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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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords

SGLT2 inhibitor Liver fibrosis Insulin resistance 

Abbreviations

NASH

Non-alcoholic steatohepatitis

IR

Insulin resistance

SGLT2

Sodium–glucose cotransporter 2

OLETF

Otsuka Long–Evans Tokushima fatty

LETO

Long–Evans Tokushima Otsuka

HSC

Hepatic stellate cell

NAFLD

Non-alcoholic fatty liver disease

DM

Diabetes mellitus

PPARγ

Peroxisome proliferator-activated receptor gamma

DPPIV

Dipeptidyl peptidase IV

DPPIV-I

Dipeptidyl peptidase IV inhibitor

CDAA

Choline-deficient l-amino acid-defined

QUICKI

Quantitative insulin sensitivity check index

SR

Sirius red

TGF-β

Transforming growth factor beta

αSMA

Alpha smooth muscle actin

RT-PCR

Real-time polymerase chain reaction

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

Alb

Albumin

T-Bil

Total bilirubin

ALT

Alanine aminotransferase

IRS

Insulin receptor substrate

PI3K

Phosphatidylinositol 3-kinase

TZD

Thiazolidinediones

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Friedman SL. Liver fibrosis—from bench to bedside. J Hepatol. 2003;38(Suppl 1):S38–53.CrossRefPubMedGoogle Scholar
  2. 2.
    Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655–69.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Iwaisako K, Taura K, Koyama Y, et al. Strategies to detect hepatic myofibroblasts in liver cirrhosis of different etiologies. Curr Pathobiol Rep. 2014;2(4):209–15.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221–31.CrossRefPubMedGoogle Scholar
  5. 5.
    Tolman KG, Fonseca V, Dalpiaz A, et al. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30(3):734–43.CrossRefPubMedGoogle Scholar
  6. 6.
    Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42(5):987–1000.CrossRefPubMedGoogle Scholar
  7. 7.
    Kahn CR. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism. 1978;27(12 Suppl 2):1893–902.CrossRefPubMedGoogle Scholar
  8. 8.
    Gastaldelli A, Cusi K, Pettiti M, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133(2):496–506.CrossRefPubMedGoogle Scholar
  9. 9.
    Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;29(2):328–33.CrossRefPubMedGoogle Scholar
  10. 10.
    Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126(3):840–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Allison ME, Wreghitt T, Palmer CR, et al. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21(6):1135–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35(2):373–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Sugimoto R, Enjoji M, Kohjima M, et al. High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation ofmitogen-activated protein kinase. Liver Int. 2005;25(5):1018–26.CrossRefPubMedGoogle Scholar
  14. 14.
    Svegliati-Baroni G, Ridolfi F, Di Sario A, et al. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology. 1999;29(6):1743–51.CrossRefPubMedGoogle Scholar
  15. 15.
    Van Wagner LB, Rinella ME. The role of insulin-sensitizing agents in the treatment of nonalcoholic steatohepatitis. Therap Adv Gastroenterol. 2011;4(4):249–63.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Caldwell SH, Hespenheide EE, Redick JA, et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96(2):519–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136–42.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mather A, Pollock C. Glucose handling by the kidney. Kidney Int Suppl. 2011;120:S1–6.CrossRefGoogle Scholar
  19. 19.
    Mather A, Pollock C. Renal glucose transporters: novel targets for hyperglycemia management. Nat Rev Nephrol. 2010;6(5):307–11.CrossRefPubMedGoogle Scholar
  20. 20.
    Kanai Y, Lee WS, You G, et al. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for d-glucose. J Clin Invest. 1994;93(1):397–404.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kurosaki E, Ogasawara H. Ipragliflozin and other sodium glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data. Pharmacol Ther. 2013;139(1):51–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Kashiwagi A, Kazuta K, Goto K, et al. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2015;17(3):304–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Watanabe Y, Nakayama K, Taniuchi N, et al. Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese type 2 diabetes. PLoS One. 2015;10(1):e0116851.Google Scholar
  24. 24.
    Vickers SP, Cheetham SC, Headland KR, et al. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet. Diabetes Metab Syndr Obes. 2014;1(7):265–75.CrossRefGoogle Scholar
  25. 25.
    Takahara M, Shiraiwa T, Matsuoka TA, et al. Ameliorated pancreatic β cell dysfunction in type 2 diabetic patients treated with a sodium-glucose cotransporter 2 inhibitor ipragliflozin. Endocr J. 2015;62(1):77–86.CrossRefPubMedGoogle Scholar
  26. 26.
    Hayashizaki-Someya Y, Kurosaki E, Takasu T, et al. Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats. Eur J Pharmacol. 2015;5(754):19–24.Google Scholar
  27. 27.
    Kodama Y, Kisseleva T, Iwaisako K, et al. c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology. 2009;137(4):1467–77.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology. 2010;139(1):323–34.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sato T, Asahi Y, Toide K, et al. Insulin resistance in skeletal muscle of the male Otsuka Long-Evans Tokushima fatty rat, a new model of NIDDM. Diabetologia. 1995;38(9):1033–41.CrossRefPubMedGoogle Scholar
  30. 30.
    Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85(7):2402–10.CrossRefPubMedGoogle Scholar
  31. 31.
    Yoshiji H, Kuriyama S, Yoshii J, et al. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34(4 Pt 1):745–50.CrossRefPubMedGoogle Scholar
  32. 32.
    Yoshiji H, Kuriyama S, Hicklin DJ, et al. KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells. Hepatology. 1999;30(5):1179–86.CrossRefPubMedGoogle Scholar
  33. 33.
    Kaji K, Yoshiji H, Ikenaka Y, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol. 2014;49:481–91.CrossRefPubMedGoogle Scholar
  34. 34.
    Kaji K, Yoshiji H, Kitade M, et al. Impact of insulin resistance on the progression of chronic liver diseases. Int J Mol Med. 2008;22(6):801–43.PubMedGoogle Scholar
  35. 35.
    Spector SA, Olson ET, Gumbs AA, et al. Human insulin receptor and insulin signaling proteins in hepatic disease. J Surg Res. 1999;83(1):32–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Bhunchet E, Eishi Y, Wake K. Contribution of immune response to the hepatic fibrosis induced by porcine serum. Hepatology. 1996;4:811–7.CrossRefGoogle Scholar
  37. 37.
    Galli A, Ceni E, Crabb DW, et al. Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPAR-gamma independent mechanisms. Gut. 2004;53(11):1688–97.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ota T, Takamura T, Kurita S, et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology. 2007;132(1):282–93.CrossRefPubMedGoogle Scholar
  39. 39.
    Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci. 2014;15(5):8591–638.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Suzuki M, Takeda M, et al. Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models. Nutr Diabetes. 2014;7(4):e125.CrossRefGoogle Scholar
  41. 41.
    Oliveira AG, Carvalho BM, Tobar N, et al. Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats. Diabetes. 2011;60(3):784–96.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gao X, Yan D, Zhao Y, et al. Moderate calorie restriction to achieve normal weight reverses β-cell dysfunction in diet-induced obese mice: involvement of autophagy. Nutr Metab (Lond). 2015;6(12):34.CrossRefGoogle Scholar

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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