Adipsin Prevents Beta-Cell Failure in a Mouse Model of Type 2 Diabetes by Blocking Dedifferentiation and Cell Death

Adipsin and its downstream molecule C3a are complement factors that regulate insulin secretion. In order to assess the effects of adipsin in chronic DM2 and beta cell failure, we used adeno-associated virus (AAV) to replenish adipsin in db/db mice. A robust increase in both serum adipsin and C3a was achieved using AAV-Adipsin compared to control AAV-GFP, even 5 months after the injection (Figure 1a). Adipsin treatment significantly ameliorated hyperglycemia and boosted insulin levels (Figure 1b). More importantly, adipsin treatment increased beta cell mass and prevented beta cell loss in the late stages of DM2 (Figure 1c). Mechanistically, adipsin decreased beta cell death and dedifferentiation (Figures 1d and e). Adipsin also augmented expression of key beta cell transcription factors. Using unbiased transcriptomics, we identified that adipsin treatment downregulated the phosphatase Dusp26 in the pancreatic islets. Interestingly, overexpression of Dusp26 in beta cells and primary islets leads to a loss of beta cell transcription factors and an increase in palmitate-induced cell death (Figures 1f and g). Pharmacological inhibition of Dusp26 increased islet survival in palmitate conditions. Collectively these data suggest that adipsin/C3a and dusp26 directed therapies may represent a novel approach to conserve beta cell mass and achieve long term beta cell health for patients with T2D. Disclosure N. Gomez-Banoy: None. B. Poirier: None. A. Rubio-Navarro: None. J. Lo: None.