TY - JOUR
T1 - Ipragliflozin improves hepatic steatosis in obese mice and liver dysfunction in type 2 diabetic patients irrespective of body weight reduction
AU - Komiya, Chikara
AU - Tsuchiya, Kyoichiro
AU - Shiba, Kumiko
AU - Miyachi, Yasutaka
AU - Furuke, Shunsaku
AU - Shimazu, Noriko
AU - Yamaguchi, Shinobu
AU - Kanno, Kazuo
AU - Ogawa, Yoshihiro
N1 - Funding Information:
The authors of this manuscript have the following competing interests: CK reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. KT reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study; grants from Astellas Pharma Inc., grants from Novartis Pharma K.K., grants from Daiichi Sankyo Company Limited., grants and personal fees from AstraZeneca K.K., grants and personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from MSD K.K., grants and personal fees from Takeda Pharmaceutical Compamy Limited., personal fees from Kissei Pharmaceutical Co., Ltd., grants from Sanofi K.K., personal fees from Novo Nordisk Pharma Ltd., grants and personal fees from Lilly Japan K.K., personal fees from Ono Pharmaceutical Co., Ltd., grants from Mochida Pharmaceutical Co., LTD., grants from Terumo Co., Ltd., outside the submitted work. KS reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. YM reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. SF reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. NS reports non-financial support from Astellas Pharma Inc., grants from Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. SY reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study. KK reports other from Astellas Pharma Inc., during the conduct of the study; personal fees from Astellas Pharma Inc., personal fees from Johnson & Johnson K.K., personal fees from Novartis Pharma K.K., personal fees from Kowa Pharmaceutical Company LTD., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from Daiichi Sankyo Company Limited., personal fees from AstraZeneca K.K., personal fees from Taisho Toyama Pharmaceutical Co., Ltd., personal fees from Nippon Boehringer Ingelheim Co., Ltd., personal fees from MSD K.K., personal fees from Takeda Pharmaceutical Compamy Limited., personal fees from Kissei Pharmaceutical Co., Ltd., personal fees from Sanofi K.K., personal fees from Novo Nordisk Pharma Ltd., personal fees from Lilly Japan K.K., personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Shionogi & Co., Ltd, personal fees from Ono Pharmaceutical Co., Ltd., outside the submitted work. YO reports non-financial support from Astellas Pharma Inc., grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, during the conduct of the study; grants from Astellas Pharma Inc., grants from Novartis Pharma K.K., grants from AstraZeneca K.K., grants from Nippon Boehringer Ingelheim Co., Ltd., grants from MSD K.K., grants from Takeda Pharmaceutical Compamy Limited., grants from Kissei Pharmaceutical Co., Ltd., grants from Sanofi K.K., grants from Lilly Japan K.K., grants from Ono Pharmaceutical Co., Ltd., grants from Mochida Pharmaceutical Co., Ltd., grants from TERUMO CORPORATION, grants from JCR Pharmaceuticals Co., Ltd, grants from ASKA Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from NIPRO Co., Ltd., grants from Nestle Japan Limited, grants from Pfizer Japan Inc., grants from Shionogi & Co., Ltd., grants from THERAVALUES CORPORATION, grants from Kyowa Hakko Kirin Co,. Ltd., grants from Kowa Pharmaceutical Co., Ltd., grants from Taisho Toyama Pharmaceutical Co., Ltd., grants from TEIJIN PHARMA LIMITED, grants from Mitsubishi Tanabe Pharma Corporation, outside the submitted work. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
Publisher Copyright:
© 2016 Komiya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/3
Y1 - 2016/3
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0151511
DO - 10.1371/journal.pone.0151511
M3 - Article
C2 - 26977813
AN - SCOPUS:84961615237
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 3
M1 - e0151511
ER -