The Stimulus‐Secretion Coupling of Glucose‐Induced Insulin Release

Abstract

The combination of Ba 2+ and theophylline provoked a dramatic release of insulin from rat pancreatic islets incubated in the absence of extracellular Ca 2+ . The secretory response was unaffected by poisons of glycolysis; inhibited by epinephrine, organic calcium‐antagonists, respiratory inhibitors, and uncoupling agents; and augmented by glucose, 2‐oxoisocaproate and 2‐oxoiso‐valerate. The latter augmentation occurred even when the nutrients were used at concentrations which did not stimulate insulin release from islets maintained in a normal ionic environment. The release of insulin evoked by the combination of Ba 2+ and theophylline was associated with an increase in the rate of oxidation of endogenous nutrients, but a fall in the concentration of both ATP and reduced pyridine nucleotides. The facilitation of insulin release by glucose (3.3 and 16.7 mM) was associated with a dose‐related increase in both the concentration of NAD(P)H and net uptake of 133 Ba. The magnitude of the augmenting action of glucose upon insulin release evoked by the combination of Ba 2+ and theophylline correlated with the rate of glucose oxidation. These data indicate that insulin release can be stimulated by non‐metabolizable secretagogues, despite a fall in the concentration of both ATP and NAD(P)H. However, the insulinotropic action of glucose, whatever its concentration, may depend on an increased generation of both reducing equivalents and high‐energy phosphate intermediates.