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BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes 
Rufeng Xu1 , Kaiyuan Wang1 , Zhengjian Yao1 , Yan Zhang1 , Li Jin2,3 , Jing Pang1 , Yuncai Zhou1 , Kai Wang1 , Dechen Liu1 , Yaqin Zhang1 , Peng Sun1 , Fuqiang Wang4 , Xiaoai Chang1 , Tengli Liu5 , Shusen Wang5 , Yalin Zhang6 , Shuyong Lin6 , Cheng Hu2,3,* , Yunxia Zhu1,* , Xiao Han1,*
1Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing 211166, China
2Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 201499, China
3Shanghai 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
4Analysis Center, Nanjing Medical University, Nanjing 210029, China
5Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
6State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China
*Correspondence to:Xiao Han , Yunxia Zhu , Cheng Hu ,
J Mol Cell Biol, Volume 15, Issue 5, May 2023, mjad033,
Keyword: type 2 diabetes mellitus, genetic variant, BRSK2, β-cell hypersecretion, hyperinsulinemia, insulin resistance

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-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 in β cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible β-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 mature β cells reversibly triggers hyperglycemia due to β-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 and β-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in β cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between β cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.