Type 1 Diabetes
Diabetes mellitus is an expanding pandemic that contributes markedly to illness and death worldwide. Understanding the causes of this widespread disease and to develop new treatments are central goals of the Diabetes & Obesity Center of Excellence (DOCE).
Diabetes is broadly classified as Type 1 or Type 2 diabetes. Both types of diabetes are characterized by high blood glucose levels due to insufficient insulin, but the underlying causes of these disease variants differ. In Type 1 diabetes, autoimmune processes destroy the pancreatic beta cells that synthesize insulin, causing a nearly complete absence of this hormone and requiring patients to take daily insulin injections. In Type 2 diabetes, patients develop decreased sensitivity to insulin’s actions, and their beta cells eventually become unable to provide adequate insulin, requiring these patients to take daily insulin injections. Both forms of diabetes result in an increased risk for complications such as blindness, kidney failure, amputations, cardiovascular disease and death.
Because impaired function of beta cells in the pancreatic islets is the major factor mediating the progression of both types of diabetes, the investigators at DOCE focus on how to prevent beta-cell death and loss of function, and how to restore beta-cell function in patients with established diabetes.
Section of the pancreas from a mouse that does not have type 1 diabetes (left). The insulin-producing cells are located in the lighter pink islet of Langerhans in the center of the photograph. Diabetes develops when the the immune system attacks and destroys the insulin-producing cells. The photograph in the center shows beginning infiltration of immune cells and accumulation around the islet. As more immune cells attack the islet, the insulin-producing cells are destroyed (right). Images courtesy of the laboratory of Renee LeBoeuf, PhD.
While islet transplants enable patients with Type 1 diabetes to discontinue insulin injections for typically 1-5 years, this treatment is limited by inadequate availability of human islets, lack of assessment methods for the viability of isolated islets, and the side effects of immunosuppressant drugs.
All three of these limitations can potentially be overcome by differentiating stem cells into beta cells. Research pursued by Dr. Vincenzo Cirulli in collaboration with scientists at the Institute for Stem Cells and Regenerative Medicine, may one day allow production of an unlimited supply of insulin-secreting cells. Ideally, these cells would be generated from a patient’s own stem cells, thus circumventing the need for immunosuppressant drugs. In addition, Dr. Laura Crisa is studying ways to increase important blood supply to the transplanted stem cell allowing them to thrive, and Dr. William Osborne is working on a method to eliminate the use of immunosuppressant drugs by protecting the transplanted tissue immunologically. Dr. Ian Sweet, in collaboration with the City of Hope Islet Transplantation Program, has developed techniques to assess the viability of both isolated islets and stem cell derived insulin secreting cells. This capability is crucial to the success of cell based therapy of diabetes.
Another approach involves gene therapy technology explored by Dr. Osborne to enhance the function of transplanted beta cells. Dr. Osborne has developed techniques to induce cells to secrete a hormone with potent beneficial effects on beta cells, and transplantation of these cells may increase beta cell mass and function.
Interest in a possible treatment strategy for Type 2 diabetes stems from the finding that certain types of bariatric surgery result in very rapid and durable remission of Type 2 diabetes. Dr. David Cummings’ research goal is to understand how these procedures improve beta-cell function and/or insulin sensitivity. These findings may lead to the development of drugs that replicate the surgery’s effects without the need for an operation.
Prediction of diabetes is necessary to implement preventative therapies. Autoantibodies to beta cell proteins appear in circulation prior to the onset of the Type 1 diabetes, and are often used to predict diabetes onset. Recently, Dr. Christiane Hampe identified a novel marker that may precede the appearance of conventional autoantibodies and thus enable an earlier identification of individuals who will later progress to Type 1 diabetes.
To evaluate therapies designed to prevent beta-cell death, the beta-cell mass needs to be assessed. Current imaging technology is not suitable for this because of the small size of the islets of the pancreas. Drs. Sweet, Hampe and Steven Chessler (at the University of California, San Diego) are developing antibody fragments to identify beta cell specific proteins, which may enable the use of Positron Emission Tomography (PET) in the assessment of beta mass.
Basic Research on Beta Cell Function
Our approach to the development of diabetes treatments is strongly backed by an emphasis on basic research that aims to resolve questions about both normal function and pathophysiology of the pancreatic islet. These fundamental questions include how glucose stimulates insulin secretion by beta cells, the effect of hyperglycemia on inflammation and death of beta cells, and the mechanisms mediating the autoimmune destruction of these cells.
To better understand why the immune system destroys beta cells in Type 1 diabetes. Dr. Hampe studies anti-idiotypic antibodies in healthy individuals that are specifically absent in patients with Type 1 diabetes. Her research, in collaboration with Drs. Gerald Nepom and Jerry Palmer, investigates whether these molecules actively prevent the onset or progression of beta-cell destruction. Dr. Sweet, in collaboration with Drs. Nepom and Jane Buckner at the Benaroya Research Institute, is using imaging technology to identify differences in the calcium signaling of immune cells in patients with Type 1 diabetes.
The mechanisms underlying inadequate insulin secretion in patients with Type 2 diabetes may include impairment of beta-cell proteins that mediate glucose-stimulated insulin secretion. Calcium is the major intracellular signal regulating insulin secretion, and studies in Dr. Sweet’s laboratory focuses on factors that couple calcium’s actions to insulin release. These hypotheses are further tested using animal models of Type 2 diabetes in collaboration with Dr. Peter Havel at the University of California at Davis.
The problems to be solved to lessen the burden of diabetes worldwide are highly complex, and they demand multidisciplinary approaches. The wide range of expertise at the DOCE in areas such as metabolism, immunology, inflammation, molecular biology, stem cell biology, and islet function – as well as the shared technologies available through core services provided by the Diabetes Research Center (DRC) – allow our investigators to conduct state-of-the-art basic and clinical diabetes research, moving us closer to a cure.