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

Chikara Komiya; Kyoichiro Tsuchiya; Kumiko Shiba; Yasutaka Miyachi; Shunsaku Furuke; Noriko Shimazu; Shinobu Yamaguchi; Kazuo Kanno; Yoshihiro Ogawa

doi:10.1371/journal.pone.0151511

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.

Authors

Chikara Komiya¹, Kyoichiro Tsuchiya¹, Kumiko Shiba¹, Yasutaka Miyachi¹, Shunsaku Furuke¹, Noriko Shimazu¹, Shinobu Yamaguchi¹, Kazuo Kanno², Yoshihiro Ogawa^{1

3}

Affiliations

¹ Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
² Kanno Clinic, Tokyo, Japan.
³ Japan Agency for Medical Research and Development, CREST, Tokyo, Japan.

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

Grants and funding

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.