Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-02537-6
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [17H05499]
- Japan Society for the Promotion of Science (JSPS) [26282022, 16K00849]
- Creation of Fundamental Technologies for Understanding and Control of Biosystem Dynamics [JPMJCR12W3]
- CREST from the Japan Science and Technology Agency (JST)
- Astellas Foundation for Research on Metabolic Disorders
- Uehara Memorial Foundation
- Takeda Science Foundation
- Novartis Pharma
- Eli Lilly Japan
- Grants-in-Aid for Scientific Research [26253046, 16K00849, 16J08117, 26282022, 15H05678, 17H05499, 15H04851] Funding Source: KAKEN
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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.
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