Journal Article

Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer

Havinga, Rick, Yu, Ruth T., Osborn, Olivia, Atkins, Annette R., Downes, Michael, Evans, Ronald M., Olefsky, Jerrold M., Yin, Yun-Qiang, Liddle, Christopher, Jonker, Johan W., Fan, Weiwei, Mohammadi, Moosa, Ahmadian, Maryam, Lackey, Denise, Suh, Jae Myoung, Goetz, Regina, Yoshihara, Eiji, Huang, Zhifeng, Liu, Weilin, van Dijk, Theo H.

2014

Overview

Pharmacological fibroblast growth factor 1 (FGF1) normalizes blood glucose in diabetic mice by means of an FGF receptor signalling pathway that is independent of its mitogenic activity. Glucose-lowering activity of 'endocrine' FGF1 As a non-endocrine member of the fibroblast growth factor (FGF) family, FGF1 is known as a classic growth factor with mitogenic and angiogenic activity. This study identifies FGF1 as a powerful metabolic regulator. Injection of recombinant FGF1 (rFGF1) results in potent, insulin-dependent glucose lowering in diabetic mice, but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses hepatic glucose production to achieve whole-body insulin sensitization. This work raises the possibility that FGF1 could have therapeutic potential for the treatment of insulin resistance and type 2 diabetes. Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation 1 , 2 . Although FGF1 is 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 lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose 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. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/21 / 38 / 38/39 / 59/57 / 631/443/319/1642/137/773 / 64 / 64/60 / 82 / 82/80 / Animals / Blood Glucose - metabolism / Body Weight - drug effects / Care and treatment / Diabetes / Diabetes Mellitus, Experimental - drug therapy / Diabetes Mellitus, Experimental - metabolism / Diabetes Mellitus, Type 2 - metabolism / Diet, High-Fat / Dose-Response Relationship, Drug / Fibroblast Growth Factor 1 - administration & dosage / Fibroblast Growth Factor 1 - adverse effects / Fibroblast Growth Factor 1 - pharmacology / Fibroblast growth factors / Glucose / Glucose - metabolism / Glucose Tolerance Test / Health aspects / Humanities and Social Sciences / Humans / Insulin / Insulin - metabolism / Insulin Resistance / letter / Liver - drug effects / Liver - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Obese / Mitogens - pharmacology / multidisciplinary / Muscle, Skeletal - drug effects / Muscle, Skeletal - metabolism / Receptor, Fibroblast Growth Factor, Type 1 - metabolism / Rodents / Science / Type 2 diabetes