The effect of weight loss and caloric restriction on plasma glucose concentration, insulin and glucagon secretion in response to oral and iv glucose and arginine infusions, and insulin binding to mononuclear cell receptors was examined in 10 subjects with newly diagnosed maturity-onset diabetes mellitus [DM; fasting plasma glucose, 260 ± 8 mg/dl (mean ± SE)] and in 10 nondiabetic control subjects. Initially, the insulin response to glucose was absent in the DM subjects, but a distinct response occurred after iv arginine (P < 0.001). Caloric restriction and weight loss led to restoration of normal fasting plasma glucose levels in the DM patients (98 ± 4 mg/dl; P < 0.001) and little change in the control subjects. Serum insulin levels in response to glucose in DM increased significantly after weight loss compared to initial values (P < 0.01) but showed no change in response to arginine. In contrast, in the control subjects, the serum insulin responses to glucose decreased significantly (P < 0.05). Plasma glucagon levels decreased significantly in both groups (P < 0.001) during iv arginine infusions, but levels in the DM patients remained above those in the controls. Fasting plasma glucagon levels were reduced and the degree of glucagon suppression in response to glucose in the DM patients was enhanced (P < 0.05) but remained impaired compared to responses in control subjects (P < 0.05). Mononuclear cell insulin binding increased after weight loss (P < 0.05) but was similar in DM and control groups both before and after caloric restriction (P = NS).

These results indicate a loss of glucose-induced insulin secretory capacity in newly diagnosed maturity-onset DM; this phenomenon is substantially reversible by amelioration of the hyperglycemia. Diminished cellular receptor binding in obese subjects, by increasing resistance to the action of insulin, aggravates hyperglycemia and thereby contributes to the loss of β-cell sensitivity to glucose.