EFFECT OF SULFONYLUREA ON GLUCOSE-STIMULATED INSULIN-SECRETION IN HEALTHY AND NON-INSULIN-DEPENDENT DIABETIC SUBJECTS - A DOSE-RESPONSE STUDY

The effect of a rapid-acting sulphonylurea, glipizide, on the dose-response relationship between the beta-cell response (insulin and C-peptide secretion) and the ambient plasma glucose concentration was examined in 12 healthy and 6 non-insulin-dependent diabetic subjects. The subjects participated in two sets of experiments which were performed in random order: (A) four hyperglycaemic clamp studies, during which the plasma glucose concentration was raised for 120 min by 1 (only in healthy subjects), 3, 7, and 17 mmol/l; and (B) the same four hyperglycaemic clamp studies preceded by ingestion of 5 mg glipizide. All subjects participated in a further study, in which glipizide was ingested and the plasma glucose concentration was maintained at the basal level. In control subjects in the absence of glipizide, the first-phase plasma insulin response (0-10 min) increased progressively with increasing plasma glucose concentration up to 10 mmol/l, above which it tended to plateau. Glipizide augmented the first-phase insulin response without changing the slope of the regression line relating plasma insulin to glucose concentrations. The second-phase plasma insulin response (20-120 min) increased linearly with increasing hyperglycaemia (r = 0.997). Glipizide alone increased the plasma insulin response by 180 pmol/l. A similar increase in plasma insulin response following glipizide was observed at each hyperglycaemic step, indicating that glipizide did not affect the sensitivity of the beta-cell to glucose. First-phase insulin secretion was reduced in the type 2 (non-insulin-dependent) diabetic patients, and was not influenced by glipizide. The dose-response curve relating second-phase insulin secretion to the ambient plasma glucose concentration was significantly (P < 0.001) flatter in the diabetic patients than in the control subjects. Glipizide alone increased the plasma insulin response by 60 pmol/l without changing the slope of the dose-response curve. It is concluded that, in both type 2 diabetic patients and healthy subjects: (A) sulphonylurea augments glucose-stimulated second-phase insulin secretion without changing the sensitivity of the beta-cell to glucose; (B) first-phase insulin secretion is reduced in non-insulin-dependent diabetic patients with fasting hyperglycaemia and is not influenced by sulphonylurea.