The JDRF Diabetes Research portfolio of funded science is among the largest in the world focused on cures and treatments for diabetes and its complication. Exceeding $122 million last year and representing almost 500 projects, JDRF science revolves around a set of targeted areas of research. JDRF calls these areas Cure Therapeutics, because they are targeted at moving scientific discoveries in each discipline into products, drugs, and treatments for people with diabetes. What follows are some of the major findings and developments in JDRF-funded research over the last year.

Autoimmunity
Protein Switches Partners to Change Immune Function
A single protein can switch a key component of the immune system on or off depending on which molecule it teams with, JDRF-funded researchers have found. The protein, NFAT, pairs with other proteins to either spur immune cells into attack mode or direct them to stand down. The discovery sheds light on what is involved in keeping the immune system in check, paving the way for researchers to develop therapies for type 1 diabetes and other autoimmune afflictions such as arthritis and allergies. The finding was reported by Anjana Rao, Ph.D., and colleagues at the JDRF Center for Immunological Tolerance in Type 1 Diabetes at Harvard Medical School. Scientists at the University of Southern California, the University of Colorado, and the University of Washington were also involved in the research, which was published in the journal Cell. (July 2006)

Complications
Molecular Link Found Between High Blood Sugar and Retinopathy
Researchers at the JDRF International Center for Diabetic Complications Research in New York, led by Michael Brownlee, M.D., identified a molecular link connecting high blood sugar inside cells to the initiation of diabetic retinopathy. The finding, reported in the journal Cell, explains how methylglyoxal (MG), a glucose-derived molecule that is overproduced in cells damaged by high blood sugar, turns on a gene called angiopoietin-2, which plays a central role in the loss of small blood vessels in the retina. This suggests that drugs that suppress MG and related molecules in cells may help treat or prevent retinopathy. (January 2006)

Researchers Shed Light on Hypoglycemic Unawareness
JDRF-funded researchers have identified a potential mechanism that may shed light on why some people with diabetes lose the ability to recognize and correct hypoglycemia (low blood sugar). Gaining a better understanding of why this happens could lead to the development of treatments for this very serious complication, which can cause a loss of consciousness, and even death. In the study, Dr. Rory McCrimmon and colleagues at the JDRF Yale Center for the Study of Hypoglycemia found that when a protein in the brain, urocortin I, is produced at abnormally high levels, it may contribute to the inability to produce a normal response to lows. The researchers demonstrated in rats that a key glucose-sensing region of the brain loses sensitivity after being exposed to urocortin I. The discovery, reported in the Journal of Clinical Investigation, is an important step toward clinical strategies that will block urocortin I’s effect in the brain and allow diabetes patients to sense when blood sugar has dropped too low. (June 2006)

Regeneration
Insulin-Making Protein in Beta Cells
JDRF-funded researchers at the University of Massachusetts have identified a protein in beta cells that regulates the production of insulin. The finding suggests that a drug or therapy that increases the activity of this protein could enable people with diabetes to boost their own insulin production and better manage type 1 diabetes. The protein, IRE1, operates in beta cells within the endoplasmic reticulum (ER), a large, intracellular membrane folded over many times on itself. Most proteins are assembled inside the ER before being transported to other sites within the cell to perform specific tasks. IRE1 helps regulate the process by which the insulin protein is folded into final form so it can function properly. The finding was made by Fumihiko Urano, M.D., Ph.D., and colleagues at the University of Massachusetts Medical School and published in the journal Cell Metabolism. (September 2006)

Researchers Identify Protein that Spurs Beta Cell Growth
JDRF-funded researchers at Rockefeller University identified a protein that regulates cell growth in pancreatic islets. The discovery, in mice, represents a critical step in regeneration, whose aim is to stimulate beta cell growth and restore insulin secretion in people with type 1 diabetes. The protein, Tmem27, appears to have its stimulatory effects only in beta cells and not other cell types. This finding provides the opportunity for drug hunters to develop therapies that boost functional beta cell mass without causing harmful side-effects in other tissues. The research was led by Markus Stoffel, Ph.D., and was published in the journal Cell Metabolism. (December 2005)
JDRF Top Ten Research Highlights November 2006

Making Islets Bigger and Bolder
JDRF-funded researchers have developed a way to protect islets after a transplant so they survive longer and perform better, reducing the amount needed to restore blood sugar control. The new method could also eventually offer a way for newly diagnosed type 1 patients to retain some insulin-secreting function. The researchers used gene therapy to trigger the release of glucacon-like peptide 1 (GLP-1), a hormone in islets that strengthens beta cells and stimulates them to secrete insulin. The study, led by Timothy Kieffer, Ph.D., at the University of British Columbia, is reported in the Proceedings of the National Academy of Sciences. (September 2006)

Islet Replacement
Researchers Find Transplant Foe May Be Friend
JDRF-funded researchers at Harvard Medical School have made a surprising discovery about certain immune cells that could improve the outlook for islet replacement therapies. The scientists found that the cells, called Natural Killer (NK) cells, reduce the chance that transplanted tissue will be rejected. Knocking them out—as current immune-suppressing therapies do—may be a mistake. The researchers found that NK cells in the transplant recipient destroy cells in the implanted tissue that migrate to the recipient’s lymph nodes and stimulate a powerful immune response, resulting in rejection of the graft. The study was led by Xian Li, M.D., Ph.D., at Harvard Medical School and published in the Journal of Experimental Medicine. (August 2006)

Transplanted Pig Islets Reverse Diabetes in Monkeys
Researchers at two JDRF islet transplant centers were able to reverse diabetes in monkeys by transplanting islet cells from pigs, providing encouragement to people with type 1 diabetes that therapies with an expandable supply of healthy islets may become available. The milestone studies, conducted at the University of Minnesota and the Emory University School of Medicine in Atlanta, were reported in the journal Nature Medicine. They showed that a combination of immune-suppressing drugs allowed the transplanted pig islets to avoid rejection and survive for several months. (February 2006)

Insulin-Secreting Cells Produced from Unused Pancreatic Tissue
JDRF-funded researchers in San Diego have discovered that non-secreting tissue in the pancreas can be transformed into insulin-producing cells. The finding suggests a new approach to treating diabetes by coaxing primitive cells in the pancreatic tissue to behave like beta cells. If researchers can grow beta cells for use in humans, there could be an unlimited supply of islets for transplantation. The research, led by Fred Levine at the University of California, San Diego and the Burnham Institute, was reported in the journal Nature Medicine. (February 2006)

Metabolic Control
Grants Awarded in JDRF Artificial Pancreas Project
In September 2006, JDRF announced grants exceeding $5.5 million in the first year alone to fund research assessing new diabetes technologies to accelerate their availability for patients. The funding will support a multi-site clinical trial to compare health outcomes of people who use continuous glucose sensors with those who do not, to quantify the benefits of these devices. The funding also will support a multi-site research consortium that will work collaboratively to research potential algorithms for a closed-loop system that links continuous glucose sensors and insulin pumps to automatically dispense insulin to patients with type 1 diabetes. (September 2006)