Despite evidence that the autonomic nervous system (ANS) makes a significant contribution to increased glucagon secretion during insulin-induced hypoglycemia in several animal species, including a recent study in nonhuman primates, the role of the ANS in mediating this important counterregulatory response in humans remains controversial. Therefore, glucagon responses to insulin-induced hypoglycemia were examined in seven nondiabetic women (BMI, 28.0 ± 2.0 kg/m2) with and without the presence of the ganglionic nicotinic receptor antagonist trimethaphan. Trimethaphan impairs neurotransmission across parasympathetic and sympathetic autonomic ganglia and in the adrenal medulla and, therefore, markedly impairs autonomic activation during insulin-induced hypoglycemia. The studies were performed in random order at least 4 weeks apart. Trimethaphan was infused at a variable rate (0.3−0.6 mg/min) to modestly lower blood pressure (∼10 mmHg) without producing hypotension. Regular human insulin was infused (0.28 pmol · m−2 · min−1) with a variable rate glucose infusion to lower the plasma glucose from 4.9 ± 0.2 to 2.6 ± 0.2 mmol/l in the control study and from 4.9 ± 0.2 to 2.5 ± 0.2 mmol/l in the trimethaphan study. Trimethaphan impaired parasympathetic and sympathoadrenal activation during insulin-induced hypoglycemia as assessed by 70% reductions of the plasma pancreatic polypeptide response and epinephrine response (both P < 0.05 vs. control study). Glucagon secretory responses during insulin-induced hypoglycemia were assessed as peak responses and as the area under the curve (AUC) above baseline values during insulin-induced hypoglycemia. Plasma glucagon increased in the control study from 44 ± 5 ng/l to a peak of 76 ± 9 ng/l (∆ = 32 ± 8 ng/l; P < 0.005 vs. baseline) and in the trimethaphan study from 41 ± 3 to 50 ± 7 ng/l (∆ = 10 ± 5 ng/l; P < 0.02 vs. control subjects). The glucagon response to insulin-induced hypoglycemia as assessed by the AUC was 948 ± 272 ng · I−1 · 45 min−1 in the control study (P < 0.01 vs. baseline), but was reduced by 75% in the trimethaphan study (AUC = 203 ± 94 ng · 1−1 · 45 min−1; P < 0.02 vs. control subjects). Trimethaphan did not affect the glucagon response to arginine administration. These results demonstrate that the ANS mediates the majority of the glucagon response to insulininduced hypoglycemia of 2.5 mmol/l in postmenopausal nondiabetic women.

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