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

Area of Science:

• Endocrinology
• Immunology
• Cell Biology

Background:

• Islet beta-cell dedifferentiation is crucial in type 2 diabetes mellitus (T2DM) progression.
• Complement C3 is implicated in T2DM, enhancing inflammatory mediator secretion.

Purpose of the Study:

• To elucidate the mechanisms by which complement C3 contributes to islet beta-cell dedifferentiation in T2DM.
• To investigate the therapeutic potential of targeting C3 for T2DM.

Main Methods:

• Quantified C3 protein levels in T2DM patients, mice, and islet beta-cells.
• Assessed the effects of insulin, gliclazide, and metformin on C3, dedifferentiation markers, and beta-cell function in vitro and in vivo.
• Investigated the role of C3 in beta-cell dedifferentiation and its interaction with the Wnt/beta-catenin pathway.

Main Results:

• Elevated C3 protein levels were observed in T2DM blood and islet beta-cells.
• Insulin, gliclazide, and metformin treatments reduced C3 levels and inhibited beta-cell dedifferentiation.
• C3 promoted, while C3 knockdown inhibited, beta-cell dedifferentiation.
• C3 activated the Wnt/beta-catenin pathway, evidenced by increased p-beta-catenin, and pathway inhibitors blocked C3-induced dedifferentiation.

Conclusions:

• Complement C3 promotes islet beta-cell dedifferentiation in T2DM through Wnt/beta-catenin pathway activation.
• Targeting complement C3 presents a promising therapeutic strategy for T2DM.