Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction
Top Cited Papers
Open Access
- 15 March 2016
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 11 (3), e0151511
- https://doi.org/10.1371/journal.pone.0151511
Abstract
Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.This publication has 41 references indexed in Scilit:
- Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosisNature Communications, 2014
- Ipragliflozin and other sodium–glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: Preclinical and clinical dataPharmacology & Therapeutics, 2013
- Lifestyle interventions for the treatment of non-alcoholic fatty liver disease in adults: A systematic reviewJournal of Hepatology, 2012
- Akt Stimulates Hepatic SREBP1c and Lipogenesis through Parallel mTORC1-Dependent and Independent PathwaysCell Metabolism, 2011
- Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studiesThe Lancet, 2010
- SGLT2 inhibition — a novel strategy for diabetes treatmentNature Reviews Drug Discovery, 2010
- Adipocyte Death, Adipose Tissue Remodeling, and Obesity ComplicationsDiabetes, 2007
- The Role of α-Cell Dysregulation in Fasting and Postprandial Hyperglycemia in Type 2 Diabetes and Therapeutic ImplicationsEndocrine Reviews, 2007
- Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humansJournal of Lipid Research, 2005
- Sterol Regulatory Element-binding Protein-1 Is Regulated by Glucose at the Transcriptional LevelOnline Journal of Public Health Informatics, 2000