Human Insulin Resistance is Associated with Increased Plasma Levels of 12α-hydroxylated Bile Acids.

Bile acids (BAs) exert pleiotropic metabolic effects, and physicochemical properties of different BAs affect their function. In rodents, insulin regulates BA composition, in part by regulating the BA 12α-hydroxylase, Cyp8b1. However, it's unclear whether a similar effect occurs in humans. To address this question, we examined the relationship between clamp-measured insulin sensitivity and plasma BA composition in a cohort of 200 healthy subjects and 35 type 2 diabetes (T2D) patients. In healthy subjects, insulin resistance (IR) was associated with increased 12hydroxylated BAs (cholic acid, deoxycholic acid, and their conjugated forms). Furthermore, ratios of 12hydroxylated/non-12hydroxylated BA were associated with key features of IR including higher insulin, proinsulin, glucose, glucagon, and triglyceride levels, and lower HDL-cholesterol. In T2D patients, BAs were nearly twofold elevated, and more hydrophobic, compared to healthy subjects, though we did not observe disproportionate increases in 12hydroxylated BAs. In multivariate analysis of the whole dataset, controlling for gender, age, BMI, and glucose tolerance status, higher 12hydroxy/non-12hydroxy BA ratios were associated with lower insulin sensitivity and higher plasma triglycerides. These findings suggest a role for 12hydroxylated BAs in metabolic abnormalities in the natural history of T2D, and raise the possibility of developing insulin-sensitizing therapeutics based on manipulations of BA composition.