Autonomic Mediation of Glucagon Secretion During Insulin-Induced Hypoglycemia in Rhesus Monkeys

Autonomic activation mediates the majority of the increase of glucagon secretion during insulin-induced hypoglycemia in several species including dogs, mice, and rats. However, the role of the autonomic nervous system to increase glucagon during hypoglycemia in humans remains controversial, and investigations in nonhuman primates have not been previously conducted. The autonomic contribution to glucagon secretion during hypoglycemia in a nonhuman primate was examined by two independent pharmacological approaches. Glucagon responses to clamped insulin-induced hypoglycemia were compared in conscious rhesus monkeys in the presence or absence of ganglionic blockade with trimethaphan, or during combined muscarinic and adrenergic receptor blockade with atropine, propranolol, and tolazoline. Insulin- induced hypoglycemia (plasma glucose = 1.9 ± 0.1 mmol/l) activated parasympathetic nerves to the pancreas as assessed by increased plasma pancreatic polypeptide (PP) levels (δ= 135.0 ± 36.8 pmol/l, P < 0.01), produced sympathoadrenal activation as assessed by elevations of plasma epinephrine (EPI) (δ = 22.3 ± 2.95 nmol/l, P < 0.0005) and norepinephrine (NE) (δ = 3.72 ± 0.77 nmol/l, P < 0.0025) and increased plasma inununoreactive glucagon (IRG) (δ = 920 ± 294 ngfl, P < 0.025). Nicotinic ganglionic blockade with trimethaphan prevented parasympathetic (δPP = 16.5 ± 16.3 pmol/l, P < 0.01 vs. control) and sympathoadrenal (δEPI = 1.52 ± 0.98 nmol/l; δNE = -0.62 ± 0.24 nmol/l, both P < 0.0025 vs. control) activation during hypoglycemia and inhibited the IRG response by 70% (δ = 278 ± 67 ng/l,P < 0.025 vs. control). Combined muscarinic and adrenergic receptor blockade reduced parasympathetic activation (δPP = 48.3 ± 16.3 pmol/l, P < 0.01 vs. control) and inhibited the IRG response by a similar degree to ganglionic blockade (δIRG = 284 ± 60 ngfl, P < 0.025 vs. control). These results demonstrate by two independent pharmacological approaches that autonomic activation makes a substantial contribution to increased glucagon secretion during hypoglycemia of ∼2.0 mmol/l in a species of nonhuman primate.