Association between circulating insulin-like growth factor 1 and risk of all-cause and cause-specific mortality

in European Journal of Endocrinology
View More View Less
  • 1 Department of Geratology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
  • | 2 Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • | 3 Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China
  • | 4 Department of Biostatistics and Epidemiology, School of Public Health, China Medical University, Shenyang, China
  • | 5 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China

Correspondence should be addressed to D Hang; Email: hangdong@njmu.edu.cn

*(Y Xie, C Huang and X Zhu contributed equally to this work)

Restricted access

Background

Insulin-like growth factor 1 (IGF1) is an important growth factor modulating development, homeostasis, and aging. However, whether and how circulating IGF1 concentrations influence early death risk in the general population remains largely unknown.

Methods

We included 380 997 participants who had serum IGF1 measurement and no history of cancer, cardiovascular disease (CVD), or diabetes at baseline from UK Biobank, a prospective cohort study initiated in 2006–2010. Restricted cubic splines and Cox proportional hazards regression models were used to assess the association between baseline IGF-1 concentrations and all-cause and cause-specific mortality.

Results

Over a median follow-up of 8.8 years, 10 753 of the participants died, including 6110 from cancer and 1949 from CVD. Dose–response analysis showed a U-shaped relationship between IGF1 levels and mortality. Compared to the fifth decile of IGF1, the lowest decile was associated with 39% (95% CI: 29–50%), 20% (95% CI: 8–34%), and 39% (95% CI: 14–68%) higher risk of all-cause, cancer, and CVD mortality, respectively, while the highest decile was associated with 17% (95% CI: 7–28%) and 38% (95% CI: 11–71%) higher risk of all-cause and CVD mortality, respectively. The results remained stable in detailed stratified and sensitivity analyses.

Conclusions

Our findings indicate that both low and high concentrations of serum IGF1 are associated with increased risk of mortality in the general population. Our study provides a basis for future interrogation of underlying mechanisms of IGF1 in early death occurrence and possible implications for mitigating the risk.

Supplementary Materials

    • Supplementary Figure 1
    • Supplementary Table 1. Association between serum IGF-1 concentrations and all-cause mortality and absolute risks within 10 years
    • Supplementary Table 2. Association between serum IGF-1 concentrations and cancer-specific mortality
    • Supplementary Table 3. Sensitivity analysis for the associations of serum IGF-1 concentrations with all-cause and cause-specific mortality after additionally adjusting for C-reactive protein, glucose, and lipids (n=346,759)
    • Supplementary Table 4. Sensitivity analysis for the associations of serum IGF-1 concentrations with all-cause and cause-specific mortality after excluding deaths within the first two years of follow-up (n=1140)
    • Supplementary Table 5. Association between serum IGF-1 concentrations and external-cause mortality

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 587 587 337
Full Text Views 58 58 42
PDF Downloads 79 79 58
  • 1

    World Health Organization. Noncommunicable Diseases Country Profiles 2018 [Internet]. Geneva: WHO, 2018. (available at: https://www.who.int/nmh/publications/ncd-profiles-2018/en/)

    • Search Google Scholar
    • Export Citation
  • 2

    World Helath Organization. Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 [Internet]. Geneva: WHO, 2013. (available at: http://www.who.int/nmh/events/ncd_action_plan/en/)

    • Search Google Scholar
    • Export Citation
  • 3

    Kvaerner AS, Hang D, Giovannucci EL, Willett WC, Chan AT, Song M. Trajectories of body fatness from age 5 to 60 y and plasma biomarker concentrations of the insulin-insulin-like growth factor system. American Journal of Clinical Nutrition 2018 108 388397. (https://doi.org/10.1093/ajcn/nqy103)

    • Search Google Scholar
    • Export Citation
  • 4

    Klement RJ, Fink MK. Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer. Oncogenesis 2016 5 e193. (https://doi.org/10.1038/oncsis.2016.2)

    • Search Google Scholar
    • Export Citation
  • 5

    Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosen T, Lindstedt G, Lundberg PA, Bengtsson BA. Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clinical Endocrinology 1994 41 351357. (https://doi.org/10.1111/j.1365-2265.1994.tb02556.x)

    • Search Google Scholar
    • Export Citation
  • 6

    Yakar S, Adamo ML. Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinology and Metabolism Clinics of North America 2012 41 23124 7. (https://doi.org/10.1016/j.ecl.2012.04.008)

    • Search Google Scholar
    • Export Citation
  • 7

    Zhang WB, Aleksic S, Gao T, Weiss EF, Demetriou E, Verghese J, Holtzer R, Barzilai N, Milman S. Insulin-like growth factor-1 and IGF binding proteins predict all-cause mortality and morbidity in older adults. Cells 2020 9 1368. (https://doi.org/10.3390/cells9061368)

    • Search Google Scholar
    • Export Citation
  • 8

    van der Spoel E, Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, Beekman M, de Craen AJ, Westendorp RG, van Heemst D. Association analysis of insulin-like growth factor-1 axis parameters with survival and functional status in nonagenarians of the Leiden Longevity Study. Aging 2015 7 956963. (https://doi.org/10.18632/aging.100841)

    • Search Google Scholar
    • Export Citation
  • 9

    Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, Barzilai N. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 2014 13 769771. (https://doi.org/10.1111/acel.12213)

    • Search Google Scholar
    • Export Citation
  • 10

    Schutte AE, Conti E, Mels CM, Smith W, Kruger R, Botha S, Gnessi L, Volpe M, Huisman HW. Attenuated IGF-1 predicts all-cause and cardiovascular mortality in a black population: a five-year prospective study. European Journal of Preventive Cardiology 2016 23 16901699. (https://doi.org/10.1177/2047487316661436)

    • Search Google Scholar
    • Export Citation
  • 11

    Bourron O, Le Bouc Y, Berard L, Kotti S, Brunel N, Ritz B, Leclercq F, Tabone X, Drouet E & Mulak G et al.Impact of age-adjusted insulin-like growth factor 1 on major cardiovascular events after acute myocardial infarction: results from the fast-MI registry. Journal of Clinical Endocrinology and Metabolism 2015 100 18791886. (https://doi.org/10.1210/jc.2014-3968)

    • Search Google Scholar
    • Export Citation
  • 12

    Brugts MP, van den Beld AW, Hofland LJ, van der Wansem K, van Koetsveld PM, Frystyk J, Lamberts SW, Janssen JA. Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality. Journal of Clinical Endocrinology and Metabolism 2008 93 25152522. (https://doi.org/10.1210/jc.2007-1633)

    • Search Google Scholar
    • Export Citation
  • 13

    Kaplan RC, Buzkova P, Cappola AR, Strickler HD, McGinn AP, Mercer LD, Arnold AM, Pollak MN, Newman AB. Decline in circulating insulin-like growth factors and mortality in older adults: cardiovascular health study all-stars study. Journal of Clinical Endocrinology and Metabolism 2012 97 19701976. (https://doi.org/10.1210/jc.2011-2967)

    • Search Google Scholar
    • Export Citation
  • 14

    Hu D, Pawlikowska L, Kanaya A, Hsueh WC, Colbert L, Newman AB, Satterfield S, Rosen C, Cummings SR & Harris TB et al.Serum insulin-like growth factor-1 binding proteins 1 and 2 and mortality in older adults: the health, aging, and body composition study. Journal of the American Geriatrics Society 2009 57 12131218. (https://doi.org/10.1111/j.1532-5415.2009.02318.x)

    • Search Google Scholar
    • Export Citation
  • 15

    Kaplan RC, McGinn AP, Pollak MN, Kuller L, Strickler HD, Rohan TE, Xue X, Kritchevsky SB, Newman AB, Psaty BM. Total insulinlike growth factor 1 and insulinlike growth factor binding protein levels, functional status, and mortality in older adults. Journal of the American Geriatrics Society 2008 56 652660. (https://doi.org/10.1111/j.1532-5415.2007.01637.x)

    • Search Google Scholar
    • Export Citation
  • 16

    Collins R What makes UK Biobank special? Lancet 2012 379 11731174. (https://doi.org/10.1016/S0140-6736(1260404-8)

  • 17

    Elliott P, Peakman TC & UK Biobank. The UK biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine. International Journal of Epidemiology 2008 37 234244. (https://doi.org/10.1093/ije/dym276)

    • Search Google Scholar
    • Export Citation
  • 18

    Zhu M, Wang T, Huang Y, Zhao X, Ding Y, Zhu M, Ji M, Wang C, Dai J & Yin R et al.Genetic risk for overall cancer and the benefit of adherence to a healthy lifestyle. Cancer Research 2021 81 46184627. (https://doi.org/10.1158/0008-5472.CAN-21-0836)

    • Search Google Scholar
    • Export Citation
  • 19

    Shi X, Miao W, Tchetgen ET. A selective review of negative control methods in epidemiology. Current Epidemiology Reports 2020 7 190202. (https://doi.org/10.1007/s40471-020-00243-4)

    • Search Google Scholar
    • Export Citation
  • 20

    Roubenoff R, Parise H, Payette HA, Abad LW, D'Agostino R, Jacques PF, Wilson PW, Dinarello CA, Harris TB. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. American Journal of Medicine 2003 115 429435. (https://doi.org/10.1016/j.amjmed.2003.05.001)

    • Search Google Scholar
    • Export Citation
  • 21

    Friedrich N, Haring R, Nauck M, Ludemann J, Rosskopf D, Spilcke-Liss E, Felix SB, Dorr M, Brabant G & Volzke H et al.Mortality and serum insulin-like growth factor (IGF)-I and IGF binding protein 3 concentrations. Journal of Clinical Endocrinology and Metabolism 2009 94 17321739. (https://doi.org/10.1210/jc.2008-2138)

    • Search Google Scholar
    • Export Citation
  • 22

    Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D. The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo study. Journal of Clinical Endocrinology and Metabolism 2004 89 114120. (https://doi.org/10.1210/jc.2003-030967)

    • Search Google Scholar
    • Export Citation
  • 23

    Saydah S, Graubard B, Ballard-Barbash R, Berrigan D. Insulin-like growth factors and subsequent risk of mortality in the United States. American Journal of Epidemiology 2007 166 518526. (https://doi.org/10.1093/aje/kwm124)

    • Search Google Scholar
    • Export Citation
  • 24

    Yeap BB, Chubb SAP, McCaul KA, Ho KKY, Hankey GJ, Norman PE, Flicker L. Associations of IGF1 and IGFBPs 1 and 3 with all-cause and cardiovascular mortality in older men: the health in men study. European Journal of Endocrinology 2011 164 715723. (https://doi.org/10.1530/EJE-11-0059)

    • Search Google Scholar
    • Export Citation
  • 25

    Raynaud-Simon A, Lafont S, Berr C, Dartigues JF, Baulieu EE, Le Bouc Y. Plasma insulin-like growth factor I levels in the elderly: relation to plasma dehydroepiandrosterone sulfate levels, nutritional status, health and mortality. Gerontology 2001 47 198206. (https://doi.org/10.1159/000052799)

    • Search Google Scholar
    • Export Citation
  • 26

    Andreassen M, Raymond I, Kistorp C, Hildebrandt P, Faber J, Kristensen . IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population. European Journal of Endocrinology 2009 160 2531. (https://doi.org/10.1530/EJE-08-0452)

    • Search Google Scholar
    • Export Citation
  • 27

    Svensson J, Carlzon D, Petzold M, Karlsson MK, Ljunggren Ö, Tivesten A, Mellstrom D, Ohlsson C. Both low and high serum IGF-I levels associate with cancer mortality in older men. Journal of Clinical Endocrinology and Metabolism 2012 97 46234630. (https://doi.org/10.1210/jc.2012-2329)

    • Search Google Scholar
    • Export Citation
  • 28

    Burgers AM, Biermasz NR, Schoones JW, Pereira AM, Renehan AG, Zwahlen M, Egger M, Dekkers OM. Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality. Journal of Clinical Endocrinology and Metabolism 2011 96 29122920. (https://doi.org/10.1210/jc.2011-1377)

    • Search Google Scholar
    • Export Citation
  • 29

    van Bunderen CC, van Nieuwpoort IC, van Schoor NM, Deeg DJ, Lips P, Drent ML. The association of serum insulin-like growth factor-I with mortality, cardiovascular disease, and cancer in the elderly: a population-based study. Journal of Clinical Endocrinology and Metabolism 2010 95 46164624. (https://doi.org/10.1210/jc.2010-0940)

    • Search Google Scholar
    • Export Citation
  • 30

    Ding J, Sackmann-Sala L, Kopchick JJ. Mouse models of growth hormone action and aging: a proteomic perspective. Proteomics 2013 13 674685. (https://doi.org/10.1002/pmic.201200271)

    • Search Google Scholar
    • Export Citation
  • 31

    Carlzon D, Svensson J, Petzold M, Karlsson MK, Ljunggren Ö, Tivesten Å, Mellstrom D, Ohlsson C. Both low and high serum IGF-1 levels associate with increased risk of cardiovascular events in elderly men. Journal of Clinical Endocrinology and Metabolism 2014 99 E2308E2316. (https://doi.org/10.1210/jc.2014-1575)

    • Search Google Scholar
    • Export Citation
  • 32

    Major JM, Laughlin GA, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. Insulin-like growth factor-I and cancer mortality in older men. Journal of Clinical Endocrinology and Metabolism 2010 95 10541059. (https://doi.org/10.1210/jc.2009-1378)

    • Search Google Scholar
    • Export Citation
  • 33

    Brahmkhatri VP, Prasanna C, Atreya HS. Insulin-like growth factor system in cancer: novel targeted therapies. BioMed Research International 2015 2015 538019. (https://doi.org/10.1155/2015/538019)

    • Search Google Scholar
    • Export Citation
  • 34

    Qian F, Huo D. Circulating insulin-like growth factor-1 and risk of total and 19 site-specific cancers: cohort study analyses from the UK Biobank. Cancer Epidemiology, Biomarkers and Prevention 2020 29 23322342. (https://doi.org/10.1158/1055-9965.EPI-20-0743)

    • Search Google Scholar
    • Export Citation
  • 35

    Fan X, Yin C, Wang J, Yang M, Ma H, Jin G, Song M, Hu Z, Shen H, Hang D. Pre-diagnostic circulating concentrations of insulin-like growth factor-1 and risk of COVID-19 mortality: results from UK Biobank. European Journal of Epidemiology 2021 36 311318. (https://doi.org/10.1007/s10654-020-00709-1)

    • Search Google Scholar
    • Export Citation
  • 36

    Borofsky ND, Vogelman JH, Krajcik RA, Orentreich N. Utility of insulin-like growth factor-1 as a biomarker in epidemiologic studies. Clinical Chemistry 2002 48 22482251. (https://doi.org/10.1093/clinchem/48.12.2248)

    • Search Google Scholar
    • Export Citation