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


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.
Kars
Marleen
M
Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Yang
Ling
L
Gregor
Margaret F
MF
Mohammed
B Selma
BS
Pietka
Terri A
TA
Finck
Brian N
BN
Patterson
Bruce W
BW
Horton
Jay D
JD
Mittendorfer
Bettina
B
Hotamisligil
Gökhan S
GS
Klein
Samuel
S
D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D009928:Organ Specificity; D010919:Placebos; D013655:Taurochenodeoxycholic Acid / Q000627:therapeutic use*; D014280:Triglycerides / Q000378:metabolism
D052242:Adiponectin; D001786:Blood Glucose; D002756:Cholagogues and Choleretics; D007328:Insulin; D010919:Placebos; D014280:Triglycerides; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine