THE USE OF TOLBUTAMIDE-INDUCED HYPOGLYCEMIA TO EXAMINE THE INTRAISLETROLE OF INSULIN IN MEDIATING GLUCAGON-RELEASE IN NORMAL HUMANS

Disruption of intraislet mechanisms could account for the impaired glu cagon response to hypoglycemia in type 1 diabetes. However, in contras t to animals, there is conflicting evidence that such mechanisms opera te in humans. Ne have used iv tolbutamide(T) (1.7 g bolus + 130 mg/h i nfusion) to create high portal insulin concentrations and compared thi s with equivalent hypoglycemia using an iv insulin infusion (I) (30 mU /m(2).min). Ten normal subjects underwent two hypoglycemic clamps; mea n glucose; I (53 +/- 1 mg/dL); and T (53 +/- 1 mg/dL) (2.9 +/- 0.04 mm ol/L vs. 2.9 +/- 0.05 mmol/L), held for 30 min. During hypoglycemia, m ean peripheral insulin levels were greater with I (59 +/- 4 mU/L) than T (18 +/- 3 mU/L), P < 0.001. Calculated peak portal insulin concentr ations were greater during T (282 +/- 28 mU/L) than I (78 +/- 4 mU/L), P < 0.00005. The demonstration of a reduced glucagon response during T-induced hypoglycemia (111 +/- 8 ng/L us. 135 +/- 12 ng/L, P < 0.05) with higher portal insulin concentrations suggests that intraislet mec hanisms may contribute to the release of glucagon during hypoglycemia in man.