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Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein

Author

Listed:
  • Hitoshi Watanabe

    (Kanazawa University)

  • Yuka Inaba

    (Kanazawa University)

  • Kumi Kimura

    (Kanazawa University)

  • Michihiro Matsumoto

    (National Center for Global Health and Medicine)

  • Shuichi Kaneko

    (Kanazawa University Graduate School of Medical Sciences)

  • Masato Kasuga

    (National Center for Global Health and Medicine)

  • Hiroshi Inoue

    (Kanazawa University)

Abstract

Impaired hepatic glucose uptake (HGU) causes postprandial hyperglycemia in type 2 diabetes. Here, we show that diminished hepatic Sirt2 activity impairs HGU in obese diabetic mice. Hepatic Sirt2 overexpression increases HGU in high-fat diet (HFD)-fed obese diabetic mice and mitigates their impaired glucose tolerance. Hepatic Sirt2 knockdown in non-diabetic mice reduces HGU and causes impaired glucose tolerance. Sirt2 promotes glucose-dependent HGU by deacetylating K126 of glucokinase regulatory protein (GKRP). Glucokinase and GKRP glucose-dependent dissociation is necessary for HGU but is inhibited in hepatocytes derived from obese diabetic mice, depleted of Sirt2 or transfected with GKRP acetylation-mimicking mutants. GKRP deacetylation-mimicking mutants dissociate from glucokinase in a glucose concentration-dependent manner in obese diabetic mouse-derived hepatocytes and increase HGU and glucose tolerance in HFD-induced or db/db obese diabetic mice. We demonstrate that Sirt2-dependent GKRP deacetylation improves impaired HGU and suggest that it may be a therapeutic target for type 2 diabetes.

Suggested Citation

  • Hitoshi Watanabe & Yuka Inaba & Kumi Kimura & Michihiro Matsumoto & Shuichi Kaneko & Masato Kasuga & Hiroshi Inoue, 2018. "Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02537-6
    DOI: 10.1038/s41467-017-02537-6
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    Cited by:

    1. Yuka Inaba & Emi Hashiuchi & Hitoshi Watanabe & Kumi Kimura & Yu Oshima & Kohsuke Tsuchiya & Shin Murai & Chiaki Takahashi & Michihiro Matsumoto & Shigetaka Kitajima & Yasuhiko Yamamoto & Masao Honda , 2023. "The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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