New Research On Islet Cells Has Important Implications for Both Diabetes Type 1 and Diabetes Type 2 Patients
BOSTON — April, 2002 — New research from scientists at Joslin Diabetes Center in Boston and their collaborators in New York, France and Tennessee reveals that a molecular pathway once thought to be critical in the early development of insulin producing islet b-cells may not play an important role in this function after all — but instead may be important in the ability of these cells to respond to glucose. This new insight may have important implications for scientists hoping to identify ways to stimulate the growth of insulin-producing b-cells to treat type 1 diabetes, as well as for scientists seeking to understand the multiple defects that result in type 2 diabetes.
This research is featured in the May issue of Nature Genetics, and appears online on the journal's website: http://www.nature.com/ng/.
Blood sugar levels are controlled by the hormone insulin, and this hormone is made in specialized cells of the body called islet b-cells. In diabetes — a disease that affects an estimated 17 million Americans and is a leading cause of blindness, heart disease, stroke, nerve damage, impotence, and limb disease leading to amputation — these islets are damaged or malfunction, leading to alterations in the ability of islet cells to release insulin.
Type 1 diabetes is caused when the body's insulin-producing b-cells are attacked and destroyed by a malfunctioning immune system. People with type 1 diabetes, which affects an estimated 500,000-1 million Americans, must take daily insulin injections to survive. Researchers have tried to identify ways to stimulate b-cells to re-grow, or to grow in culture so that they could be transplanted as a possible treatment for type 1 diabetes. Current attempts to transplant b-cells as a treatment for type 1 diabetes are stymied in part by the lack of adequate numbers of donor cadaver pancreases from which to get b-cells for transplant. Only about 3,000 pancreases become available each year, and cells from 2 pancreases are needed for each transplant.
Type 2 diabetes develops in individuals whose insulin-producing cells are still intact and functioning, but either they are not producing enough insulin to meet the body's needs, or the body's cells cannot react appropriately to the insulin being produced to use the insulin to convert food into energy. Scientists are increasingly concluding that type 2 diabetes is actually a group of diseases caused by multiple defects in the insulin-production, insulin-signaling, insulin-using system. Type 2 diabetes affects an estimated 16 million Americans.
Role of IGF-1 in Growth and Function of Insulin Producing Cells
The precise mechanisms that control the growth of insulin-producing b-cells are not fully understood. One of the factors that has been suggested to play an important role both in islet/b-cell development and growth is insulin-like-growth factor I (IGF-I). To directly define the function of IGF-I in b-cell growth, Rohit N. Kulkarni M.D., Ph.D., C. Ronald Kahn, M.D. and their colleagues used genetic engineering techniques to "knockout" the receptor for IGF-I on islet b-cells and examined the consequences on b-cell growth.
What the investigators discovered was that there was no defect in the ability of the b-cells to grow even in the absence of the receptors for this important growth factor, and in fact the "knockout" mice were born normally and survived into adulthood bearing a normal complement of insulin-producing cells.
Interestingly, however, the knockout mice showed unexpected defects in insulin secretion in response to glucose stimulation. This was due to a decrease in the level of two proteins that are important in glucose sensing by the b-cell, including the enzyme glucokinase and the specific glucose transporter of the b-cell, Glut2. Thus, the IGF-I signaling pathway is not critical in the development of the islet b-cells but is important in the regulation of glucose-stimulated insulin release from these cells.
Further studies will be required to examine whether other growth factors modulate b-cell growth and development.
Researchers at Joslin have also pinpointed several defects in the insulin signaling system that seem to contribute to type 2 diabetes. This latest research may shed light on where another of those defects resides.
Co-authors on the paper include Kulkarni, Kahn and Umut Ozcan from the Joslin Diabetes Center; Markus Stoffel, M.D., and David Shih from the Rockefeller University in New York; Mark Magnuson, M.D., from the Vanderbilt University, Tennessee, and Martin Holzenberger, Ph.D., from Inserm (the French National Medical Research Institutes) in France.
