Estimations of the secretory sensitivities of islets from 19-day pregnant rats to stimuli such as glucose, mannose and fructose, were compared with those of non-pregnant rats, and it was concluded that the hypersecretion of insulin in vitro from islets in pregnancy was through development specifically of extra responsiveness to glucose or its metabolites. The sensitisation of the glucose detecting mechanism in these islets was then investigated in a number of different ways. Higher rates of 14C-glucose oxidation were measured in islets from pregnant rats. The secretory responsiveness of islets to a variety of metabolites of glucose, e.g. dihydroxyacetone, glyceraldehyde, succinate, citrate, pyruvate, was found to be significantly increased in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) in islets from pregnant rats. The mechanism of action of these intermediates of glucose metabolism in effecting a higher rate of insulin secretion was investigated further by measuring effects of some metabolites on adenylate cyclase activity and on cyclic AMP levels in islets. Neither glucose nor any of the metabolites tested affected islet adenylate cyclase activity in vitro, but cyclic AMP levels were significantly greater in pregnant rat islets, incubated with IBMX, whether glucose or pyruvate was the substrate. These results indicate that the accelerated metabolism of glucose in islets in pregnancy may lead to the production of an intermediate which may in the longer term enhance cyclic AMP formatio and thus potentiate insulin release.