BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes

作     者：Rufeng Xu Kaiyuan Wang Zhengjian Yao Yan Zhang Li Jin Jing Pang Yuncai Zhou Kai Wang Dechen Liu Yaqin Zhang Peng Sun Fuqiang Wang Xiaoai Chang Tengli Liu Shusen Wang Yalin Zhang Shuyong Lin Cheng Hu Yunxia Zhu Xiao Han 

作者机构：Key Laboratory of Human Functional Genomics of Jiangsu ProvinceNanjing Medical UniversityNanjing 211166China Institute for Metabolic DiseaseFengxian Central Hospital Affiliated to Southern Medical UniversityShanghai 201499China Shanghai Diabetes InstituteShanghai Key Laboratory of Diabetes MellitusShanghai Clinical Center for DiabetesShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200233China Analysis CenterNanjing Medical UniversityNanjing 210029China Organ Transplant CenterTianjin First Central HospitalNankai UniversityTianjin 300192China State Key Laboratory for Cellular Stress BiologySchool of Life SciencesXiamen UniversityXiamen 361102China 

出 版 物：《Journal of Molecular Cell Biology》 (分子细胞生物学报（英文版）)

年 卷 期：2023年第15卷第5期

页      面：21-37页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：supported by research grants from the National Natural Science Foundation of China(81420108007 and 81830024 to X.H. 82270844 82070843 and 81870531 to Y.Zhu) 

主　　题：type 2 diabetes mellitus genetic variant BRSK2 β-cell hypersecretion hyperinsulinemia insulin resistance 

摘      要：Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell ***,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been ***,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese ***2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein *** with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet ***,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose ***,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin ***,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent *** enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβ*** findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.