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

Research output: Contribution to journalArticle

230 Citations (Scopus)

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 ∼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 substrateTyr and AktSer473 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.

Original languageEnglish (US)
Pages (from-to)1899-1905
Number of pages7
JournalDiabetes
Volume59
Issue number8
DOIs
StatePublished - Aug 2010

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Insulin Resistance
Adipose Tissue
Endoplasmic Reticulum Stress
Muscles
Liver
Placebos
Insulin
Therapeutics
Obese Mice
Glucose Clamp Technique
Protein Folding
Insulin Receptor
tauroursodeoxycholic acid
Bile Acids and Salts
Research Design
Obesity
Pharmacology
Biopsy

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Kars, M., Yang, L., Gregor, M. F., Mohammed, B. S., Pietka, T. A., Finck, B. N., ... Klein, S. (2010). Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes, 59(8), 1899-1905. https://doi.org/10.2337/db10-0308

Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. / Kars, Marleen; Yang, Ling; Gregor, Margaret F.; Mohammed, B. Selma; Pietka, Terri A.; Finck, Brian N.; Patterson, Bruce W.; Horton, Jay D.; Mittendorfer, Bettina; Hotamisligil, Gökhan S.; Klein, Samuel.

In: Diabetes, Vol. 59, No. 8, 08.2010, p. 1899-1905.

Research output: Contribution to journalArticle

Kars, M, Yang, L, Gregor, MF, Mohammed, BS, Pietka, TA, Finck, BN, Patterson, BW, Horton, JD, Mittendorfer, B, Hotamisligil, GS & Klein, S 2010, 'Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women', Diabetes, vol. 59, no. 8, pp. 1899-1905. https://doi.org/10.2337/db10-0308
Kars, Marleen ; Yang, Ling ; Gregor, Margaret F. ; Mohammed, B. Selma ; Pietka, Terri A. ; Finck, Brian N. ; Patterson, Bruce W. ; Horton, Jay D. ; Mittendorfer, Bettina ; Hotamisligil, Gökhan S. ; Klein, Samuel. / Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. In: Diabetes. 2010 ; Vol. 59, No. 8. pp. 1899-1905.
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AU - Yang, Ling

AU - Gregor, Margaret F.

AU - Mohammed, B. Selma

AU - Pietka, Terri A.

AU - Finck, Brian N.

AU - Patterson, Bruce W.

AU - Horton, Jay D.

AU - Mittendorfer, Bettina

AU - Hotamisligil, Gökhan S.

AU - Klein, Samuel

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N2 - 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 ∼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 substrateTyr and AktSer473 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.

AB - 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 ∼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 substrateTyr and AktSer473 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.

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