title: Insulin-Like Growth Factor Binding Protein 1 Could Improve Glucose Regulation and Insulin Sensitivity Through Its RGD Domain.
abstract: Low circulating levels of insulin-like growth factor binding protein 1 (IGFBP-1) are associated with insulin resistance and predict the development of type 2 diabetes. IGFBP-1 can affect cellular functions independently of IGF binding through an Arg-Gly-Asp (RGD) integrin-binding motif. Whether causal mechanisms underlie the favorable association of high IGFBP-1 levels with insulin sensitivity and whether these could be exploited therapeutically remain unexplored. We used recombinant IGFBP-1 and a synthetic RGD-containing hexapeptide in complementary in vitro signaling assays and in vivo metabolic profiling in obese mice to investigate the effects of IGFBP-1 and its RGD domain on insulin sensitivity, insulin secretion, and whole-body glucose regulation. The RGD integrin-binding domain of IGFBP-1, through integrin engagement, focal adhesion kinase, and integrin-linked kinase, enhanced insulin sensitivity and insulin secretion in C2C12 myotubes and INS-1 832/13 pancreatic β-cells. Both acute administration and chronic infusion of an RGD synthetic peptide to obese C57BL/6 mice improved glucose clearance and insulin sensitivity. These favorable effects on metabolic homeostasis suggest that the RGD integrin-binding domain of IGFBP-1 may be a promising candidate for therapeutic development in the field of insulin resistance.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Haywood
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cordell
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Kar Yeun
authors.initials: KY
authors.lastname: Tang
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Natallia
authors.initials: N
authors.lastname: Makova
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Nadira Y
authors.initials: NY
authors.lastname: Yuldasheva
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Helen
authors.initials: H
authors.lastname: Imrie
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Hema
authors.initials: H
authors.lastname: Viswambharan
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Bruns
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cubbon
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire, U.K. s.b.wheatcroft@leeds.ac.uk.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wheatcroft
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008820:Mice, Obese; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D000099200:Scaffold Protein ILK
chemical_list: D001786:Blood Glucose; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D000099200:Scaffold Protein ILK