Potential Role Of Leptin In Diabetes Discovered

Previous in vitro studies suggested that leptin receptors, which are found in tissues throughout the body including the pancreas as well as the brain, mediate leptin-induced inhibition of insulin secretion in islet cells, also known as beta cells.

"We wanted to further our understanding of leptin and its role in beta cells independent of its effects in the brain," said Rohit N. Kulkarni, M.D., Ph.D., principal investigator at Joslin Diabetes Center and Assistant Professor of Medicine at Harvard Medical School, who led this study. It is currently not known why obese individuals exhibit a high incidence of diabetes despite high levels of both insulin and leptin circulating in the bloodstream.

To understand the role of leptin in the islets, researchers developed a mouse model (known as a "knock out" or KO mouse) genetically engineered not to produce leptin receptors in the pancreas, while maintaining the receptors in the brain and the rest of the body. Researchers found that the mice lacking leptin receptors in the pancreas showed improved glucose tolerance and greater insulin secretion and beta cell growth. "Since the normal function of leptin is to keep insulin levels from getting too high, the lack of leptin enhances insulin action in the beta cells and promotes insulin secretion, which was the result we expected," said Dr. Kulkarni.

In the second part of the study, the KO mice and a control group of mice with intact leptin receptors were placed on a high-fat diet. Although both the control and KO mice became obese, only the KO mice developed severe glucose intolerance and insulin resistance, a precursor to the development of diabetes. "These novel results indicate that in the presence of obesity, the combination of insulin resistance in the beta cell and the lack of leptin signaling leads to poor beta cell growth and function leading to glucose intolerance. Interactions between leptin and insulin signaling in the beta cell need to be considered to understand the relationship between diabetes and obesity," said Dr. Kulkarni.

Obesity is a major risk factor for the development of type 2 diabetes, the most common form of the disease. Other risk factors are age (over 40) and a family history of diabetes, although today it is increasing prevalent in younger people, including adolescents. In type 2 diabetes, islet cells malfunction and the body is unable to compensate by growing more beta cells. By investigating the cellular mechanisms that affect islet cell development and growth, Joslin researchers hope to find better ways to prevent and treat the disease.

Follow-up studies will focus on examining the interactions between insulin and leptin signaling in beta cells and identifying the key proteins found in the pathways that regulate beta cell growth and activity. This could lead to the development of therapeutic drugs that manipulate these proteins to influence beta cell growth and function. "Unraveling the role of leptin in the regulation of beta cell biology will be especially useful in understanding the mechanisms that contribute to beta cell growth with implications for the treatment of both type 1 and type 2 diabetes," said Dr. Kulkarni.

This study appears in the October 2007 issue of The Journal of Clinical Investigation.

Funding for the study was provided by the National Institutes of Health.

Other researchers participating in the study include: Tomoaki Morioka, M.D., Ph.D., Jiang Hu, M.D., Amarnath J. Kurpad, M.D., and Hui Li, Ph.D., Research Division, Joslin Diabetes Center; Esra Asilmaz, B.S., Laboratory of Molecular Genetics, The Rockefeller University; John F. Dishinger, B.S., and Robert T. Kennedy, Ph.D., Departments of Chemistry and Pharmacology, University of Michigan; and Carol F. Elias, Ph.D. and Joel K. Elmquist, Ph.D., Center for Hypothalamic Research and Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center.