taurochenodeoxycholic-acid and Hyperglycemia

Postprandial hyperglycaemia leads to a transient impairment in endothelial function; however, the mechanisms remain largely unknown. Previous work in cell culture models demonstrate that high glucose results in endoplasmic reticulum (ER) stress and, in animal studies, ER stress has been implicated as a cause of endothelial dysfunction. In the present study, we tested the hypothesis that acute oral administration of tauroursodeoxycholic acid (TUDCA, 1500 mg), a chemical chaperone known to alleviate ER stress, would prevent hyperglycaemia-induced endothelial dysfunction. In 12 young healthy subjects (seven men, five women), brachial artery flow-mediated dilation (FMD) was assessed at baseline, and at 60 and 120 min after an oral glucose challenge. Subjects were tested on two separate visits in a single-blind randomized cross-over design: after oral ingestion of TUDCA or placebo capsules. FMD was reduced from baseline during hyperglycaemia under the placebo condition (-32% at 60 min and -28% at 120 min post oral glucose load; P<0.05 from baseline) but not under the TUDCA condition (-4% at 60 min and +0.3% at 120 min post oral glucose load; P>0.05 from baseline). Postprandial plasma glucose and insulin were not altered by TUDCA ingestion. Plasma oxidative stress markers 3-nitrotyrosine and thiobarbituric acid reactive substance (TBARS) remained unaltered throughout the oral glucose challenge in both conditions. These results suggest that hyperglycaemia-induced endothelial dysfunction can be mitigated by oral administration of TUDCA, thus supporting the hypothesis that ER stress may contribute to endothelial dysfunction during postprandial hyperglycaemia.

Topics: Adult; Blood Glucose; Cardiovascular Diseases; Endoplasmic Reticulum Stress; Endothelium, Vascular; Female; Humans; Hyperglycemia; Insulin; Male; Oxidative Stress; Postprandial Period; Taurochenodeoxycholic Acid; Thiobarbituric Acid Reactive Substances; Tyrosine; Young Adult

Despite the recent attention focused on the important role of autophagy in maintaining podocyte homeostasis, little is known about the changes and mechanisms of autophagy in podocyte dysfunction under diabetic condition. In this study, we investigated the role of autophagy in podocyte biology and its involvement in the pathogenesis of diabetic nephropathy. Podocytes had a high basal level of autophagy. And basal autophagy inhibition either by 3-methyladenenine (3-MA) or by Beclin-1 siRNA was detrimental to its architectural structure. However, under diabetic condition in vivo and under high glucose conditions in vitro, high basal level of autophagy in podocytes became defective and defective autophagy facilitated the podocyte injury. Since the dynamics of endoplasmic reticulum(ER) seemed to play a vital role in regulating the autophagic flux, the results that Salubrinal/Tauroursodeoxycholic acid (TUDCA) could restore defective autophagy further indicated that the evolution of autophagy may be mediated by the changes of cytoprotective output in the ER stress. Finally, we demonstrated in vivo that the autophagy of podocyte was inhibited under diabetic status and TUDCA could improve defective autophagy. Taken together, these data suggested that autophagy might be interrupted due to the failure of ER cytoprotective capacity upon high glucose induced unmitigated stress, and the defective autophagy might accelerate the irreparable progression of diabetic nephropathy.

Topics: Adenine; Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Diabetic Nephropathies; Endoplasmic Reticulum; Hyperglycemia; Mice; Podocytes; RNA, Small Interfering; Taurochenodeoxycholic Acid

In obesity and diabetes, adipocytes show significant endoplasmic reticulum (ER) stress. Hyperglycemia-induced ER stress has not been studied in adipocyte differentiation and adipokine expression. Taurine has been known to protect the cells against ER stress. This study examined the effect of taurine on ER stress-induced adipocyte differentiation and adipokine expression to explain the therapeutic effect of taurine on diabetes and obesity. To do this, human preadipocytes were differentiated into adipocytes, in the presence or absence of taurine, under ER stress conditions. Changes in adipokine expression in adipocytes stimulated with IL-1β were investigated in the presence or absence of taurine. Human preadipocytes were treated with thapsigargin (10 nM) or high glucose concentrations (100 mM) as ER stress inducers during differentiation into adipocytes. Thapsigargin inhibited the differentiation of adipocytes in a dose-dependent manner, but the high glucose concentration treatment did not. Taurine 100 mM treatment did not block the inhibition of differentiation of preadipcytes into adipocytes. Furthermore, the high glucose concentration treatment inhibited the expression of adiponectin and increased the expression of leptin in human adipocytes. However, taurine treatment did not affect the expression of two adipokines. In conclusion, the therapeutic mechanism of taurine in diabetes and obesity does not appear to occur by alleviating hyperglycemia-mediated ER stress. To clarify the molecular mechanism by which taurine improves diabetic symptoms and obesity in animal models, the protective effect of taurine against hyperglycemia- or overnutrition-mediated ER stress should be further evaluated under various conditions or types of ER stress.

Topics: Acetylcysteine; Adipocytes; Adiponectin; Cell Differentiation; Endoplasmic Reticulum Stress; Humans; Hyperglycemia; Leptin; Taurine; Taurochenodeoxycholic Acid; Thapsigargin

Endoplasmic reticulum (ER) stress has been implicated in glucose-induced beta cell dysfunction. However, its causal role has not been established in vivo. Our objective was to determine the causal role of ER stress and its link to oxidative stress in glucose-induced beta cell dysfunction in vivo.. Healthy Wistar rats were infused i.v. with glucose for 48 h to achieve 20 mmol/l hyperglycaemia with or without the co-infusion of the superoxide dismutase mimetic tempol (TPO), or the chemical chaperones 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid (TUDCA). This was followed by assessment of beta cell function and measurement of ER stress markers and superoxide in islets.. Glucose infusion for 48 h increased mitochondrial superoxide and ER stress markers and impaired beta cell function. Co-infusion of TPO, which we previously found to reduce mitochondrial superoxide and prevent glucose-induced beta cell dysfunction, reduced ER stress markers. Similar to findings with TPO, co-infusion of PBA, which decreases mitochondrial superoxide, prevented glucose-induced beta cell dysfunction in isolated islets. TUDCA was also effective. Also similar to findings with TPO, PBA prevented beta cell dysfunction during hyperglycaemic clamps in vivo and after hyperglycaemia (15 mmol/l) for 96 h.. Here, we causally implicate ER stress in hyperglycaemia-induced beta cell dysfunction in vivo. We show that: (1) there is a positive feedback cycle between oxidative stress and ER stress in glucose-induced beta cell dysfunction, which involves mitochondrial superoxide; and (2) this cycle can be interrupted by superoxide dismutase mimetics as well as chemical chaperones, which are of potential interest to preserve beta cell function in type 2 diabetes.

Topics: Animals; Antioxidants; Cyclic N-Oxides; Endoplasmic Reticulum Stress; Female; Glucose; Hyperglycemia; Insulin-Secreting Cells; Mitochondria; Oxidative Stress; Phenylbutyrates; Rats; Rats, Wistar; Spin Labels; Superoxides; Taurochenodeoxycholic Acid