The Stimulus-Secretion Coupling of Glucose-Induced Insulin Release. Metoabolic Effects of Menadione in Isolated Islets

Abstract

Pancreatic islets contain an enzyme system which catalyzes the donation of hydrogen from NAD(P)H to menadione (2-methyl-1,4-naphthoquinone). In high concetrations (20 to 50μM), menadione, in addition to lowering the concentratin of reduced pyridine nucletodies in the islets. also impairs glycolysis and glucosue oxidation, decreases ATP concentration, and inhibits proinsulin bioosynthesis. However, at a 10μM concentratin, medadione fails to affect the concentration of adenine nucleotides, the utilizaiton of glucose, the production of lactate and pyruvate, the oxidation of [6-14C)glucose and the synthesis of proinsulin; whereas the metabolism of glucose through hte pentose shunt is markedly increased. The sole inhibitory effect of menadion 10μM upon metabolic parameters is to reduce the concentration of both NADH and NADPH, such and effect being noticed in islets exposed to gulcose 11.1 mM but not in those inculbated at a higher glucose level (27.8 mM). Since, in the presence of glucose 11.1 mM, menabione 10 μM also severaly decreases glucose-stimulated45 calcium net uptake and subsequent insulin release, it is concluded that the availability of reduced pyrininde nucleotides may play an essential role in the sectretory sequence by coupling metabolic to cationic envents. Thus, when insulinotropic nutrients are oxidized in the B-cell, the increased avialabilty of reduced pyridine nucleotides could modify th affinity for cation of native inonophoretic systems, eventually leading to the accumalation of calcium up to a level sufficient to trigger insulin release.