Circulating Insulin-like Growth Factor-1 Concentrations Research Articles

Insulin-Like Growth Factor 1 and Risk of Cardiovascular Disease: Results From the UK Biobank Cohort Study.

Relationships between insulin-like growth factor 1 (IGF-1) levels and cardiovascular disease (CVD) in the general population remain unclear. This study aims to investigate the association of circulating IGF-1 concentrations with CVD from a population-based cohort study. A total of 394 082 participants without CVD and cancer at baseline from UK Biobank were included with measurements of serum IGF-1 at baseline. Main outcomes were incidence of CVD, including CVD mortality, coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and stroke. Over a median 11.6 years of follow-up, UK Biobank documented 35 803 incident CVD cases, including 4231 from CVD-related death, 27 051 from CHD, 10 014 from MI, 7661 from HF, and 6802 from stroke. Dose-response analysis showed a U-shaped relationship between IGF-1 levels and cardiovascular events. Compared with the third quintile of IGF-1, the lowest category of IGF-1 was associated with increased risk of CVD (hazard ratio 1.128; 95% CI, 1.093 to 1.164), CVD mortality (1.294; 1.181 to 1.418), CHD (1.118; 1.078 to 1.159), MI (1.071; 1.008 to 1.139), HF (1.185; 1.107 to 1.268), and stroke (1.149, 1.070 to 1.235); also, the highest category was associated with increased risk of CVD (1.056; 1.020 to 1.094), CVD mortality (1.111; 1.000 to 1.236), CHD (1.070; 1.028 to 1.114), MI (1.111; 1.041 to 1.187) and HF (1.098; 1.015 to 1.188) after multivariable adjustment. This study indicates that both low and high levels of circulating IGF-1 are associated with increased risk of CVD in general population. These results highlight the importance of monitoring IGF-1 status on cardiovascular health.

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

Insulin-like growth factor 1 (IGF1) is an important growth factor modulating development, homeostasis, and aging. However, whether and how circulating IGF1 concentrations influence early death risk in the general population remains largely unknown. We included 380 997 participants who had serum IGF1 measurement and no history of cancer, cardiovascular disease (CVD), or diabetes at baseline from UK Biobank, a prospective cohort study initiated in 2006-2010. Restricted cubic splines and Cox proportional hazards regression models were used to assess the association between baseline IGF-1 concentrations and all-cause and cause-specific mortality. Over a median follow-up of 8.8 years, 10 753 of the participants died, including 6110 from cancer and 1949 from CVD. Dose-response analysis showed a U-shaped relationship between IGF1 levels and mortality. Compared to the fifth decile of IGF1, the lowest decile was associated with 39% (95% CI: 29-50%), 20% (95% CI: 8-34%), and 39% (95% CI: 14-68%) higher risk of all-cause, cancer, and CVD mortality, respectively, while the highest decile was associated with 17% (95% CI: 7-28%) and 38% (95% CI: 11-71%) higher risk of all-cause and CVD mortality, respectively. The results remained stable in detailed stratified and sensitivity analyses. Our findings indicate that both low and high concentrations of serum IGF1 are associated with increased risk of mortality in the general population. Our study provides a basis for future interrogation of underlying mechanisms of IGF1 in early death occurrence and possible implications for mitigating the risk.

Increased insulin-like growth factor 1 concentrations in a retrospective population of non-diabetic cats diagnosed with hypertrophic cardiomyopathy.

The aim of the study was to document whether a proportion of non-diabetic cats with left ventricular hypertrophy (LVH) previously diagnosed with hypertrophic cardiomyopathy (HCM) have elevated circulating insulin-like growth factor 1 (IGF-1) concentrations. A retrospective analysis of residual blood samples obtained at the time of echocardiographic diagnosis of HCM from a population of 60 non-diabetic cats were analysed for circulating IGF-1 concentrations using a validated radioimmunoassay and compared with a control group of 16 apparently healthy cats without LVH. Clinical and echocardiographic data for cats with an IGF-1 level >1000 ng/ml were compared with those with an IGF-1 level <800 ng/ml. In total, 6.7% (95% confidence interval 1.8-16.2%) of cats with HCM had an IGF-1 level >1000 ng/ml. The prevalence of an IGF-1 level >1000 ng/ml in the control group was zero. A small proportion of non-diabetic cats previously diagnosed with HCM had an IGF-1 concentration at a level that has been associated with feline hypersomatotropism (fHS) in the diabetic cat population. Further prospective research is required to confirm or refute the presence of fHS in non-diabetic cats with LVH and increased IGF-1.

Pre-diagnostic circulating concentrations of insulin-like growth factor-1 and risk of COVID-19 mortality: results from UK Biobank.

Coronavirus disease 2019 (COVID-19) deteriorates suddenly primarily due to excessive inflammatory injury, and insulin-like growth factor-1 (IGF-1) is implicated in endocrine control of the immune system. However, the effect of IGF-1 levels on COVID-19 prognosis remains unknown. Using UK Biobank resource, we investigated the association between circulating IGF-1 concentrations and mortality risk (available death data updated on 07 Sep 2020) among COVID-19 patients who had pre-diagnostic serum IGF-1 measurements at baseline (2006–2010). Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence intervals (CIs) of mortality. Among 1670 COVID-19 patients, 415 deaths occurred due to COVID-19. Compared to the lowest quartile of IGF-1 concentrations, the highest quartile was associated with a 41% lower risk of mortality (OR = 0.59, 95% CI 0.41–0.86, P-trend = 0.01). In the continuous model, per 1-standard deviation increment in log-transformed IGF-1 was associated with a 15% reduction in the risk (intraclass correlation coefficients corrected OR = 0.85, 95% CI 0.73–0.99). The association was largely consistent in the various stratified and sensitivity analyses. In conclusion, our data suggest that higher IGF-1 concentrations are associated with a lower risk of COVID-19 mortality. Further studies are required to determine whether and how targeting IGF-1 pathway might improve COVID-19 prognosis.

Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with ∼430 000 women

BackgroundEpidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference.Patients and methodsWe investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls.ResultsIn the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07–1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01–1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER+) tumours, but no effect found for estrogen-negative (ER−) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97–1.04; P = 0.98).ConclusionOur results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.

Association of dietary intake of milk and dairy products with blood concentrations of insulin-like growth factor 1 (IGF-1) in Bavarian adults.

Circulating IGF-1 concentrations have been associated with higher cancer risk, particularly prostate, breast and colorectal cancer. There is evidence from observational and intervention studies that milk and dairy products intake is associated with higher IGF-1 concentrations, but results were not always consistent. The purpose of this study was to examine the relationship between dairy intake and circulating IGF-1 concentrations in participants of the Second Bavarian Food Consumption Survey, thereby providing data for a German population for the first time. In this cross-sectional study of 526 men and women aged 18-80years, in contrast to most previous investigations, dietary intake was assessed with a more detailed instrument than food frequency questionnaires (FFQs), i.e., by three 24-h dietary recalls conducted on random days close in time to the blood collection. Circulating IGF-1 concentrations were measured in blood samples. Multivariable linear regression models were used to examine the association of dairy intake with IGF-1 concentrations. Each 400g increment in daily dairy intake was associated with 16.8µg/L (95% CI 6.9, 26.7) higher IGF-1 concentrations. Each 200g increment in milk per day was associated with 10.0µg/L (95% CI 4.2, 15.8) higher IGF-1. In contrast, we observed no association between cheese or yogurt intake and IGF-1 concentrations. Our findings are in line with most previous investigations and support the hypothesis that dairy and milk intake are associated with higher IGF-1 concentrations.

Fasting Reduces the Incidence of Delayed-Type Vomiting Associated with Doxorubicin Treatment in Dogs with Lymphoma

Fasting reduces gastrointestinal cellular proliferation rates through G1 cycle blockade and can promote cellular protection of normal but not cancer cells through altered cell signaling including down-regulation of insulin-like growth factor 1 (IGF-1). Consequently, the purpose of this study was to determine the effects of fasting on delayed-type chemotherapy-induced nausea and vomiting in dogs receiving doxorubicin. This prospective randomized crossover study involved intended administration of two doses of doxorubicin. Cancer-bearing dogs were randomized to be fasted for 24 hours beginning at 6 P.M. the night before the first or second doxorubicin administration, and all treatments were administered within an hour before or after 12 P.M. Dogs were fed normally before the alternate dose. Circulating IGF-1 concentrations were determined from serum samples obtained immediately before each doxorubicin treatment. Data from 35 doses were available from 20 dogs enrolled. Dogs that were fasted exhibited a significantly lower incidence of vomiting, when compared to fed dogs (10% compared to 67%, P = .020). Furthermore, among the 15 dogs that completed crossover dosing, vomiting was abrogated in four of five dogs that experienced doxorubicin-induced vomiting when fed normally (P = .050). No differences in other gastrointestinal, constitutional, or bone marrow toxicities or serum IGF-1 levels were observed.

Mathematical modelling to restore circulating IGF-1 concentrations in children with Crohn's disease-induced growth failure: a pharmacokinetic study

ObjectivesChildren with Crohn's disease grow poorly, and inflammation depresses the response of insulin-like growth factor-1 (IGF-1) to growth hormone. Correcting the inflammation normalises growth velocity; however, removing inflammation cannot be...

Subcutaneous rhIGF-1 Significantly Increases Circulating IGF-1 Concentrations in Children With Crohn's Disease Induced Growth Failure

Introduction Faltering growth is a complication of paediatric Crohn9s disease, affecting up to a third of patients. There is no recognised treatment targeted at improving linear growth. These children have low circulating insulin-like growth factor-1 (IGF-1), a hormone essential for linear growth and the primary mediator of growth hormone (GH) action. Low IGF-1 concentrations occur despite normal GH response to stimulation testing – the children thus having a functional GH insensitivity. Injections with recombinant human IGF-1 (rhIGF-1) have been reported to improve growth in animal models of colitis and in children with genetic GH insensitivity syndrome using doses of 80–120 μg/kg bd. rhIGF-I therapy has never previously been used in children with Crohn9s disease. We hypothesised that subcutaneous injections of rhIGF-1 would significantly increase circulating IGF-1 concentrations in children with Crohn9s disease induced growth failure, and that twice daily injections would maintain these concentrations. Methods Eight children with active Crohn9s disease and growth failure were recruited for an open-label pharmacokinetics study of rhIGF-1 (Increlex). A subcutaneous injection of rhIGF-1 (dose 120 μg/kg) was given, and levels were measured over 24 h. Children were also studied over a second period (5 days) of repeated doses. Blood sugar levels were monitored as hypoglycaemia is a potential adverse effect. Protein losing enteropathy was measured by stool α1-antitrypsin and related to IGF-1 levels attained. Results The median age(range) of the children was 12 years(10–14). 4 were female, 4 male, mean (SD) Paediatric Crohn9s Disease Activity Index (PCDAI) was 31.25(14.08). All the children had poor growth (mean growth velocity standard deviation score(SDS) −3.34 (SD 1.13)). All the subjects completed the study. The rhIGF-1 was well tolerated, with only one patient having an (asymptomatic) hypoglycaemic episode. All patients except for one had low baseline IGF-1 levels (mean SDS -1.78 (SD 1.37)) and all showed an increase in 3-h circulating IGF-1 levels following administration of rhIGF-1 (mean SDS 2.70 (SD 3.06)). This increase was significant(p = 0.007). IGF-1 levels were maintained above 0.0 SDS by twice daily injections. This occurred without any change in PCDAI over the 5-day trial period (p = 0.77) Protein-losing enteropathy did not inhibit this response. Conclusion Subcutaneous administration of rhIGF-1 significantly increased circulating concentrations of IGF-1 in children with Crohn9s disease-related growth retardation. These results support the initiation of trials to assess the impact of long-term rhIGF replacement therapy on linear growth.

Subcutaneous rhIGF-1 significantly increases circulating IGF-1 concentrations in children with Crohn's disease induced growth failure

IntroductionFaltering growth is a complication of paediatric Crohn's disease, affecting up to a third of patients. There is no recognised treatment targeted at improving linear growth. These children have low...

Lifestyle, Anthropometric, and Obesity-Related Physiologic Determinants of Insulin-like Growth Factor-1 in the Third National Health and Nutrition Examination Survey (1988–1994)

Epidemiologic studies suggest that insulin-like growth factor-1 (IGF-1) is associated with obesity and, more recently, cancer. This study investigates multiple lifestyle, physiologic, and anthropometric determinants of circulating IGF-1 concentrations. Nationally representative data were used from the cross-sectional Third National Health and Nutrition Examination (NHANES III, 1988-1994) survey, which measured IGF-1 concentrations in blood, from a subsample of participants who were examined in the morning. After exclusion of persons with missing data, 6,058 men and women 20 years of age or older were included in the study. The mean IGF-1 concentrations were 260 ng/mL in the entire population and were higher among men as compared with women (278.8 vs. 241.3 ng/mL; p<0.0001). IGF-1 decreased with increasing age (p<0.0001), body mass index (p<0.0001), and waist circumference (p<0.0001). Individuals with metabolic syndrome had lower IGF-1 concentrations after adjustment for covariates (p=0.0008). IGF-1 was inversely associated with increasing number of metabolic syndrome abnormalities (p=0.0008). All associations were stronger among women compared with men except across concentrations of glucose. IGF-1 concentrations did not vary by any other lifestyle or physiologic factors. Age, adiposity, hyperglycemia, and metabolic syndrome influenced circulating IGF-1 concentrations. Diet and physical activity had no impact on IGF-1 in this nationally representative population.

No Effect of Exercise on Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor Binding Protein 3 in Postmenopausal Women: a 12-Month Randomized Clinical Trial

A meta-analysis indicated that increased circulating concentrations of insulin-like growth factor 1 (IGF-1) are associated with increased risks for colorectal, prostate, and premenopausal breast cancers, and that increased concentrations of IGF binding protein 3 (IGFBP-3) are associated with

Circulating Concentrations of Insulin-Like Growth Factor-1 in Dogs with Naturally Occurring Mitral Regurgitation

Insulin-like growth factor-1 (IGF-1), which mediates most effects of growth hormone, has effects on cardiac mass and function, and plays an important role in the regulation of vascular tone. In humans, an inverse relationship between degree of heart failure (HF) and circulating IGF-1 concentrations has been found in several studies. In dogs with HF, few studies have focused on IGF-1. We examined circulating IGF-1 concentrations in dogs with mitral regurgitation (MR) caused by myxomatous mitral valve disease. Study 1 included 88 Cavalier King Charles Spaniels (CKCSs) with a broad range of asymptomatic MR (median serum IGF-1: 76.7 microg/L; 25-75 percentile, 59.8-104.9 microg/L). As expected, standard body weight and percentage under- or overweight correlated directly with IGF-1. MR (assessed in 4 different ways) did not correlate with IGF-1. In study 2, 28 dogs with severe MR and stable, treated congestive HF had similar serum IGF-1 concentrations (median, 100.8 g/L; 25-75 percentile, 74.9-156.5 microg/L) as 11 control dogs (79.6 microg/L; 25-75 percentile, 64.1-187.4 microg/L; P = .84). In study 3, the plasma IGF-1 concentration of 15 untreated CKCSs with severe MR was 16.4 +/- 24.2 microg/L lower (P = .02) at the examination when decompensated HF had developed (80.8 +/- 30.9 microg/L) than at a visit 1-12 months earlier (97.2 +/- 39.8 microg/L), possibly in part due to an altered state of nutrition. The studies document that circulating IGF-1 concentrations are not altered before development of congestive HF in dogs with naturally occurring MR, but decrease by approximately 20% with the development of untreated HE In treated HF, circulating IGF-1 concentrations apparently return to within the reference range.

Effects of an acute enteric disease challenge on IGF-1 and IGFBP-3 gene expression in porcine skeletal muscle (2002)

Eighteen pigs (initial weight 25 lb and approximately 5 wk of age) were used in a 14-d trial to determine the effects of an acute Salmonella enterica serotype typhimurium (ST) disease challenge on both circulating insulinlike growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) and steady-state IGF-1 and IGFBP-3 mRNA levels in skeletal muscle. Muscle biopsies and blood samples were obtained from all pigs on d 0, 3, 7, and 14 relative to ST-challenge. Results suggest that an acute ST-challenge decreased circulating IGF-1 levels on d 3 and 7 but did not affect circulating IGFBP-3 concentrations. Additionally, ST-challenge had no effect on steady-state IGF-1 and IGFBP-3 mRNA levels in skeletal muscle following the onset of disease. These data suggest that an acute enteric disease insult can lower circulating IGF-1 but more chronic conditions may be necessary to affect local IGF-1 levels in skeletal muscle. Additionally, the increased muscle IGF-1 mRNA without increased IGFBP-3 levels on d 14 most likely results in increased IGF-1 synthesis that contributes to circulating IGF-1 concentrations.

Characterization of Growth Hormone Enhanced Donor Site Healing in Patients with Large Cutaneous Burns

Human growth hormone is an anabolic agent that attenuates injury-induced catabolism and stimulates protein synthesis. Recombinant human growth hormone (rhGH) administered therapeutically to patients with massive burns has been shown to increase the rate of skin graft donor site healing. It has been postulated that growth hormone affects wound healing and tissue repair by stimulating the production of insulin-like growth factor-1 (IGF-1) by the liver to increase circulating IGF-1 concentrations. The mechanism by which it improves wound healing, however, remains in question. The authors hypothesize that rhGH up-regulates IGF-1 receptors and IGF-1 levels both systemically and locally in the wound site to stimulate cell mitosis and increase synthesis of laminin, collagen types IV and VII, and cytokeratin. This hypothesis was tested in nine patients with burns covering > 40% of total body surface area. The authors assessed the efficacy of rhGH in promoting several major building materials in the donor site of patients with massive burns. Ten massively burned patients with full-thickness burns covering more than 40% of total body surface area were participants in a placebo-controlled prospective study to determine the efficacy of 0.2 mg/kg/day rhGH on donor site wound healing and to identify some of the major components involved in wound healing and its integrity. Donor sites in burn patients receiving rhGH showed an increased coverage by the basal lamina of 26% for placebo to 68% coverage of the dermal-epidermal junction. Insulin-like growth factor-1 receptors and laminin, types IV and VII collagen, and cytokeratin-14 all increased significantly. Healing times of the donor sites were significantly decreased compared with patients receiving placebo. Results indicate that growth hormone or its secondary mediators may directly stimulate the cells of the epidermis and dermis during wound healing to produce the structural proteins and other components needed to rebuild the junctional structures.

Insulin-like growth factor-1 in Syrian hamsters: interactions of photoperiod, gonadal steroids, pinealectomy, and continuous melatonin treatment.

Four experiments in Syrian hamsters examined the role and possible interaction of photoperiod, gonadal steroids, and the pineal on circulating levels of insulin-like growth factor-1 (IGF-1). In the first experiment, female hamsters were exposed to long photoperiod (LP; 14:10 LD) or short photoperiod (SP; 8:16 LD); an additional group of SP-exposed females was pinealectomized (PX). SP induced a significant depression in IGF-1 concentrations which PX partially prevented. In Experiment 2, two groups (control and castrate [CX]) of adult male hamsters were kept in LP, and three groups (intact, CX, and CX+PX) of hamsters were kept in SP for five weeks. The four groups of animals that were CX and/or maintained in SP had approximately the same mean level of IGF-1, and all four groups were significantly (P < 0.001) higher than the LP-control hamsters. In Experiment 3, four groups (intact controls, CX, CX+melatonin pellet [MEL PEL], and MEL PEL only) were kept in LP. Melatonin pellets (1 mg melatonin/24 mg beeswax/every two weeks) were implanted sc twice during the experiment. Castration induced a rise (P < 0.001) in IGF-1 levels, and this was not prevented by MEL PEL. In Experiment 4, testosterone and dihydrotestosterone pellets implanted in LP-exposed CX males prevented the CX-induced rise in IGF-1; testosterone implants also reduced IGF-1 levels in CX males treated with progesterone. In conclusion, SP treatment depresses IGF-1 in female hamsters and raises it in males. These results substantiate previous studies in other models of gonadal steroid deficient animals. They lend further credence to the hypothesis that there is a sexual dimorphism in circulating IGF-1 concentrations in the Syrian hamster that may be at least partially related to the presence of gonadal steroids.

Determination of insulin-like growth factor 1 (IGF1) and IGF binding protein levels in swine

A heterologous radioimmunoassay system was validated for the determination of IGF1 concentrations in swine sera. Parallelism, accuracy and response to physiological stimuli were obtained following the incubation of serum samples with 1M glycine-glycine HC1 buffer at a pH of 3.5±0.2 for 24 hours at 37C. Following acidification and neutralization, circulating IGF1 concentrations were significantly (P<.05) reduced in hypophysectomized swine and elevated in swine injected with porcine growth hormone (pGH) when compared to IGF1 levels in control hogs. IGF binding protein levels were also increased following GH administration and reduced by hypophysectomy. In addition, circulating IGF1 concentrations were significantly (P<.05) correlated with body size in three types of swine which differ in growth rate and mature body weight. These data suggest that IGF1 is involved in the regulation of swine growth in vivo and that its physiologic regulation is similar to that in humans.