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      Lobeglitazone, a Novel Thiazolidinedione, Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness

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          Abstract

          Despite the rapidly increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes (T2D), few treatment modalities are currently available. We investigated the hepatic effects of the novel thiazolidinedione (TZDs), lobeglitazone (Duvie) in T2D patients with NAFLD. We recruited drug-naïve or metformin-treated T2D patients with NAFLD to conduct a multicenter, prospective, open-label, exploratory clinical trial. Transient liver elastography (Fibroscan ®; Echosens, Paris, France) with controlled attenuation parameter (CAP) was used to non-invasively quantify hepatic fat contents. Fifty patients with CAP values above 250 dB/m were treated once daily with 0.5 mg lobeglitazone for 24 weeks. The primary endpoint was a decline in CAP values, and secondary endpoints included changes in components of glycemic, lipid, and liver profiles. Lobeglitazone-treated patients showed significantly decreased CAP values (313.4 dB/m at baseline vs. 297.8 dB/m at 24 weeks; P = 0.016), regardless of glycemic control. Lobeglitazone improved HbA 1C values (7.41% [57.5 mM] vs. 6.56% [48.2 mM]; P < 0.001), as well as the lipid and liver profiles of the treated patients. Moreover, multivariable linear regression analysis showed that hepatic fat reduction by lobeglitazone was independently associated with baseline values of CAP, liver stiffness, and liver enzymes, and metformin use. Lobeglitazone treatment reduced intrahepatic fat content, as assessed by transient liver elastography, and improved glycemic, liver, and lipid profiles in T2D patients with NAFLD. Further randomized controlled trials using liver histology as an end point are necessary to evaluate the efficacy of lobeglitazone for NAFLD treatment (Clinical trial No. NCT02285205).

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          Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease.

          Clinical predictors of advanced non-alcoholic liver disease (NAFLD) are needed to guide diagnostic evaluation and treatment. To better understand the demographics of NAFLD and risk factors for advanced disease, this study analysed 827 patients with NAFLD at two geographically separate tertiary medical centres. The cohort was 51% female and had a median body mass index (BMI) of 33 kg/m(2); 3% had a normal BMI. Common co-morbidities included hypertension (60%) and diabetes (35%); insulin resistance was present in 91% and advanced fibrosis in 24% of patients. When comparing patients with no fibrosis or mild fibrosis to those with advanced fibrosis, BMI > or = 28 kg/m(2), age > 50 years, and aspartate transaminase/alanine aminotransferase (AST/ALT) ratio > or = 0.8, a quantitative assessment check index (QUICKI) score 6.2) and the presence of diabetes mellitus (DM) were individually associated by univariate analysis with odds ratios (ORs) of > or = 2.4 for advanced fibrosis. Based on the results of forced entry logistic regression analysis, three variables were combined in a weighted sum (BMI > or = 28 = 1 point, AAR of > or = 0.8 = 2 points, DM = 1 point) to form an easily calculated composite score for predicting advanced fibrosis called the BARD score. A score of 2-4 was associated with an OR for advanced fibrosis of 17 (confidence interval 9.2 to 31.9) and a negative predictive value of 96%. Insulin resistance and its co-morbidities are often present in patients with NAFLD. An easily calculated score based on readily available clinical data can reliably exclude the presence of advanced fibrosis in these patients, particularly among non-diabetics.
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            Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials.

            Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liver-related complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardio-metabolic risk in NAFLD. Publications through November 2011 were systematically reviewed by two authors. Outcomes evaluated though standard methods were: histological/radiological/biochemical features of NAFLD, variables of glucose metabolism and cardiovascular risk factors. Seventy-eight randomised trials were included (38 in NASH, 40 in NAFLD): 41% assessed post-treatment histology, 71% assessed glucose metabolism and 88% assessed cardiovascular risk factors. Lifestyle intervention, thiazolidinediones, metformin and antioxidants were most extensively evaluated. Lifestyle-induced weight loss was safe and improved cardio-metabolic risk profile; a weight loss ≥7% improved histological disease activity, but was achieved by <50% patients. Statins and polyunsaturated fatty acids improved steatosis, but their effects on liver histology are unknown. Thiazolidinediones improved histological disease activity, glucose, lipid and inflammatory variables and delayed fibrosis progression. Pioglitazone also improved blood pressure. Weight gain (up to 4.8%) was common. Antioxidants yielded mixed histological results: vitamin E improved histological disease activity when administered for 2 years, but increased insulin resistance and plasma triacylglycerols. Weight loss is safe, and improves liver histology and cardio-metabolic profile. For patients not responding to lifestyle intervention, pioglitazone improves histological disease activity, slows fibrosis progression and extensively ameliorates cardio-metabolic endpoints. Further randomised controlled trials (RCTs) of adequate size and duration will assess long-term safety and efficacy of proposed treatments on clinical outcomes.
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              Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway.

              Metformin activates both PRKA and SIRT1. Furthermore, autophagy is induced by either the PRKA-MTOR-ULK1 or SIRT1-FOXO signaling pathways. We aimed to elucidate the mechanism by which metformin alleviates hepatosteatosis by examining the molecular interplay between SIRT1, PRKA, and autophagy. ob/ob mice were divided into 3 groups: one with ad libitum feeding of a standard chow diet, one with 300 mg/kg intraperitoneal metformin injections, and one with 3 g/d caloric restriction (CR) for a period of 4 wk. Primary hepatocytes or HepG2 cells were treated with oleic acid (OA) plus high glucose in the absence or presence of metformin. Both CR and metformin significantly improved body weight and glucose homeostasis, along with hepatic steatosis, in ob/ob mice. Furthermore, CR and metformin both upregulated SIRT1 expression and also stimulated autophagy induction and flux in vivo. Metformin also prevented OA with high glucose-induced suppression of both SIRT1 expression and SIRT1-dependent activation of autophagy machinery, thereby alleviating intracellular lipid accumulation in vitro. Interestingly, metformin treatment upregulated SIRT1 expression and activated PRKA even after siRNA-mediated knockdown of PRKAA1/2 and SIRT1, respectively. Taken together, these results suggest that metformin alleviates hepatic steatosis through PRKA-independent, SIRT1-mediated effects on the autophagy machinery.
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                Author and article information

                Journal
                J Korean Med Sci
                J. Korean Med. Sci
                JKMS
                Journal of Korean Medical Science
                The Korean Academy of Medical Sciences
                1011-8934
                1598-6357
                January 2017
                08 November 2016
                : 32
                : 1
                : 60-69
                Affiliations
                [1 ]Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
                [2 ]Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
                [3 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea.
                [4 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
                [5 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
                Author notes
                Address for Correspondence: Byung-Wan Lee, MD. Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. E-mail: bwanlee@ 123456yuhs.ac

                *Yong-ho Lee and Jae Hyeon Kim contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-6219-4942
                http://orcid.org/0000-0001-5001-963X
                http://orcid.org/0000-0002-5778-370X
                http://orcid.org/0000-0002-1841-2092
                http://orcid.org/0000-0002-6108-7758
                http://orcid.org/0000-0002-2331-6126
                http://orcid.org/0000-0002-9899-4992
                Article
                10.3346/jkms.2017.32.1.60
                5143300
                27914133
                a2e772a9-f2a4-40b7-afec-5c96979d42d3
                © 2017 The Korean Academy of Medical Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 June 2016
                : 15 September 2016
                Funding
                Funded by: Chong Keun Dang, Pharmaceutical Co.;
                Categories
                Original Article
                Endocrinology, Nutrition & Metabolism

                Medicine
                non-alcoholic fatty liver disease,thiazolidinedione,type 2 diabetes,transient liver elastography

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