Tauroursodeoxycholic Acid May Improve Liver and Muscle but Not Adipose Tissue Insulin Sensitivity in Obese Men and Women

Abstract

OBJECTIVEInsulin 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 METHODSTwenty 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.RESULTSHepatic 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.CONCLUSIONSThese 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.

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…The expansion of ISCs in Xbp1 /(IEC) mice, and the desire to delineate the specific tumor-promoting role of Xbp1 deficiency specifically in IECs, prompted us to Epithelial Xbp1 suppresses tumor formation in Apc min/+ mice Inflammatory signaling is an important contributor to CAC but also to sporadic and familial CRC (Rakoff-Nahoum and Medzhitov, 2007; Lee et al, 2010), with overlapping and distinct inflammatory pathways being involved (Salcedo et al, 2010). ER stress in various organs, including the liver, skeletal muscle, adipose tissue (Ozcan et al, 2004;Gregor et al, 2009;Kars et al, 2010), and intestinal crypts (Hodin et al, 2011), is associated with obesity, which is epidemiologically closely associated with increased cancer incidence, most notably CRC (Calle et al, 2003). CRC and CAC exhibit distinguishing features with regard to their molecular genetic underpinning; ;Apc min mice allowed crypt-specific stratification of Olfm4 + cell enumeration in lysozyme + and lysozyme  crypts (n = 4/4; two-sided Student's t test).…”

An Overview of the Endoplasmic Reticulum Stress and Interrelation with Obesity: Review

“…Ancak, her iki grupta da kas ve adipoz dokudaki ER stres markerlerinde bir değişiklik görülmemiştir. 110 …”

Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

“…However, it is not yet understood whether chemical chaperones could directly improve kidney function or whether these results are simply confounded by the improvement in glycaemic control observed with this class of agents. Despite a recent clinical investigation determining that oral TUDCA administration can increase both hepatic and muscular insulin sensitivities in obese non-diabetic patients (Kars et al 2010), markers of ER stress were not improved and therefore it is evident that there is still relatively little known about the long-term efficacy and target specificity of these ER stress modulators in humans. Enhanced mTORC1 activity in the PTCs not only contributes to proapoptotic pathways, but through the selective activation of the IRE1-JNK pathway could also lead to decreased responsiveness to insulin in the PTCs.…”