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

Abstract

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.

A popular fermented soybean food of Northeast India exerted promising antihyperglycemic potential via stimulating PI3K/AKT/AMPK/GLUT4 signaling pathways and regulating muscle glucose metabolism in type 2 diabetes

“…The amount of food intake was monitored daily and the body weight was recorded once in every week at a constant interval. After the experimental period was over, the animals were starved overnight and OGTT was performed following the method described previously (Dihingia et al, 2018, 2020). After OGTT experiment, the animals were euthanized via the application of a mixture of ketamine and xylazine solution.…”

“…Based on our previous studies, the fasting plasma glucose level was used as a biomarker to calculate the sample size to observe a significant change from baseline (Dihingia et al, 2018(Dihingia et al, , 2020. The effective sample size was calculated at a 5% level of significance and 95% power.…”

“…Immunoblotting was done following the protocol described in previous studies (Dihingia et al, 2018(Dihingia et al, , 2020. Samples containing equal amount of protein (20-50 μg) were resolved and separated by 10-12% SDS-PAGE followed by transferring to the nitrocellulose blotting membrane (Bio-Rad).…”

Estimation of Vitamin K Content and Its Sources in the Diet of the Polish Participants of the PURE Study

“…Researchers also report significant effects of Gas6 protein activated by vitamin K2 on blood glucose levels in type 2 diabetes and pre-diabetic conditions [22,23].…”

CYP4F2 and VKORC1 Polymorphisms Amplify the Risk of Carotid Plaque Formation

“…The activity of VKORC1 [ 10 , 11 , 12 , 13 ] and CYP4F2 [ 14 , 15 , 16 , 17 , 18 ] are able to influence the metabolism and implicitly the active levels of vitamin K and its antagonists. Moreover, vitamin K acts as a cofactor for GGCX [ 19 , 20 , 21 , 22 , 23 ] in the process of generating γ carboxylated proteins. Thus the polymorphisms influencing the activity of these enzymes can impact vitamin K metabolism, influence atherosclerotic plaque formation and increase the risk of the occurrence of cardiovascular events as previously observed in the case of VKORC1 polymorphisms [ 12 ].…”