Free Insulin-like Growth factor-I Research Articles

Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition

BackgroundCirculating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk.MethodsWe analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics.ResultsCirculating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade.ConclusionsEstimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.

Laboratory investigations in the diagnosis and follow-up of GH-related disorders.

In addition to auxiological, clinical and metabolic features measurements of growth hormone (GH) and insulin-like growth factor I (IGF-I) complement our tools in diagnosis and follow-up of GH-related disorders. While comparably robust during the pre-analytical phase, measurement and interpretation of concentrations of both hormones can be challenging due to analytical issues and biological confounders. Assay methods differ in terms of antibody specificity, interference from binding proteins, reference preparations and sensitivity. GH assays have different specificity towards different GH-isoforms (e.g. 20 kDa GH, placental GH) and interference from the GH antagonist Pegvisomant. The efficacy to prevent binding protein interference is most important in IGF-I assays. Methodological differences between assays require that reference intervals and diagnostic cut-offs are assay-specific. Among biological variables, pubertal development and age are most relevant for IGF-I, making detailed reference intervals mandatory for interpretation. GH has pulsatile secretion and short half-life. Its concentration is modified by acute factors such as stress, exercise and sleep, but also by intake of oral estrogens and anthropometric factors (e.g. BMI). Other GH dependent biomarkers such as free IGF-I, IGF binding protein 3 (IGFBP 3) and acid labile subunit (ALS) have been proposed. Their concentrations largely mirror the information obtained through measurement of IGF-I, but their measurement can be helpful in particular situations. In this review, we describe the evolution of analytical methods to measure biomarkers of GH action, the impact of the methodological changes on laboratory results and the need to include biological variables in their interpretation. Arch Endocrinol Metab. 2019;63(6):618-29.

OR07-5 A Cross-Sectional Study of IGF-I Bioavailability through Childhood: Associations with PAPP-A2 and Anthropometric Data

Insulin-like growth factor I (IGF-I) is one of the essential hormonal mediators of human growth. Circulating IGF-I exists in a ternary complex bound to the acid-labile subunit (ALS) and an IGF binding protein, predominantly IGFBP-3. Pregnancy Associated Plasma Protein-A2 (PAPP-A2), which cleaves intact IGFBP-3, liberates IGF-I from the ternary complex to interact with cell surface receptors. Genome-wide association studies have linked PAPPA2 to adult stature, and mutations in PAPPA2 cause short stature with decreased IGF-I bioavailability. As little is known about PAPP-A2 concentrations throughout childhood and its association with IGF-I bioavailability, we evaluated normal serum concentrations of free IGF-I, intact IGFBP-3, and PAPP-A2 throughout childhood and their relationship with anthropometry. We assessed serum samples from 838 individuals (Age: 3-18, Male: 48%, Caucasian: 83%) who participated in the Cincinnati Genomic Control Cohort, a population-based study of generally healthy children. Patients on medications known to affect growth or with significant medical comorbidities were excluded. Subjects were evaluated at a single visit. Height and weight were measured and a blood sample was drawn. Serum samples were aliquoted and stored at −80 ° C without thawing until the current assays were performed. Total and free IGF-I, total and intact IGFBP-3 and PAPP-A2 were measured using ELISA kits developed by Ansh Laboratories. Age-specific reference interval curves were generated by sex. Correlation and regression analyses were used to examine relationships among analytes and association between each analyte and age, sex, race, height, and BMI. Statistical analyses were performed using SAS®, version 9.4. Free IGF-I increased with age. Serum PAPP-A2 consistently decreased throughout childhood. Serum intact IGFBP-3 increased from early childhood into adolescence with a more marked rise than total IGFBP-3. In multiple regression analysis, height Z-score was positively associated with free and total IGF-I (P=0.01; P<0.0001). Free IGF-I was positively associated with total IGF-I (M; F, r=0.32; r=0.39, P<0.0001). Intact IGFBP-3 was negatively associated with PAPP-A2 (M; F, r=−0.58; r=−0.65, P<0.0001) and the percentage of free to total IGF-I in both sexes (r=−0.53, P<0.0001). PAPP-A2 was positively associated with the percentage of free to total IGF-I (M; F, r=0.18; r=0.38, P<0.001) but not with absolute free IGF-I levels. In conclusion, this is the first study describing PAPP-A2 and intact IGFBP-3 concentrations throughout childhood. Surprisingly, PAPP-A2, a positive modulator of IGF-I bioavailability, decreased with age, but was not positively associated with absolute levels of free IGF-I. Higher levels of PAPP-A2 led to more cleavage of intact IGFBP-3 and thus increased the percentage of free to total IGF-I in this population.

Prediction of metabolic clusters in early-lactation dairy cows using models based on milk biomarkers

The aim of this study was to describe metabolism of early-lactation dairy cows by clustering cows based on glucose, insulin-like growth factor I (IGF-I), free fatty acid, and β-hydroxybutyrate (BHB) using the k-means method. Predictive models for metabolic clusters were created and validated using 3 sets of milk biomarkers (milk metabolites and enzymes, glycans on the immunogamma globulin fraction of milk, and Fourier-transform mid-infrared spectra of milk). Metabolic clusters are used to identify dairy cows with a balanced or imbalanced metabolic profile. Around 14 and 35 d in milk, serum or plasma concentrations of BHB, free fatty acids, glucose, and IGF-I were determined. Cows with a favorable metabolic profile were grouped together in what was referred to as the "balanced" group (n = 43) and were compared with cows in what was referred to as the "other balanced" group (n = 64). Cows with an unfavorable metabolic profile were grouped in what was referred to as the "imbalanced" group (n = 19) and compared with cows in what was referred to as the "other imbalanced" group (n = 88). Glucose and IGF-I were higher in balanced compared with other balanced cows. Free fatty acids and BHB were lower in balanced compared with other balanced cows. Glucose and IGF-I were lower in imbalanced compared with other imbalanced cows. Free fatty acids and BHB were higher in imbalanced cows. Metabolic clusters were related to production parameters. There was a trend for a higher daily increase in fat- and protein-corrected milk yield in balanced cows, whereas that of imbalanced cows was higher. Dry matter intake and the daily increase in dry matter intake were higher in balanced cows and lower in imbalanced cows. Energy balance was continuously higher in balanced cows and lower in imbalanced cows. Weekly or twice-weekly milk samples were taken and milk metabolites and enzymes (milk glucose, glucose-6-phosphate, BHB, lactate dehydrogenase, N-acetyl-β-d-glucosaminidase, isocitrate), immunogamma globulin glycans (19 peaks), and Fourier-transform mid-infrared spectra (1,060 wavelengths reduced to 15 principal components) were determined. Milk biomarkers with or without additional cow information (days in milk, parity, milk yield features) were used to create predictive models for the metabolic clusters. Accuracy for prediction of balanced (80%) and imbalanced (88%) cows was highest using milk metabolites and enzymes combined with days in milk and parity. The results and models of the present study are part of the GplusE project and identify novel milk-based phenotypes that may be used as predictors for metabolic and performance traits in early-lactation dairy cows.

Associations of insulin-like growth factor-I and insulin-like growth factor binding protein-3 with bone quality in the general adult population.

Growth hormone (GH) and its main mediator, insulin-like growth factor-I (IGF-I), play a significant role in bone metabolism. The relations between IGF-I and bone mineral density (BMD) or osteoporosis have been assessed in previous studies but whether the associations are sex-specific remains uncertain. Moreover, only a few studies examined bone quality assessed by quantitative ultrasound (QUS). We aimed to investigate these associations in the general population of north-east Germany. Data from 1759 men and 1784 women who participated in the baseline examination of the Study of Health in Pomerania (SHIP)-Trend were used. IGF-I and IGF-binding protein-3 (IGFBP-3) concentrations were measured on the IDS-iSYS multidiscipline automated analyser (Immunodiagnostic Systems Limited). QUS measurements were performed at the heel (Achilles InSight, GE Healthcare). Sex-specific linear and multinomial logistic regression models adjusted for potential confounders were calculated. Linear regression analyses revealed significant positive associations between IGF-I and IGF-I/IGFBP-3 ratio, a marker for free IGF-I, with all QUS parameters in men. Among women, we found an inverse association between IGF-I and the QUS-based fracture risk but no association with any other QUS parameter. There was no association between IGFBP-3 and the QUS-based fracture risk. Our data suggest an important role of IGF-I on bone quality in men. The observed association of IGF-I with the QUS-based stiffness index and QUS-based fracture risk in this study might animate clinicians to refer patients with low IGF-I levels, particularly men, to a further evaluation of risk factors for osteoporosis and a detailed examination of the skeletal system.

Genetic variants and traits related to insulin-like growth factor-I and insulin resistance and their interaction with lifestyles on postmenopausal colorectal cancer risk.

Genetic variants and traits in metabolic signaling pathways may interact with lifestyle factors such as obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal colorectal cancer (CRC) risk, but these interrelated pathways are not fully understood. In this case-cohort study, we examined 33 single-nucleotide polymorphisms (SNPs) in genes related to insulin-like growth factor-I (IGF-I)/ insulin resistance (IR) traits and signaling pathways, using data from 704 postmenopausal women in Women’s Health Initiative Observation ancillary studies. Stratifying by the lifestyle modifiers, we assessed the effects of IGF-I/IR traits (fasting total and free IGF-I, IGF binding protein-3, insulin, glucose, and homeostatic model assessment–insulin resistance) on CRC risk as a mediator or influencing factor. Six SNPs in the INS, IGF-I, and IGFBP3 genes were associated with CRC risk, and those associations differed between non-obese/active and obese/inactive women and between E nonusers and users. Roughly 30% of the cancer risk due to the SNP was mediated by IGF-I/IR traits. Likewise, carriers of 11 SNPs in the IRS1 and AKT1/2 genes (signaling pathway–related genetic variants) had different associations with CRC risk between strata, and the proportion of the SNP–cancer association explained by traits varied from 30% to 50%. Our findings suggest that IGF-I/IR genetic variants interact with obesity, physical activity, and exogenous E, altering postmenopausal CRC risk, through IGF-I/IR traits, but also through different pathways. Unraveling gene–phenotype–lifestyle interactions will provide data on potential genetic targets in clinical trials for cancer prevention and intervention strategies to reduce CRC risk.

Abstract 1277: Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with obesity and lifestyle factors on postmenopausal breast cancer risk

Abstract Objectives: Genetic variants and traits in metabolic signaling pathways may interact with obesity, physical activity, and exogenous estrogen (E), influencing postmenopausal breast cancer risk, but these inter-related pathways are incompletely understood. Stratifying via obesity and lifestyle modifiers, we evaluated the effects of insulin-like growth factor-I (IGF-I)/insulin resistance (IR)–related traits on breast cancer risk as a mediator or influencing factor in this case-cohort study. Method: Using 75 single-nucleotide polymorphisms (SNPs) in genes related to IGF-I/IR traits and signaling pathways, and data from 1,003 postmenopausal women in Women’s Health Initiative Observation ancillary studies, we assessed the effects of IGF-I/IR-traits (fasting total and free IGF-I, IGF binding protein-3, glucose, insulin, and homeostatic model assessment–insulin resistance) by proportional change estimation. Using traits as mediators of the IGF-I/IR–traits genetic variants-cancer relationship, we partitioned total effect of these genetic variants on cancer risk into two putative mechanisms: 1) indirect (mediated by traits) and 2) direct (through pathways other than traits). For the effects of IGF-I/IR traits on IGF-I/IR signaling pathways–relevant genetic variants–cancer risk, we used the same algorithm as that for mediator, but interpreted as an influential factor. Results: Seven SNPs in IGF-I and INS genes were associated with breast cancer risk. These associations differed between non-obese/active and obese/inactive women and between exogenous E nonusers and users. The mediation effects of IGF-I/IR traits on these SNPs–cancer relationship differed between strata, but only roughly 35% of the cancer risk due to the SNPs was mediated by IGF-I/IR traits. Similarly, carriers of 20 SNPs in PIK3R1, AKT1/2, and MAPK1 genes (signaling pathways–related genetic variants) had different associations with breast cancer between strata, and the proportion of the SNP–cancer relationship explained by IGF-I/IR traits varied 45-50% between the strata. Conclusions: Our findings suggest that IGF-I/IR genetic variants interact with obesity and lifestyle factors, altering cancer risk partially through pathways other than IGF-I/IR traits. Citation Format: Su Yon Jung, Gloria Ho, Thomas Rohan, Howard Strickler, Jennifer Bea, Jeanette Papp, Eric Sobel, Zuo-Feng Zhang, Carolyn Crandall. Interaction of insulin-like growth factor-I and insulin resistance-related genetic variants with obesity and lifestyle factors on postmenopausal breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1277. doi:10.1158/1538-7445.AM2017-1277

Socioeconomic conditions across life related to multiple measures of the endocrine system in older adults: Longitudinal findings from a British birth cohort study

BackgroundLittle is known about how socioeconomic position (SEP) across life impacts on different axes of the endocrine system which are thought to underlie the ageing process and its adverse consequences. We examined how indicators of SEP across life related to multiple markers of the endocrine system in late midlife, and hypothesized that lower SEP across life would be associated with an adverse hormone profile across multiple axes. MethodsData were from a British cohort study of 875 men and 905 women followed since their birth in March 1946 with circulating free testosterone and insulin-like growth factor-I (IGF-I) measured at both 53 and 60–64 years, and evening cortisol at 60–64 years. Indicators of SEP were ascertained prospectively across life—paternal occupational class at 4, highest educational attainment at 26, household occupational class at 53, and household income at 60–64 years. Associations between SEP and hormones were investigated using multiple regression and logistic regression models. ResultsLower SEP was associated with lower free testosterone among men, higher free testosterone among women, and lower IGF-I and higher evening cortisol in both sexes. For example, the mean standardised difference in IGF-I comparing the lowest with the highest educational attainment at 26 years (slope index of inequality) was −0.4 in men (95% CI -0.7 to −0.2) and −0.4 in women (−0.6 to −0.2). Associations with each hormone differed by SEP indicator used and sex, and were particularly pronounced when using a composite adverse hormone score. For example, the odds of having 1 additional adverse hormone concentration in the lowest compared with highest education level were 3.7 (95% CI: 2.1, 6.3) among men, and 1.6 (1.0, 2.7) among women (P (sex interaction) = 0.02). We found no evidence that SEP was related to apparent age-related declines in free testosterone or IGF-I. ConclusionsLower SEP was associated with an adverse hormone profile across multiple endocrine axes. SEP differences in endocrine function may partly underlie inequalities in health and function in later life, and may reflect variations in biological rates of ageing. Further studies are required to assess the likely functional relevance of these associations.

Effect of acute sleep deprivation and recovery on Insulin-like Growth Factor-I responses and inflammatory gene expression in healthy men.

Acute sleep deprivation in humans has been found to increase inflammatory markers and signaling pathways in the periphery through a possible Toll-like receptor 4 (TLR-4). In addition, short duration sleep has been associated with low circulating total Insulin-like Growth Factor-I (IGF-I) concentrations. We aimed to determine whether a total sleep deprivation (TSD) protocol with recovery altered whole-blood gene expression of the proinflammatory cytokines TNF-α and IL-6, as well as TLR-4 expression, and to examine the relationship with circulating concentrations of the IGF-I system. Twelve healthy men participated in a five-day TSD (two control nights followed by one night of sleep deprivation and one night of recovery). Blood was sampled at 0800, before and after sleep deprivation (D2 and D4), and after recovery (D5). It is shown that 25 h of sleep deprivation (D4) induced significant increases in mRNA levels of TNF-α and its soluble receptor R1 (P<0.01 respectively), as well as TLR-4 (P<0.05), while IL-6 mRNA levels remained unchanged. Circulating concentrations of free IGF-I were decreased at D4 (P<0.001). One night of recovery was sufficient to restore basal expression levels for TNF-α, sTNF-R1, TLR-4 and circulating IGF-I. Changes in TLR-4 mRNA levels during the protocol correlated positively with those of TNF-α and sTNF-R1 (r=0.393 and r=0.490 respectively), and negatively with circulating free IGF-I (r=-0.494). In conclusion, 25 h of sleep deprivation in healthy subjects is sufficient to induce transient and reversible genomic expression of the pro-inflammatory cytokine TNF-α and its R1 receptor, and its mediator TLR-4, with a possible link to IGF-I axis inhibition.

Porcine follicular fluid concentration of free insulin-like growth factor-I collected from different diameter ovarian follicles

The study aimed to quantify the concentrations of free IGF-I in serum and fluid of ovarian follicles in pre-pubertal gilts and describe the ovarian morphology by measuring the size of the ovaries and counting the number of surface follicles. Ovaries (n=1,000) from pre-pubertal gilts were obtained immediately after slaughter. A total of 10 samplings were performed, with ovaries obtained from 50 females for each collection. The follicles situated on the surface of each ovary were classified as small (SFs, 2 to 5mm in diameter) or large (LFs 6 to 10mm in diameter) and the follicular fluid was obtained by follicle aspiration. The collection of serum samples was performed after the gilts exsanguination using sterile tubes. From the pool of serum and follicular fluid obtained from 50 females, the concentration of free IGF-I was determined in each sample using an enzyme immunoassay kit (ELISA). The description of ovarian morphometry was performed in 100 ovaries from randomly selected gilts. The larger and smaller lengths of ovaries were measured, and the total number of SFs and LFs present on the surface of each ovary were also counted. The IGF-I concentration was greater (P&lt;0.05) in LFs (170.92±88.29 ng/mL) compared with SFs (67.39±49.90ng/mL) and serum (73.48±34.63ng/mL). The largest and smallest length of the ovaries was 26.0±3.0 and 19.0mm ±2.0mm, respectively. The number of SFs (70.86±25.76) was greater (P&lt;0.01) than LFs (6.54±5.26). The study concluded that LFs present greater levels of IGF-I when compared with SFs and blood, which is related to increased activity of the LFs and its differentiation to ovulation. In addition, ovaries of pre-pubertal gilts have a higher number of SFs compared to LFs. Therefore, our study demonstrated unique data regarding the physiological concentration of free IGF-I in ovarian follicles, that can be used in future research to evaluate the addition of this hormone in the in vitro production media of porcine embryos with the goal to improve the technique efficiency.

The association between insulin-like growth factor I and bone turnover markers in the general adult population

ObjectivesGrowth hormone (GH) and its main mediator, insulin-like growth factor I (IGF-I), play a fundamental role in human metabolism. Previous epidemiological studies investigating the association of IGF-I and bone turnover markers (BTMs) yielded conflicting results and were limited by study design or sample size. Therefore, we aimed to investigate the associations between serum levels of IGF-I or the IGF-I/IGF binging protein 3 (IGFBP-3) ratio and levels of BTMs including procollagen type 1 N-terminal propeptide (PINP), C-terminal telopeptides of type 1 collagen (CTX), and bone-specific alkaline phosphatase (BAP). MethodsData from 1463 men and 1481 women who participated in the first follow-up of the Study of Health in Pomerania were used. IGF-I and IGFBP-3 levels were measured using chemiluminescent immunometric assays on an Immulite 2500 analyzer. BTM levels were measured on the IDS-iSYS Multi-Discipline Automated Analyser. Analyses of variance (ANOVA) and quantile regression models were calculated. ResultsIn men <55years and premenopausal women ANOVA and quantile regression analyses revealed positive associations between IGF-I or even stronger the IGF-I/IGFBP-3 ratio and PINP [per unit increase in IGF-I/IGFBP-3 ratio in men: beta (95%-CI) 2.33ng/ml (0.91; 3.75), p<0.01; women: 3.63ng/ml (2.31; 4.95), p<0.01] or CTX [men: 20.8ng/l (3.5; 38.0), p=0.02; women: 12.0ng/l (−1.2; 25.2), p=0.07]. Furthermore in postmenopausal women, IGF-I and the IGF-I/IGFBP-3 ratio were inversely related with CTX levels, whereas an inverse U-shaped relation between IGF-I/IGFBP-3 ratio and PINP was found. Regarding BAP, we observed borderline significant associations with IGF-I or the IGF-I/IGFBP-3 ratio in older subjects only. ConclusionIGF-I levels and particularly free IGF-I, estimated by the IGF-I/IGFBP-3 ratio, are positively related with PINP as a bone formation marker and CTX as a bone resorption marker in healthy adult men younger than 55years and premenopausal women. In older subjects the found positive as well as negative relations with BTMs have to be further investigated.

Does insulin-like growth factor-1 mediate protein-induced kidney growth in infants?: A secondary analysis from a randomized controlled trial

Animal models have shown that insulin-like growth factor I (IGF-I) may mediate protein-induced kidney growth. Our aim was to analyze the effect of IGF-I on protein-induced kidney growth in healthy infants. This is a secondary analysis of a randomized trial that compared growth of infants fed with a higher-protein (HP) (n = 169) vs. lower-protein (LP) (n = 182) formula (in the first year of life). Outcome measures were anthropometric parameters, kidney volume (cm(3)), and total and free IGF-I (ng/ml). The highest levels of total and free IGF-I were found in the HP group. Both parameters correlated significantly with BMI z-score (r = 0.229, P < 0.001 and r = 0.223, P < 0.001, respectively), kidney volume (r = 0.115, P = 0.006 and r = 0.208, P < 0.001, respectively), and kidney volume/body length (r = 0.109, P = 0.010 and r = 0.194, P < 0.001, respectively) at 6 mo. Linear regression analyses showed a significant effect of free IGF-I on kidney volume in models, including significant effects of HP formula and anthropometry. The structural equation model revealed a significant direct effect of the HP formula on kidney volume and an indirect effect mediated by free IGF-I. This study suggests that IGF-I partly mediates protein-induced kidney growth in healthy infants. IGF-I could be involved in a pathway for the programming of the renal system.

Insulin-like growth factor-I (IGF-I) and clinical nutrition

IGF-I (insulin-like growth factor-I) is a peptide hormone, produced predominantly by the liver in response to pituitary GH (growth hormone), which is involved in a wide variety of physiological processes. It acts in an endocrine, paracrine and autocrine manner to promote growth. The production of IGF-I signals the availability of nutrients needed for its anabolic actions. Recently, there has been growing interest in its role in health and disease. IGF-I has long been known to be regulated by nutrition and dysregulated in states of under- and over-nutrition, its serum concentrations falling in malnutrition and responding promptly to refeeding. This has led to interest in its utility as a nutritional biomarker. A considerable evidence base supports utility for measurement of IGF-I in nutritional contexts. Its concentration may be valuable in providing information on nutritional status, prognosis and in monitoring nutritional support. However, it is insufficiently specific for use as a screening test for under nutrition as its serum concentration is influenced by many factors other than nutritional status, notably the APR (acute-phase response) and endocrine conditions. Concentrations should be interpreted along with clinical findings and the results of other investigations such as CRP (C-reactive protein). More recently, there has been interest in free IGF-I which holds promise as a nutritional marker. The present review covers nutritional regulation of IGF-I and its dysregulation in disease, then goes on to review recent studies supporting its utility as a nutritional marker in clinical contexts. Although not currently recommended by clinical guidelines, it is likely that, in time, measurement of IGF-I will become a routine part of nutritional assessment in a number of these contexts.

The ratio of insulin-like growth factor-I/insulin-like growth factor–binding protein-3 in sera of patients with hepatitis C virus–related chronic liver disease as a predictive marker of insulin resistance

Recent studies have elucidated a lower level of serum insulin-like growth factor-I (IGF-I) or a decrease in the IGF-I/IGF-binding protein-3 (IGFBP-3) ratio in patients with type 2 diabetes mellitus or hepatic steatosis. Persistent hepatitis C virus (HCV) infection often evokes metabolic abnormalities including hepatic steatosis and insulin resistance. We hypothesized that the relationship between the ratio of IGF-I/IGFBP-3 and the severity of hepatic steatosis or insulin resistance would be observed in patients with HCV-related chronic liver disease (CLD). On the basis of the classifications proposed by Brunt and colleagues (Am J Gastroenterol 1999; 94: 2467-2474), among the 42 enrolled patients with HCV-related CLD, 23 of them had no hepatic steatosis (grade 0), 14 had grade 1 steatosis, and 5 had grade 2 steatosis. The levels of serum IGF-I in the enrolled patients declined in proportion to the severity of hepatic steatosis, whereas serum IGFBP-3 levels did not affect its severity. Therefore, the ratio of IGF-I/IGFBP-3, which corresponds to the circulating free IGF-I status, was significantly lower in those patients with hepatic steatosis (grades 1 and 2) than in those without hepatic steatosis. Serum IGF-I levels significantly correlated with serum zinc levels (r = 0.370, P = .0266), but IGFBP-3 levels did not. However, the linear regression analysis revealed an inverse correlation between the IGF/IGFBP-3 ratio and the value of homeostasis model for assessment of insulin resistance (r =−0.411, P = .0094). These findings suggest that the decline of the circulating free IGF-I level, which derives from zinc deficiency, may contribute to hepatic steatosis and insulin resistance in patients with HCV-related CLD.

IGF-I measurement across blood, interstitial fluid, and muscle biocompartments following explosive, high-power exercise

Insulin-like growth factor-I (IGF-I) resides across different biocompartments [blood, interstitial fluid (ISF), and muscle]. Whether circulating IGF-I responses to exercise reflect local events remains uncertain. We measured the IGF-I response to plyometric exercise across blood, ISF, and muscle biopsy from the vastus lateralis. Twenty volunteers (8 men, 12 women, 22 ± 1 yr) performed 10 sets of 10 plyometric jump repetitions at a 40% 1-repetition maximum. Blood, ISF, and muscle samples were taken pre- and postexercise. Circulating IGF-I increased postexercise: total IGF-I (preexercise = 546 ± 42, midexercise = 585 ± 43, postexercise = 597 ± 45, +30 = 557 ± 42, +60 = 536 ± 40, +120 = 567 ± 42 ng/ml; midexercise, postexercise, and +120 greater than preexercise, P < 0.05); Free IGF-I (preexercise = 0.83 ± 0.09, midexercise = 0.78 ± 0.10, postexercise = 0.79 ± 0.11, +30 = 0.93 ± 0.10, +60 = 0.88 ± 0.10, + 120 = 0.91 ± 0.11 ng/ml; +30 greater than all other preceding time points, P < 0.05). No exercise-induced changes were observed for ISF IGF-I (preexercise = 2.35 ± 0.29, postexercise = 2.46 ± 0.35 ng/ml). No changes were observed for skeletal muscle IGF-I protein, although IGF-I mRNA content increased ∼40% postexercise. The increase in circulating total and free IGF-I was not correlated with increases in ISF IGF-I or muscle IGF-I protein content. Our data indicate that exercise-induced increases in circulating IGF-I are not reflective of local IGF-I signaling.

Female recruits sustaining stress fractures during military basic training demonstrate differential concentrations of circulating IGF-I system components: A preliminary study

ObjectiveStress fracture injuries sustained during military basic combat training (BT) are a significant problem and occur at a higher rate in female recruits than male recruits. Insulin-like growth factor-I (IGF-I) is an easily measured biomarker that is involved in bone formation and positively correlated with bone mineral density, especially in women. This study examined the response of the IGF-I system between female soldiers that sustained a stress fracture (SFX, n=13) during BT and female soldiers who did not (NSFX, n=49). DesignFemale soldiers (n=62, 18.8±0.6yr) from 2 companies of a gender-integrated combat battalion in the Israeli Defense Forces participated in this study. Height, weight and blood draws were taken upon entry to BT (preBT) and after a four-month BT program (postBT). Stress fractures were diagnosed by bone scan. Serum was analyzed for total IGF-I, free IGF-I, IGF binding proteins (IGFBP)1–6, BAP, calcium, CTx, IL1β, IL6, PINP, PTH, TNFα, TRAP, and 25(OH)D. Statistical differences between SFX and NSFX groups and time points were assessed by RM ANOVA with Fisher post-hoc (p≤0.05). ResultsThe SFX group was significantly taller and had lower BMI than NSFX (p≤0.05). Serum concentrations of total IGF-I, bioavailable IGF-I, other bone biomarkers, and cytokines were not significantly different between SFX and NSFX preBT. Serum IGFBP-2 and IGFBP-5 were significantly higher in the SFX compared to the NSFX preBT (p≤0.05). In both groups, total IGF-I increased pre to postBT (p≤0.05). Additionally, a significant difference was observed in the bioavailable IGF-I response pre to postBT for both groups. The SFX group demonstrated a significant decrease in bioavailable IGF-I pre to postBT (preBT: 0.58±0.58ng/mL; postBT 0.39±0.48; p≤0.05) whereas the NSFX group demonstrated a significant increase in bioavailable IGF-I pre to postBT (preBT: 0.53±0.37ng/mL; postBT: 0.63±0.45; p≤0.05). ConclusionsOur study demonstrated that serum IGF-I changes during basic training and that women sustaining stress fractures during BT significantly decreased bioavailable IGF-I, whereas their uninjured counter parts increased bioavailable IGF-I. These results suggest that stress fracture susceptibility may be related to differential IGF-I system concentrations and response to physical training.

Change of Coronary Flow Velocity During the Cold Pressor Test Is Related to Endothelial Markers in Subjects With Chest Pain and a Normal Coronary Angiogram

Several studies demonstrated that endothelial or atherosclerotic biomarkers, including plasma free insulin-like growth factor-I(IGF-I), soluble CD40 ligand (sCD40L), adiponectin, and leptin have an influence on coronary endothelial function. The aim of the present study was to investigate whether change of coronary flow velocity of the distal left anterior descending artery (LAD) during the cold pressor test (CPT) with transthoracic Doppler echocardiography (TTE) was associated with these biomarkers in subjects with chest pain and a normal coronary angiogram. In 190 subjects (mean age, 54±11 years; male:female, 113:77) with chest pain and a normal coronary angiogram, peak diastolic velocity (PDV) of the distal LAD during the CPT with TTE was assessed. Acetylcholine provocation test was performed in 58 subjects (mean age, 51±10 years) who were clinically suspected of vasospasm. CPT%PDV was defined as the percent change in PDV during the CPT. Associations between CPT%PDV and clinical parameters were analyzed. According to multiple regression analysis, CPT%PDV was associated with plasma free IGF-I in the entire study population (β=0.295, P<0.001 in all subjects; β=0.341, P=0.001 in males; β=0.243, P=0.037 in females; β=0.303, P=0.002 in nonsmokers; and β=0.256, P=0.047 in smokers), and sCD40L in males (β=-0.269, P=0.008)and smokers (β=-0.261, P=0.046). Subjects with vasospasm to intracoronary acetylcholine had lower plasma free IGF-I(6.9±3.3 vs 8.9±3.4, P=0.026) and CPT%PDV (8.8±24.9 vs 52.7±26.0, P<0.001) than the others. Plasma adiponectin and leptin were not associated with CPT%PDV. Change of coronary flow velocity assessed using the CPT with TTE may be related to endothelial markers, especially plasma free IGF-I.

Normalisation of insulin‐like growth factor‐I does not improve insulin action in cirrhosis

Cirrhosis of the liver is characterised by insulin resistance and low levels of insulin-like growth factor I (IGF-I). Lack of IGF-I may contribute to this insulin resistance, as IGF-I increases insulin sensitivity. This study aimed to determine the effects of normalisation of IGF-I on insulin action in cirrhosis. This article is a randomised sequence-crossover placebo controlled study. Eight patients with cirrhosis and eight controls were studied following treatment with IGF-I (50 μg/kg twice daily) or saline. Insulin action, glucose utilisation and endogenous glucose production were measured during the euglycaemic hyperinsulinaemic clamp. The patients with cirrhosis had normal fasting glucose level, but increased levels of insulin (P < 0.05) and C-peptide (P < 0.05). Insulin resistance resulted from a defect in glycogen synthesis, whereas insulin-mediated suppression of glucose production was unaltered. In cirrhosis, IGF-I treatment normalised free (from 0.07 ± 0.01 to 0.26 ± 0.05 μg/L) and total IGF-I (from 73 ± 6 to 250 ± 39 μg/L), whereas in controls, the IGF-I level increased into the upper physiological range (free IGF-I from 0.23 ± 0.02 to 0.61 ± 0.06 μg/L; total IGF-I from 200 ± 19 to 500 ± 50 μg/L) (all P-values < 0.05). In cirrhosis, IGF-I treatment did not change fasting glucose, insulin or C-peptide levels (P > 0.05). In the controls, insulin and C-peptide levels decreased (P < 0.05). IGF-I treatment did not improve insulin sensitivity in cirrhosis. Because normalisation of IGF-I levels did not affect insulin sensitivity lack of IGF-I is unlikely to result in insulin resistance in cirrhosis. IGF-I supplementation is therefore unlikely to improve insulin action in patients with cirrhosis.

Metabolic imbalance of the insulin-like growth factor–I axis in Zucker diabetic fatty rats

In healthy conditions, insulin-like growth factor-I (IGF-I) acts in a coordinated fashion with insulin to lower glycemia, mainly by increasing insulin sensitivity in peripheral tissues. The aim of this study was to explore the relationship between glucose homeostasis and the endocrine IGF-I axis in Zucker diabetic fatty (ZDF) rats. The plasma levels of glucose, insulin, growth hormone, free IGF-I, total IGF-I (associated to insulin-like growth factor binding proteins plus free), and corticosterone were measured in 13-week-old ZDF rats and in age-matched controls under fasting and postprandial conditions. The plasma IGF-I binding capacity was measured by radioligand binding. In ZDF rats, fasting total and free IGF-I levels were reduced by 22% and 92%, respectively, compared with controls. Postprandial free IGF-I was reduced by 35%, whereas total IGF-I was unaffected. The plasma IGF-I binding capacity in ZDF rats was reduced by 24% after fasting and by 13% under postprandial conditions. A clear correlation between free IGF-I and insulin was observed in postprandial controls but not in ZDF rats. A principal component analysis clearly separated ZDF and control rats into 2 main components under both fasting and postprandial conditions. The first component was determined equally by total IGF-I, bound IGF-I, the free to total IGF-I ratio, and the IGF-I binding capacity. The second component was determined mostly by glucose and insulin. Our results show a marked alteration of the plasma IGF-I levels and of the capacity of plasma to bind IGF-I, and a disturbed relationship between IGF-I and postprandial insulinemia in a rat model of type 2 diabetes mellitus.

A novel, noninvasive transdermal fluid sampling methodology: IGF-I measurement following exercise

This study tested the hypothesis that transdermal fluid (TDF) provides a more sensitive and accurate measure of exercise-induced increases in insulin-like growth factor-I (IGF-I) than serum, and that these increases are detectable proximal, but not distal, to the exercising muscle. A novel, noninvasive methodology was used to collect TDF, followed by sampling of total IGF-I (tIGF-I) and free IGF-I (fIGF-I) in TDF and serum following an acute bout of exercise. Experiment 1: eight men (23 ± 3 yrs, 79 ± 7 kg) underwent two conditions (resting and 60 min of cycling exercise at 60% Vo(2)(peak)) in which serum and forearm TDF were collected for comparison. There were no significant changes in tIGF-I or fIGF-I in TDF obtained from the forearm or from serum following exercise (P > 0.05); however, the proportion of fIGF-I to tIGF-I in TDF was approximately fourfold greater than that of serum (P ≤ 0.05). These data suggest that changes in TDF IGF-I are not evident when TDF is sampled distal from the working tissue. To determine whether exercise-induced increases in local IGF-I could be detected when TDF was sampled directly over the active muscle group, we performed a second experiment. Experiment 2: fourteen subjects (22 ± 4 yr, 68 ± 11 kg) underwent an acute plyometric exercise condition consisting of 10 sets of 10 plyometric jumps with 2-min rest between sets. We observed a significant increase in TDF tIGF-I following exercise (P ≤ 0.05) but no change in serum tIGF-I (P > 0.05). Overall, these data suggest that TDF may provide a noninvasive means of monitoring acute exercise-induced changes in local IGF-I when sampled in proximity to exercising muscles. Moreover, our finding that the proportion of free to tIGF-I was greater in TDF than in serum suggests that changes in local IGF-I may be captured more readily using this system.