Hexose metabolism in pancreatic islets: Participation of Ca 2+-sensitive 2-ketoglutarate dehydrogenase in the regulation of mitochondrial function

Abstract

A rise in extracellular d-glucose concentration results in a preferential and Ca 2+-dependent stimulation of mitochondrial oxidative events in pancreatic islet cells. The possible participation of Ca 2+-dependent mitochondrial dehydrogenases, especially 2-ketoglutarate dehydrogenase, in such an unusual metabolic situation was explored in intact islets, islet homogenates and isolated islet mitochondria. In intact islets exposed to a high concentration of d-glucose, the removal of extracellular Ca 2+ impaired d-[6- 14C]glucose oxidation whilst failing to affect the cytosolic or mitochondrial ATP ADP ratios. In islet homogenates, the activity of 2-ketoglutarate dehydrogenase displayed exquisite Ca 2+-dependency, the presence of Ca 2+ causing a 10-fold increase in affinity for 2-ketoglutarate. In intact islet mitochondria, the oxidation of 2-[1- 14C]ketoglutarate also increased as a function of extramitochondrial Ca 2+ availability. Moreover, prior stimulation of intact islets by d-glucose resulted in an increased capacity of mitochondria to oxidize 2-[1- 14C]ketoglutarate. The absence of extracellular Ca 2+ during the initial stimulation of intact islets impaired but did not entirely suppress such a memory phenomenon. It is proposed that the mitochondrial accumulation of Ca 2+ in nutrient-stimulated islets indeed accounts, in part at least, for the preferential stimulation of mitochondrial oxidative events in this fuel-sensor organ.