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The role of the pentose phosphate shunt in glucose-induced insulin release: In vitro studies with 6-aminonicotinamide, methylene blue, NAD+, NADH, NADP+, NADPH and nicotinamide on isolated pancreatic rat islets

1973; Elsevier BV; Volume: 297; Issue: 2 Linguagem: Inglês

10.1016/0304-4165(73)90083-4

1872-8006

H. P. T. Ammon, T PATEL, John W. Steinke,

Diabetes and associated disorders

The possible role of the pentose phosphate shunt in insulin release was investigated in vitro with collagenase isolated pancreatic islets of rats. Parameters measured were insulin released into the medium and measured by an immunoassay and formation of 14CO2 from glucose labeled either in the C-1 or C-6 position. The in vitro effect of the following substances was studied: 1. 6-Aminonicotinamide, an antimetabolite in the synthesis of pyridine nucleotides. In islets of animals pretreated with 6-amino nicotinamide 6 h previously and in the presence of 3 mg/ml glucose in the incubation medium, 6-aminonicotinamide markedly reduced oxidation of [1-14C]glucose but did not affect that of glucose labeled in C-6. Concomitantly there was a marked decrease in insulin release. This action of 6-aminonicotinamide did not take place when it was added only to the incubation medium. Pretreatment with 6-aminonicotinamide did not change the insulin concentration of the islets, making it unlikely that it interfered with insulin synthesis. The effect of 6-aminonicotinamide is consistent with partial inhibition of the pentose shunt. 2. Methylene blue: this agent was selected because it is known from studies with red blood cells that it will oxidize NADPH and thus stimulate activity of the pentose shunt. In concentrations of 0.5 and 2 μg/ml, methylene blue markedly stimulated oxidation of [1-14C]glucose but not that of C-6. Simultaneously there was a dose related decrease of insulin released. 3. Pyridine nucleotides: in the absence of glucose only NADPH exhibited a significant effect of insulin release. If glucose (3 mg/ml) was present 1 or 10 mM of NAD+ or NADH exhibited a significant effect, NADP+ or NADPH were less effective. If the pentose shunt was blocked by pretreatment with 6-aminonicotinamide, all 4 pyridine nucleotides stimulated insulin release. Similarly there was an increase in oxidation of [1-14C]glucose, consitent with restimulation of the pentose shunt. 4. Nicotinamide by itself exhibited a small effect; however, it was much less than the one produced by equimolar concentrations of the pyridine nucleotides. Conclusion: Restricted availability of NADPH either less production or by fast removal leads to a decrease in glucose-induced insulin release. Pyridine nucleotides will restimulate 6-aminonicotinamide blockade insulin release and glucose oxidation by the pentose shunt. Recently it has been proposed by others that the polyol pathway may play a key role in insulin release, our data are consistent with such a hypothesis. Furthermore they do support a major role of the pentose shunt in insulin release.