Time-dependent inhibition of insulin release: suppression of the arginine effect by hyperglycaemia

Brief stimulation of the pancreas with arginine causes a refractory state which reduces the insulin response to subsequent stimulations (time-dependent inhibition). In control subjects, a pair of arginine injections (75 mg/kg) at a 30-min interval resulted in 20% reduction of peak and integrated insulin responses to the second injection. In Type 2 (non-insulin-dependent) diabetic patients and in obese subjects, the inhibitory effect of repeated arginine stimuli was abolished. Healthy subjects were made acutely hyperglycaemic (9.3 +/- 0.3 mmol/l) by the glucose clamp technique. This induced a three- to fivefold greater insulin response to arginine. Compared to the response of diabetic subjects with similar hyperglycaemia, the control subjects secreted four to nine times more insulin. When the arginine stimulation was repeated 30 min later, no inhibition was observed, the second insulin response being instead augmented 1.5- to 1.8-fold. We conclude that (1) the insulin response to arginine is markedly reduced in Type 2 diabetes; (2) arginine-induced time-dependent inhibition of insulin release is abolished in patients with minimal to moderate hyperglycaemia; (3) this is probably due to the acute synergistic action of glucose and arginine on the B cell; (4) time-dependent inhibition of insulin release may be a protective mechanism against insulin oversecretion following repetitive stimulation of the pancreas; its abolition in hyperglycaemic states may be a compensatory mechanism, allowing substantial increases in insulin output.