The Use of Tolbutamide-Induced Hypoglycemia to Examine the Intraislet Role of Insulin in Mediating Glucagon Release in Normal Humans

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Abstract
Disruption of intraislet mechanisms could account for the impaired glucagon response to hypoglycemia in type 1 diabetes. However, in contrast to animals, there is conflicting evidence that such mecha- nisms operate in humans. We have used iv tolbutamide (T) (1.7 g bolus 1 130 mg/h infusion) to create high portal insulin concentrations and compared this with equivalent hypoglycemia using an iv insulin in- fusion (I) (30 mU/m2zmin). Ten normal subjects underwent two hy- poglycemic clamps; mean glucose; I (53 6 1 mg/dL); and T (53 6 1 mg/dL) (2.9 6 0.04 mmol/L vs. 2.9 6 0.05 mmol/L), held for 30 min. During hypoglycemia, mean peripheral insulin levels were greater with I (59 6 4 mU/L) than T (18 6 3 mU/L), P , 0.001. Calculated peak portal insulin concentrations were greater during T (282 6 28 mU/L) than I (78 6 4 mU/L), P , 0.00005. The demonstration of a reduced glucagon response during T-induced hypoglycemia (111 6 8 ng/L vs. 135 6 12 ng/L, P , 0.05) with higher portal insulin concentrations suggests that intraislet mechanisms may contribute to the release of glucagon during hypoglycemia in man. (J Clin Endocrinol Metab 82: 1458 -1461, 1997)

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