∆nFGF1 Protects β-Cells against High Glucose-Induced Apoptosis via the AMPK/SIRT1/PGC-1α Axis.

Abstract

Long-term exposure to high glucose leads to β-cell dysfunction and death. Fibroblast growth factor 1 (FGF1) has emerged as a promising diabetes treatment, but its pharmaceutical role and mechanism against glucolipotoxicity-induced β-cell dysfunction remain uncharacterized. Wild-type FGF1 (FGF1WT) may exhibit in vivo mitogenicity, but deletion of N-terminal residues 1-27 gives a nonmitogenic variant, ∆nFGF1, that does not promote cell proliferation and still retains the metabolic activity of FGF1WT. To investigate the roles of ∆nFGF1 on glucose regulation and potential islet β-cell dysfunction, db/db mice were used as a model of type 2 diabetes. The results showed that insulin secretion and apoptosis of islet β-cells were dramatically improved in ∆nFGF1-treated db/db mice. To further test the effects of ∆nFGF1 treatment, pancreatic β-cell (MIN6) cells were exposed to a mixture of palmitic acid (PA) and high glucose (HG) to mimic glucolipotoxic conditions in vitro. Treatment with ∆nFGF1 significantly inhibited glucolipotoxicity-induced apoptosis. Mechanistically, ∆nFGF1 exerts a protective effect on β-cells via activation of the AMPK/SIRT1/PGC-1α signaling pathway. These findings demonstrate that ∆nFGF1 protects pancreatic β-cells against glucolipotoxicity-induced dysfunction and apoptosis.