The goal of Dr. Philipson’s laboratory is to better understand how pancreatic ß-cells "know" when to secrete insulin and define defects in this process in diabetes that could be therapeutic targets. The main focus is the study of ion channels, metabolism, and mitochondria that together regulate intracellular calcium concentration and energy production and thereby regulate insulin secretion in pancreatic islet ß-cells. ß-cell calcium regulatory processes have been shown to be dysfunctional in several models of diabetes mellitus and hypoglycemia.

One ongoing aim is to define the identity of the repolarizing K+ channels in ß-cells – responsible for the islet correlate of the T wave in the cardiac electrocardiogram. Dr. Philipson has found that Ca2+ oscillations in insulinoma cells and rat islets are suppressed by the endogenous voltage-dependent K+ channels and insulin secretion can be dramatically enhanced by blocking only one case of sulfonylurea-insensitive K+ channels. This project has resulted in the generation of a transgenic mouse which expresses a K+ channel- green fluorescent fusion protein in the pancreatic ß-cells, allowing the insulin-containing cells to be directly visualized in real time using fluorescence microscopy. These studies are also being pursued in human islets, as part of an overall study evaluating the secretagogue-induced calcium responses of human islets prepared for transplantation in collaboration with Dr. B. Hering (U. Minnesota).

An important target is calcium channels in ß cells, and Dr. Philipson recently cloned, expressed and produced null mice for the novel Ca2+ channel termed alpha-1E (CACNA1E). This and other channels such as LTRPC7 are under investigation for their role in insulin secretion.

Other ongoing projects have focused on the role of SK channels in ß cell oscillations, the relationship of islet gap-junctions to ß-cell calcium signaling in collaboration with Dr. Beyer, and novel subcellular targetted indicators for ions and IP3 release in collaboration with Dr. Roe. Dr. Philipson is co-director of the Human Islet Transplantation project at the University of Chicago, for which a new GMP-standard laboratory is under construction.