A new Joslin Diabetes Center-led study has shown conclusively that a neuropeptide, melanin concentrating hormone (MCH), found in the brain and known for its role in increasing appetite in people, plays a role in the growth of insulin-producing beta cells and the secretion of insulin. This finding has the potential to spur the development of new treatments for diabetes that stimulate the production of insulin-producing beta cells in the pancreas. This latest research, conducted with researchers at Beth Israel Deaconess Medical Center in Boston and other institutions, will appear in the February 2007 issue of Diabetes.
An earlier Joslin-led study examined the connection between obesity and MCH, which plays a critical role in energy balance and appetite, observing an increase in the number of beta cells when MCH levels are high. This was a new finding that had not been observed before. Although MCH's role in appetite control is well known, its effects on the secretion of endocrine hormones has not been fully understood.
"It's a very logical connection," says Rohit N. Kulkarni, M.D., Ph.D., investigator at Joslin Diabetes Center and Assistant Professor of Medicine at Harvard Medical School, who led the study. "Whenever you eat food, your body needs more insulin. When MCH induces appetite, it simultaneously increases insulin secretion from beta cells and enhances growth of beta cells. If the proteins that mediate the growth mechanism can be identified, it could lead to the development of new drugs that would enhance beta cell growth to treat type 1 and type 2 diabetes."
In type 1 diabetes (insulin-dependent) diabetes, which accounts for 5 to 10 percent (between 700,000 and 1.4 million people) of diabetes cases in the United States, an autoimmune process has destroyed the insulin-producing islet cells in the pancreas. In type 2 diabetes, the far more common form of the disease, the body doesn't produce enough insulin and/or can't use insulin properly (insulin resistance). Both diseases could benefit from treatments that stimulate beta cells in the pancreas to produce insulin.
In the first study, in which mice were genetically engineered to over-express MCH, Dr. Kulkarni and his colleagues observed changes in beta cell mass out of proportion with the degree of obesity, suggesting that MCH had a direct effect on islets. To build on these previous findings, the researchers focused this study on gaining a deeper understanding of how MCH and its receptors influence growth of beta cells.
The investigators first confirmed that MCH and its receptors are indeed expressed in islet cells of mice and humans. They then treated human donor or mouse pancreatic islet cells with MCH and found that it increased insulin secretion, compared to islet cells without MCH, which did not show the same effect.
In the next phase, the researchers examined genetically-engineered mice that did not produce MCH and consequently had abnormally small islets. "This indicated to us that MCH is important for growth of islets," says Dr. Kulkarni.
The next step in the research process is to pinpoint exactly how MCH is regulating the growth of beta cells and identify which proteins are involved in this growth process. "We know MCH is having an effect on both growth and function likely by recruiting different proteins. It will be worth exploring which proteins are being activated by MCH to cause the growth effect," Dr. Kulkarni explains.
A follow-up study has been designed and is currently awaiting funding. It will look at how MCH interacts with glucagon-like peptide 1 (GLP-1), a hormone involved in beta cell growth. An analogue of GLP-1 hormone has already been approved by the FDA for treating type 2 diabetes. The goal is to understand how GLP-1 and MCH can work together to promote beta cell growth.
Other Joslin researchers participating in the study include: Jason Karamchandani, M.D., Amarnath Kurpad, M.D., C.W. Liew, Ph.D., Siming Liu, M.D., Ph.D., Terumasa Okada, M.D., Ph.D., and Umut Ozcan, M.D. Others participating in the study include: Eleftheria Maratos-Flier, M.D., and Pavlos Pissios, Ph.D., Efi Kokkotou Ph.D., Beth Israel Deaconess Medical Center; Gabriella Dahlgren, Ph.D., Robert T. Kennedy, Ph.D., and Jennifer N. Peters, Ph.D., University of Michigan; and Yogish C. Kudva, M.D., Mayo Clinic.
Funding for the study was provided by the National Institutes of Health, Yamanouchi Foundation and a Pilot and Feasibility grant from the Harvard Clinical Nutrition Research Center.
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