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Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model.

ABSTRACT: Background:The options for the treatment of nonalcoholic steatohepatitis (NASH) are limited. We examined the effects of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on the fatty liver Shionogi (FLS)-ob/ob mice, a non-alcoholic steatohepatitis mouse model. Methods:FLS-ob/ob male mice were treated with vehicle (n = 10) and ipragliflozin (n = 8). Serum metabolic markers, histopathology of the liver, hepatic cholesterol and triglyceride levels and hepatic mRNA levels related to fibrosis, lipid metabolism and endoplasmic reticulum (ER) stress were compared between the two groups. Results:The body weight and hepatic cholesterol and triglyceride levels were significantly decreased in the ipragliflozin group compared with the control group. Hepatic steatosis and fibrosis were significantly ameliorated by the treatment with ipragliflozin. Hepatic infiltration of macrophage, expression levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and hepatic mRNA levels of ER stress markers were not significantly modulated by the treatment with ipragliflozin. Conclusion:Ipragliflozin can be a therapeutic option for patients with NASH. The precise mechanisms of action need to be clarified in future studies.

SUBMITTER: Yamane M

PROVIDER: S-EPMC6437417 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model.

Yamane Masafumi M Matono Tomomitsu T Okano Jun-Ichi JI Nagahara Ran R Matsuki Yukako Y Okamoto Toshiaki T Miyoshi Ken-Ichi KI Sugihara Takaaki T Nagahara Takakazu T Koda Masahiko M Isomoto Hajime H

Yonago acta medica 20190328 1

<h4>Background</h4>The options for the treatment of nonalcoholic steatohepatitis (NASH) are limited. We examined the effects of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on the fatty liver Shionogi (FLS)-<i>ob/ob</i> mice, a non-alcoholic steatohepatitis mouse model.<h4>Methods</h4>FLS-<i>ob/ob</i> male mice were treated with vehicle (<i>n</i> = 10) and ipragliflozin (<i>n</i> = 8). Serum metabolic markers, histopathology of the liver, hepatic cholesterol and triglyceride levels ...[more]

PMID: 30962742

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Project description:Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and more than half of individuals diagnosed with type 2 diabetes concurrently present with NAFLD. There is a bidirectional pathological relationship between the two conditions, whereby NAFLD increases the risk of type 2 diabetes, and type 2 diabetes contributes to and accelerates the progression of NAFLD. Furthermore, over 30% of patients with NAFLD progress to non-alcoholic liver steatohepatitis (NASH), which then increases the risk of cirrhosis and hepatocellular carcinoma. Despite its high prevalence and the potential clinical implications, the underlying pathogenesis of NAFLD has yet to be fully elucidated, and there is no consensus regarding standard diagnosis and treatment for either NALFD or NASH. As patients with both NASH and type 2 diabetes have impaired hepatic function owing to chronic inflammation and the resulting structural changes caused by hepatic fat accumulation, they face reduced options for antidiabetic treatment. SGLT-2 inhibitors inhibit glucose reabsorption in the proximal tubule, with increased excretion of glucose in urine and decreased glucose levels in plasma, and their glycemia-lowering effect is insulin-independent. Several other beneficial effects have been reported for SGLT-2 inhibitors, including reduced risks of cardiovascular and renal diseases, improved blood pressure control, body weight reduction, and reductions in liver fat content. Experimental studies in mouse models have suggested that SGLT-2 inhibitors may have beneficial modulatory effects on NAFLD/NASH. Several trials in patients with type 2 diabetes have also suggested that these drugs may be useful in treating both type 2 diabetes and NAFLD or NASH. However, further research is needed to identify the mechanisms by which SGLT-2 inhibitors affect fatty liver and steatohepatitis. In this state-of-the-art review, we explore the literature on the efficacy of SGLT-2 inhibitors in patients with type 2 diabetes and NASH, and present arguments for and against the use of SGLT-2 inhibitors in this patient population.

Project description:IntroductionSodium-dependent glucose cotransporter 2 (SGLT2) inhibitors inhibit the reabsorption of glucose from the kidneys and increase urinary glucose excretion (UGE), thereby lowering the blood glucose concentration in people suffering from type 1 and type 2 diabetes mellitus (T2DM). In a previous study, we reported a pharmacokinetics/pharmacodynamics model to estimate individual change in UGE (ΔUGE), which is a direct pharmacological effect of SGLT2 inhibitors. In this study, we report our enhancement of the previous model to predict the long-term effects of ipragliflozin on clinical outcomes in patients with T2DM.MethodsThe time course of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) in patients with T2DM following ipragliflozin treatment that had been observed in earlier clinical trials was modeled using empirical models combined with the maximum drug effect (Emax) model and disease progression model. As a predictive factor of drug effect, estimated ΔUGE was introduced into the Emax model, instead of ipragliflozin exposure. The developed models were used to simulate the time course of FPG and HbA1c following once-daily treatment with placebo or ipragliflozin at doses of 12.5, 25, 50 and 100 mg, and the changes at 52 weeks at the approved dose of 50 mg were summarized by renal function category.ResultsThe developed models that included UGE as a dependent variable of response were found to well describe observed time courses in FPG and HbA1c. Baseline blood glucose level and renal function had significant effects on the glucose-lowering effect of ipragliflozin, and these models enabled quantification of these impacts on clinical outcomes. Simulated median changes in HbA1c in T2DM patients with mild and moderate renal impairment were 25 and 63% lower, respectively, than those in T2DM patients with normal renal function. These results are consistent with the observed clinical data from a previous renal impairment study.ConclusionsEmpirical models established based on the effect of UGE well predicted the renal function-dependent long-term glucose-lowering effects of ipragliflozin in patients with T2DM.

Project description:This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

Dataset Information

Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model.

Publications

Protective Effects of Ipragliflozin, a Sodium-glucose Cotransporter 2 Inhibitor, on a Non-alcoholic Steatohepatitis Mouse Model.

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