Program Directors: Steinunn Baekkeskov and Gerold Grodsky 

The emphasis of the Islet Cell Biology Program is on basic questions, which ultimately may teach us how to improve the outcome of ß cell loss and/or dysfunction as they are manifested in type 1 and type 2 diabetes. The program will focus its efforts on investigations into islet cell growth and expansion, translating translate findings related to beta cell expansion and optimal regulation to a clinical setting;  studies of signaling mechanisms involved in ß cell function; test how aspects of the cell biology of ß cell autoantigens relate to their autoimmunity; test the relevance of findings related to ß cell function for metabolism in general and obesity in particular.

Specific research objectives are as below:

Pancreatic ß cell protein synthesis, folding and targeting
The protein syntheses and transport machinery of the pancreatic ß cell devotes about 25% of its total output to the hormone insulin, which is synthesized as a pre-proinsulin and undergoes several folding and processing steps along the secretory pathway. The ß cell is tightly packed with large dense core secretory granules containing insulin, IAPP, IA-2 and glima 38 and with synaptic vesicle like microvesicles containing GABA and GAD65. The objective of the faculty involved in this component of the program is to study mechanisms and pathways of protein biogenesis, folding, and targeting of these proteins with emphasis on how their mis-folding and/or trafficking relate to the pathogenesis of type 1 and/or type 2 diabetes. The faculty in this section interacts with the DERC Programs in Autoimmunity and Metabolism, Obesity, and Type 2 Diabetes test the relevance of their findings in animal models of type 1 and type 2 diabetes.  

Islet cell growth, angiogenesis, and apoptosis
The faculty members in this section have made seminal discoveries related to the induction of ß cell proliferation by oncogenes, the role of angiogenesis in sustaining ß cell expansion and the delicate balance between induction of proliferation and induction of apoptosis. These areas will be exploited in the program to understand the underlying mechanisms of islet cell growth with the ultimate goal of developing methods for i) controlled expansion of islet cell mass; and ii) improve angiogenesis of transplanted islets. The faculty in this section work closely with the DERC Developmental Biology and Islet Transplantation and Immunity Programs to develop such methods and to test them in a transplantation setting.

Pancreatic ß cell function
The ATP-sensitive potassium channel in pancreatic ß cells is a key regulator of insulin secretion and GABA-secreted by pancreatic ß cells may inhibit insulin secretion by an indirect effect on this channel via GABA-B receptors. This section will study molecular mechanisms of the functional regulation of the ATP-sensitive potassium channel in pancreatic ß cells and the role of GABA as a negative regulator. The faculty in this section work closely with the DERC Receptors and Signaling Program to interchange methods and expertise relevant for molecular mechanisms of signaling through receptors and with the DERC Metabolism, Obesity and Type 2 Diabetes Program to explore how regulation of ß cell function/signaling relates to aspects of type 2 diabetes.

Program members:

Steinunn Baekkeskov	Gerard Evan
Gerold Grodsky	Doug Hanahan
Viswanath Lingappa	Lily Jan
Peter Walter	Zena Werb