Differential Effects of Tolbutamide on First and Second Phase Insulin Secretion in Noninsulin-dependent Diabetes Mellitus

Immunoreactive insulin responses to a 20-g iv glucose challenge during a 7.5 mg/m2/min tolbutamide infusion were studied in 21 untreated noninsulin-dependent male diabetics. All data were analyzed by paired t tests. During the tolbutamide infusion, compared to the saline control period in the same subjects, glucose levels were lowered [217 +/- 17 vs. 196 +/- 16 mg/dl (mean +/- SEM); P less than 0.005], and there was an increase in both first phase (2 +/- 1 vs. 16 +/- 4 micro U/ml; P less than 0.005) and second phase insulin responses (296 +/- 71 vs. 499 +/- 101 micro U. min/ml; P less than 0.05; n = 21). However, when the prestimulus glucose level was lowered by an insulin infusion (214 +/- 20 vs. 145 +/- 17 mg/dl; P less than 0.001), no effect on first phase insulin secretion was observed, and the second phase response decreased (290 +/- 78 vs. 124 +/ 55 micro U. min/ml; P less than 0.005; n = 11; saline control vs. insulin infusion). In 8 subjects, the plasma glucose level during the tolbutamide infusion was kept constant by a concurrent variable glucose infusion. First phase insulin secretion was still increased, though no more than in studies were plasma glucose was not kept constant. However, there was further augmentation of the second phase response (tolbutamide alone, 443 +/- 142 micro U. min/ml; tolbutamide plus glucose, 802 +/- 232 micro U. min/ml; P less than 0.05). These findings indicate that tolbutamide augments first phase insulin secretion in untreated diabetics independently of the prestimulus glucose level. However, changes in the glucose level significantly modulate the sulfonylurea influence on the second phase insulin response to glucose. This effect of glucose level is an important consideration when evaluating the insulinotropic effects of a sulfonylurea.