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....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.展开更多
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).
文摘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.
