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 

机构地区：[1]Key Laboratory of Human Functional Genomics of Jiangsu Province,Nanjing Medical University,Nanjing 211166,China [2]Institute for Metabolic Disease,Fengxian Central Hospital Affiliated to Southern Medical University,Shanghai 201499,China [3]Shanghai Diabetes Institute,Shanghai Key Laboratory of Diabetes Mellitus,Shanghai Clinical Center for Diabetes,Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200233,China [4]Analysis Center,Nanjing Medical University,Nanjing 210029,China [5]Organ Transplant Center,Tianjin First Central Hospital,Nankai University,Tianjin 300192,China [6]State Key Laboratory for Cellular Stress Biology,School of Life Sciences,Xiamen University,Xiamen 361102,China

出　　处：《Journal of Molecular Cell Biology》2023年第5期21-37,共17页分子细胞生物学报（英文版）

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).

摘　　要：Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The 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 inβcells.These 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.

关 键 词：type 2 diabetes mellitus genetic variant BRSK2 β-cell hypersecretion HYPERINSULINEMIA insulin resistance 

分 类 号：R587.1[医药卫生—内分泌]