ANGPTL8 enhances insulin sensitivity by directly activating insulin-mediated AKT phosphorylation.

ANGPTL8 is a 22-KDa protein in the angiopoietin-like family. It is a liver-derived hormone that dynamically regulates glucose metabolism after refeeding. The mechanism of its regulation of glucose metabolism is unclear. We analyzed the effect of ANGPTL8 overexpression on glucose tolerance in the mouse liver by tail vein hydrodynamic transfection. The mechanism of ANGPTL8 improving insulin sensitivity was analyzed by the overexpression or knockdown of ANGPTL8 in mouse primary hepatocytes through in vitro synthetic mRNA and siRNA technology. The key site of ANGPTL8 protein regulating this signal pathway was screened by DNA point mutation and fragment truncation. The results showed that ANGPTL8 may directly regulate AKT protein phosphorylation in the insulin-mediated PI3K/AKT signaling pathway to improve insulin sensitivity. Ser94 and Thr98 are the key sites of ANGPTL8 protein in activating AKT protein phosphorylation. Present results indicate that ANGPTL8 may be a potential new agent to reduce postprandial blood glucose.