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.