Preliminary report: genetic variation within the GPBAR1 gene is not associated with metabolic traits in white subjects at an increased risk for type 2 diabetes mellitus.

Bile acids are signaling molecules with important endocrine functions. Some of these, including the induction of energy expenditure in brown adipose tissue and skeletal muscle as well as the stimulation of glucagon-like peptide-1 (GLP-1) production in enteroendocrine L-cells, are mediated by the G-protein-coupled bile acid receptor 1 (GPBAR1). Therefore, we investigated in a cohort of white subjects at increased risk for type 2 diabetes mellitus whether a genetic variation within the GPBAR1 gene contributes to prediabetic phenotypes, such as disproportionate fat distribution, insulin resistance, or beta-cell dysfunction. We genotyped 1576 subjects (1043 women, 533 men) for the single nucleotide polymorphism rs3731859 in the GPBAR1 gene. All subjects underwent an oral glucose tolerance test; a subset additionally had a hyperinsulinemic-euglycemic clamp. Regional fat distribution, ectopic hepatic and intramyocellular lipids were determined by magnetic resonance techniques. Peak aerobic capacity, a surrogate parameter for oxidative capacity of skeletal muscle, was measured by an incremental exercise test on a motorized treadmill. Total GLP-1 and gastric inhibitory peptide levels were determined by radioimmunoassay. After appropriate adjustment and Bonferroni correction for multiple comparisons, rs3731859 was not significantly associated with regional or ectopic fat distribution, peak aerobic capacity, levels of incretins, insulin sensitivity, or indices of insulin secretion. Nominal associations were found between rs3731859 and body mass index, waist circumference, fasting GLP-1 levels, and intramyocellular lipids in the soleus muscle (P = .02, P = .02, P = .05, and P = .03, respectively). Our data suggest that a common genetic variation within the GPBAR1 gene may not play a major role in the development of prediabetic phenotypes in our white population.