Insulin-like Growth Factor-1 Status 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.

Sex Differences in Long-Term Safety and Tolerability of GH Replacement Therapy in GH Deficient Adults.

Previous studies report that outcomes of growth hormone (GH) replacement therapy (GHRT) might be less beneficial in growth hormone deficient (GHD) women compared with men. This study investigated possible contributing factors regarding this previously found sex difference. This retrospective cohort study, conducted at a nationwide outpatient clinic (the Dutch National Registry of GH Treatment in Adults), included Dutch adult GHD men (n = 1335) and women (n = 1251) treated with GHRT. The patients' baseline characteristics, details of GHRT, and the tolerability and long-term safety of GHRT were measured. During treatment, sensitivity analysis showed that insulin-like growth factor-1 (IGF-1) SD scores remained subnormal more often in women (P < 0.001), while scores above normal were more frequent in men (P < 0.001). Women reported more adverse events (P < 0.001), especially symptoms related to fluid retention, and more often needed a dose reduction or temporary stop of GHRT (P = 0.001). In percentages, both sexes equally discontinued GHRT, as was also true for the risk in developing type 2 diabetes mellitus, benign neoplasms, and tumor recurrence. The risk of developing malignant neoplasms was higher in men (P = 0.012). Data obtained from the Dutch National Registry of GH Treatment in Adults indicate that GHD women might be treated suboptimally, reflected as lower IGF-1 status and lower GHRT tolerability, leading to more frequent changes in treatment regimen but not discontinuation of GHRT. Regarding long-term safety, we found a higher risk for development of malignancies in GHD men.

Monitoring and Identifying Insulin-Like Growth Factor 1 Variants by Liquid Chromatography-High-Resolution Mass Spectrometry in a Clinical Laboratory.

Protein and peptide hormones often exist as sequence variants with different molecular mass. Monitoring these variants of different molecular mass by mass spectrometry using mass-to-charge (m/z) ratio that is indicative of the wild type may lead to inaccurate quantitative results. However, liquid chromatography-high-resolution mass spectrometry (LC-HRMS)-based techniques can capture these differences and provide an opportunity to resolve, or partially resolve, variant complexity. In this chapter, we describe a general approach for monitoring a set of peptide variants with similar m/z ratios and isotopic envelopes, but different in amino acid sequences. As an example, we use insulin-like growth factor-1 (IGF-1) to demonstrate a DNA database-guided approach to monitor protein variants by LC-HRMS in a clinical laboratory. The workflow is automated and therefore avoids manual calculations that are prone to human error. The method can also monitor multiple IGF-1 variants and discover new ones. It can also provide a profile of a patient's IGF-1 status and be used to explore genotype-phenotype relationships in IGF-1 variants.

Isotopic Peak Index, Relative Retention Time, and Tandem MS for Automated High Throughput IGF-1 Variants Identification in a Clinical Laboratory.

Measuring insulin-like growth factor-1 (IGF-1) is useful for assessing and managing growth-related disorders, such as acromegaly and growth hormone deficiency. High-resolution liquid chromatography-mass spectrometry (LC-MS) is used for measuring IGF-1 due to its molecular specificity, quantitative performance, well-characterized reference materials, and detailed age/sex-specific reference intervals. However, polymorphisms in the IGF1 gene may cause mass shifts in the polypeptide, which can impede quantitation and cause errors in clinical interpretation. We (1) developed a concept of "isotopic peak index", which allows simultaneous monitoring of 15 IGF-1 variants by using only four m/z ratios; (2) developed a "relative retention time" parameter that allows distinction of previously unresolved variants; and (3) utilized tandem mass spectrometry (MS/MS) to distinguish between the most common pair of variants: isobaric A67T and A70T. All methods were validated with DNA sequencing. This approach identified six variants from the ExAC database, P66A, A67S, S34N, A38 V, A67T, and A70T; two previously reported V44M and A67V variants; and discovered six unreported variants, Y31H, S33P, R50Q, R56K, T41I, and A62T. Major improvements in our workflow include enhanced automation, avoiding detailed manual calculations that are prone to human error, and the ability to monitor more, and discover new, IGF-1 variants. The workflow provides a profile of a patient's IGF-1 status and can be used to explore genotype-phenotype relationships in IGF-1 variants.

The Association of Insulin-Like Growth Factor-1 With Bone Mineral Density in Survivors of Childhood Acute Leukemia

Abstract Background: The purpose of the current study is to investigate bone mineral deficit of children in survivors of childhood acute leukemia and examine the association of insulin-like growth factor-1 (IGF-1) with bone mineral density (BMD) status and the presence of osteoporosis. Methods: In a cross-sectional study of children diagnosed with different types of acute leukemia at age between 6 months and 18 years, serum IGF-1 and IGFBP-3, were assessed in relation to lumbar spine BMD (LSBMD) by using dual-energy x-ray absorptiometry and non-traumatic vertebral fracture by lateral thoracolumbar spine radiographs. Standard deviation scores (SDS) were calculated based on the age- and gender-adjusted population mean. Results: Among 189 children after completion of acute leukemia treatment, 22 (11.6%) children had LSBMD SDS less than -2.0 while 80 (42.3 %) children were diagnosed with osteoporosis. Mean areal BMD and LSBMD SDS of the subjects were 0.862±0.197 g/cm2 and -0.6±1.6, respectively. IGF-1 and IGFBP-3 were lower in children with LSBMD lower than -2.0 (P&amp;lt;0.05) and those with osteoporosis (P&amp;lt;0.05). LSBMD SDS showed linear correlation with serum IGF-1 (P=0.041). Low serum IGF-1 level (OR=0.724, P=0.042) and elder age of leukemia diagnosis (OR=1.089, P=0.023) were suggested risk factor of the occurrence of osteoporosis. Conclusions: Substantial number of survivors from childhood acute leukemia undergo bone mineral deficits, and serum IGF-1 status could be a prognostic factor associated with bone mass acquisition and future occurrence of osteoporosis.

Insulin-like growth factor-1 status is associated with insulin resistance in young patients with spinal muscular atrophy

Insulin-like growth factor-1 (IGF-1) is an anabolic hormone with myotrophic effects on muscle tissue. Patients with spinal muscular atrophy (SMA) sustain early-onset sarcopenia, which contributes to an increased prevalence of insulin resistance. Our aim was to determine the IGF-1 status in 5q-SMA patients and its association with insulin resistance. Real-life clinical and laboratory data of 34 patients (15 males; age 3 months-24 years) included: anthropometric measurements [weight, height/length, body mass index or weight-to-length ratio, delta-height standard deviation score (∆Ht SDS) as the difference between height/length SDS and mid-parental height (MPHt) SDS] and laboratory measurements [Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and IGF-1]. HOMA-IR levels categorized patients as insulin-resistant [HOMA-IR ≥1.9 (n = 20)] or insulin-sensitive [HOMA-IR <1.9 (n = 14)]. The collective height/length SDS was −0.29±1.34 and ∆Ht SDS was −0.11±1.47. IGF-1 levels were within the normal population range for all patients. Insulin-resistant patients had higher IGF-1 SDS levels compared to insulin-sensitive patients (0.87±0.78 vs. −0.67±0.96, respectively, P<0.001). The IGF-1 SDS was significantly associated with HOMA-IR for all subjects (r = 0.547, P = 0.001), and linear growth parameters (height/length SDS, ∆Ht SDS) were significantly associated with IGF-1 SDS in the insulin-resistant subgroup (r = 0.649, P = 0.002 and r = 0.605, P = 0.005, respectively). Our findings suggest that IGF-1 status is associated with insulin resistance in patients with early-onset sarcopenia.

Body Composition, IGF1 Status, and Physical Functionality in Nonagenarians: Implications for Osteosarcopenia

ObjectivesBody composition alterations occur during aging. The purpose of the present analysis was to explore the functional consequences of the overlap of sarcopenia and osteoporosis, and the potential role of insulin-like growth factor 1 (IGF1) in their development in the oldest old. Setting and ParticipantsEighty-seven nonagenarians from the Louisiana Healthy Aging Study were included. MeasuresThe definition of sarcopenia was based on appendicular lean mass (ALM). Osteoporosis was diagnosed based on bone mineral density (BMD) T score. Four phenotypes were compared: (1) healthy body composition, that is, nonosteoporotic nonsarcopenic (CO, control group), (2) osteoporotic (O, low BMD T score), (3) sarcopenic (S, low ALM), and (4) osteosarcopenic (OS, low BMD T score and low ALM). Sex- and age-specific IGF1–Standard Deviation Scores (SDS) were calculated. The Continuous Scale–Physical Functional Performance (CS-PFP) test was performed. ResultsIn OS men, IGF1-SDS values (−0.61 ±0.37 vs −0.04 ± 0.52, P = .02) were lower than those in CO males (control group), whereas IGF1-SDS were similar in the 4 body composition phenotypes in women. In men only, ALM was positively associated with IGF1-SDS values (P = .01) independent of age and C-reactive protein concentration. Regarding bone health, we found no association between IGF1-SDS values and BMD. IGF1-SDS was not associated with functional performance (CS-PFP) in men and women. Conclusions/ImplicationsIGF1 sensitivity in skeletal muscle and bone may differ by sex in the oldest old. IGF1 status did not appear to affect physical functionality. Determinants and clinical and functional characteristics of osteosarcopenia need to be further investigated in order to define conclusive diagnostic criteria.

Insulin-Like Growth Factor-1 and Selected Insulin-Like Growth Factor Binding Protein Concentrations during an Ultramarathon Sled Dog Race.

The objective of this study was to investigate the effects of running a 1000-mile (1600 km) endurance sled dog race on serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding proteins 1 and 3 (IGFBP-1 and IGFBP-3). Serum was examined from 12 sled dogs prior to the race, at midrace (approximately 690 km), and again at the finish. IGF-1, IGFBP-1, and IGFBP-3 were assessed using radioimmunoassay or enzyme linked immune-absorbance assays. Mean prerace concentrations were significantly higher than midrace and end-race concentrations at 215.93 ± 80.51 ng/mL, 54.29 ± 25.45 ng/mL, and 55.53 ± 28.25 ng/mL, respectively (P < 0.001). Mean IGFBP-1 concentrations were not different across these time periods at 24.1 ± 15.8 ng/mL, 25.7 ± 14.0 ng/mL, and 26.6 ± 17.6 ng/mL, respectively. IGFBP-3 concentrations showed a modest significant decrease across time periods at 3,067 ± 2,792 ng/mL, 2,626 ± 2,310 ng/mL, and 2,331 ± 2,301 ng/mL, respectively (P < 0.01). Endurance sled dogs show a precipitous drop in serum IGF-1 concentrations. These differences may be related to fuel utilization and excessive negative energy balance associated with the loss of body condition during racing. The relative stability of IGFBP-1 and IGFBP-3 suggests that IGF-1 anabolic signaling is diminished during ultramarathon racing. Further studies comparing the influence of time and duration of exercise versus negative energy balance on serum IGF-1 status are warranted to better understand exercise versus negative energy balance differences.

SHOX Gene Variants: Growth Hormone/Insulin-Like Growth Factor-1 Status and Response to Growth Hormone Treatment

Context: Short stature homeobox-containing gene (SHOX) variants of unknown clinical significance occur frequently among children with short stature, yet their growth hormone (GH)/insulin-like growth factor-1 (IGF-1) status and response to GH have not been studied. Objective: To define GH and IGF-1 status in children with SHOX variants and assess their response to GH. Patients and Methods: This is a retrospective review of children with short stature. Children with SHOX variants were compared to those with no variants. Height standard deviation scores (SDS) and IGF-1 SDS at baseline and during GH treatment at 6, 12, and 24 months were analyzed. Growth velocity (GV), maximum GH dose, IGF-BP3, and changes in height SDS, IGF-1 SDS, and GV were compared. Results: Among 355 children, 83 (23%) had SHOX variants. Nineteen different SHOX variants were detected. There was no difference in age, height SDS, IGF-1 SDS, or IGF-BP3 between children with SHOX variants and those with normal SHOX. Height SDS, IGF-1 SDS, IGF-BP3, GV, and GH dose were not different between patients with SHOX variants and those without. Conclusions: The GH and IGF-1 characteristics of children with short stature were not different between children with SHOX+ variants and children with no variants. Although these findings suggest that SHOX variants are polymorphisms, studies prospectively comparing individual SHOX variants are needed.

Lycopene Status is not Associated with Insulin-Like Growth Factor-1 Concentration in a Healthy Male Population

The aim of this study was to assess the relationship between lycopene and insulin-like growth factor-1 levels in a healthy male population. Insulin-like growth factor-1 status was assessed in healthy men aged 30-49 years (n = 104) with either high or low lycopene concentrations. There was no significant difference between insulin-like growth factor-1 levels in the high- and low-lycopene groups; high lycopene group; 8.21 (2.73) nmol/L; low lycopene group; 7.65 (2.14) nmol/L, p = 0.46 (Mean (SD)). In this small observational study, no association was found between lycopene concentration and insulin-like growth factor-1 concentration.

Lead attenuation of episodic growth hormone secretion in male rats.

The purpose of this study was to characterize the effects of chronic lead exposure on growth hormone and insulin-like growth factor-1 status in growing male rats. Pituitary growth hormone content, episodic growth hormone release, plasma insulin-like growth factor-1 levels, and growth hormone response to exogenous growth hormone-releasing factor were quantified in young rats given lead nitrate. Twenty male Sprague-Dawley weanling rats were given lead nitrate (1000 ppm lead) in drinking water for a period of 6 weeks. Lead treatment significantly reduced body weight gain. Pituitary growth hormone content was not altered by lead treatment. Mean plasma growth hormone levels were reduced 44.6% by lead treatment (46.41 +/- 6.2 ng/ml; p = .003) as compared to controls (83.82 +/- 10 ng/ml). Lead treatment reduced mean growth hormone peak amplitude by 37.5%, mean nadir concentration by 60%, and growth hormone peak area by 35%. These findings are consistent with decreased hypothalamic growth hormone-releasing factor secretion or reduced somatotrope responsiveness. Exogenous growth hormone-releasing factor increased plasma growth hormone in lead-treated and control rats. However, this response was blunted by the lead treatment (lead treated: 485.6 +/- 57.8 vs. controls: 870.2 +/- 127 ng/ml; p = .03). Plasma insulin-like growth factor-1 concentration was not significantly affected by lead treatment. These results demonstrate that lead intoxication attenuates growth hormone release without abolishing the hypothalamic endocrine mechanisms driving growth hormone pulsatility. This suggests that lead acts at the level of the pituitary somatotroph rather than at the level of the hypothalamus.

The effects of frequency of feeding of supplementary concentrates on performance and metabolite and IGF-1 status of ewes given silage in late pregnancy

AbstractEiues on grass silage-based diets were offered, during the last 6 weeks of pregnancy, an increasing allowance of a barley-soya-fish meal concentrate (400 g/day in weeks 15/16; 600 g/day in weeks 17/18; 800 g/day in weeks 19/20) as either one, two or three feeds daily or as a complete mix with silage. Silage dry-matter intake increased with concentrate feeding frequency (P &lt; 0·01) and was greatest with the mixed diet at an average of 1·38 of that with a single daily concentrate meal. The effect on silage intake was evident even at the lowest level of concentrate supplementation during weeks 15/16 and was independent of silage quality. Ewes gained more live weight (P &lt; 0·01), and maintained a higher live weight post partum, as a result of increasing the frequency of feeding of concentrates but mean lamb birth weight was unaffected. Maternal serum metabolites were measured in weeks 17/18 and 19/20 only. Mean [i-hydroxybutyrate was higher, but not significantly so, in weeks 19/20 despite the increased concentrate allowance and was higher overall (P &lt; 0·05) in ewes offered concentrates once daily compared with those receiving concentrates three times daily or mixed with the silage. Insulin-like growth factor 1 (IGF-1) was higher in serum of ewes given frequent concentrate meals compared with those offered concentrate once daily (P &lt; 0·05). Serum albumin and globulin increased as concentrate intake increased between weeks 17/18 and 19/20 (P &lt; 0·05) and also, when concentrates were offered more than once daily (P &lt; 0·05). Serum urea level was higher with more frequent concentrate meals (P &lt; 0·01) and was affected by silage quality (P &lt; 0·001).