한빛사 논문
Abstract
Jae Myoung Suh1*, Johan W. Jonker2*, Maryam Ahmadian1, Regina Goetz3, Denise Lackey4, Olivia Osborn4, Zhifeng Huang3†, Weilin Liu2, Eiji Yoshihara1, Theo H. van Dijk2, Rick Havinga2, Weiwei Fan1, Yun-Qiang Yin1, Ruth T. Yu1, Christopher Liddle5, Annette R. Atkins1, Jerrold M. Olefsky4, Moosa Mohammadi3, Michael Downes1 & Ronald M. Evans1,6
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. 2Center 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. 3Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA. 4Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA. 5The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia. 6Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA. †Present address: School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
*These authors contributed equally to this work.
Correspondence to: Ronald M. Evans or Michael Downes
Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation1, 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 homeostasis3, 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.
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