Gamma-glutamyl-carboxylated Gas6 mediates positive role of vitamin K on lowering hyperglycemia in type 2 diabetes.

The role of gamma-glutamyl-carboxylated growth arrest-specific 6 (cGas6) in mediating the beneficial effect of vitamin K (VK) on regulating glucose metabolism remains elusive. We took a three-pronged approach-evaluating human type 2 diabetes (T2D), high-fat diet (HFD)-fed mice, and in vitro cultured myotubes-to address this. Blood samples were collected from both T2D patients and control subjects; skeletal muscle and blood samples were collected from HFD-fed mice with or without VK supplementation (1, 3, and 5 µg/kg BW, 8 weeks); and the molecular mechanism of cGas6 was dissected using GGCX, Gas6, AXL, or IR siRNA-transfected cultured myotubes. Plasma cGas6 and VK were significantly lower in T2D patients compared with control; and cGas6 and the cGas6/Gas6 ratio were positively correlated with VK and inversely correlated with fasting glucose in T2D patients, suggesting an important role for plasma VK and cGas6 in maintaining glucose homeostasis in T2D. Animal studies revealed that VK supplementation dose-dependently upregulated plasma cGas6; stimulated the protein expression of cGas6, PI3K, pAKT, and GLUT4 in skeletal muscle; and reduced hyperglycemia in HFD-fed T2D mice. And in vitro mRNA knockdown studies demonstrated the requirement of cGas6 in mediating the positive effect of VK on glucose metabolism via stimulating the PI3K/pAKT/GLUT4 signaling pathway in high glucose-treated myotubes. These results demonstrate a significant involvement of cGas6 in mediating the beneficial effect of VK on regulating glucose homeostasis in T2D.