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

Area of Science:

• Immunology
• Metabolic disease research
• Complement system biology

Background:

• Complement factor D (FD), also known as adipsin, is an adipokine crucial for activating the complement alternative pathway (AP).
• FD contributes to inflammation and metabolic homeostasis via C3a production.
• The regulation of FD and its role in metabolic disorders require further investigation.

Purpose of the Study:

• To investigate the metabolic regulation of complement factor D (Cfd) gene expression.
• To explore the relationship between insulin levels, Cfd expression, and complement activation in diabetes models.

Main Methods:

• Utilized diet-induced insulin resistance and two independent type 1 diabetes (T1D) mouse models.
• Measured expression of complement components (Cfd, C3, factor B) in adipose tissue and liver.
• Assessed ex vivo serum AP activation and in vivo serum C3b levels.
• Correlated adipose Cfd expression with serum insulin levels and evaluated effects of insulin treatment.

Main Results:

• Diet-induced insulin resistance decreased adipose Cfd, hepatic C3, and factor B expression.
• T1D models showed increased adipose Cfd and hepatic C3 expression, with elevated serum AP activation and C3b.
• Adipose Cfd expression negatively correlated with serum insulin levels; insulin treatment normalized Cfd in T1D mice.

Conclusions:

• Adipose Cfd and hepatic C3 expression are oppositely regulated in type 1 versus type 2 diabetes models.
• Insulin significantly influences Cfd expression and systemic complement activity.
• These findings reveal a critical link between insulin regulation, complement system activity, and metabolic disease pathogenesis.