SIRT2 ablation inhibits glucose-stimulated insulin secretion through decreasing glycolytic flux

被引:39
作者
Zhou, Feiye [1 ]
Zhang, Linlin [1 ]
Zhu, Kecheng [1 ]
Bai, Mengyao [1 ]
Zhang, Yuqing [2 ]
Zhu, Qin [1 ]
Wang, Shushu [1 ]
Sheng, Chunxiang [1 ]
Yuan, Miaomiao [1 ]
Liu, Yun [1 ]
Lu, Jieli [1 ]
Shao, Li [3 ]
Wang, Xiao [1 ]
Zhou, Libin [1 ]
机构
[1] Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Inst Endocrine & Metab Dis, Dept Endocrine & Metab Dis,Sch Med, 197 Ruijin Rd 2, Shanghai 200025, Peoples R China
[2] Shandong Univ, Ctr Reprod Med, Jinan 250000, Peoples R China
[3] Tongji Univ, Shanghai East Hosp, Sch Med, Dept VIP Clin, 1800 Yuntai Rd, Shanghai 200123, Peoples R China
来源
THERANOSTICS | 2021年 / 11卷 / 10期
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
SIRT2; islets; acetylation; glucokinase regulatory protein; glucose-stimulated insulin secretion; glycolysis; GLUCOKINASE REGULATORY PROTEIN; FATTY-ACID-METABOLISM; ADIPOCYTE DIFFERENTIATION; CALORIE RESTRICTION; AMPLIFYING PATHWAYS; ACETYLATION; DEACETYLASE; CELLS; LIVER; TRANSPORTERS;
D O I
10.7150/thno.55330
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Rationale: Sirtuins are NAD(+)-dependent protein deacylases known to have protective effects against age-related diseases such as diabetes, cancer, and neurodegenerative disease. SIRT2 is the only primarily cytoplasmic isoform and its overall role in glucose homeostasis remains uncertain. Methods: SIRT2-knockout (KO) rats were constructed to evaluate the role of SIRT2 in glucose homeostasis. The effect of SIRT2 on beta-cell function was detected by investigating the morphology, insulin secretion, and metabolomic state of islets. The deacetylation and stabilization of GKRP in beta-cells by SIRT2 were determined by western blot, adenoviral infection, and immunoprecipitation. Results: SIRT2-KO rats exhibited impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS), without change in insulin sensitivity. SIRT2 deficiency or inhibition by AGK2 decreased GSIS in isolated rat islets, with lowered oxygen consumption rate. Adenovirus-mediated overexpression of SIRT2 enhanced insulin secretion from rat islets. Metabolomics analysis revealed a decrease in metabolites of glycolysis and tricarboxylic acid cycle in SIRT2-KO islets compared with control islets. Our study further demonstrated that glucokinase regulatory protein (GKRP), an endogenous inhibitor of glucokinase (GCK), was expressed in rat islets. SIRT2 overexpression deacetylated GKRP in INS-1 beta-cells. SIRT2 knockout or inhibition elevated GKRP protein stability in islet beta-cells, leading to an increase in the interaction of GKRP and GCK. On the contrary, SIRT2 inhibition promoted the protein degradation of ALDOA, a glycolytic enzyme. Conclusions: SIRT2 ablation inhibits GSIS through blocking GKRP protein degradation and promoting ALDOA protein degradation, resulting in a decrease in glycolytic flux.
引用
收藏
页码:4825 / 4838
页数:14
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