Adrenergic mediation of hypoglycemia-associated autonomic failure

Abstract

Objective: We tested the hypothesis that adrenergic activation, cholinergic activation, or both, mediate the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans.

Research design and methods: Seventeen healthy adults were studied on 2 consecutive days on three occasions. Day 1 involved hyperinsulinemic euglycemic (90 mg/dL × 1 h), then hypoglycemic (54 mg/dL × 2 h) clamps, in the morning and afternoon on all three occasions with 1) saline infusion, 2) adrenergic blockade with the nonselective α-adrenergic and β-adrenergic antagonists phentolamine and propranolol, or 3) adrenergic blockade plus cholinergic blockade with the muscarinic cholinergic antagonist atropine in random sequence. Day 2 involved similar morning euglycemic and hypoglycemic clamps, with saline infusion, on all three occasions.

Results: Compared with the responses to hypoglycemia during saline infusion on day 1, the plasma epinephrine and norepinephrine responses to hypoglycemia were reduced on day 2 (351 ± 13 vs. 214 ± 22 pg/mL for epinephrine and 252 ± 4 vs. 226 ± 7 pg/mL for norepinephrine during the last hour; both P < 0.0001). However, the plasma epinephrine and norepinephrine responses to hypoglycemia were not reduced on day 2 when adrenergic or adrenergic plus cholinergic blockade was produced during hypoglycemia on day 1.

Conclusions: Adrenergic blockade prevents the effect of hypoglycemia to reduce the plasma catecholamine responses to subsequent hypoglycemia. Thus, adrenergic activation mediates the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans.

Figures

FIG. 1.

Mean (SEs within the symbols) plasma glucose concentrations are shown during morning and afternoon hyperinsulinemic euglycemic and hypoglycemic clamps with intravenous infusions of saline (○), phentolamine plus propranolol (PTL + PRP, □) or phentolamine plus propranolol with injection of atropine (PTL + PRP + Atropine, △) on day 1 and during morning hyperinsulinemic euglycemic and hypoglycemic clamps with intravenous infusion of saline on day 2 after saline (●), PTL + PRP (■) or PTL + PRP + Atropine (▲) on day 1 on three separate occasions.

FIG. 2.

Mean (± SE) plasma epinephrine, norepinephrine, and pancreatic polypeptide concentrations are shown during morning hyperinsulinemic euglycemic and hypoglycemic clamps with intravenous infusions of saline (○), phentolamine plus propranolol (PTL + PRP, □), or phentolamine plus propranolol with atropine (△) on day 1. The P values represent comparisons with the values during saline infusion (both P < 0.0001) for epinephrine and norepinephrine and comparisons with values during phentolamine plus propranolol with atropine (P < 0.0001) for pancreatic polypeptide.

FIG. 3.

Mean (± SE) plasma insulin, glucagon, growth hormone, and cortisol concentrations are shown during morning hyperinsulinemic euglycemic and hypoglycemic clamps with intravenous infusions of saline (○), phentolamine plus propranolol (□), or phentolamine plus propranolol with atropine (△) on day 1. The P values represent comparisons with the values during saline, both P < 0.0001 for insulin, growth hormone, and cortisol.

FIG. 4.

Mean (± SE) plasma epinephrine, norepinephrine, and pancreatic polypeptide concentrations are shown during morning hyperinsulinemic euglycemic and hypoglycemic clamps on day 1 with saline infusion (○) and on day 2 after saline (●), phentolamine plus propranolol (PTL + PRP, ■), or phentolamine plus propranolol with atropine (PTL + PRP + Atropine, ▲) during the clamps on day 1. The P values represent comparisons with the values during saline infusion on day 1 (○), P < 0.0001 for epinephrine and norepinephrine on day 2 (●), and P < 0.0001 for pancreatic polypeptide under all three conditions on day 2 (●, ■, and ▲).

FIG. 5.

Mean (± SE) plasma insulin, glucagon, growth hormone, and cortisol concentrations are shown during morning hyperinsulinemic euglycemic and hypoglycemic clamps on day 1 with saline infusion (○) and on day 2 after saline (●), phentolamine plus propranolol (■), or phentolamine plus propranolol with atropine (▲) during the clamps on day 1. The P values represent comparisons with the values during saline on day 1 (○); see text for details.