title: Opioid receptor blockade improves hypoglycemia-associated autonomic failure in type 1 diabetes mellitus.
abstract: BACKGROUND
  Recurrent hypoglycemia induces hypoglycemia-associated autonomic failure (HAAF), characterized by deterioration in counterregulatory responses. Endogenous opioids may mediate the development of HAAF, and blockade of opioid receptors with naloxone prevented HAAF in nondiabetic subjects.
  
  
  OBJECTIVE
  We hypothesized that opioid receptor blockade with naloxone during antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM) would prevent the development of HAAF.
  
  
  METHODS
  Eight subjects with T1DM (three women, aged 34 ± 7.4 yr, hemoglobin A1c 7.3 ± 1.1%) were studied on 2 consecutive days on three separate occasions. Day 1 consisted of: 1) two 90-min hypoglycemic clamps (60 mg/dl, N-); 2) two 90-min hypoglycemic clamps (60 mg/dl) with concomitant naloxone infusion (N+); or 3) two 90-min euglycemic clamps (90 mg/dl) with concomitant naloxone infusion (control). Day 2 consisted of hyperinsulinemic stepped hypoglycemic clamps (90, 80, 70, and 60 mg/dl plasma glucose steps).
  
  
  METHODS
  Day 2 hypoglycemia counterregulatory hormonal response and glucose turnover [(3-(3)H)-glucose] as indicators of recovery from hypoglycemia.
  
  
  RESULTS
  Antecedent hypoglycemia in N- group resulted in a markedly decreased epinephrine response and a lower rate of endogenous glucose production (EGP) during subsequent hypoglycemia compared with control (75 ± 17 vs. 187 ± 21 pg/ml, P < 0.05 and 0.8 ± 0.1 vs. 1.4 ± 0.2 mg/kg · min, P < 0.05, respectively). In contrast, in the N+ studies, plasma epinephrine was 164 ± 18 pg/ml and EGP was 1.3 ± 0.2 mg/kg · min during subsequent hypoglycemia, both levels similar to those seen in control studies (P = NS vs. control). Plasma glucagon did not increase with hypoglycemia.
  
  
  CONCLUSIONS
  Blockade of endogenous opioids with naloxone during antecedent hypoglycemia improves HAAF in patients with T1DM by ameliorating the epinephrine response and restoring EGP.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Belfer 702, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Septimiu
authors.initials: S
authors.lastname: Vele
authors.forename: Sofiya
authors.initials: S
authors.lastname: Milman
authors.forename: Harry
authors.initials: H
authors.lastname: Shamoon
authors.forename: Ilan
authors.initials: I
authors.lastname: Gabriely
mesh_terms: D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D001786:Blood Glucose / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000503:physiopathology*; D004837:Epinephrine / Q000097:blood*; D005260:Female; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000503:physiopathology*; D008297:Male; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D054970:Pure Autonomic Failure / Q000097:blood / Q000503:physiopathology*
chemical_list: D001786:Blood Glucose; D009292:Narcotic Antagonists; D009270:Naloxone; D004837:Epinephrine