Publication Date:
2014-07-22
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184286/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184286/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suh, Jae Myoung -- Jonker, Johan W -- Ahmadian, Maryam -- Goetz, Regina -- Lackey, Denise -- Osborn, Olivia -- Huang, Zhifeng -- Liu, Weilin -- Yoshihara, Eiji -- van Dijk, Theo H -- Havinga, Rick -- Fan, Weiwei -- Yin, Yun-Qiang -- Yu, Ruth T -- Liddle, Christopher -- Atkins, Annette R -- Olefsky, Jerrold M -- Mohammadi, Moosa -- Downes, Michael -- Evans, Ronald M -- DE13686/DE/NIDCR NIH HHS/ -- DK-033651/DK/NIDDK NIH HHS/ -- DK-063491/DK/NIDDK NIH HHS/ -- DK-074868/DK/NIDDK NIH HHS/ -- DK057978/DK/NIDDK NIH HHS/ -- DK090962/DK/NIDDK NIH HHS/ -- ES010337/ES/NIEHS NIH HHS/ -- HL088093/HL/NHLBI NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P01 DK054441/DK/NIDDK NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P01 HL088093/HL/NHLBI NIH HHS/ -- P01-DK054441-14A1/DK/NIDDK NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- P42 ES010337/ES/NIEHS NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R24 DK090962/DK/NIDDK NIH HHS/ -- R37 DK033651/DK/NIDDK NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- T32 DK007494/DK/NIDDK NIH HHS/ -- T32-DK-007494/DK/NIDDK NIH HHS/ -- U54 HD012303/HD/NICHD NIH HHS/ -- U54-HD-012303-25/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 18;513(7518):436-9. doi: 10.1038/nature13540. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA [2]. ; 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]. ; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA. ; 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. ; 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. ; The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043058" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Blood Glucose/metabolism
;
Body Weight/drug effects
;
Diabetes Mellitus, Experimental/drug therapy/metabolism
;
Diabetes Mellitus, Type 2/metabolism
;
Diet, High-Fat
;
Dose-Response Relationship, Drug
;
Fibroblast Growth Factor 1/administration & dosage/adverse effects/*pharmacology
;
Glucose/*metabolism
;
Glucose Tolerance Test
;
Humans
;
Insulin/*metabolism
;
Insulin Resistance
;
Liver/drug effects/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Mice, Obese
;
Mitogens/pharmacology
;
Muscle, Skeletal/drug effects/metabolism
;
Receptor, Fibroblast Growth Factor, Type 1/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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