Grant: Project Grant

Pancreatic islet beta-cells increase their ability to secrete insulin as metabolic demand requires, but become impaired early in the development of type 2 diabetes (T2D). In the face of increasing insulin requirements, such as in obesity and insulin resistance, the beta-cell has a remarkable capacity to up-regulate insulin secretion. This can be seen as either an increase fasting (basal) insulin secretion, or increased insulin responses to elevated sugar. These changes occur rapidly, even prior to any change in pancreatic insulin content or islet mass. Importantly, it is recognized that a failure of beta-cells to maintain elevated insulin secretory capacity in the face of insulin resistance drives high glucose levels in T2D. The underlying molecular and functional changes responsible for tuning insulin secretory capacity to metabolic needs remain unresolved, and are a matter of some controversy. We hypothesize that key intracellular signals regulate protein targets to differentially control basal and glucose-stimulated insulin release, thus tuning insulin secretory capacity to meet metabolic demands. We will explore these pathways using a combination of animal models, human islet tissue, and methods that include analysis of cell function and protein modification. We will study the cellular machinery responsible for beta-cell functional changes in adaptation, and identify proteins that are the target(s) of intracellular signalling to mediate this. This study will help us to better understand exactly how pancreatic islet beta cells tune their ability to secrete insulin, maintaining blood sugar control in response to metabolic challenges.