title: Glucagon regulates orexin A secretion in humans and rodents.
abstract: OBJECTIVE
  Orexin A (OXA) modulates food intake, energy expenditure, and lipid and glucose metabolism. OXA regulates the secretion of insulin and glucagon, while glucose regulates OXA release. Here, we evaluate the role of glucagon in regulating OXA release both in vivo and in vitro.
  
  
  METHODS
  In a double-blind crossover study, healthy volunteers and type 1 diabetic patients received either intramuscular glucagon or placebo. Patients newly diagnosed with type 2 diabetes underwent hyperinsulinaemic-euglycaemic clamp experiments, and insulin-hypoglycaemia tests were performed on healthy volunteers. The primary endpoint was a change in OXA levels after intramuscular glucagon or placebo administration in healthy participants and patients with type 1 diabetes. Secondary endpoints included changes in OXA in healthy participants during insulin tolerance tests and in patients with type 2 diabetes under hyperinsulinaemic-euglycaemic conditions. Participants and staff conducting examinations and taking measurements were blinded to group assignment. OXA secretion in response to glucagon treatment was assessed in healthy and obese mice, the streptozotocin-induced mouse model of type 1 diabetes, and isolated rat pancreatic islets.
  
  
  RESULTS
  Plasma OXA levels declined in lean volunteers and in type 1 diabetic patients injected with glucagon. OXA levels increased during hyperinsulinaemic hypoglycaemia testing in healthy volunteers and during hyperinsulinaemic euglycaemic conditions in type 2 diabetic patients. Plasma OXA concentrations in healthy lean and obese mice and in a mouse model of type 1 diabetes were lower after glucagon treatment, compared with vehicle control. Glucagon decreased OXA secretion from isolated rat pancreatic islets at both low and high glucose levels. OXA secretion declined in pancreatic islets exposed to diazoxide at high and low glucose levels, and after exposure to an anti-insulin antibody. Glucagon further reduced OXA secretion in islets pretreated with diazoxide or an anti-insulin antibody.
  
  
  CONCLUSIONS
  Glucagon inhibits OXA secretion in humans and animals, irrespective of changes in glucose or insulin levels. Through modifying OXA secretion, glucagon may influence energy expenditure, body weight, food intake and glucose metabolism.
authors: Department of Endocrinology, Diabetes and Nutrition, Charité-University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Ayman M
authors: AM
authors: Arafat
authors: Przemysław
authors: P
authors: Kaczmarek
authors: Marek
authors: M
authors: Skrzypski
authors: Ewa
authors: E
authors: Pruszyńska-Oszmałek
authors: Paweł
authors: P
authors: Kołodziejski
authors: Aikaterini
authors: A
authors: Adamidou
authors: Stephan
authors: S
authors: Ruhla
authors: Dawid
authors: D
authors: Szczepankiewicz
authors: Maciej
authors: M
authors: Sassek
authors: Maria
authors: M
authors: Billert
authors: Bertram
authors: B
authors: Wiedenmann
authors: Andreas F H
authors: AF
authors: Pfeiffer
authors: Krzysztof W
authors: KW
authors: Nowak
authors: Mathias Z
authors: MZ
authors: Strowski
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism
chemical_list: C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D005934:Glucagon; D005947:Glucose