title: Evaluation of the counter-regulatory responses to hypoglycaemia in patients with type 1 diabetes during opiate receptor blockade with naltrexone.
abstract: Hypoglycaemia is the major limiting factor in achieving optimal glycaemic control in people with type 1 diabetes (T1DM), especially intensively treated patients with impaired glucose counter-regulation during hypoglycaemia. Naloxone, an opiate receptor blocker, has been reported to enhance the acute counter-regulatory response to hypoglycaemia when administered intravenously in humans. The current study was undertaken to investigate the oral formulation of the long-acting opiate antagonist, naltrexone, and determine if it could have a similar effect, and thus might be useful therapeutically in treatment of T1DM patients with a high risk of hypoglycaemia.
  
  
  
  We performed a randomized, placebo-controlled, double-blinded, cross-over study in which 9 intensively treated subjects with T1DM underwent a 2-step euglycaemic-hypoglycaemic-hyperinsulinaemic clamp on 2 separate occasions. At 12 hours and at 1 hour before the clamp study, participants received 100 mg of naltrexone or placebo orally. Counter-regulatory hormonal responses were assessed at baseline and during each step of the hyperinsulinaemic-clamp.
  
  
  
  Glucose and insulin levels did not differ significantly between the naltrexone and placebo visits; nor did the glucose infusion rates required to keep glucose levels at target. During hypoglycaemia, naltrexone, in comparison with the placebo group, induced an increase in epinephrine levels ( P  = .05). However, no statistically significant differences in glucagon, cortisol and growth hormone responses were observed.
  
  
  
  In contrast to the intravenous opiate receptor blocker naloxone, overnight administration of the oral long-acting opiate receptor blocker, naltrexone, at a clinically used dose, had a limited effect on the counter-regulatory response to hypoglycaemia in intensively treated subjects with T1DM.
authors.affiliation: Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, Connecticut.|Department of Diabetes and Endocrinology, University College Hospital, London, UK.
authors.forename: Sarita
authors.initials: S
authors.lastname: Naik
authors.affiliation: Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Renata
authors.initials: R
authors.lastname: Belfort-DeAguiar
authors.affiliation: Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, Connecticut.|Department of Cardiology, Nephrology and Endocrinology, Nordsjaellands Hospital, Hillerød, Denmark.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Sejling
authors.affiliation: Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, Connecticut.|Heart Research Follow-Up Program, University of Rochester Medical Center, Rochester, New York.
authors.forename: Barbara
authors.initials: B
authors.lastname: Szepietowska
authors.affiliation: Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sherwin
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D003237:Connecticut / Q000453:epidemiology; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D016903:Drug Monitoring; D004837:Epinephrine / Q000097:blood / Q000378:metabolism; D005260:Female; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D061386:Insulin, Regular, Human / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D009271:Naltrexone / Q000009:adverse effects / Q000627:therapeutic use*; D009325:Nausea / Q000139:chemically induced; D012306:Risk; D018689:Sensory System Agents / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D004837:Epinephrine; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D061386:Insulin, Regular, Human; D009271:Naltrexone; D018689:Sensory System Agents; C517652:hemoglobin A1c protein, human
keywords: counter-regulatory hormonal response; hypoglycaemia; naltrexone