Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction

PLoS One. 2016 Mar 15;11(3):e0151511. doi: 10.1371/journal.pone.0151511. eCollection 2016.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Adult
  • Animals
  • Body Weight / drug effects
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diet, High-Fat / adverse effects
  • Drug Evaluation, Preclinical
  • Energy Intake / drug effects
  • Epididymis / drug effects
  • Epididymis / metabolism
  • Glucose / metabolism
  • Glucosides / pharmacology
  • Glucosides / therapeutic use*
  • Humans
  • Hyperphagia / chemically induced
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance
  • Leptin / deficiency
  • Lipids / analysis
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology
  • Non-alcoholic Fatty Liver Disease / prevention & control
  • Obesity / complications*
  • Organ Size / drug effects
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiophenes / pharmacology
  • Thiophenes / therapeutic use*
  • Weight Loss

Substances

  • Glucosides
  • Hypoglycemic Agents
  • Leptin
  • Lipids
  • SLC5A2 protein, human
  • Slc5a2 protein, mouse
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Thiophenes
  • ipragliflozin
  • Glucose

Grant support

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Ipragliflozin was provided by Astellas Pharma Inc. The clinical study at Kanno clinic was financially supported by Astellas Pharma Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.