TUDCA (Tauroursodeoxycholic Acid ) and Diabetes

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

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.

The ability of insulin to decrease hepatic glucose production, suppress adipose tissue lipolytic rate, and stimulate skeletal muscle glucose uptake is critical for normal metabolic function. Obesity is an important cause of multiorgan insulin resistance (1–3), and insulin sensitivity decreases linearly with increasing BMI (4,5). Insulin resistance has important clinical implications because it is involved in the pathogenesis of many of the metabolic complications associated with obesity. The precise mechanisms responsible for the link between obesity and insulin resistance are not known but likely involve alterations in fatty acid metabolism, excess triglyceride accumulation in the liver and muscle (6–11), and systemic low-grade inflammation (12–14).

Recently, endoplasmic reticulum (ER) stress has been identified as a contributor to insulin resistance associated with obesity in experimental models (15,16). The ER is responsible for the synthesis, folding, and trafficking of secretory and membrane proteins. Disruption of ER homeostasis results in an adaptive unfolded protein response (UPR), which aims to restore ER folding capacity and mitigate stress. ER stress can also inhibit insulin signaling, at least in part, by activating the c-Jun NH2-terminal kinase (JNK) pathway through inositol-requiring enzyme (IRE)-1 (15,17–20) or RNA-dependent protein kinase (PKR)-mediated mechanisms (21). Increased ER stress is associated with impaired insulin action in obese mice (15), and chemical or genetic amelioration of this stress improves insulin sensitivity and glucose homeostasis (18). Increased ER stress in liver and adipose tissue and insulin resistance are also associated with obesity in humans (22,23), whereas weight loss decreases ER stress and improves insulin sensitivity (22).

Tauroursodeoxycholic acid (TUDCA) is a bile acid derivative that has been used in Europe to treat cholelithiasis and cholestatic liver disease. TUDCA can also act as a chemical chaperone to enhance protein folding and protect cells against ER stress (18). In obese mice, parenteral TUDCA treatment reduces ER stress, improves systemic insulin resistance, and decreases intrahepatic triglyceride (IHTG) content (18). Although data from studies conducted in animal models and cell systems demonstrate beneficial metabolic effects, the effect of TUDCA on insulin action has not been studied in human subjects.

The purpose of the present study was to determine whether chemical interventions targeting the ER stress pathway results in metabolic benefits in people. Accordingly, we conducted a randomized controlled trial in insulin-resistant, obese subjects to evaluate the effect of treatment with TUDCA on insulin sensitivity in the liver (glucose production), muscle (glucose uptake), and adipose tissue (lipolysis). We hypothesized that treatment with TUDCA would improve multiorgan insulin signaling and sensitivity and other metabolic factors associated with insulin resistance. The hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusions, was used to determine in vivo insulin sensitivity, and adipose tissue and skeletal muscle biopsies were obtained to assess ER stress markers, phosphorylation of JNK, and components of the insulin-signaling pathway before and after 4 weeks of treatment with TUDCA or placebo.

http://diabetes.diabetesjournals.org/content/59/8/1899.full

Type 1 Diabetes Prevention with TUDCA, Phase-1 Trial

https://healthesolutions.com/phase-1-trial-for-type-1-diabetes-prevention-with-tudca/

"Tauroursodeoxycholic Acid (also known as TUDCA or Taurolite) is a chemical found in bile (especially bear bile). Mouse and rat studies have found that TUDCA can preserve beta cells, and it is already approved for us in Europe for relatively rare liver diseases. It is also widely available as a “dietary supplement” in the US."

(snip)

Why Test TUDCA? TUDCA has been found to relieve stress in a particular part of the beta cell (called the ER). The hope is, by lowering this stress, beta cells will not be killed, and either type 1 diabetes will not occur, or it will be less severe, or be delayed. This is based on type-1 diabetes being caused by the following chain of events:

Autoimmune attack –causes→ ER stress –causes→ Type-1 Diabetes

If you can stop/lessen/delay the ER stress you can stop/lessen/delay type-1 diabetes.

Role of endoplasmic reticulum stress and thrombosis in type 2 diabetes-induced vascular dysfunction


Abstract

Endoplasmic reticulum (ER) stress and thrombosis are important mechanisms that underlie many of the serious consequences of type 2 diabetes. However, the interaction between the ER stress and thrombosis in diabetes-induced endothelial dysfunction remains unknown. Ten-weeks-old type 2 diabetic mice (db-/db-) and their controls (db-/db+) treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day, for 2 weeks) were used to determine the in vivo contribution of ER stress in vascular dysfunction. Blood pressure was similar in all groups of mice. Blood glucose and body weight were reduced in (db-/db-) mice treated with TUDCA. The impaired endothelium-dependent relaxation (EDR), in response to acetylcholine, in (db-/db-) mice was restored after treatment with TUDCA in both aorta and mesenteric resistance arteries (MRA). Additionally, ER stress markers (CHOP and ATF4), NADPH oxidase activity and the mRNA levels of Nox2 and Nox4, which were increased in MRA and aorta from (db-/db-) mice, were significantly reduced after TUDCA treatment. Moreover, the vasoconstriction to thrombin and the mRNA levels of thrombin receptor (PAR1) were increased only in MRA from (db-/db-) mice and reduced after treatment with TUDCA. This study unveiled novel role of ER stress in the regulation of thrombin signaling and therefore vascular dysfunction in type 2 diabetes.

http://www.fasebj.org/content/29/1_Supplement/636.4

The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases.

Abstract

Tauroursodeoxycholic acid (TUDCA) is the taurine conjugate of ursodeoxycholic acid (UDCA), a US Food and Drug Administration-approved hydrophilic bile acid for the treatment of certain cholestatic liver diseases. There is a growing body of research on the mechanism(s) of TUDCA and its potential therapeutic effect on a wide variety of non-liver diseases. Both UDCA and TUDCA are potent inhibitors of apoptosis, in part by interfering with the upstream mitochondrial pathway of cell death, inhibiting oxygen-radical production, reducing endoplasmic reticulum (ER) stress, and stabilizing the unfolded protein response (UPR). Several studies have demonstrated that TUDCA serves as an anti-apoptotic agent for a number of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition, TUDCA plays an important role in protecting against cell death in certain retinal disorders, such as retinitis pigmentosa. It has been shown to reduce ER stress associated with elevated glucose levels in diabetes by inhibiting caspase activation, up-regulating the UPR, and inhibiting reactive oxygen species. Obesity, stroke, acute myocardial infarction, spinal cord injury, and a long list of acute and chronic non-liver diseases associated with apoptosis are all potential therapeutic targets for T/UDCA. A growing number of pre-clinical and clinical studies underscore the potential benefit of this simple, naturally occurring bile acid, which has been used in Chinese medicine for more than 3000 years.

http://www.ncbi.nlm.nih.gov/pubmed/24891994