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The stimulus-secretion coupling of glucose-induced insulin release. Metabolism of glucose in K+-deprived islets.

ABSTRACT: 1. When pancreatic islets were exposed to a K(+)-free medium, the intracellular concentration of K(+) was decreased and that of Na(+) increased. 2. In the K(+)-deprived islets, the utilization of [5-(3)H]glucose, output of lactic acid and oxidation of [U-(14)C]-glucose were decreased by about 30-40% below the control values found at normal extracellular K(+) concentration (5.0mm). However, the oxidation of [U-(14)C]pyruvate was unaffected. 3. The omission of extracellular K(+) little affected the production of (14)CO(2) from islets prelabelled with [U-(14)C]palmitate and incubated in the absence of glucose, despite the fact that K(+) deprivation significantly increased the ATP concentration and ATP/ADP concentration ratio in the glucose-deprived islets. 4. At normal K(+) concentration, glucose increased the concentrations of phosphoenolpyruvate, NAD(P)H and ATP in the islets. In the glucose-stimulated islets, the concentration of phosphoenolpyruvate, but not that of either NAD(P)H or ATP, was higher in the absence than in the presence of extracellular K(+). In islet homogenates, the activity of pyruvate kinase (EC 2.7.1.40) was stimulated by K(+) (optimal activity at 100-150mm-K(+)) and inhibited by Na(+) (except at very low K(+) concentrations). 5. K(+) could be replaced by NH(4) (+), Rb(+), Cs(+) or Na(+) to maintain, at least to some extent, pyruvate kinase activity in islet homogenates. Addition of Rb(+) or Cs(+), but not NH(4) (+), to K(+)-deprived media also increased [U-(14)C]glucose oxidation by intact islets. 6. The omission of K(+) did not cause any obvious anomaly in the apparent dependency of (45)Ca(2+) net uptake on NAD(P)H concentration in the islets. 7. These data suggest that the coupling between metabolic and ionic events in the islet cells involves feedback mechanisms through which glucose oxidation may be modulated by cationic factors.

SUBMITTER: Sener A

PROVIDER: S-EPMC1161518 | biostudies-other | 1980 Jan

REPOSITORIES: biostudies-other

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Project description:1. In isolated pancreatic islets, pyruvate causes a shift to the left of the sigmoidal curve relating the rate of insulin release to the ambient glucose concentration. The magnitude of this effect is related to the concentration of pyruvate (5--90 mM) and, at a 30 mM concentration, is equivalent to that evoked by 2 mM-glucose. Pyruvate also enhances insulin release in the presence of fructose, leucine and 4-methyl-2-oxopentanoate. 2. In the presence of glucose 8 mM), the secretory response to pyruvate is an immediate process, displaying a biphasic pattern. 3. The insulinotropic action of pyruvate coincides with an inhibition of 45Ca efflux and a stimulation of 45Ca net uptake. The relationship between 45Ca uptake and insulin release displays its usual pattern in the presence of pyruvate. 4. Exogenous pyruvate rapidly accumulates in the islets in amounts close to those derived from the metabolism of glucose. The oxidation of [2-14C]pyruvate represents 64% of the rate of [1-14C]pyruvate decarboxylation and, at a 30 mM concentration, is comparable with that of 8 mM-[U-14C]glucose. 5. When corrected for the conversion of pyruvate into lactate, the oxidation of 30 mM-pyruvate corresponds to a net generation of about 314 pmol of reducing equivalents/120 min per islet. 6. Pyruvate does not affect the rate of glycolysis, but inhibits the oxidation of glucose. Glucose does not affect pyruvate oxidation. 7. Pyruvate (30 mM) does not affect the concentration of ATP, ADP and AMP in the islet cells. 8. Pyruvate (30 mM) increases the concentration of reduced nicotinamide nucleotides in the presence but not in the absence of glucose. A close correlation is seen between the concentration of reduced nicotinamide nucleotides and the net uptake of 45Ca. Menadione inhibits the effect of pyruvate on insulin release, without altering its rate of oxidation. 9. Pyruvate, like glucose, modestly stimulates lipogenesis. 10. Pyruvate, in contrast with glucose, markedly inhibits the oxidation of endogenous nutrients. The latter effect accounts for the apparent discrepancy between the rate of pyruvate oxidation and the magnitude of its insulinotropic action. 11. Dichloroacetate fails to affect glucose oxidation and glucose-stimulated insulin release. 12. It is concluded that the effect of pyruvate to stimulate insulin release depends on its ability to increase the concentration of reduced nicotinamide nucleotides in the islet cells.

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The stimulus-secretion coupling of glucose-induced insulin release. Metabolism of glucose in K+-deprived islets.

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