Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein

Hitoshi Watanabe, Yuka Inaba, Kumi Kimura, Michihiro Matsumoto, Shuichi Kaneko, Masato Kasuga and Hiroshi Inoue ()
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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

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02537-6

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