Alpha- to Beta-Cell Communication in Health and Disease

Summary of Work Glucagon is canonically viewed as an essential counterregulatory hormone that prevents hypoglycemia by driving endogenous glucose production (EGP) in the liver. We and others have revealed additional roles for glucagon that emphasize a much more complex control of metabolism beyond hypoglycemia. On such role is our studies revealing the potent insulinotropic actions of glucagon in β-cells, which we have shown to be essential for postprandial glucose control. Glucagon production in α-cells comes from the specific processing of a proglucagon peptide by prohormone convertase 2 (PC2). Emerging literature has proposed that α-cells can differentially process the proglucagon hormone to produce glucagon-like peptide 1 (GLP-1) through a distinct prohoromone convertase; PC1. GLP-1 is a much more potent insulinotropic peptide, which would enhance α- to β-cell communication and insulin secretion to a greater extent than glucagon. Our work in human subjects has suggested that α- to β-cell communication becomes greater contributor to insulin secretion with increase metabolic stress, raising the hypothesis that mechanisms that enhance this axis may do so a compensatory mechanism to enhance insulin secretion in the setting of increase peripheral insulin resistance that associates with obesity and/or type 2 diabetes (T2D). We have generated several mouse models that support this hypothesis with strong preliminary data and propose here to move this hypothesis into a translational setting. We will utilize preclinical studies in human islets as well as clinical studies in human subjects to test the importance of α- to β- cell communication for insulin secretion across the metabolic spectrum and enhance our understanding of how α-cells process proglucagon peptides to support β-cell function. This work has direct implications in the understanding of the pathogenesis of T2D as well as the mechanisms by which incretin-based drugs control glucose homeostasis.