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Fibroblast Growth Factor-21 Improves Pancreatic ß-Cell Function and Survival by Activation of Extracellular Signal–Regulated Kinase 1/2 and Akt Signaling Pathways

¹ Lilly Research Laboratories, Hamburg, Germany
² Lilly Research Laboratories, Division of Eli Lilly, Indianapolis, Indiana

Address correspondence and reprint requests to Dr. Alexander Efanov, Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany. E-mail: efanov_alexander{at}lilly.com

Abbreviations: BAD, Bcl-XL/Bcl-2–associated death promoter; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal–regulated kinase; FGF, fibroblast growth factor; FRS, FGF receptor substrate; GLP, glucagon-like peptide; p90RSK, 90-kDa ribosomal S6 kinase; PCNA, proliferating cellular nuclear antigen

Fibroblast growth factor-21 (FGF-21) is a recently discovered metabolic regulator. Here, we investigated the effects of FGF-21 in the pancreatic ß-cell. In rat islets and INS-1E cells, FGF-21 activated extracellular signal–regulated kinase 1/2 and Akt signaling pathways. In islets isolated from healthy rats, FGF-21 increased insulin mRNA and protein levels but did not potentiate glucose-induced insulin secretion. Islets and INS-1E cells treated with FGF-21 were partially protected from glucolipotoxicity and cytokine-induced apoptosis. In islets isolated from diabetic rodents, FGF-21 treatment increased islet insulin content and glucose-induced insulin secretion. Short-term treatment of normal or db/db mice with FGF-21 lowered plasma levels of insulin and improved glucose clearance compared with vehicle after oral glucose tolerance testing. Constant infusion of FGF-21 for 8 weeks in db/db mice nearly normalized fed blood glucose levels and increased plasma insulin levels. Immunohistochemistry of pancreata from db/db mice showed a substantial increase in the intensity of insulin staining in islets from FGF-21–treated animals as well as a higher number of islets per pancreas section and of insulin-positive cells per islet compared with control. No effect of FGF-21 was observed on islet cell proliferation. In conclusion, preservation of ß-cell function and survival by FGF-21 may contribute to the beneficial effects of this protein on glucose homeostasis observed in diabetic animals.

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