The Arg16Gly variant of the beta2-adrenergic receptor predisposes to hypoglycemia unawareness in type 1 diabetes mellitus.

Hypoglycemia unawareness has been linked to desensitization of the beta2-adrenergic receptor. Desensitization of the beta2-adrenergic receptor (ADRB2) is genetically determined by the Arg16Gly variant of this receptor. We tested the hypothesis that hypoglycemia unawareness is more common among patients homozygous for the Gly16 variant. We performed genotyping of the A265G (Arg16Gly) polymorphism in the ADRB2 gene in 85 patients with type 1 diabetes and classified them according to hypoglycemia awareness status. A total of 45 patients (53%) were homozygous for Gly16, 32 patients (38%) were heterozygous and eight patients (9%) were homozygous for Arg16. Hypoglycemia unawareness was 3.4-fold more common among patients homozygous for Gly16 than among patients with other variants of the Arg16Gly polymorphism (P=0.014). We conclude that patients with type 1 diabetes who carry two alleles of the Gly16 variant of ADRB2 are at increased risk of developing hypoglycemia unawareness. Future studies are required to confirm these results in larger, independent populations.