Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents

Abstract

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide1. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors2,3,4, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes5. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.

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Figure 1: Diabetes remission induced by a single i.c.v. FGF1 injection in ob/ob mice.
Figure 2: Diabetes remission induced by a single i.c.v. FGF1 injection across multiple rodent models of T2D.
Figure 3: Effect of a single i.c.v. injection of FGF1 on whole-body glucose kinetics in ob/ob mice.
Figure 4: HSP25 expression in whole-mounts of the third-ventricle wall in response to i.c.v. mFGF1.

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Acknowledgements

The authors are grateful to the Vanderbilt University Mouse Metabolic Phenotyping Center (DK059637) for the performance of the basal glucose turnover, FSIGT and [2-14C]DG studies, the Nutrition Obesity Research Center (DK035816), the Diabetes Research Center (DK017047) at the University of Washington, and the technical assistance provided by T. Meek, V. Damian, L. Nguyen, T. Harvey, and J. Brown (all at University of Washington) and by D. Bracy and A. Locke (both at Vanderbilt University). We gratefully acknowledge L. Schäffer (Novo Nordisk) for providing the insulin receptor antagonist (S961). This work was supported by the US National Institute of Diabetes and Digestive and Kidney Diseases (grant nos. DK083042 (M.W.S.), DK090320 (M.W.S.), DK101997 (M.W.S.), DK089056 (G.J.M.), DK007742 (J.M.S.), DK104461 (J.M.S.), DK007247 (J.M.R.), DK103375 (J.M.R.), DK27619 (R.N.B.), and DK29867 (R.N.B.)), the Department of Veterans Affairs Merit Review Program (T.G.U.), and by funding supplied by Novo Nordisk (M.W.S.).

Author information

J.M.S., J.M.R., L.L., D.H.W., G.J.M., and M.W.S., designed, funded, and supervised the research; J.M.S., J.M.R., M.D.D., Z.M., and M.E.M. performed the research; T.G.U. generated the LIRFKO mice; J.M.S., J.M.R., K.J.K., D.S., M.D.D., Z.M., H.T.N., R.N.B., L.L., D.H.W., G.J.M., and M.W.S. analyzed the data; and J.M.S., J.M.R., and M.W.S. wrote the manuscript. M.W.S. has final responsibility for the hypothesis, the study design, the data analysis, the interpretation and conclusions, and the final approval of the manuscript.

Correspondence to Michael W Schwartz.

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Competing interests

Funding for these studies was provided to M.W.S. in part by Novo Nordisk.

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Scarlett, J., Rojas, J., Matsen, M. et al. Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 22, 800–806 (2016). https://doi.org/10.1038/nm.4101

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