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 incl uding dogs, mice, and rats. However, the role of the autonomic nervous system to increase glucagon during hypoglycemia in humans remains con troversial, and investigations in nonhuman primates have not been prev iously conducted. The autonomic contribution to glucagon secretion dur ing hypoglycemia in a nonhuman primate was examined by two independent pharmacological approaches. Glucagon responses to clamped insulin-ind uced hypoglycemia were compared in conscious rhesus monkeys in the pre sence or absence of ganglionic blockade with trimethaphan, or during c ombined muscarinic and adrenergic receptor blockade with atropine, pro pranolol, and tolazoline. Insulin-induced hypoglycemia (plasma glucose = 1.9 +/- 0.1 mmol/l) activated parasympathetic nerves to the pancrea s as assessed by increased plasma pancreatic polypeptide (PP) levels ( Delta = 135.0 +/- 36.8 pmol/l, P < 0.01), produced sympathoadrenal act ivation as assessed by elevations of plasma epinephrine (EPI) (Delta = 22.3 +/- 2.95 nmol/l, P < 0.0005) and norepinephrine (NE) (Delta = 3. 72 +/- 0.77 nmol/l, P < 0.0025) and increased plasma immunoreactive gl ucagon (IRG) (Delta = 920 +/- 294 ng/l, P < 0.025). Nicotinic ganglion ic blockade with trimethaphan prevented parasympathetic (Delta PP = 16 .5 +/- 16.3 pmol/l, P < 0.01 vs. control) and sympathoadrenal (Delta E PI = 1.52 +/- 0.98 nmol/l; Delta NE = -0.62 +/- 0.24 nmol/l, both P < 0.0025 vs. control) activation during hypoglycemia and inhibited the I RG response by 70% (Delta = 278 +/- 67 ng/l, P < 0.025 vs. control). C ombined muscarinic and adrenergic receptor blockade reduced parasympat hetic activation (Delta PP = 48.3 +/- 16.3 pmol/l, P < 0.01 vs. contro l) and inhibited the IRG response by a similar degree to ganglionic bl ockade (Delta IRG = 284 +/- 60 ng/l, P < 0.025 vs. control). These res ults demonstrate by two independent pharmacological approaches that au tonomic activation makes a substantial contribution to increased gluca gon secretion during hypoglycemia of similar to 2.0 mmol/l in a specie s of nonhuman primate.