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      Resveratrol reduces liver endoplasmic reticulum stress and improves insulin sensitivity in vivo and in vitro

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          Abstract

          Purpose: The aim of the study was to examine the effects of resveratrol upon hepatic endoplasmic reticulum stress (ERS) and insulin sensitivity in vivo and in vitro.

          Material and methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks, and insulin resistance was evaluated by the intraperitoneal glucose tolerance test (IPGTT). Mice were then treated with resveratrol for 12 weeks and blood and liver samples collected. Blood biochemical indicators were determined by kits, liver protein expression was determined by western blot, and morphological changes were observed by histological staining. Palmitic acid (PA)-induced insulin-resistant HepG2 cells were established. Cells were exposed to 100, 50 or 20 μM resveratrol for 24 hrs, and proliferation/cytotoxicity was determined. Cells were divided into five groups: control, PA, PA + Rev (100 μM), PA + Rev (50 μM) and PA + Rev (20 μM) groups. After 24 hrs of treatment, cellular proteins were analyzed the same way as animal tissues.

          Results: The IPGTT confirmed that the insulin resistance model was established successfully. After resveratrol treatment, fasting blood glucose and cholesterol levels declined and the quantitative insulin sensitivity check index increased. Western-blot results showed that resveratrol-treated HFD mice had reduced hepatic levels of p-PERK, ATF-4 and TRIB3, and increased the levels of ATF-6, p-AKT and p-GSK3β. In the cell model, resveratrol with 100 and 50 μM enhanced ERS and insulin resistance, whereas 20 μM had beneficial effects, similar to the animal model.

          Conclusion: Resveratrol reduced hepatic ERS, thereby improving insulin sensitivity and glucose levels. However, high doses of resveratrol had harmful effects on cells, elevating ERS and insulin resistance. The safe dose of resveratrol needs further investigation.

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          Most cited references 27

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          Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.

           S Nambi,  K Mather,  A. Katz (2000)
          Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.
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            Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus.

            Resveratrol is a naturally occurring polyphenolic compound. Numerous animal studies have been reported on its wide-ranging beneficial effects in the biological system including diabetes mellitus (DM). We hypothesized, therefore, that oral supplementation of resveratrol would improve the glycemic control and the associated risk factors in patients with type 2 diabetes mellitus (T2DM). The present clinical study was therefore carried out to test the hypothesis. Sixty-two patients with T2DM were enrolled from Government Headquarters Hospital, Ootacamund, India, in a prospective, open-label, randomized, controlled trial. Patients were randomized into control and intervention groups. The control group received only oral hypoglycemic agents, whereas the intervention group received resveratrol (250 mg/d) along with their oral hypoglycemic agents for a period of 3 months. Hemoglobin A(1c), lipid profile, urea nitrogen, creatinine, and protein were measured at the baseline and at the end of 3 months. The results reveal that supplementation of resveratrol for 3 months significantly improves the mean hemoglobin A(1c) (means ± SD, 9.99 ± 1.50 vs 9.65 ± 1.54; P < .05), systolic blood pressure (mean ± SD, 139.71 ± 16.10 vs 127.92 ± 15.37; P < .05), total cholesterol (mean ± SD, 4.70 ± 0.90 vs 4.33 ± 0.76; P < .05), and total protein (mean ± SD, 75.6 ± 4.6 vs 72.3 ± 6.2; P < .05) in T2DM. No significant changes in body weight and high-density lipoprotein and low-density lipoprotein cholesterols were observed. Oral supplementation of resveratrol is thus found to be effective in improving glycemic control and may possibly provide a potential adjuvant for the treatment and management of diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease.

              Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem in recent decades. However, the underlying mechanisms leading to the development of NAFLD are not fully understood. The endoplasmic reticulum (ER) stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis. ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins. However, delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences, including fat accumulation, insulin resistance, inflammation, and apoptosis, all of which play important roles in the pathogenesis of NAFLD. Therefore, understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation. This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                02 May 2019
                2019
                : 13
                : 1473-1485
                Affiliations
                [1 ]Department of Internal Medicine, Hebei Medical University , Shijiazhuang, Hebei 050017, People’s Republic of China
                [2 ]Endocrinology Department, Hebei General Hospital , Shijiazhuang, Hebei 050051, People’s Republic of China
                [3 ]Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital , Shijiazhuang, Hebei 050051, People’s Republic of China
                Author notes
                Correspondence: Guangyao Song Endocrinology Department, Hebei General Hospital , 348, Heping West Road, Shijiazhuang, Hebei050051, People’s Republic of ChinaTel +86 311 8598 8556Email guangyaosong123@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                203833
                10.2147/DDDT.S203833
                6505469
                © 2019 Zhao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 10, Tables: 2, References: 32, Pages: 13
                Categories
                Original Research

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