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P R van Dijk Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands

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S J J Logtenberg Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands

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K H Groenier Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands

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N Kleefstra Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands

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H J G Bilo Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands

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H J Arnqvist Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands
Diabetes Centre, Departments of Internal Medicine, General Practice, Langerhans Medical Research Group, Department of Internal Medicine, Division of Cell Biology, Faculty of Health Sciences, Isala Clinics, PO Box 10400, 8000 G.K. Zwolle, The Netherlands

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regulation (1, 2, 3) . In plasma, IGF1 is bound to IGF-binding proteins (IGFBPs), among which IGFBP3 binds to ∼80% of the total amount of IGF1 present in the circulation. It is only the free fraction of IGF1, comprising <1% of the circulating IGF1, that is

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Anna Kistner Women and Child Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden

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Mireille Vanpée Women and Child Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden

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Kerstin Hall Women and Child Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden

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are conflicting concerning leptin levels (5, 17, 18, 19) but elevated levels have been observed in prepubertal SGA children with catch-up growth (19) . IGF-binding protein-1 (IGFBP1) modulates the effect of IGF1 at target tissue. IGFBP1 levels are

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Lisa Arnetz Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes

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Neda Rajamand Ekberg Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes

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Kerstin Brismar Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes

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Michael Alvarsson Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes
Departments of Endocrinology, Molecular Medicine and Surgery, Metabolism and Diabetes

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) . IGF1 levels may be low in subjects with T2D (14, 15) . IGF binding protein 1 (IGFBP1) binds IGF1 and functions as a transport protein, as well as regulating IGF1 bioavailability (16) . Insulin inhibits IGFBP1 production via reduced gene transcription

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Mieke Van Hemelrijck
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Thurkaa Shanmugalingam
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Cecilia Bosco
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Wahyu Wulaningsih
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Sabine Rohrmann Cancer Epidemiology Group, Division of Chronic Disease Epidemiology, Division of Cancer Studies, King's College London, London, UK

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, proliferation, and apoptosis. IGF1 is mainly carried in the blood within a ternary complex with IGF-binding protein 3 (IGFBP3). This complex stabilises IGF1 such that its clearance is reduced and its supply to target cells is prolonged (5, 6) . Different

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Mette Faurholdt Gude Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

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Rikke Hjortebjerg Department of Molecular Endocrinology, University of Southern Denmark, Odense, Denmark
Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark

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Mette Bjerre Medical/Steno Aarhus Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

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Morten Haaning Charles Department of Public Health, Aarhus University, Aarhus, Denmark
Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark

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Daniel R Witte Department of Public Health, Aarhus University, Aarhus, Denmark
Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark

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Annelli Sandbæk Department of Public Health, Aarhus University, Aarhus, Denmark
Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark

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Jan Frystyk Endocrine Research Unit, Department of Endocrinology, Odense University Hospital & Department of Clinical Research, Faculty of Health, University of Southern Denmark, Odense, Denmark

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likely related to its ability to increase insulin-like growth factor-1 (IGF1) action. PAPP-A activates IGF1 through proteolytic cleavage of IGF-binding proteins (IGFBP) -2, -4 and -5, which provides IGFBP fragments with low ligand affinity. By this

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Ram P Narayanan Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Bo Fu Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Adrian H Heald Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Kirk W Siddals Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Robert L Oliver Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Julie E Hudson Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Antony Payton Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Simon G Anderson Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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Anne White Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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William E R Ollier Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK
Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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J Martin Gibson Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK
Vascular Research Group, School of Community Based Medicine, Centre for Integrated Genomic Medical Research, Cardiovascular Research Group, Endocrinology and Diabetes, Salford R&D, Department of Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences, The University of Manchester, Manchester M13 9PT, UK

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complications of diabetes. The IGF system comprises the two primary ligands, namely IGF1 and IGF2, six high-affinity fully characterised IGF-binding proteins (IGFBP1IGFBP6) and the IGF receptors. IGF1 and IGF2 are anabolic peptides with extensive structural and

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Alexandra Kiess Department of Pediatric Cardiology, Faculty of Medicine, Heart Center Leipzig, University of Leipzig, Strümpellstraße, Leipzig, Germany
Department of Child and Adolescent Medicine, Section of Pediatric Cardiology, University Hospital Jena, Am Klinikum, Jena, Germany

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Jessica Green Alder Hey Children's NHS Foundation Trust, Pediatric Intensive Care Unit, Eaton Road Liverpool, Great Britain

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Anja Willenberg Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (ILM), University of Leipzig, Liebigstrasse, Leipzig, Germany

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Uta Ceglarek Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (ILM), University of Leipzig, Liebigstrasse, Leipzig, Germany

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Ingo Dähnert Department of Pediatric Cardiology, Faculty of Medicine, Heart Center Leipzig, University of Leipzig, Strümpellstraße, Leipzig, Germany

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Wieland Kiess LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Philipp-Rosenthal-Strasse, Leipzig, Germany
Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany

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Mandy Vogel LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Philipp-Rosenthal-Strasse, Leipzig, Germany
Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany

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childhood development remains not well understood. Recent studies have investigated influences of growth hormone factors on cardiac markers in different adult cohorts and small pediatric patient groups. For example, positive correlations of IGF-BP1 and IGF-BP

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Monika Bilic Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
Department of Nutritional Sciences, University of Toronto, Toronto, Canada

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Huma Qamar Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
Department of Nutritional Sciences, University of Toronto, Toronto, Canada

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Akpevwe Onoyovwi Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada

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Jill Korsiak Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada

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Eszter Papp Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada

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Abdullah Al Mahmud Nutrition and Clinical Services Division, icddr,b, Dhaka, Bangladesh

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Rosanna Weksberg Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
Molecular and Medical Genetics, University of Toronto, Toronto, Canada
Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada

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Alison D Gernand Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania, USA

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Jennifer Harrington Division of Endocrinology, Hospital for Sick Children, Toronto, Canada

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Daniel E Roth Centre for Global Child Health, Hospital for Sick Children, Toronto, Canada
Department of Nutritional Sciences, University of Toronto, Toronto, Canada
Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada

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serum IGFs exist bound to one of six binding proteins that together regulate IGF function ( 10 ). The primary binding protein for IGF-I during fetal development is IGF-binding protein 1 (IGFBP-1), which inhibits IGF-I function via its sequestration in

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Xu Chen Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People’s Republic of China

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Yi Tang Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People’s Republic of China

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Shen Chen Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China

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Wenhua Ling Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People’s Republic of China
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People’s Republic of China

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Qing Wang Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China
Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People’s Republic of China

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important role in the pathophysiological process. In the analysis of PPI network by the MCC method, the genes with top 10 MCC value were MYC, ANXA2, GDF15, AGTR1, NAMPT, LEPR, IGFBP-2, IL1RN, MMP7, and APLNR. The hub genes relationship in the STRING database

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R C S van Adrichem
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L J Hofland
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R A Feelders
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M C De Martino
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P M van Koetsveld
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C H J van Eijck Department of Internal Medicine, Department of Surgery, Department of Pathology, Sector of Endocrinology, Erasmus MC, ‘s Gravendijkwal 230, Room D-430, 3015 CE Rotterdam, The Netherlands

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R R de Krijger Department of Internal Medicine, Department of Surgery, Department of Pathology, Sector of Endocrinology, Erasmus MC, ‘s Gravendijkwal 230, Room D-430, 3015 CE Rotterdam, The Netherlands

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D M Sprij-Mooij
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J A M J L Janssen
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W W de Herder
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-A and IR-B), and six IGF-binding proteins (IGFBPs). Upon binding to the IGF1R and IR-A, IGFs predominantly generate mitogenic effects. Binding to IR-B predominantly exerts metabolic effects (3, 4) . Almost all IGFs are bound to one of the six high

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