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

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

  • J Mol Cell Biol. 2023 Nov 27;15(5):mjad033. doi: 10.1093/jmcb/mjad033.
Rufeng Xu 1,  Kaiyuan Wang 1,  Zhengjian Yao 1,  Yan Zhang 1,  Li Jin 2 3,  Jing Pang 1,  Yuncai Zhou 1,  Kai Wang 1,  Dechen Liu 1,  Yaqin Zhang 1,  Peng Sun 1,  Fuqiang Wang 4,  Xiaoai Chang 1,  Tengli Liu 5,  Shusen Wang 5,  Yalin Zhang 6,  Shuyong Lin 6,  Cheng Hu 2 3,  Yunxia Zhu 1,  Xiao Han 1
Affiliations

Affiliations

  • 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.
PMID: 37188647 DOI: 10.1093/jmcb/mjad033
Abstract

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.

Keywords

BRSK2; genetic variant; hyperinsulinemia; insulin resistance; type 2 diabetes mellitus; β-cell hypersecretion.

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