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

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-cell biology. Whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) is never appreciated. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in Chinese population. The BRSK2 protein levels are significantly accumulated in β cells from T2DM patients and high-fat-diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible loss-of-function Brsk2 (βKO) are metabolic normal with high potential of insulin secretion under chow-diet condition. Moreover, βKO mice prevent 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 with HFD feeding or β-cell gain-of-function BRSK2. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplaying between β cells and insulin-sensitive tissues in human genetic variant population or under nutrient-overload conditions.