Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer

Abstract

FGF1 is an autocrine/paracrine regulator whose binding to heparan sulfate proteoglycans effectively precludes its circulation 1,2. Though known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high fat diet, suggesting a potential role in nutrient homeostasis 3,4. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice that is dose-dependent, but does not lead to hypoglycemia. Chronic pharmacological rFGF1 treatment increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin sensitizing therapies. Furthermore, we demonstrate that the glucose lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 (FGFR1) signaling. In summary, we have uncovered an unexpected, neomorphic insulin sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for treatment of insulin resistance and type 2 diabetes.

Fibroblast growth factor 1 levels are elevated in newly diagnosed type 2 diabetes compared to normal glucose tolerance controls

“…In our research, we observed that serum FGF1 concentrations were positively correlated with TC, which suggested that FGF1 might be also involved in lipid metabolism. This result corresponds with the observations by Suh et al in which chronic treatment with rFGF1 decreased TG [18]. Nevertheless, Jonker et al observed that FGF1 −/− mice showed no significant changes in triglycerides or cholesterol compared to wild-type mice [17].…”

“…In addition, human adipocytes differentiated exposed to FGF1 were more insulin responsive and secreted increased levels of adiponectin [23]. Potent glucose lowering was observed by Suh et al in variety of mice with impaired insulin sensitivity following the administration of FGF1 [18]. They demonstrated an increase in insulin-dependent glucose uptake in skeletal muscle, suppression of hepatic glucose production and improvement of wholebody insulin sensitization as a long-term consequence of recombinant FGF1 (rFGF1) injection [18].…”

“…Potent glucose lowering was observed by Suh et al in variety of mice with impaired insulin sensitivity following the administration of FGF1 [18]. They demonstrated an increase in insulin-dependent glucose uptake in skeletal muscle, suppression of hepatic glucose production and improvement of wholebody insulin sensitization as a long-term consequence of recombinant FGF1 (rFGF1) injection [18]. Perry et al also found that 10 μg intracerebroventricular injection of FGF1 was sufficient to attain > 50% reductions in plasma glucose in 6-h fasted type 1 diabetes rats by suppression of the hypothalamic-pituitary-adrenal axis [24].…”

“…Therefore, the PPARγ-FGF1 axis is an unexpected mediator of adipose tissue homeostasis [17]. However, a recent study made by Suh et al revealed that ob/ob mice injected with rFGF1 for 35 days exhibited minimal changes in body weight [18]. Further studies are needed to elucidate the mechanisms underlying the association between obesity and FGF1.…”

“…In a paper published in a recent issue of Nature has shown that treatment with FGF1 resulted in insulin-dependent lowering of glucose levels and conferred novel insulin-sensitizing properties to this molecule in diabetic mice but avoided many of the side effects such as hypoglycaemia, weight gain, liver steatosis and bone loss [18]. So far, little is known about the role of FGF1 in humans, especially in association with metabolic diseases.…”