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  • Review Article
  • Published:

FGF1 — a new weapon to control type 2 diabetes mellitus

Nature Reviews Endocrinology volume 13, pages 599–609 (2017)Cite this article

Subjects

Key Points

  • Peripherally or centrally injected fibroblast growth factor 1 (FGF1) confers potent metabolic benefits in type 2 diabetes mellitus (T2DM)

  • FGF1 produced by ependymal cells of the central nervous system interacts with tanycytes, astrocytes and glucose-sensing neurons of the hypothalamus to influence feeding and glycaemic control

  • Functional recovery of hypothalamic glucose-sensing neurons, as well as neural regeneration and synaptic plasticity, might be fundamental in achieving sustained remission of T2DM

  • FGF1 has the potential to improve glycaemic control, in addition to microvascular and macrovascular complications, in patients with T2DM

Abstract

A hypercaloric diet combined with a sedentary lifestyle is a major risk factor for the development of insulin resistance, type 2 diabetes mellitus (T2DM) and associated comorbidities. Standard treatment for T2DM begins with lifestyle modification, and includes oral medications and insulin therapy to compensate for progressive β-cell failure. However, current pharmaceutical options for T2DM are limited in that they do not maintain stable, durable glucose control without the need for treatment intensification. Furthermore, each medication is associated with adverse effects, which range from hypoglycaemia to weight gain or bone loss. Unexpectedly, fibroblast growth factor 1 (FGF1) and its low mitogenic variants have emerged as potentially safe candidates for restoring euglycaemia, without causing overt adverse effects. In particular, a single peripheral injection of FGF1 can lower glucose to normal levels within hours, without the risk of hypoglycaemia. Similarly, a single intracerebroventricular injection of FGF1 can induce long-lasting remission of the diabetic phenotype. This Review discusses potential mechanisms by which centrally administered FGF1 improves central glucose-sensing and peripheral glucose uptake in a sustained manner. Specifically, we explore the potential crosstalk between FGF1 and glucose-sensing neuronal circuits, hypothalamic neural stem cells and synaptic plasticity. Finally, we highlight therapeutic considerations of FGF1 and compare its metabolic actions with FGF15 (rodents), FGF19 (humans) and FGF21.

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Figure 1: Unique and shared properties of central and peripheral injections of FGF1.
Figure 2: Mechanisms potentially engaged by FGF1 after central injection.

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Acknowledgements

E.G. is supported by the Swiss National Science Foundation (grant P2EZP3_172178). C.P.M. is a Howard Hughes Medical Institute Medical Research Fellow. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology, and is supported by NIH grants (DK057978, HL088093, HL105278 and ES010337), an National Cancer Institute (NCI) Cancer Center Support Grant (CA014195), the Glenn Foundation for Medical Research, and grants from Steven and Lisa Altman and the Leona M. and Harry B. Helmsley Charitable Trust (2012-PG-MED002).

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  1. Emanuel Gasser and Christopher P. Moutos: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene Expression Laboratory, Salk Institute for Biological Studies,

    Emanuel Gasser, Christopher P. Moutos, Michael Downes & Ronald M. Evans

  2. Howard Hughes Medical Institute, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Christopher P. Moutos & Ronald M. Evans

  3. College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, 72205, Arkansas, USA

    Christopher P. Moutos

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E.G., C.P.M., M.D. and R.M.E. researched data for the article and wrote the manuscript. All authors contributed to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Ronald M. Evans.

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Competing interests

M.D. and R.M.E are co-inventors of mutated FGF1 proteins and methods of their use (US Patent No. 8,906,854) and might be entitled to royalties.

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Gasser, E., Moutos, C., Downes, M. et al. FGF1 — a new weapon to control type 2 diabetes mellitus. Nat Rev Endocrinol 13, 599–609 (2017). https://doi.org/10.1038/nrendo.2017.78

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