Decreased Sensitivity of the Pancreatic Beta Cells to Glucose in Prediabetic and Diabetic Subjects: A Glucose Dose-Response Study

Abstract

The dose-response curve for glucose-induced insulin release obtained by infusing glucose at four to five different rates to normal subjects was sine-shaped, the insulin secretion starting at a blood glucose concentration of about 100 to 125 mg. per 100 ml. The steepest rise in plasma insulin occurred between blood glucose levels of 200 and 350 mg. per 100 ml. When blood sugar was increased further, the plasma insulin curve started to level off. There were no differences in the dose-response characteristics of the early and late insulin responses to glucose infusion. In prediabetic subjects variations in blood glucose concentration between the fasting level and about 300 mg. per 100 ml. were accompanied by only a minor insulin response. Further eleva-ation of blood glucose to 450 to 650 mg. per 100 ml. induced a normal initial insulin response in two out of the eight prediabetics, while the late response was normalized in almost all of them. Thus, the insulin-glucose dose-response curves in the prediabetics seemed to be similar to those of the normals but shifted toward higher blood glucose concentrations. In subjects with mild maturity-onset diabetes or glucose intolerance only, there seemed to exist a further shift to the right of the dose-response curves. These findings suggest that (1) the mechanisms governing the early and late insulin responses to glucose are of identical nature, and (2) the decreased insulin response to glucose in prediabetics and mild diabetics is a relative one, very high glucose concentrations being capable of eliciting normal responses. These findings are compatible with our hypothesis that the defective insulin release in prediabetes and diabetes is due to a decrease in the sensitivity of the glucose receptor of the pancreatic β cell which transmits the glucose signal for insulin release.