title: Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer.
abstract: Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. 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. 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.
authors.affiliation: 1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA [2].
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Suh
authors.affiliation: 1] Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands [2].
authors.forename: Johan W
authors.initials: JW
authors.lastname: Jonker
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadian
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Regina
authors.initials: R
authors.lastname: Goetz
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Lackey
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Osborn
authors.affiliation: 1] Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA [2] School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Weilin
authors.initials: W
authors.lastname: Liu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yoshihara
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.affiliation: Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Fan
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Yun-Qiang
authors.initials: YQ
authors.lastname: Yin
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Annette R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Moosa
authors.initials: M
authors.lastname: Mohammadi
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: 1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D016220:Fibroblast Growth Factor 1 / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008934:Mitogens / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008934:Mitogens; D016220:Fibroblast Growth Factor 1; D051496:Receptor, Fibroblast Growth Factor, Type 1; D005947:Glucose