The role of glucose as a stimulant to pancreatic insulin release was studied in the intact dog and in rat pancreas incubated in vitro. The infusion of the metabolizable sugars, glucose, fructose, and mannose, as well as tolbutamide into the pancreatico-duodenal and splenic arteries in the anesthetized dog resulted in increased portal vein insulin-like activity, using the epididymal fat pad assay. Normal saline and pyruvate infusions resulted in no significant increase in insulin-like activity. Infusion into the dog of the glucose analogue, 2-deoxyglucose, at high concentration resulted in no stimulation of insulin release, but in fact blocked the pancreaic response to simultaneous glucose infusion. It appeared that the ratio of glucose: 2-deoxyglucose was a determinant in the degree of inhibition. Plasma ratios of < 1.5 resulted in inhibition.

Incubation of rat pancreas with 2-deoxyglucose in the presence of glucose showed that 2-deoxyglucose inhibited the release of immunoassayable insulin. The inhibition was dependent upon the concentration of 2-deoxyglucose and the ratio of glucose: 2-deoxyglucose.

In view of the metabolic blocking action of 2-deoxyglucose in the utilization of glucose-6-phosphate, it is suggested that the glucose stimulated insulin release occurs after the formation and further metabolism of glucoses-6-phosphate.