Journal of Gastroenterology

, Volume 51, Issue 12, pp 1141–1149 | Cite as

Ipragliflozin, a sodium–glucose cotransporter 2 inhibitor, ameliorates the development of liver fibrosis in diabetic Otsuka Long–Evans Tokushima fatty rats

  • Norihisa Nishimura
  • Mitsuteru KitadeEmail author
  • Ryuichi Noguchi
  • Tadashi Namisaki
  • Kei Moriya
  • Kosuke Takeda
  • Yasushi Okura
  • Yosuke Aihara
  • Akitoshi Douhara
  • Hideto Kawaratani
  • Kiyoshi Asada
  • Hitoshi Yoshiji
Original Article—Liver, Pancreas, and Biliary Tract



It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have proved that anti-IR treatment can alleviate liver fibrosis. Sodium–glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long–Evans Tokushima Otsuka (LETO) rats.


Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12 weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6 mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro.


OLETF rats, but not LETO rats, received 12 weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-β), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs.


In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.


SGLT2 inhibitor Liver fibrosis Insulin resistance 



Non-alcoholic steatohepatitis


Insulin resistance


Sodium–glucose cotransporter 2


Otsuka Long–Evans Tokushima fatty


Long–Evans Tokushima Otsuka


Hepatic stellate cell


Non-alcoholic fatty liver disease


Diabetes mellitus


Peroxisome proliferator-activated receptor gamma


Dipeptidyl peptidase IV


Dipeptidyl peptidase IV inhibitor


Choline-deficient l-amino acid-defined


Quantitative insulin sensitivity check index


Sirius red


Transforming growth factor beta


Alpha smooth muscle actin


Real-time polymerase chain reaction


Glyceraldehyde 3-phosphate dehydrogenase




Total bilirubin


Alanine aminotransferase


Insulin receptor substrate


Phosphatidylinositol 3-kinase




Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Japanese Society of Gastroenterology 2016

Authors and Affiliations

  • Norihisa Nishimura
    • 1
  • Mitsuteru Kitade
    • 1
    Email author
  • Ryuichi Noguchi
    • 1
  • Tadashi Namisaki
    • 1
  • Kei Moriya
    • 1
  • Kosuke Takeda
    • 1
  • Yasushi Okura
    • 1
  • Yosuke Aihara
    • 1
  • Akitoshi Douhara
    • 1
  • Hideto Kawaratani
    • 1
  • Kiyoshi Asada
    • 1
  • Hitoshi Yoshiji
    • 1
  1. 1.Third Department of Internal MedicineNara Medical University, KashiharaNaraJapan

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