title: The effect of antecedent hypoglycaemia on β₂-adrenergic sensitivity in healthy participants with the Arg16Gly polymorphism of the β₂-adrenergic receptor.
abstract: OBJECTIVE
  Homozygosity for glycine at codon 16 (GlyGly) of the β(2)-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on β(2)-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the β(2)-adrenergic receptor.
  
  
  METHODS
  We enrolled 16 healthy participants, who were either GlyGly (n = 8) or ArgArg (n = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the β(2)-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC(25)).
  
  
  RESULTS
  The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p = 0.078), consistent with increased β(2)-adrenergic receptor sensitivity. This effect was driven by a significant increase in β(2)-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC(25) in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p = 0.047).
  
  
  CONCLUSIONS
  Antecedent hypoglycaemia did not affect β(2)-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in β(2)-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00160056.
authors.affiliation: Department of Pharmacology-Toxicology 149, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, PO Box 9101, 6500HB Nijmegen, the Netherlands. b.schouwenberg@pharmtox.umcn.nl
authors.forename: B J J W
authors.initials: BJ
authors.lastname: Schouwenberg
authors.forename: P
authors.initials: P
authors.lastname: Smits
authors.forename: C J
authors.initials: CJ
authors.lastname: Tack
authors.forename: B E
authors.initials: BE
authors.lastname: de Galan
mesh_terms: D000328:Adult; D000420:Albuterol / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D005260:Female; D006720:Homozygote; D006801:Humans; D007003:Hypoglycemia / Q000097:blood* / Q000235:genetics*; D008297:Male; D011110:Polymorphism, Genetic / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D018343:Receptors, Adrenergic, beta-2; D014665:Vasodilator Agents; D000420:Albuterol