Impact of polymorphism in the β₂-receptor gene on metabolic responses to repeated hypoglycaemia in healthy humans

CONTEXT: The Arg 16 variant in the β₂-receptor gene is associated with increased risk of severe hypoglycaemia in subjects with type 1 diabetes mellitus.

OBJECTIVE: We hypothesized that the Arg 16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycaemia.

DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg 16 (AA; n=13) or Gly 16 (GG; n=12) participated in two consecutive trial days with three periods of hypoglycaemia (H1-H3) induced by a hyperinsulinemic hypoglycaemic clamp.

MAIN OUTCOME MEASURE: Mean glucose infusion rate (GIR) during H1-H3.

RESULTS: During H1-H3, there was neither difference between AA or GG subjects in GIR, counterregulatory hormones (glucagon, epinephrine, cortisol, growth hormone) or substrate levels of lactate, glycerol, and free fatty acids (FFA), nor symptom response score nor cognitive performance (trail making test, Stroop test). At H3 lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean ± SEM of area under the curve) of glycerol (-13.1 ± 3.8 μmol l -1 h; P = 0.0052), FFA (-30.2 ± 11.1 μmol l -1 h; P = 0.021), and ß-hydroxybutyrate (-0.008 ± 0.003 mmol l -1 h; P = 0.027), while in GG subjects alanine response was increased (negative response values)(-53.9 ± 20.6 μmol l -1 h; P = 0.024).

CONCLUSION: There was no difference in GIR between genotype groups, but secondary outcomes suggest, a down-regulation of the lipolytic and ß-hydroxybutyrate responses to recurrent hypoglycaemia in AA subjects, in contrast to the responses in GG subjects.