title: Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans.
abstract: The aim of the study was to determine the effects of specific levels of antecedent hypoglycemia on subsequent autonomic, neuroendocrine, and metabolic counterregulatory responses. Eight healthy, overnight-fasted male subjects were studied during 2-day protocols on four separate randomized occasions separated by at least 2 months. On day 1, insulin was infused at a rate of 9 pmol x kg(-1) x min(-1) and 2-h clamped euglycemia (plasma glucose 5.2 +/- 0.2 mmol/l) or differing hypoglycemia (plasma glucose 3.9 +/- 0.1, 3.3 +/- 0.1, or 2.9 +/- 0.1 mmol/l) was obtained during morning and afternoon. The next morning after an evening meal and 10-h overnight fast, each subject underwent a 2-h hyperinsulinemic (9 pmol x kg(-1) x min[-1]) hypoglycemic (2.9 +/- 0.1 mmol/l) clamp study. Despite equivalent day 2 plasma glucose and insulin levels, differing levels of antecedent hypoglycemia produced specific blunting of subsequent counterregulatory responses. Day 1 hypoglycemia of 3.9 mmol/l resulted in significantly (P < 0.01) blunted epinephrine, muscle sympathetic nerve activity, and glucagon responses. Day 1 hypoglycemia of 3.3 mmol/l resulted in additional significant blunting (P < 0.01) of pancreatic polypeptide, norepinephrine, growth hormone, endogenous glucose production, and lipolytic responses. Deeper day 1 hypoglycemia of 2.9 mmol/l produced similar day 2 counterregulatory failure as day 1 hypoglycemia of 3.3 mmol/l. In summary, in healthy overnight-fasted men, mild antecedent hypoglycemia of 3.9 mmol/l significantly blunts sympathoadrenal and glucagon, but not other forms of neuroendocrine counterregulatory responses, to subsequent hypoglycemia. Antecedent hypoglycemia of 3.3 mmol/l resulted in additional significant blunting of all major neuroendocrine and metabolic responses to subsequent hypoglycemia. We conclude that in normal humans, there is a hierarchy of blunted counterregulatory responses that are determined by the depth of antecedent hypoglycemia.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6303, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Davis
authors.forename: C
authors.initials: C
authors.lastname: Shavers
authors.forename: R
authors.initials: R
authors.lastname: Mosqueda-Garcia
authors.forename: F
authors.initials: F
authors.lastname: Costa
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000097:blood; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006943:Hyperglycemia / Q000097:blood* / Q000503:physiopathology; D007003:Hypoglycemia / Q000097:blood* / Q000503:physiopathology; D007328:Insulin / Q000008:administration & dosage / Q000097:blood; D008297:Male; D009490:Neurosecretory Systems / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood; D010191:Pancreatic Polypeptide / Q000097:blood; D016037:Single-Blind Method; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D007328:Insulin; D019382:Human Growth Hormone; D010191:Pancreatic Polypeptide; D005934:Glucagon; D005947:Glucose; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine