Louis H. Philipson, MD, PhD

Regulation of glucose signaling and insulin secretion
The overall goal of my research program is to further understand insulin secretion from the pancreatic beta cell and how it is perturbed in diabetes mellitus. Our emphasis is on the integrated physiology of islet function in health and disease, and primary approaches employ molecular biology and genetics, electrophysiology, modeling and advanced optical imaging using biosensors. I also collaborate with other investigators on islet transplantation, islet development, and related areas.

In terms of glucose signaling for insulin secretion, we are studying the role of K+ channels and TRP channels in the regulation of insulin secretion. Excitation-secretion coupling in insulin-secreting ß-cells is a calcium-dependent process that involves a dynamic interplay between K+ and Ca2+ channels. Ca2+ channels mediate the action potential allowing calcium influx but K+ channels regulate the membrane potential (Vm). Repolarization of Vm is critical in the regulation of insulin secretion, but knowledge of the specific K+ channels and their regulation is incomplete, particularly in human islets. We have shown that the Kv2.x family (Kv2.1/2.2) of Kv channels plays an essential role in ß-cell repolarization and insulin secretion. We are currently testing the role of specific Kv2 and calcium-activated K channel isoforms and their modulators in ß-cell physiology.

Another important area is the study of metabolism and exocytosis in the beta cell. We have developed optical techniques to simultaneously measure combinations of reporters for membrane potential, ROS generation, intracellular calcium, IP3 dynamics, mitochondrial membrane potential and dynamics, and tracking of insulin granules. These approaches are being employed to study aspects of beta cell physiology, diabetes and human islets prepared for islet transplantation, and models of beta cell regeneration.

A new area is neonatal diabetes. Working closely with Dr Graeme Bell and collaborating with Dr Andrew Hattersley we have identified 9 patients thought to have T1DM that actually have KCNJ11 mutations that are responsive to sulfonylureas. All of these patients are either off insulin or in the process of transitioning to oral agents. We have a very active group of collaborators, both within the Diabetes Research Center and outside of the University of Chicago. Some of our key collaborators include Michael Roe (biosensors), Chris Rhodes (adenoviral vectors for expression of biosensors and granule-targeted probes), Norbert Scherer (multiphoton tracking of insulin granules using FCS), Anita Chong (islet regeneration), Vicky Prince (islet function and development in zebra fish), Manami Hara (mice expressing GFP and biosensors), Graeme Bell, and Donald Steiner.