Impact of genetic polymorphism in the β₂-receptor gene on risk of severe hypoglycemia in patients with type 1 diabetes

Context and Objective: Severe hypoglycemic events are unevenly distributed in subjects with type 1 diabetes making a genetic influence probable. The adrenergic beta-2-receptor gene (ADRB2) has several common polymorphisms of which the Arg16 allele is associated with receptor down-regulation and reduced agonist-mediated endogenous glucose production. We tested the hypothesis that the Arg16 variant is associated with severe hypoglycaemia.

Method: A cohort of 311 subjects with type 1 diabetes reported severe hypoglycemic events retrospectively in a validated questionnaire. The subjects were characterized by diabetes history, state of hypoglycemia awareness (Clarke, Gold, and Hillerød methods), C-peptide status, hemoglobin A1c (HbA1c), and ADRB2 genotype.

Results: The ADRB2 Gly16Arg genotype distribution was in Hardy-Weinberg equilibrium. There was a difference in rate of severe hypoglycemia between all genotypes (P=0.01). Subjects homozygous for the Arg16 genotype (AA, n=60) had a relative rate of severe hypoglycemia of 2.2 (CI95 1.3-3.6) compared to subjects homozygous for the Gly16 genotype (GG, n=116) (P=0.002). Among subjects with impaired awareness or unawareness (n=175) those with the AA genotype (n=33) had a relative rate of severe hypoglycemia of 3.2 (CI95 1.7-6.0) compared to subjects with the GG genotype (n=58) (P<0.000). Genotype was not associated with state of hypoglycemia awareness per se as assessed by any of three classification methods. The difference was not explained by other risk factors (duration of diabetes, HbA1c, C-peptide).

Conclusions: Genetic polymorphism in the beta-2-receptor gene is associated with risk of severe hypoglycemia in individuals with type 1 diabetes, especially in those with impaired hypoglycemia awareness.