Achieving euglycemia in diabetics ultimately requires understanding of the cellular and molecular mechanisms controlling insulin secretion. We have recently confirmed the central role of ATP-sensitive potassium (KATP) channels in linking blood glucose levels to the secretion of insulin, and demonstrated that inherited hyperinsulinemia is causally associated with lack of pancreatic KATP channel activity. We have cloned and expressed the high affinity sulfonylurea receptor (SUR1) and inward rectifier K channel subunits that are the necessary molecular components of KATP channel activity, and are performing extensive mutagenic analysis to determine the structural basis of channel activity and regulation by intracellular nucleotides. We have also used transgenic approaches to define the role of glucose transporters in diabetes and insulin resistance diseases. Together these efforts provide the basis for the current proposal in which we will generate transgenic mice with altered pancreatic KATP channel activity, in order to understand the consequences of altered pancreatic KATP channel activity for regulation of blood glucose. Transgenic animals expressing mutated KATP channels with altered nucleotide sensitivity, and gene knockout animals will allow a new and powerful approach to understanding the role of KATP channels in pancreatic function within the intact animal. The availability of KATP transgenic animals, and answers to the specific questions posed below, will provide a critical foundation for the development of new treatment approaches to infant-onset diabetes and hyperinsulinemia.
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