Complement C3 promotes islet β-cell dedifferentiation by activating Wnt/β-catenin pathway

Islet 13- cell dedifferentiation is a key step in the progression of diabetes, and complement C3 enhances secretion of several inflammatory mediators and cytokines in type 2 diabetes mellitus (T2DM). Here, we identified the underlying mechanisms of complement C3 in islet 13- cell dedifferentiation. The protein level of C3 is increased in blood of T2DM patients and mice, as well as in T2DM islet 13 cells. Insulin, gliclazide, and metformin decreased complement C3, Nga3, and Oct4 levels but increased Pdx1 and MafA expressions; these treatments inhibit islet 13- cell dedifferentiation in in vitro and in vivo models. We also observed that C3 promoted islet 13- cell dedifferentiation, whereas C3 knockdown inhibited 13- cell dedifferentiation. Moreover, C3 activates Wnt/13-catenin 13- catenin pathway by upregulating p-13-catenin 13- catenin levels, Wnt/13-cat- 13- cat- enin inhibitors significantly blocked C3-induced upregulation of islet 13- cell dedifferentiation. In conclusion, C3 promoted islet 13- cell dedifferentiation by activation of Wnt/13-catenin 13- catenin in T2DM. Targeting C3 might be a potential therapeutic strategy for T2DM treatment.