Can FGF1 help win the battle against type 2 diabetes mellitus?

Type 2 diabetes mellitus (T2DM) is a chronic incurable condition affecting more than 9% of the adult world population with an incidence of this disease continuing to increase1. Different drug classes that are currently available in the market, namely oral antidiabetic drugs and insulins, are relatively effective in managing this condition and an increasing number of novel antidiabetic agents are being developed. However, despite these efforts, all current therapeutic approaches have specific shortfalls, resulting in insufficient glycaemic control and adverse effects in patients with T2DM.

Over the past years, preclinical studies based on animal models have provided exciting novel data on fibroblast growth factor 1 (FGF1) and positioned it as a promising molecule able to combat abnormally elevated glucose levels and restore sensitivity to insulin in experimental models. While FGF1-knockout mice show neither developmental defects nor tissue pathology, they develop striking hyperglycaemia and insulin resistance when challenged with a high fat diet2. Similarly, when a single dose of FGF1 is administered in diet-induced obesity mouse models, normalisation of blood glucose levels occurs without hypoglycaemia events, whereas a chronic administration of FGF1 restores sensitivity to insulin2.

Mechanistically, action of FGF1 is multifaceted and complex. FGF1 was suggested to suppress food intake through an early response mediated by hypothalamic astrocytes and a subsequent late response executed in a neuron-dependent fashion. Glucose-sensing neurons and their subpopulations have been identified in hypothalamus and when extracellular glucose levels are elevated to abnormal levels, the neurons change their firing activity and become either glucose-excited or glucose-inhibited neurons3, 4. FGF1 has been linked to glucose-sensing neurons in lateral hypothalamic areas (5). However, FGF1-induced glucose-lowering effect ultimately depends on an intact insulin signalling pathway6.

Mechanistic insights of glucose-lowering capability of peripheral FGF1 are just starting to emerge and the experimental evidence has suggested that an adipose tissue is a primary target upon peripheral delivery of FGF12.

More research is needed to elucidate mechanisms of the effects of FGF1 on glucose-sensing neurons that control sympathetic and parasympathetic branches of the autonomic nervous system, both of which govern essential glucose clearance mechanisms and glucagon and insulin secretion, as well as a number of other important processes linked to regulation of exogenous glucose levels. In spite of this, future applications of FGF1 as a therapeutic agent capable of exerting glycaemic control when injected centrally or peripherally can only be hypothesised at present. Although intracranial injection of FGF1 may not be feasible, such route of administration may be replaced with intranasal injections. Rodent models have shown that FGF1 administered via intranasal route is able to reach the brain through a migration along the olfactory nerve, nasal mucosal capillaries and through cerebrospinal fluid7. However, this approach has a long way to go and other methods of accurate delivery of FGF1 to the neurons in specific brain regions need to be explored and developed.

Although the mechanisms of pharmacologic actions of FGF1 have not been fully explained, FGF1 is an exciting molecule with a remarkable ability to normalise blood glucose levels and restore sensitivity to insulin through a number of different ways, acting in the central nervous system and peripherally.

1 Jaacks LM, et al.Type 2 diabetes: A 21st century epidemic. Best Pract Res Clin Endocrinol Metab. 2016;30(3):331–43. 2 Suh JM, al. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer. Nature. 2014;513(7518):436–9 3 Jordan SD, et al.Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis. Cell Mol Life Sci. 2010;67(19):3255–73 4 Routh VH, et al. Hypothalamic glucose sensing: making ends meet. Front Syst Neurosci. 2014;8:236 5 Stuber GD, Wise RA. Lateral hypothalamic circuits for feeding and reward. Nat Neurosci. 2016;19(2):198–205 6 García-Cáceres C, et al.Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell. 7 Lou G, et al.Intranasal TAT-haFGF improves cognition and amyloid-β pathology in an AβPP/PS1 mouse model of Alzheimer's disease. J Alzheimers Dis. 2016;51(4):985–90

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