Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women

Marleen Kars, Ling Yang, Margaret F Gregor, B Selma Mohammed, Terri A Pietka, Brian N Finck, Bruce W Patterson, Jay D Horton, Bettina Mittendorfer, Gökhan S Hotamisligil, Samuel Klein, Marleen Kars, Ling Yang, Margaret F Gregor, B Selma Mohammed, Terri A Pietka, Brian N Finck, Bruce W Patterson, Jay D Horton, Bettina Mittendorfer, Gökhan S Hotamisligil, Samuel Klein

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 multiorgan insulin action and metabolic factors associated with insulin resistance in obese men and women.

Research design and methods: Twenty obese subjects ([means +/- SD] aged 48 +/- 11 years, BMI 37 +/- 4 kg/m2) were randomized to 4 weeks of treatment with TUDCA (1,750 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 signaling, and cellular markers of ER stress. RESULTS Hepatic and muscle insulin sensitivity increased by approximately 30% (P < 0.05) after treatment with TUDCA but did not change after placebo therapy. In addition, therapy with TUDCA, but not placebo, increased muscle insulin signaling (phosphorylated insulin receptor substrate(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.

Conclusions: 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.

Figures

FIG. 1.
FIG. 1.
Liver, muscle, and adipose tissue insulin sensitivity before (□) and after () 4 weeks of placebo or TUDCA treatment. A: Hepatic insulin sensitivity index. B: Glucose rate of disappearance (Rd); data represent only 8 of 10 subjects who received TUDCA treatment because of technical difficulties in obtaining blood samples in two subjects. C: Palmitate rate of appearance. Values are means ± SD. *Value significantly different from corresponding value before treatment, P < 0.05. †Main effect of insulin, P < 0.0001.
FIG. 2.
FIG. 2.
Effect of placebo (□) or TUDCA () treatment on skeletal muscle IRSTyr, AktSer473, and JNKThr183/Tyr185 levels. Values are means ± SD and expressed relative to values before treatment, which were set to one for each person. *Value significantly different from corresponding placebo value, P < 0.05.
FIG. 3.
FIG. 3.
Endoplasmic reticulum stress markers before (□) and after () placebo or TUDCA therapy. A: Gene expression (relative to 18S rRNA). B: Protein content (relative to actin). Values are medians and quartiles.

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