Editors' ChoiceMetabolism

Treating Diabetes with FGF1

Science Signaling  23 Sep 2014:
Vol. 7, Issue 344, pp. ec258
DOI: 10.1126/scisignal.2005930

Type 2 diabetes typically results from loss of insulin responsiveness in target tissues, such as the liver and skeletal muscle. Currently available therapies, the thiazolidinediones, have serious side effects, such as weight gain, bone loss, and heart failure, that limit their use. Fibroblast growth factor 1 (FGF1) and FGF21 are encoded by genes regulated by the transcriptional regulator targeted by thiazolidinediones, and Fgf1-knockout mice are insulin resistant. Suh et al. injected subcutaneously, intraperitoneally, or intravenously FGF1 into mice representing either genetic or diet-induced models of obesity and insulin-resistance and found that FGF1 normalized the blood glucose in these mice. Chronic treatment by injecting every other day produced a sustained reduction in circulating glucose, improved insulin sensitivity, decreased gene expression of markers of macrophages in the liver and hepatic inflammatory damage, decreased circulating proinflammatory cytokines, and increased liver glycogen content, indicating that the insulin responsiveness of both the skeletal muscle and liver was improved. Both liver and skeletal muscle had increased indicators of insulin-stimulated signaling by the kinase AKT. These beneficial effects were not associated with weight gain, reduced feeding, or a decrease in bone density. FGF1 injections did not reduce circulating glucose in mice in which the pancreatic β cells had been destroyed, indicating that the effects required functional β cells and insulin secretion. However, FGF1 did not stimulate insulin secretion from isolated pancreatic islets. The insulin-sensitizing effects of FGF1 were absent in Fgfr1-knockout mice lacking one of the four FGF receptors. A modified form of FGF1 lacking a portion of the N terminus (FGF1ΔNT) exhibited reduced binding to all of the FGFRs, but still bound to FGFR1c and FGFR2c, and when applied to cultured cells had reduced mitogenic activity. However, injection of FGF1ΔNT produced a dose-dependent reduction in circulating glucose in the mouse models of obesity, suggesting that its mitogenic activity and insulin-sensitizing activity were separable. Thus, synthetic variants of FGF1 may provide a new option for treating type 2 diabetes.

J. M. Suh, J. W. Jonker, M. Ahmadian, R. Goetz, D. Lackey, O. Osborn, Z. Huang, W. Liu, E. Yoshihara, T. H. van Dijk, R. Havinga, W. Fan, Y.-Q. Yin, R. T. Yu, C. Liddle, A. R. Atkins, J. M. Olefsky, M. Mohammadi, M. Downes, R. M. Evans. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature 513, 436–439 (2014). [PubMed]