Top Research Highlights JDRF Research Department in Action
Scientists Identify Key Differences in the Microbiome of People with Type 1 Diabetes
In June, JDRF played a prominent role at two of the world’s largest research conferences. The American Diabetes Association held its 71st Scientific Sessions in San Diego, CA, this year, where JDRF’s senior research scientists actively participated in several symposia, and the organization featured a booth at the exhibit hall for the second year in a row. With more than 14,000 professional attendees and more than 17,500 in total attendance, the conference program focused on research and medical treatments for all types of diabetes—and JDRF-funded research was showcased throughout.
The human body shelters ten times more microbes than it contains human cells. Microbes, which are also referred to as microorganisms, include bacteria and fungi. Now, JDRFfunded scientists from the University of Florida are asking how the microbes in our bodies—collectively known as the microbiome—interact with the body and affect health. Using genetic tools to compare the microbiome of people with and without type 1 diabetes, researchers have found key differences in the composition and genetic makeup of the microbes living in the gut that could help explain the increased incidence of type 1 diabetes worldwide.
The following week brought the 2011 BIO International Convention in Washington, D.C., the largest global event for the biotechnology industry, where industry leaders and scientists come together to network and find opportunities to translate basic research into clinical devices and therapies. In an effort to highlight the urgency for continued research for better treatments and a cure for type 1 diabetes, BIO and JDRF co-hosted a two-day diabetes forum, the first forum that BIO has ever dedicated to a specific disease.
Microbes live in every nook and cranny of our bodies, but those that make their home in the gut are especially important in keeping us healthy. These microbes, particularly those that live in the small intestine, play a role in shaping the immune system early in life—and in type 1 diabetes, it is thought that this immune interaction with gut microbes may go awry at a very young age. In their work, researchers led by Eric W. Triplett, Ph.D., chair of the University of Florida’s microbiology and cell science department, found that the microbiomes of children with type 1 diabetes are less diverse—that is, there are fewer types of microbes—than those without the disease. They also found that the microbes produce more of a specific substance that allows them to stick to the intestinal walls of the gut, which could be involved in triggering the autoimmune response that occurs in type 1 diabetes.
Throughout both conferences, JDRF facilitated communications about the most recent advances in type 1 diabetes therapies and worked to strengthen collaborations between leading scientists, policymakers, and CEOs, pushing the boundaries of type 1 diabetes research and accelerating the pace at which new discoveries are made. JDRF’s goal of curing, treating, and preventing type 1 diabetes relies on scientists in multiple disciplines coming together to address the toughest issues from multiple angles, and JDRF is making sure that as a leader in type 1 diabetes research, it is in all the right places to make these collaborations possible.
“JDRF is focused on identifying and understanding the contribution of the intestinal microbiome to the development of type 1 diabetes, which may provide novel approaches for its prevention,” says Richard A. Insel, M.D., chief scientific officer at JDRF.
Following are some of the top research highlights from JDRFsupported research from these events.
To better understand how the differences in the microbiome may be causing the immune system to go awry, Dr. Triplett and his team looked at the genes of the major bacteria within the microbiome and their functions. They found that the 1
Top Research Highlights
bacteria in people with type 1 diabetes have significantly more genes that allow the bacteria to metabolize carbohydrates and respond to and survive under stressful conditions.
Now, Dr. Bresson and Matthias von Herrath, M.D., director of the Type 1 Diabetes Center at the La Jolla Institute, demonstrated that the oral insulin–anti-CD3 combination therapy, when administered early enough, may be most effective in mice whose immune systems specifically attack insulin-producing beta cells, one of the main targets in type 1 diabetes. “We previously showed that we need an antigenspecific therapy to boost the effects of a non-antigen-specific therapy,” says Dr. von Herrath. “Here, we show which mice best respond to this therapy—those whose immune systems turn against insulin.”
Ultimately, the work on the microbiome may lead to preventive therapies for children who are at risk for developing type 1 diabetes. The overarching goal of this work, says Dr. Triplett, is to identify children with unhealthy microbiomes well before autoimmunity starts to set in and reshape it, and to treat those children with beneficial bacteria that can protect them from ever developing the disease. Key Point: People with type 1 diabetes may have a different makeup of gut flora—the microbes that live in the human digestive tract—compared to that found in people without the disease. By studying the collection of genes within this microbiome and assessing their functions, researchers hope to understand if, and how, an altered microbiome contributes to autoimmunity and the onset of type 1 diabetes.
Along with predicting which people will benefit most from the combination treatment, the team also describes the mechanism behind its ability to be effective. It works by boosting the number of regulatory T cells, a component of the immune system that tames the autoimmune attack on insulin-producing beta cells. Because clinicians can measure these regulatory cells during treatment, this finding also gives the researchers a possible way to test whether the therapy is working.
Synergy between Two Drugs Proves Especially Beneficial for Population of Diabetic Mice
The team says that the findings may be a big step forward in helping to bring this therapy into the clinic. If the therapy works in people, researchers would be able to select participants who are most likely to respond to it, and then continue treatment only in those who are successfully responding to it. These tools will help cut the costs of clinical trials while increasing the benefit to patients.
Type 1 diabetes is a complicated disease, and not every therapy works for everybody. That’s why researchers are looking to tailor, or in a sense “personalize,” treatments for different people with the disease. Now, longtime JDRF-funded scientists from the La Jolla Institute for Allergy and Immunology, in collaboration with life sciences technology company Entelos, have done exactly that. They are taking a therapy they started to develop five years ago and identifying a population of diabetic mice that best responds to it. The findings, if translated to humans, would accelerate clinical trials and help identify people who are most likely to benefit from the therapy.
“We really believe that this combination therapy is ready to be tested in humans,” says Dr. Bresson, citing the long history both drugs have in clinical trials, and their well-established safety profiles. “We can envision the use of this approach for treating people who have been recently diagnosed with type 1 diabetes, as well as patients who have received transplants, where a sustained control of the autoimmune attack is required.”
The treatment is composed in part of an anti-CD3 drug, which is a drug that suppresses the immune system. This type of drug was first used to treat transplant rejection and now is being investigated for the treatment of autoimmune diseases such as type 1 diabetes. It has long been known that the drug, when given at low doses, benefits mice and humans, but its effects do not last long. Higher doses or repeated treatment may increase anti-CD3’s protective effects, but at the cost of compromising the immune system. Recently, a JDRF-funded project led by La Jolla Institute researcher Damien Bresson, Ph.D., showed in animal models that oral insulin, when combined with a low dose of anti-CD3, can significantly prolong the protection against the autoimmune attack associated with type 1 diabetes without drastic immune disturbances and unwanted side effects.
Key Point: Taking oral insulin in combination with low-dose anti-CD3 results in long-term reversal of type 1 diabetes in mice whose immune systems specifically attack insulin. The findings, if translated to humans, would help not only to identify people who are most likely to benefit from the therapy, but also to determine whether the therapy is working.
Top Research Highlights
Simple Warming Device Speeds Up the Delivery of Insulin into the Bloodstream
In their work, Dr. Cengiz and her team recruited 13 participants, ages 12 to 18 and each with an insulin pump, for two study visits: during one of the visits, the participants wore the InsuPatch device; during the other, they did not wear it. The data show that when the participants used the InsuPatch, not only was insulin delivered more quickly, but also there were higher peak concentrations sooner than what was seen when the participants did not use the device.
When people with type 1 diabetes eat, their blood sugar levels spike almost immediately. The hormone insulin, on the other hand, takes 90 to 120 minutes before it is absorbed into the bloodstream and starts lowering glucose levels, leaving a long window of “lag-time” during which glucose levels can remain dangerously high. JDRF-funded researchers at Yale University now show that a simple device that warms the site of the insulin injection, called the InsuPatch, speeds up delivery and results in faster-acting insulin.
Although the InsuPatch is currently designed for use with insulin pumps and future closed-loop artificial pancreas systems, another form of the patch will be designed for those who self-administer insulin injections, says Dr. Cengiz.
“This shorter period of time between infusion or injection and action means that people with type 1 diabetes will have less time during which their glucose and insulin levels are out of sync,” says Eda Cengiz, M.D., the principal investigator of the study. “That means tighter glucose control, and potentially fewer complications that result from the disease.”
“Our subjects are very excited about these results, and we were also happy to see tremendous interest in this study at the American Diabetes Association Scientific Sessions in June,” says Dr. Cengiz. “Eventually, we would like to see the InsuPatch fully integrated into an artificial pancreas so that we can have one integrated system working optimally to beat this disease. That would really mean the world to our patients.”
The InsuPatch, a product developed by InsuLine Medical, a company based in Israel, is designed to warm the skin and locally increase blood flow at the site where insulin is infused via an insulin pump. The increased blood flow, it is thought, ensures that insulin injected directly underneath the skin is quickly absorbed and delivered to the rest of the body.
Key Point: A simple insulin-infusion warming device, called the InsuPatch, accelerates insulin delivery into the bloodstream by as much as 35 minutes. Speeding up the delivery and action of insulin and reducing the amount of time patients spend in a hyperglycemic state potentially reduces the risk of complications that result from the disease.
JDRF Co-Hosts First Diabetes Forum at the 2011 BIO International Convention In an effort to raise awareness for type 1 diabetes, one of the most costly chronic diseases in the world, JDRF co-hosted a two-day diabetes forum at the 2011 BIO International Convention, the first forum that BIO—the largest global event for the biotechnology industry—has ever dedicated to a specific disease. JDRF’s senior research staff actively participated as moderators in the six sessions, where leading policymakers, scientists, CEOs, and newsmakers from all over the world showcased key opportunities and developments in type 1 and type 2 diabetes, including the latest research in innovative therapies, vaccines, and biomarkers. The forum also addressed the global burden of diabetes on the healthcare system, as well as novel financing approaches to support opportunities that originate in academic institutions. JDRF also took part in the BIO Business Forum. This event is a unique platform for biotechnology and pharmaceutical companies, academic research institutions, and investors from around the world to gather and discuss strategic opportunities and forge discussions on developing products and therapies that will ultimately benefit the lives of the millions of Americans living with diabetes. JDRF’s participation in the BIO convention was covered by C-SPAN’s Washington Journal, featuring Richard A. Insel, M.D., chief scientific officer at JDRF, and Scott Whitaker, chief operating officer of BIO International. A three-hour radio media tour was also arranged for Aaron J. Kowalski, Ph.D., assistant vice president for treatment therapies at JDRF, and Julia L. Greenstein, Ph.D., assistant vice president for cure therapies, to discuss the diabetes forum. 3