A hypercaloric diet combined with a sedentary lifestyle is a major risk factor in the development of insulin resistance, type 2 diabetes mellitus (T2DM) and associated co-morbidities. Standard treatment for T2DM begins with lifestyle modification, and includes oral medications and insulin therapy to compensate for progressive β-cell failure. Current pharmaceutical options for T2DM, however, 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 ranging from hypoglycaemia to weight gain or bone loss. Unexpectedly, FGF1 and its low mitogenic variants have emerged as potentially safe candidates in restoring euglycaemia, without causing overt adverse effects. In particular, a single peripheral injection of FGF1 can lower glucose to normal levels in 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 fashion. 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 to FGF15/FGF19 and FGF21.

Background In bone, NADPH oxidase (NOX)-derived reactive oxygen species (ROS) superoxide and/or hydrogen peroxide are an important stimulus for osteoclast differentiation and activity. Previously, we have demonstrated that chronic ethanol (EtOH) consumption generates excess NOX-dependent ROS in osteoblasts, which functions to stimulate NFκB receptor ligand (RANKL)—RANK signaling, thus increasing osteoclastogenesis and activity. This activity can be blocked by co-administration of EtOH with the pan-NOX inhibitor diphenylene idonium (DPI). Methods To test if EtOH-induced bone loss is dependent on a functional NOX2 enzyme, six week old female C57BL/6J-Ncf1/p47phox-/- (p47phox KO) and wild-type (WT) mice were pair-fed EtOH diets for 40 days. Bone loss was assessed by 3-point bending, μCT and static histomorphometric analysis. Additionally, ST2 cultured cells were co-treated with EtOH and NOX inhibitors, DPI, gliotoxin and plumbagin, after which changes in ROS production, and in RANKL and NOX mRNA expression were analyzed. Results In WT mice, EtOH treatment significantly reduced bone density and mechanical strength, and increased total osteoclast number and activity. In EtOH-treated p47phoxKO mice, bone density and mechanical strength were completely preserved. EtOH p47phoxKO mice had no changes in osteoclast numbers or activity, and no elevations in serum CTX or RANKL gene expression (p<0.05). In both WT and p47phox KO mice, EtOH-feeding reduced biochemical markers of bone formation (P<0.05). In vitro EtOH exposure of ST2 cells increased ROS, which was blocked by pre-treating with DPI or the NOX2 inhibitor gliotoxin. EtOH induced RANKL and NOX2 gene expression which was inhibited by the NOX4-specific inhibitor plumbagin. Conclusion These data suggest that NOX2-derived ROS is necessary for EtOH-induced bone resorption. In osteoblasts NOX2 and NOX4 appear to work in tandem to increase RANKL expression whereas EtOH-mediated inhibition of bone formation occurs via a NOX2-independent mechanism.