The Joslin Diabetes Centre in Boston, have conducted a study that now proves conclusively that two receptors in the insulin-producing beta cell do not affect in the developmental growth, which was much against a long-held hypothesis in diabetes research. This finding would help scientists in their efforts to isolate the growth factors that do stimulate beta cell growth and to understand the defects in insulin production and the reduced secretion that cause diabetes.
These two receptors have always been a major focus of research on beta cell development. Scientists have always been seeking ways to promote the growth of these essential insulin-producing cells in diabetes patients. The past two studies conducted by Joslin, the insulin receptor, a protein that mediates the action of insulin, and the receptor for insulin-like growth factor I (IGF-I), a hormone, both of which were suggested as being critical for mediating islet/beta cell development and growth, were individually 'knocked out' in beta cells in genetically altered mice.
Rohit N. Kulkarni, M.D., Ph.D., Investigator at Joslin Diabetes Centre and Assistant Professor of Medicine at Harvard Medical School, who led the latest study and was lead author in the two previous Joslin studies explained that the researchers were surprised to discover that the beta cells developed and grew normally without these receptors. He explained that previously when they knocked out one receptor at a time, the remaining receptor had compensated for the other since both are so similar. But Dr. Kulkarni, stated that this time round when they knocked out both at the same time they still didn't find any defect in the developmental growth of beta cells. This he said made them conclude that there are growth factors and pathways independent of IGF-I and insulin that are necessary for the development of beta cells.
It is known that beta cell function, or lack of it, is critical in both type 1 and type 2 diabetes. Type 1 diabetes occurs when the beta cells in the pancreas are attacked by a malfunctioning immune system, while in type 2 diabetes, the beta cells function but do not produce enough insulin to meet the body's needs or do not respond appropriately to the insulin that is produced. The researchers were trying to investigae a hypothesis that type 1 diabetes may be caused by an underlying dysfunction in insulin/IGF-I signalling and increased vulnerability of beta cells to stress during the weaning period instead of the long viewed theory that it was an autoimmune disease. Their recent research suggested that type 2 diabetes includes a variety of diseases caused by multiple defects in the insulin-production, insulin-signalling and insulin-using system.
The older studies using traditional techniques did suggest that IGF-I affected beta cell growth. But on using more precise genetic engineering techniques, the Joslin studies have revealed that the absence of receptors for IGF-I or insulin don't affect development. But they do play a critical role in insulin secretion by regulating the glucose-stimulated insulin release from the beta cell. The study provides further evidence to explore the role of the insulin receptor in insulin secretion, which may lead to a greater understanding of why beta cells in type 2 diabetes cannot secrete insulin.
In the study, they found that the mice they had knocked out the receptors in were born with the same number of beta cells as the control group. At two weeks, however, they had an abnormally small mass of beta cells and developed diabetes at three weeks. They died at five to six weeks; the normal mouse lifespan is two years. Compared to the mice that had only one receptor knocked out, these mice developed more severe diabetes. Dr. Kulkarni explained that without the activation of proteins necessary for survival provided by the "knocked-out" receptors, the beta cells became susceptible to cell death as the mice aged.
Dr. Kulkarni's laboratory in the Section on Cellular and Molecular Physiology at Joslin is currently conducting experiments using mice that lack both receptors and exploring what growth factors are altered. He said that it would give them a clue about which growth factors are critical for development of beta cells in the absence of the two receptors.
He said that if they could understand how the beta cells grow, they hope they would be able to think of ways to promote growth that would ultimately aid in diabetes treatment. He explained that if the exact growth factor is identified, that could then be used to promote beta cell growth. He also stated that another treatment option would probably be to grow beta cells outside the body and transplanting them into patients with type 1 or type 2 diabetes.