Abstract

Objective: Insulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical chaperone to enhance protein folding and ameliorate ER stress, increases insulin sensitivity. The purpose of this study was to determine the effect of TUDCA therapy on multi-organ insulin action and metabolic factors associated with insulin resistance in obese men and women.

Research Design and Methods: Twenty obese subjects (age: 48 ± 11 y, body mass index: 37 ± 4 kg/m²; means ± SD) were randomized to 4 weeks of treatment with TUDCA (1750 mg/day) or placebo. A two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions and muscle and adipose tissue biopsies were used to evaluate in vivo insulin sensitivity, cellular factors involved in insulin signalling, and cellular markers of ER stress.

Results: Hepatic and muscle insulin sensitivity increased by ∼30% after treatment with TUDCA, but did not change after placebo therapy (P <0.05). In addition, therapy with TUDCA, but not placebo, increased muscle insulin signalling (phosphorylated IRS^Tyr and Akt^Ser473 levels) (P <0.05). Markers of ER stress in muscle or adipose tissue did not change after treatment with either TUDCA or placebo.

Conclusion: These data demonstrate that TUDCA might be an effective pharmacological approach for treating insulin resistance. Additional studies are needed to evaluate the target cells and mechanisms responsible for this effect.