Type 2 and type 1 diabetes have opposing effects on the systemic murine complement alternative pathway

Complement factor D (FD) (adipsin), is an adipokine essential for the activation of the complement alternative pathway (AP), contributing to inflammation but also to metabolic homeostasis through C3a production. We investigated the metabolic regulation of Cfd expression in mouse models. A diet-induced model of insulin resistance reduced expression of key AP components, including adipose Cfd, hepatic C3, and factor B. In contrast, two independent type 1 diabetes (T1D) models increased adipose Cfd and hepatic C3 expression, leading to elevated ex vivo serum AP activation, and increased serum C3b, indicating enhanced complement activation in vivo. Across models, adipose Cfd expression showed a strong negative correlation with serum insulin levels, and insulin treatment in T1D mice restored Cfd to baseline. These findings reveal opposing regulation of adipose Cfd and liver C3 in type 1 versus type 2 diabetes models, with corresponding effects on systemic complement activity, highlighting a link between insulin, complement regulation, and metabolic disease.