Insulin Sensitivity and Body Weight Changes in Young White Carriers of the Codon 64 Amino Acid Polymorphism of the β₃-Adrenergic Receptor Gene

Abstract

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the β₃-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the β₃-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstNl. The allelic frequency of the mutated allele was 7% (95% CI: 5–10%), and it was similar in obese and nonobese subjects. The β₃-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (S_I) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 ± 1.3 vs. 23.5 ± 3.7 kg/m² [mean ± SD]; P = 0.032), lower S_I [4.9 ± 2.9 vs. 15.4 ± 9.0 10⁻⁵ × (min × pmol/l)⁻¹; P = 0.013], and higher fasting serum C-peptide (730 ± 155 vs. 471 ± 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO_2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the S_I (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the β₃-adrenergic receptor may be associated with obesity and, independent of BMI, with a low S_I Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed.