Hexose Metabolism in Pancreatic Islets: Regulation of the Mitochondrial NADH/NAD + Ratio

Abstract

In rat pancreatic islets, D-glucose in concentrations exceeding 5.6 mM caused a concentration-related decrease of the mitochondrial NADH/NAD + ratio, as judged from the changes in the islet content of glutamate, NH 4 +, and 2-ketoglutarate, and assuming that the glutamate dehydrogenase reaction is near equilibrium with the mitochondrial NAD system. The concentration dependency of the response to D-glucose was vastly different in islet and parotid cells, respectively, L-Leucine, 2-ketoisocaproate, BCH (a nonmetabolized but insulinotropic analog of L-leucine) and 3-phenylpyruvate also lowered the mitochondrial NADH/NAD + ratio. In the presence of D-glucose, the latter ratio was also decreased by NH 4 + or the absence of extracellular Ca 2+, but dramatically increased by aminooxyacetate. Taking into account prior metabolic findings, the nutrient-induced fall in the mitochondrial redox state is thought to reflect an increased clearance of mitochondrial NADH through both the respiratory chain and malate-aspartate shuttle. The nutrient-induced decrease in the mitochondrial NADH/NAD + ratio might favor both the circulation of metabolites in the Krebs cycle and the exit of Ca 2+ from the mitochondria.