Open Access

Impact of insulin resistance on the progression of chronic liver diseases

  • Authors:
    • Kosuke Kaji
    • Hitoshi Yoshiji
    • Mitsuteru Kitade
    • Yasuhide Ikenaka
    • Ryuichi Noguchi
    • Junichi Yoshii
    • Koji Yanase
    • Tadashi Namisaki
    • Masaharu Yamazaki
    • Kei Moriya
    • Tatsuhiro Tsujimoto
    • Hideto Kawaratani
    • Takemi Akahane
    • Masahito Uemura
    • Hiroshi Fukui
  • View Affiliations

  • Published online on: December 1, 2008     https://doi.org/10.3892/ijmm_00000088
  • Pages: 801-808
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Abstract

Recent studies have revealed a close relationship between insulin resistance (IR) and the progression of chronic liver diseases, although relatively little is known regarding the possible mechanisms involved. The aim of this study was to elucidate the impact of IR on the development of liver fibrosis and hepatocarcinogenesis using obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Liver fibrosis development and glutathione-S-transferase placental form (GST-P)-positive pre-neoplastic lesions were both markedly accelerated in OLETF rats, being induced by pig serum and diethylnitrosamine (DEN), respectively. In the fibrosis experiment, α-smooth muscle actin-positive activated hepatic stellate cells (HSCs) also significantly increased in OLETF rats along with augmentation of the hepatic collagen content and transforming growth factor-β1. Our in vitro study showed that both glucose and insulin stimulated the proliferation of activated HSCs, and the combination treatment exerted an additive effect. In the DEN model, neovascularization, which plays a pivotal role in hepatocarcinogenesis, was up-regulated in OLETF rats almost in parallel with pre-neoplastic lesion development and a potent angiogenic factor, vascular endothelial growth factor. High glucose and insulin also significantly augmented the in vitro neovascularization via extracellular signal-regulated kinase 1/2 phosphorylation. Similar to the effect on the activated HSCs, co-existence of both factors exerted a more potent effect than either single factor. In conclusion, these results indicated that the IR status directly accelerated liver fibrosis development and hepatocarcinogenesis at least partly through the stimulation of activated HSC proliferation and hepatic neovascularization, respectively, in the rat.

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December 2008
Volume 22 Issue 6

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Kaji K, Yoshiji H, Kitade M, Ikenaka Y, Noguchi R, Yoshii J, Yanase K, Namisaki T, Yamazaki M, Moriya K, Moriya K, et al: Impact of insulin resistance on the progression of chronic liver diseases. Int J Mol Med 22: 801-808, 2008.
APA
Kaji, K., Yoshiji, H., Kitade, M., Ikenaka, Y., Noguchi, R., Yoshii, J. ... Fukui, H. (2008). Impact of insulin resistance on the progression of chronic liver diseases. International Journal of Molecular Medicine, 22, 801-808. https://doi.org/10.3892/ijmm_00000088
MLA
Kaji, K., Yoshiji, H., Kitade, M., Ikenaka, Y., Noguchi, R., Yoshii, J., Yanase, K., Namisaki, T., Yamazaki, M., Moriya, K., Tsujimoto, T., Kawaratani, H., Akahane, T., Uemura, M., Fukui, H."Impact of insulin resistance on the progression of chronic liver diseases". International Journal of Molecular Medicine 22.6 (2008): 801-808.
Chicago
Kaji, K., Yoshiji, H., Kitade, M., Ikenaka, Y., Noguchi, R., Yoshii, J., Yanase, K., Namisaki, T., Yamazaki, M., Moriya, K., Tsujimoto, T., Kawaratani, H., Akahane, T., Uemura, M., Fukui, H."Impact of insulin resistance on the progression of chronic liver diseases". International Journal of Molecular Medicine 22, no. 6 (2008): 801-808. https://doi.org/10.3892/ijmm_00000088