Insulin Receptors Play A Critical Role In Promoting Islet Growth

"The failure to grow more functional beta cells (also called compensatory islet cell growth response) leads to overt diabetes," said 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. "If we can identify the key signaling proteins critical for the islet cell growth response, we can develop potential therapeutic targets to enhance the growth of beta cells."

There are two proteins that mediate the effects of growth factors in beta cells, the insulin-producing cells in the pancreas: insulin receptor, a protein that mediates the action of insulin, and IGF-1 receptor, another protein that closely resembles the insulin receptor and mediates the action of insulin-like-growth factor (IGF-I), a hormone and growth factor. These two receptors have been a major focus of research studies by Dr. Kulkarni and others at Joslin Diabetes Center who want to better understand beta cell growth and functioning so that these essential cells can be increased in people with diabetes.

In type 2 diabetes, the body doesn't produce enough insulin and/or is unable to use insulin properly (insulin resistance). This form of diabetes usually occurs in people who are over 40, overweight, and have a family history of diabetes, although today it is increasingly occurring in younger people, including adolescents. For reasons that are still unknown, islet cells malfunction in people with type 2 diabetes and their bodies are unable to compensate. By investigating the cellular mechanisms that affect islet cell growth and development, Joslin researchers hope to improve the process to better treat type 2 diabetes, the most common form of diabetes.

This study investigated whether insulin receptors in the beta cell play a key role in promoting their growth as a response to overcome insulin resistance. A state of transient insulin resistance occurs naturally during pregnancy and puberty, but without causing diabetes in most people because the beta cells are able to grow and secrete more insulin to easily overcome the insulin resistance. It is when the beta cells fail to grow and secrete more insulin in these states that overt diabetes develops.

Two mouse models were used in the study. In the first model, an insulin-resistant mouse was crossed with a mouse lacking insulin receptors in the beta cell. The resulting offspring had insulin resistance with no receptors in the beta cell. In spite of their insulin resistance, the mice didn't show an appropriate growth response in the islets because the beta cells lacked insulin receptors. "This provided genetic evidence that insulin receptors are important for the islet cell growth response to insulin resistance," said Dr. Kulkarni.

In the second part of the study, researchers examined the role of the two related receptors--insulin and IGF-1. They used two mouse models--beta-cell-specific insulin receptor knockouts (beta-IRKO), which lack insulin receptors in beta cells, and IGF-1 receptor knockout (beta-IGF1RKO), which lack IGF-1 receptors in beta cells. Both these mouse models were then compared to a control group of mice normally expressing both insulin and IGF-1 receptors in their beta cells. All three groups were placed on a high-fat diet to induce insulin resistance.

The researchers assessed the beta cell growth response in the pancreas: the beta-IRKO mice failed to show the growth of islet cells while the control and beta-IGF1RKO mice did exhibit this growth response. "The results clearly showed that it is the insulin receptor -- not the IGF-1 receptor -- that is critical for the islet cell growth response to insulin resistance," said Dr. Kulkarni.

Joslin researchers are working on a follow up study that aims to identify the proteins that control the signaling pathway. "We are excited about the possibilities to make further progress in this area," Kulkarni said.

The study appears in the early online edition of this week's Proceedings of the National Academy of Sciences.

Funding for the study was provided by the National Institutes of Health, the Harvard Stem Cell Institute and the Adler and Iacocca Foundations.

Other researchers participating in the study include: Terumasa Okada, M.D., Ph.D., Chong Wee Liew, Ph.D., Jiang Hu, M.D., Charlotte Hinault, Ph.D., M. Dodson Michael, Ph.D., and Catherine Yin B.S., Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School; Jan Krützfeldt, M.D., and Markus Stoffel, M.D., Ph.D., Laboratory of Metabolic Diseases, Rockefeller University; and Martin Holzenberger, M.D., Ph.D., Inserm U515, Hôpital Saint-Antoine, Paris, France.