Of all the known secretogogues, glucose is the only one that produces a biphasic secretory response (an early, rapid release of insulin followed by a long, sustained release) and is the only metabolite that stimulates both insulin secretion and biosynthesis at physiologic concentrations. The initial phase is a major determinant of the rate at which the organism utilizes glucose. An enteric receptor system in man recognizes whether glucose is being ingested or given parenterally. Dynamics of insulin secretion following oral glucose differ markedly from those following parenteral administration. It is suggested that the excessive plasma insulin levels in some maturityonset diabetics during an oral GTT are related primarily to the enteric receptor system and to a delayed release of insulin. Normally, glucose is extracted by the liver due to the early release of insulin. A delay in the release of insulin by maturity-onset diabetics permits glucose to escape hepatic extraction. Thus, the glycemic stimulus is much greater. Known enteric secretogogues enhance the secretory effect of the elevated plasma glucose. Hypoglycemia may develop. A critical level of glucose is needed to demonstrate the enhancement of insulin secretion by glucagon in children. Intravenous glucagon failed to elicit insulin release when plasma glucose was below 50 mg. per 100 ml. It is suggested that the genetically determined defect in diabetes mellitus involves the glucoreceptor mechanism. The inability to perceive a glucose signal accounts for the hypoinsulinemic response observed in prediabetic subjects. The insulin-resistant characteristic of the obese state is a secondary adaptation to the hyperinsulinemia produced by excessive carbohydrate intake. It may represent an adaptive mechanism whereby the individual who eats excessive carbohydrate is protected from intermittent hypoglycemia.