An increase in the production rate of reduced pyridine nucleotides is currently considered as a coupling factor between metabolic and distal events in the process of glucose-stimulated insulin release. The possible participation in such a coupling of thiol: disulfide interchanges was investigated in rat pancreatic islets. NADPH-dependent glutathione reductase and glutathione-cystine transhydrogenase activities were present in islet homogenates, whereas no glutathione peroxidase activity could be detected. In intact islets, glucose (16.7 mM) augmented both the GSH/GSSG ratio (from a basal value of 6.7 +/- 0.6 to 8.4 +/- 0.4) and the tissue content of sulphydryl groups (from a basal value of 119 +/- 7 to 170 +/- 9 pmol/microgram protein). The latter effect was mimicked by D-glyceraldehyde, 2-ketoisocaproate, anoxia and KCN; it failed to be reproduced by L-glucose or D-fructose, was unaffected by theophylline, and was inhibited by D-mannoheptulose, iodoacetate, menadione, cytochalasin B and the absence of extracellular Ca2+. These findings support the view that a glucose-induced reduction of disulphide bridges to sulphydryl groups participates in the stimulus-secretion coupling of nutrient-induced insulin release.