Contribution of Apoptosis to Physiologic Remodeling of the Endocrine Pancreas and Pathophysiology of Diabetes

Abstract

Introduction Homeostatic control of blood glucose levels is critically dependent on the balance of glucagon and insulin, two counteracting pancreatic hormones secreted by endocrine cells within the islets of Langerhans – alpha and beta cells, respectively. Elegant biochemical studies combined with metabolic flux analysis uncovered the unique ability of beta cells to sense blood glucose fluctuations and to fine tune insulin secretion accordingly. A high-capacity glucose transport system, a low-Km glucose phosphorylating activity catalyzed by glucokinase (GK), and the ability to channel the majority of glycolytically derived pyruvate to the mitochondrial tricarboxylic acid (TCA) cycle constitute essential metabolic design features that endow beta cells with a specialized secretory function. The increase in intracellular adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ratio on mitochondrial metabolism of nutrients is among the metabolic coupling factors connecting fuel oxidation to insulin secretion. A rise in ATP/ADP ratio in turn leads to closure of ATP-sensitive K (KATP) channels at the plasma membrane, followed by membrane depolarization and influx of Ca + necessary for release of insulin granules. The two aspects of beta cell biology that contribute significantly to euglycemia are glucose dose responsiveness of insulin secretion and the remarkable plasticity of beta cell mass to meet insulin demand under physiologic and pathophysiologic nutrient stress. Beta cell mass is the net outcome of neogenesis (formation of new beta cells from non–beta cell precursors), replication of preexisting beta cells, beta cell size, and apoptosis. The integration of beta cell function and mass is further ensured through nutrient sensing pathways that concomitantly signal insulin secretion and modulate beta cell replication and survival. This chapter highlights the apoptotic mechanisms operative in beta cells that influence the dynamic control of beta cell mass during the developmental remodeling of the endocrine pancreas and in the pathogenesis of diabetes.