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.