Fasting serum annexin A2 is associated with peripheral insulin sensitivity and may enhance glucose uptake via Src‐dependent signaling

BACKGROUND AND AIM: Subcellular annexin A2 (ANXA2) is known to regulate membrane dynamics and GLUT4 trafficking in adipocytes; however, the role of serum ANXA2 in glucose metabolism remains unclear. We aimed to investigate the association between fasting serum ANXA2 and insulin sensitivity in humans and to examine the role of extracellular ANXA2 in glucose uptake in cultured skeletal myocytes. METHODS: We conducted a clinical study in 15 non-diabetic Japanese adults who underwent hyperinsulinemic-euglycemic glucose clamp studies to assess peripheral insulin sensitivity. Fasting serum ANXA2 levels were measured and correlated with metabolic parameters. Cultured C2C12 myotubes were treated with recombinant human ANXA2 and the effects of ANXA2 on glucose uptake and insulin signaling mediators were evaluated. RESULTS: Fasting serum ANXA2 showed a significant positive correlation with mean glucose infusion rate (mean GIR; r = 0.76, P = 0.00095). In C2C12 myotubes, both ANXA2 and insulin significantly increased glucose uptake compared with controls. ANXA2 enhanced IRS-1 and Akt phosphorylation independently of insulin, and this effect was suppressed by the Src-kinase inhibitor PP2. CONCLUSIONS: In conclusion, these results indicated that fasting serum ANXA2 is associated with peripheral insulin sensitivity in humans, and that exogenous ANXA2 may enhance glucose uptake in association with IRS-1/Akt signaling and Src-dependent pathways. Together, these findings support further evaluation of serum ANXA2 as a potential indicator reflecting peripheral insulin sensitivity.