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1.  Hyperglycemia, Insulin Resistance, Impaired Pancreatic β-Cell Function, and Risk of Pancreatic Cancer 
Background
Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction.
Methods
This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided.
Results
The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001).
Conclusions
Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.
doi:10.1093/jnci/djt123
PMCID: PMC3714020  PMID: 23847240
2.  Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism 
Cancer research  2013;73(14):4429-4438.
Metformin inhibits cancer cell proliferation and epidemiology studies suggest an association with increased survival in cancer patients taking metformin, however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation while increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer.
doi:10.1158/0008-5472.CAN-13-0080
PMCID: PMC3930683  PMID: 23687346
4.  Inflammatory Plasma Markers and Pancreatic Cancer Risk: a Prospective Study of 5 U.S. Cohorts 
Chronic inflammation may play a role in the development of pancreatic cancer. However, few prospective studies have examined the association between plasma inflammatory markers and pancreatic cancer risk. Therefore, we investigated the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α-receptor II (TNF-αR2) with subsequent pancreatic cancer risk in a prospective, nested case-control study of 470 cases and 1094 controls from Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. The median follow-up time of cases was 7.2 years (range 1-26 years). No association was observed between plasma CRP, IL6, and TNF-αR2 and risk of pancreatic cancer. Comparing extreme quintiles, the multivariate ORs were 1.10 (95% CI, 0.74-1.63; Ptrend= 0.81) for CRP, 1.19 (95% CI, 0.81-1.76; Ptrend = 0.08) for IL6, and 0.88 (95% CI, 0.58-1.33; Ptrend = 0.57) for TNF-αR2. In conclusion, pre-diagnostic levels of circulating CRP, IL6, and TNF-αR2 were not associated with risk of pancreatic cancer, suggesting that systemic inflammation as measured by circulating inflammatory factors is unlikely to play a major role in the development of pancreatic cancer.
doi:10.1158/1055-9965.EPI-12-1458
PMCID: PMC3650127  PMID: 23462920
5.  Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial 
Introduction
Osteopontin (OPN) is a malignancy-associated glycoprotein that contributes functionally to tumor aggressiveness. In metastatic breast cancer, we previously demonstrated that elevated OPN in primary tumor and blood was associated with poor prognosis.
Methods
We measured OPN in plasma by ELISA, and in tumors by immunohistochemistry, in 624 (94%) and 462 (69%), respectively, of 667 postmenopausal women with hormone responsive early breast cancer treated by surgery followed by adjuvant treatment with tamoxifen +/− octreotide in a randomized trial (NCIC CTG MA.14; National Cancer Institute of Canada Clinical Trials Group Mammary.14).
Results
Plasma OPN was measured in 2,540 samples; 688 at baseline and 1,852 collected during follow-up. Mean baseline plasma OPN was 46 ng/ml (range 22.6 to 290) which did not differ from normal levels. Mean percentage OPN tumor cell positivity was 33.9 (95% CI: 30.2 to 37.9). There was no correlation between plasma and tumor OPN values. In multivariate analysis, neither was associated with event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), bone RFS or non-bone RFS. An exploratory analysis in patients with recurrence showed higher mean OPN plasma levels 60.7 ng/ml (23.9 to 543) in the recurrence period compared with baseline levels.
Conclusions
The hypothesis that OPN tumor expression would have independent prognostic value in early breast cancer was not supported by multivariate analysis of this study population. Plasma OPN levels in women with hormone responsive early breast cancer in the MA.14 trial were not elevated and there was no evidence for prognostic value of plasma OPN in this defined group of patients. However, our finding of elevated mean OPN plasma level around the time of recurrence warrants further study.
Trial registration
NCT00002864, http://clinicaltrials.gov/show/NCT00002864
doi:10.1186/bcr3600
PMCID: PMC3978736  PMID: 24451146
6.  A Prospective Study of Plasma Adiponectin and Pancreatic Cancer Risk in Five US Cohorts 
Background
The adipocyte-secreted hormone adiponectin has insulin-sensitizing and anti-inflammatory properties. Although development of pancreatic cancer is associated with states of insulin resistance and chronic inflammation, the mechanistic basis of the associations is poorly understood.
Methods
To determine whether prediagnostic plasma levels of adiponectin are associated with risk of pancreatic cancer, we conducted a nested case–control study of 468 pancreatic cancer case subjects and 1080 matched control subjects from five prospective US cohorts: Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Women’s Health Initiative, and Women’s Health Study. Control subjects were matched to case subjects by prospective cohort, year of birth, smoking status, fasting status, and month of blood draw. All samples for plasma adiponectin were handled identically in a single batch. Odds ratios were calculated with conditional logistic regression, and linearity of the association between adiponectin and pancreatic cancer was modeled with restricted cubic spline regression. All statistical tests were two-sided.
Results
Median plasma adiponectin was lower in case subjects versus control subjects (6.2 vs 6.8 µg/mL, P = .009). Plasma adiponectin was inversely associated with pancreatic cancer risk, which was consistent across the five prospective cohorts (P heterogeneity = .49) and independent of other markers of insulin resistance (eg, diabetes, body mass index, physical activity, plasma C-peptide). Compared with the lowest quintile of adiponectin, individuals in quintiles 2 to 5 had multivariable odds ratios ([ORs] 95% confidence intervals [CIs]) of OR = 0.61 (95% CI = 0.43 to 0.86), OR = 0.58 (95% CI = 0.41 to 0.84), OR = 0.59 (95% CI = 0.40 to 0.87), and OR = 0.66 (95% CI = 0.44 to 0.97), respectively (P trend = .04). Restricted cubic spline regression confirmed a nonlinear association (P nonlinearity < .01). The association was not modified by sex, smoking, body mass index, physical activity, or C-peptide (all P interaction > .10).
Conclusions
In this pooled analysis, low prediagnostic levels of circulating adiponectin were associated with an elevated risk of pancreatic cancer.
doi:10.1093/jnci/djs474
PMCID: PMC3545904  PMID: 23243202
7.  The Use of Metformin and the Incidence of Lung Cancer in Patients With Type 2 Diabetes 
Diabetes Care  2012;36(1):124-129.
OBJECTIVE
Observational studies have associated metformin use with a decreased risk of lung cancer incidence in patients with type 2 diabetes, but the studies had important methodological shortcomings. The objective of this study was to determine whether metformin use is associated with a decreased risk of lung cancer in patients with type 2 diabetes, while avoiding previous biases.
RESEARCH DESIGN AND METHODS
Using the U.K. General Practice Research Database, we assembled a cohort of patients newly treated with oral hypoglycemic agents (OHAs) between 1988 and 2009. A nested case–control analysis was conducted, where case subjects with lung cancer occurring during follow-up were matched with up to 10 control subjects for age, sex, calendar time, and duration of follow-up. Conditional logistic regression was used to estimate adjusted rate ratios of lung cancer associated with ever use of metformin, along with measures of duration and cumulative dose. Models were adjusted for potential confounders, which included smoking.
RESULTS
The cohort included 115,923 new users of OHAs, with 1,061 patients diagnosed with lung cancer during follow-up (rate 2.0/1,000 person-years). Metformin use was not associated with a decreased rate of lung cancer (rate ratio 0.94 [95% CI 0.76–1.17]). No dose-response was observed by number of prescriptions received, cumulative duration of use, and dose.
CONCLUSIONS
Metformin use is not associated with a decreased risk of lung cancer in patients with type 2 diabetes. The decreased risk reported in other observational studies is likely due to bias from methodological shortcomings. Nonetheless, greater consideration should be given to clarify inconsistencies between experimental models and population studies.
doi:10.2337/dc12-0740
PMCID: PMC3526233  PMID: 22923670
8.  Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, growth hormone, and mammographic density in the Nurses' Health Studies 
Higher circulating insulin-like growth factor I (IGF-1) levels have been associated with higher mammographic density among women in some, but not all studies. Also, few studies have examined the association between mammographic density and circulating growth hormone (GH) in premenopausal women. We conducted a cross-sectional study among 783 premenopausal women and 436 postmenopausal women who were controls in breast cancer case–control studies nested in the Nurses' Health Study (NHS) and NHSII. Participants provided blood samples in 1989–1990 (NHS) or in 1996–1999 (NHSII), and mammograms were obtained near the time of blood draw. Generalized linear models were used to assess the associations of IGF-1, IGF-binding protein-3 (IGFBP-3), IGF-1:IGFBP-3 ratio, and GH with percent mammographic density, total dense area, and total non-dense area. Models were adjusted for potential confounders including age and body mass index (BMI), among others. We also assessed whether the associations varied by age or BMI. In both pre- and postmenopausal women, percent mammographic density was not associated with plasma levels of IGF-1, IG-FBP-3, or the IGF-1:IGFBP-3 ratio. In addition, GH was not associated with percent density among premenopausal women in the NHSII. Similarly, total dense area and non-dense area were not significantly associated with any of these analytes. In postmenopausal women, IGF-1 was associated with higher percent mammographic density among women with BMI <25 kg/m2, but not among overweight/obese women. Overall, plasma IGF-1, IGFBP-3, and GH levels were not associated with mammographic density in a sample of premenopausal and postmenopausal women.
doi:10.1007/s10549-012-2303-2
PMCID: PMC3696995  PMID: 23085768
Insulin-like growth factor 1; Insulin-like growth factor-binding protein-3; Mammographic density; Breast cancer
9.  Glycemic load effect on fasting and post-prandial serum glucose, insulin, IGF-1 and IGFBP-3 in a randomized, controlled feeding study 
European journal of clinical nutrition  2012;66(10):1146-1152.
Background/Objectives
The effect of a low glycemic load (GL) diet on insulin-like growth factor-1 (IGF-1) concentration is still unknown but may contribute to lower chronic disease risk. We aimed to assess the impact of GL on concentrations of IGF-1 and IGFBP-3.
Subjects/Methods
We conducted a randomized, controlled crossover feeding trial in 84 overweight-obese and normal weight healthy individuals using two 28-day weight-maintaining high- and low-GL diets. Measures were fasting and post-prandial concentrations of insulin, glucose, IGF-1 and IGFBP-3. 20 participants completed post-prandial testing by consuming a test breakfast at the end of each feeding period. We used paired t-tests for diet-component and linear mixed models for biomarker analyses.
Results
The 28-day low-GL diet led to 4% lower fasting concentrations of IGF-1 (10.6 ng/mL, p=0.04) and a 4% lower ratio of IGF-1/IGFBP-3 (0.24, p=0.01) compared to the high-GL diet. The low-GL test breakfast led to 43% and 27% lower mean post-prandial glucose and insulin responses, respectively; mean incremental areas under the curve for glucose and insulin, respectively, were 64.3±21.8 (mmol/L/240min) (p<0.01) and 2253±539 (μU/mL/240min) (p<0.01) lower following the low- compared to the high-GL test meal. There was no effect of GL on mean HOMA-IR or on mean integrated post-prandial concentrations of glucose-adjusted insulin, IGF-1 or IGFBP-3. We did not observe modification of the dietary effect by adiposity.
Conclusions
Low-GL diets resulted in 43% and 27% lower post-prandial responses of glucose and insulin, respectively, and modestly lower fasting IGF-1 concentrations. Further intervention studies are needed to weigh the impact of dietary GL on risk for chronic disease.
doi:10.1038/ejcn.2012.107
PMCID: PMC3463643  PMID: 22892437
Adiposity; Glycemic Index; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Binding Protein 3; Randomized Controlled Trial [Publication Type]
10.  Racial variation in vitamin D cord blood concentration in White and Black male neonates 
Cancer causes & control : CCC  2012;24(1):91-98.
Background
To evaluate racial variation in umbilical cord blood concentration of vitamin D and to explore its correlation with markers of the insulin-like growth factor axis (IGFs) and sex steroid hormones in white and black male neonates.
Methods
In 2004/2005 venous umbilical cord blood samples were collected from 75 black and 38 white male neonates, along with maternal and birth characteristics from two hospitals in Maryland, US. 25-hydroxyvitamin D [25(OH)D], and 1,25-dihydroxyvitamin D [1,25(OH)2D] were measured by radioimmunoassay (RIA), testosterone, estradiol and sex hormone binding globulin (SHBG) by immunoassay and IGF-1, IGF-2, and IGF-binding protein-3 (IGFBP-3) by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed.
Results
Mean 25(OH)D levels were lower in black than in white neonates (11.44; 95% CI 10.10–12.95 ng/mL vs. 18.24; 95% CI 15.32–21.72 ng/mL; p<0.0001). Black neonates were at higher risk of suboptimal vitamin D levels [25(OH)D < 20 ng/mL] than whites (84% vs. 63%). 25(OH)D concentrations varied by season in whites but not in blacks and were significantly inversely correlated with mother’s parity (number of live births) in blacks but not in whites. Mean concentration of 1,25(OH)2D did not differ by race. 25(OH)D and 1,25(OH)2D did not correlate with IGFs, sex steroid hormones and SHBG.
Conclusions
Suboptimal vitamin D levels were prevalent especially in blacks and influenced by mother’s parity and by season. The observed vitamin D differences between black and white neonates warrant further evaluation of the etiology of the disparity in chronic diseases in adulthood.
doi:10.1007/s10552-012-0093-9
PMCID: PMC3529856  PMID: 23139102
Vitamin D; umbilical cord blood; black and white Americans
11.  Alterations in Cellular Energy Metabolism Associated with the Antiproliferative Effects of the ATM Inhibitor KU-55933 and with Metformin 
PLoS ONE  2012;7(11):e49513.
KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM), an important tumor suppressor gene with key roles in DNA repair. Unexpectedly for an inhibitor of a tumor suppressor gene, KU-55933 reduces proliferation. In view of prior preliminary evidence suggesting defective mitochondrial function in cells of patients with Ataxia Telangiectasia (AT), we examined energy metabolism of cells treated with KU-55933. The compound increased AMPK activation, glucose uptake and lactate production while reducing mitochondrial membrane potential and coupled respiration. The stimulation of glycolysis by KU-55933 did not fully compensate for the reduction in mitochondrial functions, leading to decreased cellular ATP levels and energy stress. These actions are similar to those previously described for the biguanide metformin, a partial inhibitor of respiratory complex I. Both compounds decreased mitochondrial coupled respiration and reduced cellular concentrations of fumarate, malate, citrate, and alpha-ketogluterate. Succinate levels were increased by KU-55933 levels and decreased by metformin, indicating that the effects of ATM inhibition and metformin are not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metformin perturb the TCA cycle as well as oxidative phosphorylation.
doi:10.1371/journal.pone.0049513
PMCID: PMC3504012  PMID: 23185347
12.  Serum C-Reactive Protein and Risk of Pancreatic Cancer in Two Nested, Case-Control Studies 
Background
Many epidemiologic studies have examined the association between CRP and risk of cancer with inconsistent results.
Methods
We conducted two nested, case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial to test whether pre-diagnostic circulating CRP concentrations were associated with pancreatic adenocarcinoma. Between 1985 and 2004, 311 cases occurred in ATBC and between 1994 and 2006, 182 cases occurred in PLCO. Controls (n=510 in ATBC, n=374 in PLCO) were alive at the time the case was diagnosed and were matched by age, date of blood draw, sex, and race. We used conditional logistic regression adjusted for smoking to calculate odds ratios (OR) and 95% confidence intervals (CI) for pancreatic cancer.
Results
CRP concentrations (ng/ml) tended to be inversely or not associated with pancreatic cancer risk in ATBC, PLCO, and combined analyses (per standardized quintile increase in CRP, continuous OR= 0.94, 95% CI 0.89, 0.99; OR=0.99, 95% CI 0.95, 1.04; OR=0.98, 95% CI 0.95, 1.01, respectively). In combined analyses, we observed a significant interaction (p-interaction=0.02) such that inverse associations were suggestive in younger (OR=0.95; 95% CI, 0.90–1.01), but not older participants.
Conclusion
Our results do not support the hypothesis that higher CRP concentrations are associated with incident pancreatic cancer.
Impact
Our results highlight the importance of investigating more specific biomarkers for inflammation that may reflect the biological mechanisms underlying pancreatic cancer in prospective cohort studies.
doi:10.1158/1055-9965.EPI-10-1024
PMCID: PMC3495286  PMID: 21173171
CRP; ATBC; PLCO; Pancreatic; Case-Control
13.  Body Size in Early Life and Adult Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 
American Journal of Epidemiology  2011;174(6):642-651.
Body size in early life has been associated with breast cancer risk. This may be partly mediated through the insulin-like growth factor (IGF) pathway. The authors assessed whether birth weight, body fatness at ages 5 and 10 years, and body mass index (BMI; weight (kg)/height (m)2) at age 18 years were associated with plasma concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 in 6,520 women aged 32–70 years at blood draw from the Nurses’ Health Study (1990–2006) and Nurses’ Health Study II (1997–2005). Birth weight, body fatness in childhood, and BMI at age 18 years were inversely associated with adult IGF-1 levels. For example, IGF-1 levels were 11.9% lower in women who reported being heaviest at age 10 years than in those who were leanest at age 10 (P-trend < 0.0001). Further, women who reported their birth weight as ≥10 pounds (≥4.5 kg) (vs. <5.5 pounds (<2.5 kg)) had 7.9% lower IGF-1 levels (P-trend = 0.002). Women whose BMI at age 18 years was ≥30 (vs. <20) had 14.1% lower IGF-1 levels (P-trend < 0.0001). Similar inverse associations were observed for insulin-like growth factor binding protein 3. These observations did not vary by adult BMI or menopausal status at blood draw. These findings suggest that altered IGF-1 levels in adulthood may be a mechanism through which early-life body size influences subsequent breast cancer risk.
doi:10.1093/aje/kwr123
PMCID: PMC3166705  PMID: 21828371
birth weight; body mass index; breast neoplasms; child; growth; insulin-like growth factor 1; insulin-like growth factor binding protein 3; obesity
14.  Racial variation in umbilical cord blood sex steroid hormones and the insulin-like growth factor axis in African-American and white female neonates 
Cancer causes & control : CCC  2012;23(3):445-454.
Purpose
To evaluate whether there is racial variation in venous umbilical cord blood concentrations of sex steroid hormones and the insulin-like growth factor (IGF)-axis between female African-American and white neonates.
Methods
Maternal and birth characteristics and venous umbilical cord blood samples were collected from 77 African-American and 41 white full-term uncomplicated births at two urban hospitals in 2004 and 2005. Cord blood was measured for testosterone, dehydroespiandrosterone-sulfate (DHEAS), estradiol, sex-steroid hormone binding globulin (SHBG) by immunoassay. IGF-1, IGF-2, and IGF binding protein-3 (IGFBP-3) were measured by ELISA. Crude and multivariable-adjusted geometric mean concentrations were computed for the hormones.
Results
African-American neonates weighed less at birth (3,228 vs. 3,424 grams, p<0.004) than whites. Birth weight was positively correlated with IGF-1, IGFBP-3 and the molar ratio of IGF1 to IGFBP-3, but inversely correlated with the molar ratio of IGF-2 to IGFBP-3. Adjusted models showed higher testosterone (1.82 vs. 1.47 ng/mL, p=0.006) and the molar ratio of testosterone to SHBG (0.42 vs. 0.30, p=0.03) in African-American compared to white female neonates. IGF-1, IGF-2, and IGFBP-3 were lower in African-American compared to white female neonates, but only the difference for IGF-2 remained significant (496.5 vs. 539.2 ng/mL, p=0.04).
Conclusion
We provide evidence of racial variation in cord blood testosterone and testosterone to SHBG in African-American compared to white female neonates, and higher IGF-2 in white compared to African-American female neonates. Findings suggest plausible explanations for a prenatal influence on subsequent breast cancer risk and mortality. Further work is needed to confirm these observations.
doi:10.1007/s10552-011-9893-6
PMCID: PMC3333795  PMID: 22252677
umbilical cord blood; IGF axis; sex steroid hormones; African American
15.  Vitamin D Status in Patients With Stage IV Colorectal Cancer: Findings From Intergroup Trial N9741 
Journal of Clinical Oncology  2011;29(12):1599-1606.
Purpose
Previous studies have suggested that higher plasma 25-hydroxyvitamin D3 [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival, but the prevalence of vitamin D deficiency in advanced colorectal cancer and its influence on outcomes are unknown.
Patients and Methods
We prospectively measured plasma 25(OH)D levels in 515 patients with stage IV colorectal cancer participating in a randomized trial of chemotherapy. Vitamin D deficiency was defined as 25(OH)D lower than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as ≥ 30 ng/mL. We examined the association between baseline 25(OH)D level and selected patient characteristics. Cox proportional hazards models were used to calculate hazard ratios (HR) for death, disease progression, and tumor response, adjusted for prognostic factors.
Results
Among 515 eligible patients, 50% of the study population was vitamin D deficient, and 82% were vitamin D insufficient. Plasma 25(OH)D levels were lower in black patients compared to white patients and patients of other race (median, 10.7 v 21.1 v 19.3 ng/mL, respectively; P < .001), and females compared to males (median, 18.3 v 21.7 ng/mL, respectively; P = .0005). Baseline plasma 25(OH)D levels were not associated with patient outcome, although given the distribution of plasma levels in this cohort, statistical power for survival analyses were limited.
Conclusion
Vitamin D deficiency is highly prevalent among patients with stage IV colorectal cancer receiving first-line chemotherapy, particularly in black and female patients.
doi:10.1200/JCO.2010.31.7255
PMCID: PMC3082978  PMID: 21422438
16.  A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3 
Human Molecular Genetics  2011;20(6):1241-1251.
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 × 10−8 (P = 3.3 × 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 × 10−26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10−21) and higher IGF-I (P = 4.9 × 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 × 10−11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 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 × 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.
doi:10.1093/hmg/ddq560
PMCID: PMC3043664  PMID: 21216879
17.  Insulin-like growth factor-1, insulin-like growth factor binding protein-3 and lobule type in the Nurses' Health Study II 
Introduction
Previous research in the Nurses' Health Study (NHS) and the NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans.
Methods
We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (that is, type 1, type 2, or type 3) and whether any type 1 or any type 3 lobules were present. Lobule type was then classified as: predominant type 1/no type 3 lobules, which is suggestive of complete involution; or other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and the ratio of IGF-1:IGFBP-3 levels with lobule type.
Results
In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type 1/no type 3 lobules (P < 0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.37, 95% confidence interval = 0.15 to 0.89). Greater ratios of IGF-1:IGFBP-3 levels were also associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.26, 95% confidence interval = 0.11 to 0.64). These results were slightly attenuated after adjustment for other potential predictors of lobule type.
Conclusions
Higher IGF-1 levels and a greater IGF-1:IGFBP-3 ratio were associated with decreased odds of having predominant type 1 lobules/no type 3 lobules among women with proliferative BBD in the NHSII. This study provides further evidence for the role of insulin-like growth factors in the structure of breast lobules and lobular involution.
doi:10.1186/bcr3141
PMCID: PMC3446378  PMID: 22414675
18.  High insulin-like growth factor binding protein-1 (IGFBP-1) level predicts incident congestive heart failure in the elderly 
American Heart Journal  2008;155(6):1006-1012.
Background
Low insulin-like growth factor–1 (IGF-I) may influence the development of age-related cardiovascular diseases including congestive heart failure (CHF). Insulin-like growth factor binding protein-1 (IGFBP-1), which increases during catabolic states and inhibits anabolic IGF-I effects, is increased in CHF patients and has been associated prospectively with increased mortality among older adults and myocardial infarction survivors. 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 (CHS).
Methods
From among 5,888 65+ year-old adults in the Cardiovascular Health Study (CHS), we studied 566 incident CHF cases and 1,072 comparison subjects, after exclusion of underweight individuals (BMI < 18.5 kg/m2) and insulin users. Hazard ratios (HR) with 95% confidence intervals (CIs) for CHF were estimated after adjustment for age, race, gender, hypertension, systolic blood pressure, lipid levels, left ventricular hypertrophy, coronary disease, C-reactive protein, health status, diabetes, and BMI.
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 < 0.01). Relative to the lowest IGFBP-1 tertile, the HR was 1.29 (95% CI=0.96–1.74, p=0.09) for the second IGFBP-1 tertile and 1.47 (95% CI=1.06–2.04; p=0.02) for the highest IGFBP-1 tertile (tertile cutpoints 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 may be a CHF risk factor among older adults.
doi:10.1016/j.ahj.2007.12.031
PMCID: PMC3286655  PMID: 18513511
19.  Plasma insulin-like growth factor 1 is positively associated with low-grade prostate cancer in the Health Professionals Follow-up Study 1993–2004 
The insulin-like growth factor (IGF) axis plays a role in growth and progression of prostate cancer. High circulating IGF-1 levels have been associated with an increased risk of prostate cancer. Results for IGF binding protein 3 (IGFBP-3) are inconclusive. Some studies have indicated that the positive association with IGF-1 is observed only for low-grade prostate cancer (Gleason sum <7). We previously reported in the Health Professionals Follow-up Study (HPFS) a direct positive association between ELISA-measured plasma IGF-1 and IGFBP-3 and risk of prostate cancer (462 cases diagnosed after providing a blood specimen (between 1993 and 1995), but before February 1998). With additional follow-up through January 31st 2004, and 1331 case-control pairs in total, we were now able to investigate low-grade (Gleason sum <7, n=635) and high-grade (Gleason sum ≥7, n=515) prostate cancer separately. Matched odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. ORs of total prostate cancer comparing top to bottom quartiles were 1.41 (95% CI 1.12–1.78, p-trend=0.001) for IGF-1 and 1.58 (95% CI 1.24–2.01, p-trend=0.003) for IGFBP-3. IGF-1 was more strongly associated with low-grade (OR=1.61 top versus bottom quartile, 95% CI 1.16–2.25, p-trend=0.01), than with high-grade (OR=1.29, 95% CI 0.89–1.88, p-trend-0.12) prostate cancer (p-heterogeneity=0.08). We hypothesize that these findings reflect that high-grade prostate cancers are more autonomous, and, thus, less sensitive to the action of IGF-1 than low-grade cancers.
doi:10.1002/ijc.25381
PMCID: PMC2948057  PMID: 20473871
20.  Interactions between Plasma Levels of 25-Hydroxyvitamin D, Insulin-Like Growth Factor (IGF)-1 and C-Peptide with Risk of Colorectal Cancer 
PLoS ONE  2011;6(12):e28520.
Background
Vitamin D status and levels of insulin-like growth factor (IGF)-1 and C-peptide have been implicated in colorectal carcinogenesis. However, in contrast to vitamin D IGF-1 is not an easily modifiable risk factor.
Methods
Combining data from the Health Professionals Follow up Study (HPFS) and the Nurses' Health Study cohort (NHS) additive and multiplicative interactions were examined between plasma 25-hydroxyvitamin D (25(OH)D) and IGF-1, IGFBP-3 as well as C-peptide levels in 499 cases and 992 matched controls. For the various analytes, being high or low was based on being either above (or equal) or below the medians, respectively.
Results
Compared to participants with high 25(OH)D and low IGF-1/IGFBP-3 ratio (reference group), participants with a high IGF-1/IGFBP-3 ratio were at elevated risk of colorectal cancer when 25(OH)D was low (odds ratio (OR): 2.05 (95% CI: 1.43 to 2.92), but not when 25(OH)D was high (OR:1.20 (95% CI: 0.84 to 1.71, p(interaction): additive  = 0.06, multiplicative  = 0.25). Similarly, compared to participants with high 25(OH)D and low molar IGF-1/IGFBP-3 ratio and low C-peptide levels (reference group), participants with a combination of either high IGF-1/IGFBP-3 ratio or high C-peptide were at elevated risk for colorectal cancer when 25(OH)D was low (OR = 1.90, 95% CI: 1.22 to 2.94) but not when 25(OH)D was high (OR = 1.15, 95% CI: 0.74 to 1.77, p(interaction): additive = 0.004; multiplicative  = 0.04).
Conclusion
The results from this study suggest that improving vitamin D status may help lower risk of colorectal cancer associated with higher IGF-1/IGFBP-3 ratio or C-peptide levels.
doi:10.1371/journal.pone.0028520
PMCID: PMC3247212  PMID: 22216097
21.  Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 
Background
Experimental evidence suggests that an overexpression of insulin-like growth factor-I (IGF-I) is implicated in human pancreatic tumors. Increased IGF-II and decreased insulin-like growth factor binding protein-3 (IGFBP-3) serum concentrations have been linked to a number of other cancers.
Methods
We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55–74 years of age at baseline, to test whether pre-diagnostic circulating IGF-I, IGF-II, IGFBP-3, andIGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk. Between 1994 and 2006, 187 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n=374), who were alive at the time the case was diagnosed, were selected for each case and matched by age, race, sex and date of blood draw. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for smoking.
Results
IGF-I, IGF-II, and IGFBP-3 concentrations were not significantly associated with pancreatic cancer (highest compared with lowest quartile, OR=1.58, 95% CI 0.91–2.76, p-trend=0.25; OR=0.86, 95% CI 0.49–1.50, p-trend=0.31; and OR=0.88, 95% CI 0.51–1.51, p-trend=0.47, respectively). However, a significant positive trend was observed with high IGF-I/IGFBP-3 molar ratio levels (highest compared with lowest quartile OR=1.54, 95% CI 0.89–2.66, p-trend=0.04).
Conclusion
A higher IGF-I/IGFBP-3 molar ratio represents increased free IGF-I, which maybe a risk factor for pancreatic cancer.
Impact
Our results highlight the importance of this biomarker for further investigation in large prospective cohort studies and pooled analysis with other prospective cohorts.
doi:10.1158/1055-9965.EPI-10-0400
PMCID: PMC2936681  PMID: 20699371
IGF-I; IGF-II; IGFBP-3; IGF-I/IGFBP-3; Pancreatic
22.  A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians† 
Human Molecular Genetics  2010;19(15):3089-3101.
The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) ≥ 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (Padj = 8.8 × 10−43) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90–1.14) and 1.20 (99% CI: 1.06–1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 × 10−3. IGF-I levels were significantly associated with PCa risk (Ptrend = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.
doi:10.1093/hmg/ddq210
PMCID: PMC2901143  PMID: 20484221
23.  Androgens, growth factors and risk of prostate cancer: the Multiethnic Cohort 
The Prostate  2010;70(8):906-915.
Androgens and growth factors are thought to be associated with prostate cancer risk, though past research has produced mixed results. We conducted a nested case-control study of biomarkers of prostate cancer risk within the Multiethnic Cohort. We compared prediagnostic levels of testosterone, dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), 3α-androstanediol glucuronide (3α-diol G), insulin-like growth factor I (IGF-I), IGF-II, insulin-like growth factor binding protein 1 (IGFBP-1), and IGFBP-3 in serum from 467 incident prostate cancer cases and 934 cancer-free controls. Controls were matched to the cases on geographic site (HI, LA), ethnicity, age at specimen collection (± 1 year), date (± 1 month) and time of day (± 2 hours) of sample collection, and fasting status (<6, 6-7, 8-9, 10+ hours). Multivariate conditional logistic regression models were used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Serum concentrations of testosterone, DHT, SHBG, 3α-diol G, IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were not associated with risk of prostate cancer. Tests for trend of quartiles of serum concentrations also did not show any association. Results were relatively unchanged for men with advanced prostate cancer and their matched controls. However, the follow-up period was relatively short (mean of 1.9 years). Analysis by ethnic group showed an increased risk for Latino men in the second (OR=3.67, 95% CI: 1.63-8.24) and third (OR=2.96, 95% CI:1.19-7.40) tertiles of IGF-I serum levels compared to the first tertile. The suggested increased risk for IGF-I in Latino men merits further study, with greater statistical power.
doi:10.1002/pros.21125
PMCID: PMC2860643  PMID: 20166103
IGFs; androgens; prostate cancer; risk; ethnicity
24.  A Prospective Evaluation of Insulin and Insulin-like Growth Factor-I as Risk Factors for Endometrial Cancer 
Obesity is a major risk factor for endometrial cancer, a relationship thought to be largely explained by the prevalence of high estrogen levels in obese women. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed whether insulin and/or insulin-like growth factor-I (IGF-I), a related hormone, are associated with endometrial cancer while accounting for estrogen levels. We therefore conducted a case-cohort study of incident endometrial cancer in the Women’s Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. The study involved all 250 incident cases and a random subcohort of 465 subjects for comparison. Insulin, total IGF-I, free IGF-I, IGF-binding protein-3, glucose, and estradiol levels were measured in fasting baseline serum specimens. Cox models were used to estimate associations with endometrial cancer, particularly endometrioid adenocarcinomas, the main histologic type (n = 205). Our data showed that insulin levels were positively associated with endometrioid adenocarcinoma [hazard ratio contrasting highest versus lowest quartile (HRq4-q1), 2.33; 95% confidence interval (95% CI), 1.13–4.82] among women not using hormone therapy after adjustment for age and estradiol. Free IGF-I was inversely associated with endometrioid adenocarcinoma (HRq4-q1, 0.53; 95% CI, 0.31–0.90) after adjustment for age, hormone therapy use, and estradiol. Both of these associations were stronger among overweight/obese women, especially the association between insulin and endometrioid adenocarcinoma (HRq4-q1, 4.30; 95% CI, 1.62–11.43). These data indicate that hyperinsulinemia may represent a risk factor for endometrioid adenocarcinoma that is independent of estradiol. Free IGF-I levels were inversely associated with endometrioid adenocarcinoma, consistent with prior cross-sectional data.
doi:10.1158/1055-9965.EPI-07-2686
PMCID: PMC3090086  PMID: 18398032
25.  Fasting Plasma Insulin, C-Peptide and Cognitive Change in Older Men without Diabetes: Results from the Physicians’ Health Study II 
Neuroepidemiology  2010;34(4):200-207.
Background
Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes.
Methods
Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60–92 years (mean = 71.3 years), in the Physicians’ Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5–4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline.
Results
Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was −0.62 (−1.15, −0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03).
Conclusions
Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.
doi:10.1159/000289351
PMCID: PMC2883838  PMID: 20197703
Insulin; C-Peptide; Cognitive decline; Dementia; Diabetes

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