finlay McAlister, Gavin Oudit, Raj Padwal, Ray Rajotte, Gina Rayat, Elizabeth Rosolowsky, Edmond Ryan, Yves Sauvé, Peter Senior, James Shapiro, Arya Sharma, Gita Sharma, Matthew Tennant, Ellen Toth, Amy Tse, Dennis Vance, Lori West, Rachel Wevrick, Roseanne Yeung, Jessica Yue, Douglas Zochodne

Faculty of Pharmacy and Pharmaceutical Sciences Scot Simpson, John Ussher

Faculty of Physical Education and Recreation Normand Boulé, Margie Davenport, Wendy Rodgers, Jane Yardley

School of Public Health Tim Caulfield, Dean Eurich, Jeff Johnson

Outside the University of Alberta

Member list - September 2016

Mark Ungrin—University of Calgary, Steven Johnson—Athabasca University

51

52


Members Retreat Opportunity for members to connect and discuss ADI strategy and key areas of diabetes research

Institute Membership Faculty of Agricultural, Life and Environmental Sciences Rhonda Bell, Jean Buteau, Cathy Chan, Tom Clandinin, Catherine Field, René Jacobs, Diana Mager, Vera Mazurak, Carla Prado, Spencer Proctor, Donna Vine, Jens Walter, Noreen Willows

Faculty of Medicine and Dentistry Babita Agrawal, Colin Anderson, Geoff Ball, Chris Bleackley, Denise Campbell-Scherer, Chris Cheeseman, Jason Dyck, John Elliott, Maria Febbraio, Rose Girgis, Andrea Haqq, Kailish Jindal, Greg Korbutt, Harley Kurata, Richard Lehner, Peter Light, Gary Lopaschuk, Patrick MacDonald, Sumit Majumdar, Finlay McAlister, Gavin Oudit, Raj Padwal, Ray Rajotte, Gina Rayat, Elizabeth Rosolowsky, Edmond Ryan, Yves Sauvé, Peter Senior, James Shapiro, Arya Sharma, Gita Sharma, Matthew Tennant, Ellen Toth, Amy Tse, Dennis Vance, Lori West, Rachel Wevrick, Roseanne Yeung, Jessica Yue, Douglas Zochodne

Faculty of Pharmacy and Pharmaceutical Sciences Scot Simpson, John Ussher

Faculty of Physical Education and Recreation Normand Boulé, Margie Davenport, Wendy Rodgers, Jane Yardley

School of Public Health Tim Caulfield, Dean Eurich, Jeff Johnson

Outside the University of Alberta

Member list - September 2016

Mark Ungrin—University of Calgary, Steven Johnson—Athabasca University

51

52


Trainee Opportunities Optimal Learning Environment Clinical research at the Alberta Diabetes Institute provides numerous undergraduates, graduates and post-doctoral fellows with the opportunity to participate in human based studies—part of an intentional strategy to better link discovery scientists with clinical research. Alberta Cell Therapy Manufacturing (ACTM) will further expand the trainees’ experience to manufacturing cell-based therapies in ultra-clean environments. The ADI provides an optimal training environment for undergraduate and graduate students as well as post-doctoral fellows supervised by ADI members. Financial support is provided by the Institute through various bursaries and awards, including summer studentships. The total number of trainees whose primary supervisor was an ADI member rose from 174 in 2014 to 187 in 2015.

53

Publications Transplantation PLoS One Nature Publications Lancet Journal of Nutrition JAMA International Journal of Obesity Diabetologia Diabetes, Obesity and Metabolism Diabetes Care Diabetes British Journal of Nutrition BMJ American Journal of Transplantation

2014

2015

370 publications in 2015 with median 5 / member

0

2

4

6

34% of publications

have international collaborations

8

10

12

14

16 total of patents

/ disclosures 2014–15 combined

54


Trainee Opportunities Optimal Learning Environment Clinical research at the Alberta Diabetes Institute provides numerous undergraduates, graduates and post-doctoral fellows with the opportunity to participate in human based studies—part of an intentional strategy to better link discovery scientists with clinical research. Alberta Cell Therapy Manufacturing (ACTM) will further expand the trainees’ experience to manufacturing cell-based therapies in ultra-clean environments. The ADI provides an optimal training environment for undergraduate and graduate students as well as post-doctoral fellows supervised by ADI members. Financial support is provided by the Institute through various bursaries and awards, including summer studentships. The total number of trainees whose primary supervisor was an ADI member rose from 174 in 2014 to 187 in 2015.

53

Publications Transplantation PLoS One Nature Publications Lancet Journal of Nutrition JAMA International Journal of Obesity Diabetologia Diabetes, Obesity and Metabolism Diabetes Care Diabetes British Journal of Nutrition BMJ American Journal of Transplantation

2014

2015

370 publications in 2015 with median 5 / member

0

2

4

6

34% of publications

have international collaborations

8

10

12

14

16 total of patents

/ disclosures 2014–15 combined

54


Operating Grants

2015 Operating Grants

Grant Value – The total value of grants held by the Alberta Diabetes Institute members is over $100M for operations alone. Amounts for 2014–15 are shown in the following charts:

2014 Operating Grants OPERATING

INFRASTRUCTURE

Federal

$ 8,924,304

$ 1,952,922

Provincial

$ 5,718,970

$ 1,580,952

Foundation

$ 2,551,626

$

87,500

University

$ 459,296

$

Industry

$ 376,530

87,500 -

Other

$

-

TOTAL

$ 18,063,436

Median

$ 161,032

for all members

55

32,710

$ 3,708,874

OPERATING

INFRASTRUCTURE

Federal

$ 9,477,445

$ 2,478,106

Provincial

$ 5,500,807

$ 1,781,283

Foundation

$ 2,862,394

$

87,500

University

$ 648,457

$

Industry

$ 457,198

87,500 -

Other

$

-

TOTAL

$ 19,048,801

Median

$ 186,271

for all members

102,500

$ 4,434,389

Population Health $6,461,347

Clinical $3,281,878

Total value of operating grants held by research pillar in 2015

$19,048,801 Nonclinical $9,305,576

56


Operating Grants

2015 Operating Grants

Grant Value – The total value of grants held by the Alberta Diabetes Institute members is over $100M for operations alone. Amounts for 2014–15 are shown in the following charts:

2014 Operating Grants OPERATING

INFRASTRUCTURE

Federal

$ 8,924,304

$ 1,952,922

Provincial

$ 5,718,970

$ 1,580,952

Foundation

$ 2,551,626

$

87,500

University

$ 459,296

$

Industry

$ 376,530

87,500 -

Other

$

-

TOTAL

$ 18,063,436

Median

$ 161,032

for all members

55

32,710

$ 3,708,874

OPERATING

INFRASTRUCTURE

Federal

$ 9,477,445

$ 2,478,106

Provincial

$ 5,500,807

$ 1,781,283

Foundation

$ 2,862,394

$

87,500

University

$ 648,457

$

Industry

$ 457,198

87,500 -

Other

$

-

TOTAL

$ 19,048,801

Median

$ 186,271

for all members

102,500

$ 4,434,389

Population Health $6,461,347

Clinical $3,281,878

Total value of operating grants held by research pillar in 2015

$19,048,801 Nonclinical $9,305,576

56


Alberta Advanced Education and Technology Alberta Diabetes Foundation Alberta Heritage Foundation for Medical Research (AHFMR) Alberta Innovates AIHS/Pfizer Industry Partnered Translational Fund Alberta Livestock and Meat Agency Alberta Canola Producers Alberta Crop Industry Development Fund Alberta Health Alberta Livestock and Individual grantors for Meat Agency Alberta Transplant Institute Allard Family member-held grants Blanch Family Boehringer Ingelheim Canada Canada Research Chairs Program Canadian Dermatology Foundation Canadian Foundation for Dietetic Practice and Research Canadian Society of Transplantation Capital Health Research Chair in Cardiac Outcomes Canadian Diabetes Association Major Science Initiatives Fund/Canadian Foundation for Innovation CIHR (Canadian Institutes of Health Research) COM DEV Dairy Farmers of Canada of Canada Danone Institute of Canada DRIFCan Edmonton Civic Employees Charitable Assistance Fund Eidem Family Eli Lilly Foundation for Prader-Willi Research GTx, Inc Government of Alberta Heart and Stroke Foundation of Canada International Life Sciences Institute - North America Ivari JDRF Kidney Foundation of Canada Johnson & Johnson Lawson Foundation Mazankowski Alberta Heart Institute - University Hospital Foundation Merck Morgan-Wegmann Immunology Research Fund Mount Sinai Hospital Foundation Novo Nordisk Natural Sciences and Engineering Research Pfizer Public Health Agency of Canada Queen Elizabeth II Graduate Scholarship Recombinetics, Inc Royal Saudi Embassy Sernova Corp Simons Foundation Autism Research Initiative Sports Science Association of Alberta Stem Cell Network University of Alberta University Hospital Foundation University of Calgary - Eyes High Postdoctoral Scholarship University of Calgary - Office of the President Faculty Grant University of Calgary Startup Funds Wirtanen Family Women and Children’s Health Research Institute World University Network

Thank you for supporting diabetes research

57

58


Alberta Advanced Education and Technology Alberta Diabetes Foundation Alberta Heritage Foundation for Medical Research (AHFMR) Alberta Innovates AIHS/Pfizer Industry Partnered Translational Fund Alberta Livestock and Meat Agency Alberta Canola Producers Alberta Crop Industry Development Fund Alberta Health Alberta Livestock and Individual grantors for Meat Agency Alberta Transplant Institute Allard Family member-held grants Blanch Family Boehringer Ingelheim Canada Canada Research Chairs Program Canadian Dermatology Foundation Canadian Foundation for Dietetic Practice and Research Canadian Society of Transplantation Capital Health Research Chair in Cardiac Outcomes Canadian Diabetes Association Major Science Initiatives Fund/Canadian Foundation for Innovation CIHR (Canadian Institutes of Health Research) COM DEV Dairy Farmers of Canada of Canada Danone Institute of Canada DRIFCan Edmonton Civic Employees Charitable Assistance Fund Eidem Family Eli Lilly Foundation for Prader-Willi Research GTx, Inc Government of Alberta Heart and Stroke Foundation of Canada International Life Sciences Institute - North America Ivari JDRF Kidney Foundation of Canada Johnson & Johnson Lawson Foundation Mazankowski Alberta Heart Institute - University Hospital Foundation Merck Morgan-Wegmann Immunology Research Fund Mount Sinai Hospital Foundation Novo Nordisk Natural Sciences and Engineering Research Pfizer Public Health Agency of Canada Queen Elizabeth II Graduate Scholarship Recombinetics, Inc Royal Saudi Embassy Sernova Corp Simons Foundation Autism Research Initiative Sports Science Association of Alberta Stem Cell Network University of Alberta University Hospital Foundation University of Calgary - Eyes High Postdoctoral Scholarship University of Calgary - Office of the President Faculty Grant University of Calgary Startup Funds Wirtanen Family Women and Children’s Health Research Institute World University Network

Thank you for supporting diabetes research

57

58


Alberta Diabetes Foundation Our Foundation Partner Supporting Life Changing Diabetes Research in Alberta The Alberta Diabetes Foundation works in tandem with the Alberta Diabetes Institute to allocate funding where and when it is needed most, ensuring that important diabetes research and projects do not become stalled. The Foundation funds projects from early stage to near commercialization, often filling in gaps left by traditional granting organizations. Through signature events such as the Hummingbird Gala,

Halloween Howl and Jeans and Jersey as well as third-party events including Rock’n August — the Alberta Diabetes Foundation is part of the Alberta community focused on a global goal overcoming diabetes and improving the lives of people with diabetes. The researchers in Alberta are confident that a world without diabetes is possible, and today they are doing more than providing sustainable solutions to managing diabetes – our researchers are on their way to a cure.

2014

2015

CLINICAL RESEARCH UNIT & ISLETCORE

$180,000

$180,000

PILOT PROJECTS

$150,000

$120,000

STUDENTSHIPS

$116,636

$115,100

SCIENTIFIC RECRUITMENT

$300,000

(GRADUATE & SUMMER STUDENTS)

TRANSLATIONAL RESEARCH

$48,928

POSTDOCTORAL FELLOW

$25,000

CONFERENCES

$11,000

ANNUAL TOTAL $757,636

59

$12,500

$501,528

60


Alberta Diabetes Foundation Our Foundation Partner Supporting Life Changing Diabetes Research in Alberta The Alberta Diabetes Foundation works in tandem with the Alberta Diabetes Institute to allocate funding where and when it is needed most, ensuring that important diabetes research and projects do not become stalled. The Foundation funds projects from early stage to near commercialization, often filling in gaps left by traditional granting organizations. Through signature events such as the Hummingbird Gala,

Halloween Howl and Jeans and Jersey as well as third-party events including Rock’n August — the Alberta Diabetes Foundation is part of the Alberta community focused on a global goal overcoming diabetes and improving the lives of people with diabetes. The researchers in Alberta are confident that a world without diabetes is possible, and today they are doing more than providing sustainable solutions to managing diabetes – our researchers are on their way to a cure.

2014

2015

CLINICAL RESEARCH UNIT & ISLETCORE

$180,000

$180,000

PILOT PROJECTS

$150,000

$120,000

STUDENTSHIPS

$116,636

$115,100

SCIENTIFIC RECRUITMENT

$300,000

(GRADUATE & SUMMER STUDENTS)

TRANSLATIONAL RESEARCH

$48,928

POSTDOCTORAL FELLOW

$25,000

CONFERENCES

$11,000

ANNUAL TOTAL $757,636

59

$12,500

$501,528

60


Donors and Awards Individual and Corporate Funding Thanks to funding directly from families and other groups, along with other funding support, the Alberta Diabetes Institute was able to provide over 65 awards throughout 2014–2015 totaling well over $1,000,000. Funding is continuously being awarded including the 2016 Porylo Diabetes/Cancer ADI Pilot Project grant competition aimed at studying links between diabetes and cancer. Thank you to all of our donors for supporting diabetes research and striving towards a cure. Without the support of donations from the community, important research would simply not happen.

Blanch Graduate Award

In support of students at the graduate level and post doctoral trainees researching diabetes

Edmonton Civic Employees Charitable Assistance Fund

Pilot Project annual grant supporting islet transplantation aimed at finding a cure for Type 1 diabetes

61

Gladys Woodrow Wirtanen Studentships

An annual graduate student award for studying/researching Type 1 diabetes funded by Morley and Val Blanch

University Hospital Foundation / C.F. “Curly” and Gladys B. MacLachlan Fund / Paddy and Ken Webb Family Fund

Alberta Diabetes Institute : Johnson & Johnson Diabetes Research Fund Partnership with Johnson & Johnson, Alberta Diabetes Foundation and Government of Alberta

Muttart Diabetes Research and Training Centre

Ivari Supporting islet signaling & biology research

ADI Graduate Studentship and 2015 Capacity Building

Funds specifically used to support pilot projects research in islet transplantation

Dr. Charles A. Allard Chair in Diabetes Research

Rod Eidem Research Fund Donation with a focus on innovation and cross disciplinary research

Held by the Scientific Director of the Alberta Diabetes Institute

62


Donors and Awards Individual and Corporate Funding Thanks to funding directly from families and other groups, along with other funding support, the Alberta Diabetes Institute was able to provide over 65 awards throughout 2014–2015 totaling well over $1,000,000. Funding is continuously being awarded including the 2016 Porylo Diabetes/Cancer ADI Pilot Project grant competition aimed at studying links between diabetes and cancer. Thank you to all of our donors for supporting diabetes research and striving towards a cure. Without the support of donations from the community, important research would simply not happen.

Blanch Graduate Award

In support of students at the graduate level and post doctoral trainees researching diabetes

Edmonton Civic Employees Charitable Assistance Fund

Pilot Project annual grant supporting islet transplantation aimed at finding a cure for Type 1 diabetes

61

Gladys Woodrow Wirtanen Studentships

An annual graduate student award for studying/researching Type 1 diabetes funded by Morley and Val Blanch

University Hospital Foundation / C.F. “Curly” and Gladys B. MacLachlan Fund / Paddy and Ken Webb Family Fund

Alberta Diabetes Institute : Johnson & Johnson Diabetes Research Fund Partnership with Johnson & Johnson, Alberta Diabetes Foundation and Government of Alberta

Muttart Diabetes Research and Training Centre

Ivari Supporting islet signaling & biology research

ADI Graduate Studentship and 2015 Capacity Building

Funds specifically used to support pilot projects research in islet transplantation

Dr. Charles A. Allard Chair in Diabetes Research

Rod Eidem Research Fund Donation with a focus on innovation and cross disciplinary research

Held by the Scientific Director of the Alberta Diabetes Institute

62


Supporting Events

STUDENT AWARD WINNER 2015 Full Oral Presentation Jonathan Gotzman (Sauve Lab) Mini Oral Presentation John Wink (Shapiro Lab)

ADI Research Day

Senior Poster (Postdocs, Research Assoc, Techs) Shereen Hamza (Dyck Lab)

ADI’s Annual Research Day providing trainees the opportunity to present their ongoing research in either speaker symposiums or poster sessions. Research Day is a popular event that showcases the talent, scope and collaboration of the ADI members and trainees and the immense impact research is making in diabetes. The ADI graciously acknowledges Eli Lilly Canada and Merck Canada for their sponsorship of ADI’s Annual Research Day in 2014 and 2015.

STUDENT AWARD WINNER 2014 Full Oral Presentation Julie Hayward (Korbutt Lab) Mini Oral Presentation Amanda Wang (Shapiro Lab)

Keynote Speaker 2014

Keynote Speaker 2015

Timothy J Kieffer Head of the Diabetes Research Group University of Britsh Columbia

Daniel J Drucker Professor of Medicine, University of Toronto Senior Investigator, Lunenfeld-Tanenbaum Research Institute, Toronto

Title of Talk: Cell Based Therapies for Diabetes

63

Senior Poster (PhD) Antonio Bruni (Shapiro Lab) - Group 1 Julie Hayward (Krobutt Lab) - Group 2

Title of Talk: Incretin-based therapies —mechanisms, complexity and controversy

Junior Poster Yumna ZIA (Jacob Lab) - MSc Students Zosia Czarnecka (Light Lab) - Summer Students Trainee Coice Award Katarina Ondrusova (Light Lab)

Senior Poster (Postdocs, Research Assoc, Techs) Andrew Pepper (Shapiro Lab) Senior Poster (PhD) Anne-Francoise Close (Buteau Lab) Junior Poster Shara Khan (MacDonald Lab) Trainee Coice Award Erin Lewis (Field Lab)

Merck & Eli Lilly Canada Thank you for the support for ADI Research Day and Research in Progress Speaker Series seminars

64


Supporting Events

STUDENT AWARD WINNER 2015 Full Oral Presentation Jonathan Gotzman (Sauve Lab) Mini Oral Presentation John Wink (Shapiro Lab)

ADI Research Day

Senior Poster (Postdocs, Research Assoc, Techs) Shereen Hamza (Dyck Lab)

ADI’s Annual Research Day providing trainees the opportunity to present their ongoing research in either speaker symposiums or poster sessions. Research Day is a popular event that showcases the talent, scope and collaboration of the ADI members and trainees and the immense impact research is making in diabetes. The ADI graciously acknowledges Eli Lilly Canada and Merck Canada for their sponsorship of ADI’s Annual Research Day in 2014 and 2015.

STUDENT AWARD WINNER 2014 Full Oral Presentation Julie Hayward (Korbutt Lab) Mini Oral Presentation Amanda Wang (Shapiro Lab)

Keynote Speaker 2014

Keynote Speaker 2015

Timothy J Kieffer Head of the Diabetes Research Group University of Britsh Columbia

Daniel J Drucker Professor of Medicine, University of Toronto Senior Investigator, Lunenfeld-Tanenbaum Research Institute, Toronto

Title of Talk: Cell Based Therapies for Diabetes

63

Senior Poster (PhD) Antonio Bruni (Shapiro Lab) - Group 1 Julie Hayward (Krobutt Lab) - Group 2

Title of Talk: Incretin-based therapies —mechanisms, complexity and controversy

Junior Poster Yumna ZIA (Jacob Lab) - MSc Students Zosia Czarnecka (Light Lab) - Summer Students Trainee Coice Award Katarina Ondrusova (Light Lab)

Senior Poster (Postdocs, Research Assoc, Techs) Andrew Pepper (Shapiro Lab) Senior Poster (PhD) Anne-Francoise Close (Buteau Lab) Junior Poster Shara Khan (MacDonald Lab) Trainee Coice Award Erin Lewis (Field Lab)

Merck & Eli Lilly Canada Thank you for the support for ADI Research Day and Research in Progress Speaker Series seminars

64


title

World Diabetes Day Hula Hoops Around Diabetes

of

A-BC Islet Workshop The goal bringing together investigators and trainees from across western Canada to share their newest research on pancreatic islet biology and diabetes is to build new relationships and collaborations between Alberta and British Columbia islet researchers through scientific and social interactions and hitting the ski slopes. Topics include stem cells and regeneration, cell biology and signalling, transplantation, biomaterials and more. The itinerary consisting of presentations from principal investigators and student throughout the morning sessions forllowed by an afternoon on the ski hill and evening keynote speakers. In 2014 keynotes included Dr Vincent Poitout, Université de Montréal – GPR40 as a new target for type 2 diabetes...or not? and Jake Kushner, Baylor College of Medicine – Cell Based Therapies for Diabetes. Keynote speakers for 2015 were Alan Attie, University of Wisconsin – Insights into Type 2 Diabetes from Mouse Genetics and Dr. Marc Prentki, Université de Montréal – Visiting metabolic cycling, ß-cell and adipose function, and revisiting diabetes dogmas.

65

UAlberta Diabetes Awareness Week In 2015 the Alberta Diabetes Institute invited the University of Alberta campus to Get in the Loop and participate in a variety of events to raise diabetes awareness in support of World Diabetes Day. Events included Walk Away from Diabetes at UWALK.ca with a total of 9,628,338 steps shared for the campaign; Get in the Loop featuring tables in the Student Unions' Building showcasing the vast support groups and opportunities the university offers in support of healthy lifestyles and health education; and finally, Hula Hoops around Diabetes, engaging participants in physical activity using hula hoops to signify the international diabetes symbol and sharing photos and videos on social media.

66


title

World Diabetes Day Hula Hoops Around Diabetes

of

A-BC Islet Workshop The goal bringing together investigators and trainees from across western Canada to share their newest research on pancreatic islet biology and diabetes is to build new relationships and collaborations between Alberta and British Columbia islet researchers through scientific and social interactions and hitting the ski slopes. Topics include stem cells and regeneration, cell biology and signalling, transplantation, biomaterials and more. The itinerary consisting of presentations from principal investigators and student throughout the morning sessions forllowed by an afternoon on the ski hill and evening keynote speakers. In 2014 keynotes included Dr Vincent Poitout, Université de Montréal – GPR40 as a new target for type 2 diabetes...or not? and Jake Kushner, Baylor College of Medicine – Cell Based Therapies for Diabetes. Keynote speakers for 2015 were Alan Attie, University of Wisconsin – Insights into Type 2 Diabetes from Mouse Genetics and Dr. Marc Prentki, Université de Montréal – Visiting metabolic cycling, ß-cell and adipose function, and revisiting diabetes dogmas.

65

UAlberta Diabetes Awareness Week In 2015 the Alberta Diabetes Institute invited the University of Alberta campus to Get in the Loop and participate in a variety of events to raise diabetes awareness in support of World Diabetes Day. Events included Walk Away from Diabetes at UWALK.ca with a total of 9,628,338 steps shared for the campaign; Get in the Loop featuring tables in the Student Unions' Building showcasing the vast support groups and opportunities the university offers in support of healthy lifestyles and health education; and finally, Hula Hoops around Diabetes, engaging participants in physical activity using hula hoops to signify the international diabetes symbol and sharing photos and videos on social media.

66


Timeline of diabetes research Building upon a legacy of world-leading diabetes research at the University of Alberta

Our ultimate goal is to improve the lives of people living with diabetes and to find the cure

67


Timeline of diabetes research Building upon a legacy of world-leading diabetes research at the University of Alberta

Our ultimate goal is to improve the lives of people living with diabetes and to find the cure

67


Alberta Diabetes Institute University of Alberta Li Ka Shing Centre for Health Research Innovation Edmonton, Alberta, Canada (1) 780.492.4660 AlbertaDiabetes@ualberta.ca www.adi.ualberta.ca @AlbertaDiabetes

Alberta Diabetes Institute - Building Upon a Legacy  
Alberta Diabetes Institute - Building Upon a Legacy  

An overview of diabetes research and the facilities at the Alberta Diabetes Institute, including biennial reporting for 2015/16.

Advertisement