title: 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.
  
  
  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.
authors.affiliation: Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ranjani
authors.initials: R
authors.lastname: Ramanathan
authors.forename: Philip E
authors.initials: PE
authors.lastname: Cryer
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000704:Analysis of Variance; D001285:Atropine / Q000494:pharmacology; D001341:Autonomic Nervous System / Q000187:drug effects*; D001786:Blood Glucose; D004837:Epinephrine / Q000097:blood*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007003:Hypoglycemia / Q000097:blood*; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000097:blood*; D010646:Phentolamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D001786:Blood Glucose; D007328:Insulin; D018727:Muscarinic Antagonists; D001285:Atropine; D011433:Propranolol; D009638:Norepinephrine; D004837:Epinephrine; D010646:Phentolamine