@article {940, title = {Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke.}, journal = {J Clin Endocrinol Metab}, volume = {92}, year = {2007}, month = {2007 Apr}, pages = {1319-25}, abstract = {

CONTEXT: Prior observational studies have demonstrated that the GH/IGF axis is associated with cardiovascular disease. However, this association has not been extensively studied among older adults.

OBJECTIVE: The objective of this study was to assess the association between levels of total IGF-I and IGF binding proteins (IGFBP-1, IGFBP-3) and risk of incident coronary events and ischemic stroke.

DESIGN AND PARTICIPANTS: A case-cohort analysis was conducted among adults 65 yr and older in the Cardiovascular Health Study.

MAIN OUTCOME MEASURES: A total of 534 coronary events [316 nonfatal myocardial infarctions (MIs), 48 fatal MIs, and 170 fatal coronary heart disease events] and 370 ischemic strokes were identified on follow-up. Comparison subjects were 1122 randomly selected participants from the Cardiovascular Health Study.

RESULTS: Mean follow-up time was 6.7 yr for coronary events, 5.6 yr for strokes, and 9.3 yr for comparison subjects. Hazard ratios (95\% confidence intervals) associated with baseline levels of total IGF-I and IGFBPs were estimated using multivariate adjusted Cox proportional hazards models. Neither IGF-I nor IGFBP-1 levels predicted risk of incident coronary events or stroke. IGFBP-3 had an inverse association with risk of coronary events [adjusted hazard ratio per sd=0.88 (0.78-1.00), P=0.05] but was not associated with stroke. Exploratory analyses suggested that low IGF-I and low IGFBP-3 levels were significantly associated with higher risk of nonfatal MI (P<0.05) but not with risk of fatal MI or fatal coronary heart disease.

CONCLUSION: Circulating levels of total IGF-I or IGFBP-1 were not associated with risk of total coronary events or ischemic stroke among older adults, whereas low IGFBP-3 level was associated with increased risk of incident coronary events.

}, keywords = {Aged, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Coronary Disease, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Multivariate Analysis, Risk Factors, Stroke}, issn = {0021-972X}, doi = {10.1210/jc.2006-1631}, author = {Kaplan, Robert C and McGinn, Aileen P and Pollak, Michael N and Kuller, Lewis H and Strickler, Howard D and Rohan, Tom E and Cappola, Anne R and Xue, XiaoNan and Psaty, Bruce M} } @article {1035, title = {High insulinlike growth factor binding protein 1 level predicts incident congestive heart failure in the elderly.}, journal = {Am Heart J}, volume = {155}, year = {2008}, month = {2008 Jun}, pages = {1006-12}, abstract = {

BACKGROUND: Low levels of insulinlike growth factor 1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulinlike growth factor binding protein 1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in patients with CHF and has been associated prospectively with increased mortality among older adults and survivors of myocardial infarction. We investigated the association between fasting plasma levels of IGF-I, IGFBP-1, IGFBP-3, and insulin and risk of incident CHF in the prospective Cardiovascular Health Study.

METHODS: From among 5,888 adults 65 years old and older in the Cardiovascular Health Study, we studied 566 incident CHF cases and 1,072 comparison subjects after exclusion of underweight individuals (body mass index <18.5 kg/m(2)) and insulin users. Hazard ratios (HRs) with 95\% CIs for CHF were estimated after adjustment for age, race, sex, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and body mass index.

RESULTS: High baseline IGFBP-1 level was a significant predictor of CHF, independent of established CHF risk factors and inflammation markers. The HR per SD of IGFBP-1 was 1.22 (95\% CI 1.07-1.39, P < .01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95\% CI 0.96-1.74, P = .09) for the second IGFBP-1 tertile and 1.47 (95\% CI 1.06-2.04; P = .02) for the highest IGFBP-1 tertile (tertile cut points 19.5 and 35.8 ng/mL). Total IGF-I, IGFBP-3, or insulin levels had no association with CHF after adjustment for CHF risk factors.

CONCLUSIONS: High circulating IGFBP-1 level may be a CHF risk factor among older adults.

}, keywords = {Aged, Aged, 80 and over, Female, Heart Failure, Humans, Incidence, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Predictive Value of Tests, Prospective Studies, Risk Factors}, issn = {1097-6744}, doi = {10.1016/j.ahj.2007.12.031}, author = {Kaplan, Robert C and McGinn, Aileen P and Pollak, Michael N and Kuller, Lewis and Strickler, Howard D and Rohan, Thomas E and Cappola, Anne R and Xue, XiaoNan and Psaty, Bruce M} } @article {1021, title = {Total insulinlike growth factor 1 and insulinlike growth factor binding protein levels, functional status, and mortality in older adults.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Apr}, pages = {652-60}, abstract = {

OBJECTIVES: To assess the association between total insulinlike growth factor (IGF)-1, IGF binding protein-1 (IGFBP-1), and IGFBP-3 levels and functioning and mortality in older adults.

DESIGN: Cohort study.

SETTING/PARTICIPANTS: One thousand one hundred twenty-two individuals aged 65 and older without prior cardiovascular disease events participating in the Cardiovascular Health Study.

MEASUREMENTS: Baseline fasting plasma levels of IGF-1, IGFBP-1, and IGFBP-3 (defined as tertiles, T1-T3) were examined in relationship to handgrip strength, time to walk 15 feet, development of new difficulties with activities of daily living (ADLs), and mortality.

RESULTS: Higher IGFBP-1 predicted worse handgrip strength (P-trend(T1-T3)<.01) and slower walking speed (P-trend(T1-T3)=.03), lower IGF-1 had a borderline significant association with worse handgrip strength (P-trend(T1-T3)=.06), and better grip strength was observed in the middle IGFBP-3 tertile than in the low or high tertiles (P=.03). Adjusted for age, sex, and race, high IGFBP-1 predicted greater mortality (P-trend(T1-T3)<.001, hazard ratio (HR)(T3vsT1)=1.48, 95\% confidence interval (CI)=1.15-1.90); this association was borderline significant after additional confounder adjustment (P-trend(T1-T3)=.05, HR(T3vsT1)=1.35, 95\% CI=0.98-1.87). High IGFBP-1 was associated with greater risk of incident ADL difficulties after adjustment for age, sex, race, and other confounders (P-trend(T1-T3)=.04, HR(T3vsT1)=1.40, CI=1.01-1.94). Neither IGF-1 nor IGFBP-3 level predicted mortality or incident ADL difficulties.

CONCLUSION: In adults aged 65 and older, high IGFBP-1 levels were associated with greater risk of mortality and poorer functional ability, whereas IGF-1 and IGFBP-3 had little association with these outcomes.

}, keywords = {Activities of Daily Living, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Enzyme-Linked Immunosorbent Assay, Fasting, Female, Follow-Up Studies, Hand Strength, Humans, Incidence, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Middle Aged, Prognosis, Prospective Studies, Risk Factors, Survival Rate, United States, Walking}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2007.01637.x}, author = {Kaplan, Robert C and McGinn, Aileen P and Pollak, Michael N and Kuller, Lewis and Strickler, Howard D and Rohan, Thomas E and Xue, XiaoNan and Kritchevsky, Stephen B and Newman, Anne B and Psaty, Bruce M} } @article {1104, title = {Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity.}, journal = {Aging Cell}, volume = {8}, year = {2009}, month = {2009 Aug}, pages = {460-72}, abstract = {

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan > or = 92 years (y), mean +/- standard deviation (SD) = 95.3 +/- 2.2y) and 603 average-lifespan controls (lifespan < or = 79y, mean = 75.7 +/- 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95\%CI = 0.68-0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95\%CI = 1.15-1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.

}, keywords = {Aged, Aged, 80 and over, Female, Follow-Up Studies, Forkhead Box Protein O3, Forkhead Transcription Factors, Genome, Human, Genotype, Humans, Insulin, Insulin-Like Growth Factor I, Longevity, Male, Osteoporosis, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-akt, Signal Transduction}, issn = {1474-9726}, doi = {10.1111/j.1474-9726.2009.00493.x}, author = {Pawlikowska, Ludmila and Hu, Donglei and Huntsman, Scott and Sung, Andrew and Chu, Catherine and Chen, Justin and Joyner, Alexander H and Schork, Nicholas J and Hsueh, Wen-Chi and Reiner, Alexander P and Psaty, Bruce M and Atzmon, Gil and Barzilai, Nir and Cummings, Steven R and Browner, Warren S and Kwok, Pui-Yan and Ziv, Elad} } @article {1088, title = {Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Nov}, pages = {1103-6}, abstract = {

The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.

}, keywords = {Aged, Aging, Cross-Sectional Studies, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Leukocytes, Linear Models, Male, Sex Characteristics, Telomere}, issn = {1758-535X}, doi = {10.1093/gerona/glp036}, author = {Kaplan, Robert C and Fitzpatrick, Annette L and Pollak, Michael N and Gardner, Jeffrey P and Jenny, Nancy S and McGinn, Aileen P and Kuller, Lewis H and Strickler, Howard D and Kimura, Masayuki and Psaty, Bruce M and Aviv, Abraham} } @article {1261, title = {A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Mar 15}, pages = {1241-51}, abstract = {

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 {\texttimes} 10(-8) (P = 3.3 {\texttimes} 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 {\texttimes} 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 {\texttimes} 10(-21)) and higher IGF-I (P = 4.9 {\texttimes} 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 {\texttimes} 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 {\texttimes} 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5\% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 {\texttimes} 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

}, keywords = {Aged, Chromosomes, Human, Pair 7, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Polymorphism, Single Nucleotide}, issn = {1460-2083}, doi = {10.1093/hmg/ddq560}, author = {Kaplan, Robert C and Petersen, Ann-Kristin and Chen, Ming-Huei and Teumer, Alexander and Glazer, Nicole L and D{\"o}ring, Angela and Lam, Carolyn S P and Friedrich, Nele and Newman, Anne and M{\"u}ller, Martina and Yang, Qiong and Homuth, Georg and Cappola, Anne and Klopp, Norman and Smith, Holly and Ernst, Florian and Psaty, Bruce M and Wichmann, H-Erich and Sawyer, Douglas B and Biffar, Reiner and Rotter, Jerome I and Gieger, Christian and Sullivan, Lisa S and V{\"o}lzke, Henry and Rice, Kenneth and Spyroglou, Ariadni and Kroemer, Heyo K and Ida Chen, Y-D and Manolopoulou, Jenny and Nauck, Matthias and Strickler, Howard D and Goodarzi, Mark O and Reincke, Martin and Pollak, Michael N and Bidlingmaier, Martin and Vasan, Ramachandran S and Wallaschofski, Henri} } @article {6737, title = {Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults.}, journal = {J Am Geriatr Soc}, volume = {63}, year = {2015}, month = {2015 May}, pages = {902-9}, abstract = {

OBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.

DESIGN: Retrospective analysis of a cohort study.

SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).

MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).

RESULTS: At baseline, mean age was 76.3{\textpm}3.6, and 18.5\% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3\% for IGF-I, 59.7\% for IGFBP-1, -13.4\% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7\% for IGF-I, 25.6\% for IGFBP-1, -6.4\% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.

CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.

}, keywords = {Aged, Blood Glucose, Cohort Studies, Diabetes Mellitus, Type 2, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Male, Retrospective Studies}, issn = {1532-5415}, doi = {10.1111/jgs.13390}, author = {Aneke-Nash, Chino S and Parrinello, Christina M and Rajpathak, Swapnil N and Rohan, Thomas E and Strotmeyer, Elsa S and Kritchevsky, Stephen B and Psaty, Bruce M and B{\r u}zkov{\'a}, Petra and Kizer, Jorge R and Newman, Anne B and Strickler, Howard D and Kaplan, Robert C} } @article {7547, title = {The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, volume = {102}, year = {2017}, month = {2017 Dec 01}, pages = {4541-4547}, abstract = {

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.

Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.

Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged >=65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.

Setting: General community.

Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.

Interventions: Not applicable.

Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) >=126 mg/dL, non-FPG >=200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare \& Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.

Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95\% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.

Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Blood Glucose, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Female, Humans, Incidence, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Longitudinal Studies, Male, New England, Prospective Studies, Risk}, issn = {1945-7197}, doi = {10.1210/jc.2017-01273}, author = {Aneke-Nash, Chino S and Xue, XiaoNan and Qi, Qibin and Biggs, Mary L and Cappola, Anne and Kuller, Lewis and Pollak, Michael and Psaty, Bruce M and Siscovick, David and Mukamal, Kenneth and Strickler, Howard D and Kaplan, Robert C} }