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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
Abstract
The IGF system has been implicated in cardiovascular disease (CVD) development. The prospective association of serum IGF-I and IGF-binding protein-1 (IGFBP-1) with all cause, ischemic heart disease (IHD), and non-IHD CVD mortality was examined in 633 men and 552 nonestrogen-using postmenopausal women, aged 51-98 yr (mean, 74 yr) in 1988-1992, who were followed through July 2001 (96% follow-up). During the 9- to 13-yr follow-up, there were 522 deaths; 224 were attributed to CVD, and 105 were caused by IHD. IGF-I and IGFBP-1 were independently and jointly related to risk of IHD mortality. In a proportional hazards model including both IGF-I and IGFBP-1 and adjusting for CVD risk factors, the relative risk of IHD mortality was 38% higher for every 40 ng/ml (1 SD) decrease in IGF-I (95% confidence interval, 1.09-1.76; P = 0.005) and 3.11 times greater for those in the lowest quintile of IGFBP-1 (95% confidence interval, 1.74-5.56; P < 0.001) compared with those with higher IGFBP-1 levels. IGF-I and IGFBP-1 (alone or in combination) were not related to risk of all cause or non-IHD CVD mortality. We conclude that low baseline levels of IGF-I and IGFBP-1 increase the risk of fatal IHD among elderly men and women independent of prevalent IHD and CVD risk factors.
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“IGF levels [56] and height [5, 12] are also inversely related to coronary heart disease in some studies.”
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“It has to be emphasized that two recent prospective population studies made the opposite observation on IGF-I, namely low rather than high IGF-I levels were associated with an increased risk of myocardial infarction (Juul et al., 2002; Laughlin et al., 2004).”
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“Lower IGF-I levels were associated with an increased risk of cardiovascular disease such as congestive heart failure, ischemic heart disease, and an increased cardiovascular mortality [34, 35].”
BackgroundApoptosis and the cardiac action of insulin-like growth factor I
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“. Lastly, we performed all models examining the association between serum IL-6 and CVD, cancer, and liver-related mortality by excluding participants with prevalent CVD, cancer, or liver disease at baseline. Information on prevalent CVD (including angina, myocardial infarction, cardiac revascularization, stroke or tra…”
MethodSelf-citationFriedrich, N., Alte, D., Völzke, H., Spilcke-Liss, E., Lüdemann, J., Lerch, M. M., Kohlmann, T., Nauck, M. A., & Wallaschofski, H. (2007) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2007.09.005 · Cited by 74
“During the last decade, several studies investigated the potential role of IGF-1 in different diseases, including cardiovascular disease [7– 9], cancer [10], or osteoporosis [11].”
BackgroundProbiotics: Protecting Our Health from the Gut
Varela-Trinidad, G. U., Domínguez-Díaz, C., Solórzano-Castanedo, K., Íñiguez-Gutiérrez, L., Hernández-Flores, T. D. J., & Fafutis‐Morris, M. (2022) · Microorganisms · doi:10.3390/microorganisms10071428 · Cited by 80
“Through the gut microbiota and heart communication axis, ID may trigger or exacerbate heart diseases, such as hypertension, atherosclerosis, CAD, and even heart failure.”
BackgroundInfluentialInsulin-like growth factors and subsequent risk of mortality in the United States
Saydah, S., Graubard, B., Ballard-Barbash, R., & Berrigan, D. (2007) · American Journal of Epidemiology · doi:10.1093/aje/kwm124 · Cited by 71
“In contrast to our study, a prospective study from the Rancho Bernardo cohort (22) found that lower levels of IGF-I were associated with an increased risk of cardiovascular disease mortality.”
BackgroundResultAssociation of diet with serum insulin-like growth factor I in middle-aged and elderly men
Larsson, S. C., Wolk, K., Brismar, K., & Wolk, A. (2005) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/81.5.1163 · Cited by 84
GH and ageing: Pitfalls and new insights
Bartke, A., & Darcy, J. (2017) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2017.02.005 · Cited by 74
Bailey‐Downs, L. C., Sosnowska, D., Tóth, P., Mitschelen, M. C., Gautam, T., Henthorn, J., Ballabh, P., Koller, Á., Farley, J. A., Sonntag, W. E., et al. (2011) · The Journals of Gerontology Series A · doi:10.1093/gerona/glr197 · Cited by 69
Insulin-like growth factor-1 signaling in cardiac aging
Lee, W. S., & Kim, J. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.08.029 · Cited by 70
“This result was supported by another prospective study of 1185 adults who were followed up for over a decade, showing that circulating IGF-1 levels are a predictor of fatal ischemic heart disease [129].”
ResultControl of aging and longevity by IGF-I signaling
Yang, J., Anzo, M., & Cohen, P. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.08.001 · Cited by 66
Oliveira, J. L. M., Aguiar-Oliveira, M. H., D’Oliveira, A., Pereira, R. M. C., Oliveira, C. R. P., Farias, C. T., Barreto‐Filho, J. A., Anjos-Andrade, F. D., Marques-Santos, C., Nascimento-Junior, A. C., et al. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1636 · Cited by 67
Engström, B. E., Burman, P., Holdstock, C., Öhrvall, M., Sundbom, M., & Karlsson, F. A. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.02069 · Cited by 67
A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3
Kaplan, R. C., Petersen, A.-K., Chen, M., Teumer, A., Glazer, N. L., Döring, A., Lam, C. S. P., Friedrich, N., Newman, A. B., Müller‐Nurasyid, M., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddq560 · Cited by 67
Colao, A., Spiezia, S., Somma, C. D., Pivonello, R., Marzullo, P., Rota, F., Musella, T., Auriemma, R. S., Martino, M. C. D., & Lombardi, G. (2005) · Journal of Endocrinological Investigation · doi:10.1007/bf03347225 · Cited by 67
Zhang, W. B., Aleksic, S., Gao, T., Weiss, E. F., Demetriou, E., Verghese, J., Holtzer, R., Barzilai, N., & Milman, S. (2020) · Cells · doi:10.3390/cells9061368 · Cited by 64
“This was particularly relevant for the interpretation of IGFBP-1 levels, which normally fluctuate in relation to prandial status; yet, not all prior studies have been able to establish these conditions [39].”
BackgroundResultIGF-I/IGFBP-3 ratio: a mechanistic insight into the metabolic syndrome
Sierra‐Johnson, J., Romero‐Corral, A., Somers, V. K., López-Jiménez, F. A., Mälarstig, A., Brismar, K., Hamsten, A., Fisher, R. M., & Hellénius, M.-L. (2008) · Clinical Science · doi:10.1042/cs20080382 · Cited by 63
Colao, A., Somma, C. D., Rota, F., Pivonello, R., Savanelli, M. C., Spiezia, S., & Lombardi, G. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2247 · Cited by 62
Colao, A., Somma, C. D., Spiezia, S., Savastano, S., Rota, F., Savanelli, M. C., & Lombardi, G. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2810 · Cited by 61
IGF-1 and atherothrombosis: relevance to pathophysiology and therapy
Conti, E., Musumeci, B., Giusti, M., Dito, E., Mastromarino, V., Autore, C., & Volpe, M. (2011) · Clinical Science · doi:10.1042/cs20100400 · Cited by 61
Hoeflich, A., David, R., & Hjortebjerg, R. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00388 · Cited by 60
Role of IGF-1 in glucose regulation and cardiovascular disease
Abbas, A., Grant, P. J., & Kearney, M. T. (2008) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.6.8.1135 · Cited by 61
Norling, A. M., Gerstenecker, A. T., Buford, T. W., Khan, B., Oparil, S., & Lazar, R. M. (2019) · GeroScience · doi:10.1007/s11357-019-00139-2 · Cited by 58
“These findings corroborate other studies that showed a reduced level of IGF-1 to be a strong predictor of cardiovascular disease (Juul et al. 2002; Laughlin et al. 2004).”
ResultSavanelli, M. C., Scarano, E., Muscogiuri, G., Barrea, L., Vuolo, L., Rubino, M., Savastano, S., Colao, A., & Di Somma, C. (2016) · Endocrine · doi:10.1007/s12020-015-0779-3 · Cited by 59
Growth Hormone and the Cardiovascular System
Palmeiro, C., Anand, R. G., Dardi, I. K., Balasubramaniyam, N., Schwarcz, M., & Weiss, I. A. (2012) · Cardiology in Review · doi:10.1097/crd.0b013e318248a3e1 · Cited by 57
Metformin stimulates IGFBP-2 gene expression through PPARalpha in diabetic states
Kang, H. S., Cho, H., Lee, J., Oh, G. T., Koo, S., Park, B., Lee, I., Choi, H., Song, D., & Im, S. (2016) · Scientific Reports · doi:10.1038/srep23665 · Cited by 59
Miller, M. H., Walsh, S. V., Atrih, A., Huang, J. T.-J., Ferguson, M. A. J., & Dillon, J. F. (2014) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.12614 · Cited by 55
Yeap, B. B., Paul Chubb, S. A., Lopez, D., Ho, K. K. Y., Hankey, G. J., & Flicker, L. (2013) · Clinical Endocrinology · doi:10.1111/cen.12052 · Cited by 53
Martin, R. M., Holly, J. M. P., Smith, G. D., & Gunnell, D. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0745 · Cited by 54
Vascular Insulin-Like Growth Factor-I Resistance and Diet-Induced Obesity
Imrie, H., Abbas, A., Viswambharan, H., Rajwani, A., Cubbon, R. M., Gage, M., Kahn, M., Ezzat, V., Duncan, E. R., Grant, P. J., et al. (2009) · Endocrinology · doi:10.1210/en.2008-1641 · Cited by 54
Kaplan, R. C., McGinn, A. P., Pollak, M., Kuller, L. H., Strickler, H. D., Rohan, T. E., Xue, X., Kritchevsky, S. B., Newman, A. B., & Psaty, B. M. (2008) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2007.01637.x · Cited by 55
“In the Rancho Bernardo cohort, high IGFBP-1 levels were associated with lower risk of ischemic heart disease mortality, although results for nonischemic heart disease or all-cause mortality were null.(26) IGFBP-1 levels in the Rancho Bernardo study were nonfasting, which makes interpretation of these results uncertain…”
BackgroundGrowth hormone/insulin-like growth factor-I axis in obstructive sleep apnea syndrome: An update
Lanfranco, F., Motta, G., Minetto, M. A., Ghigo, E., & Maccario, M. (2010) · Journal of Endocrinological Investigation · doi:10.1007/bf03346580 · Cited by 52
Revisiting the Relationship Between Blood Pressure and Insulin-Like Growth Factor-1
Schutte, A. E., Volpe, M., Tocci, G., & Conti, E. (2014) · Hypertension · doi:10.1161/hypertensionaha.113.03057 · Cited by 52
“8±15 y; cross-sectional analysis of controls at study entry (n=200)20; (29) men and women from the general population aged 40±9 y (n=3496); cross-sectional analysis of first examination of prospective study, adjusted for sex and age.”
BackgroundEndothelial IGF-1 Receptor Signalling in Diabetes and Insulin Resistance
Cubbon, R. M., Kearney, M. T., & Wheatcroft, S. B. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.11.009 · Cited by 51
“In the Rancho Bernardo study, every 40-ng/ml decrement in IGF-1 was associated with a 38% increase in risk of death from coronary artery disease [23].”
BackgroundInsulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus
Kim, M. S., & Lee, D. (2015) · Annals of Pediatric Endocrinology & Metabolism · doi:10.6065/apem.2015.20.2.69 · Cited by 51
Drogan, D., Schulze, M. B., Boeing, H., & Pischon, T. (2016) · American Journal of Epidemiology · doi:10.1093/aje/kwv188 · Cited by 51
Metadata
- Authors
- Laughlin, G. A., Barrett-Connor, E., Criqui, M. H., & Kritz-Silverstein, D.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Barrett-Connor, Elizabeth
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-01
- Volume
- 89
- Issue
- 1
- Pages
- 114-120
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2115525455
- Cited by
- 374
- References
- 40
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 9 · 2023: 9 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 17 · 2018: 8 · 2017: 19 · 2016: 13 · 2015: 10 · 2014: 13 · 2013: 12 · 2012: 26
- FWCI
- 15.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG07181)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK031801, DK-31801)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin-like growth factor I, IGF-binding protein-1, cardiovascular mortality, ischemic heart disease mortality, all-cause mortality, older adults, postmenopausal women, IGF system, cardiovascular risk markers
- MeSH terms
- Age Factors, Aged, Blood Pressure, Cardiovascular Diseases, Cholesterol, Female, Humans, Insulin-Like Growth Factor I, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Pregnancy Proteins, Prospective Studies, Risk Factors, Sex Factors, Triglycerides, Body Mass Index, Myocardial Ischemia, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor Binding Protein 1
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