Impact of Polymorphism in the [[beta].sub.2]-Receptor Gene on Metabolic Responses to Repeated Hypoglycemia in Healthy Humans

Context: The [Arg.sup.16] variant in the [[beta].sub.2]-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus. Objective: We hypothesized that the [Arg.sup.16] variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia. Methods: Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either [Arg.sup.16] (AA; n = 13) or [Gly.sup.16] (GG; n = 12) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3. Results: During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean [+ or -] standard error of the mean of area under the curve) of glycerol (-13.1 [+ or -] 3.8 [micro]mol [L.sup.-1] hours; P = .0052), FFA (-30.2 [+ or -] 11.1 [micro]mol [L.sup.-1] hours; P = .021), and [beta]-hydroxybutyrate (-0.008 [+ or -] 0.003 mmol [L.sup.-1] hour; P = .027), while in GG subjects alanine response was increased (negative response values) (-53.9 [+ or -] 20.6 [micro]mol [L.sup.-1] hour; P = .024). Conclusion: There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and [beta]-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects. Key Words: hypoglycemia, genetic polymorphism, [[beta].sub.2]-receptor gene Abbreviations: AA, homozygous for the Arg16 allele of the [[beta].sub.2]-receptor gene; ADRB2, [[beta].sub.2]-receptor gene; AUC, area under the curve; [CI.sub.95], 95% confidence interval; CO, cardiac output; DIA, diastolic pressure; E1, E2, E3, E4, euglycemic period 1-4; EGP, endogenous glucose production; FFA, free fatty acid; GG, homo-zygous for the Gly16 allele of the [[beta].sub.2]-receptor gene; GH, growth hormone; GIR, glucose infusion rate; H1, H2, H3, hypoglycemia period 1-3; HAAF, hypoglycemia associated autonomic failure; HR, heart rate; MAP, mean arterial pressure; SEM, standard error of the m