Metabolism-secretion Coupling and Mitochondrial Calcium Activities in Clonal Pancreatic β-cells

Pancreatic β-cells are the only cells capable of lowering blood glucose by secreting insulin. The β-cell continuously adjusts its secretory activity to substrate availability in order to keep blood glucose levels within the physiological range--a process called metabolism-secretion coupling. Glucose is readily taken up by the β-cell and broken down into intermediates that fuel oxidative metabolism inside the mitochondria to generate ATP. The resulting increase in the ATP/ADP ratio causes closure of plasma membrane KATP channels, thereby depolarizing the cell and triggering the opening of voltage-gated Ca²⁺ channels. Consequential oscillations of cytosolic Ca²⁺ not only mediate the exocytosis of insulin granules but are also relayed to other subcellular compartments including the mitochondria, where Ca²⁺ is required to accelerate mitochondrial metabolism in response to nutrient stimulation. The mitochondrial Ca²⁺ uptake machinery plays a fundamental role in this feed-forward mechanism that guarantees sustained insulin secretion and, thus, represents a promising therapeutic target for type 2 diabetes.