The finding, unraveled by researchers at the Joslin Diabetes Center, brings in new avenues for studying leptin and its role in islet cell biology, which may lead to new treatments for diabetes.
Preceding in vitro studies have found 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.
It is currently not known why obese individuals display a high incidence of diabetes in spite of high levels of both insulin and leptin circulating in the bloodstream.
"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.
To comprehend 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.
After analysis, 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 researchers placed the KO mice and a control group of mice with intact leptin receptors on a high-fat diet. The results showed that though 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.
He added that follow-up studies, which 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, could lead to the development of therapeutic drugs that manipulate these proteins to influence beta cell growth and function.
The study appears in the October 2007 issue of The Journal of Clinical Investigation. (ANI)