| First Author | Xu R | Year | 2023 |
| Journal | J Mol Cell Biol | Volume | 15 |
| Issue | 5 | PubMed ID | 37188647 |
| Mgi Jnum | J:359530 | Mgi Id | MGI:7787262 |
| Doi | 10.1093/jmcb/mjad033 | Citation | Xu R, et al. (2023) BRSK2 in pancreatic beta cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes. J Mol Cell Biol 15(5) |
| abstractText | Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and beta-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 beta cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible beta-cell-specific Brsk2 knockout (betaKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, betaKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature beta cells reversibly triggers hyperglycemia due to beta-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 beta-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in beta cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between beta cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions. |
