Low Insulin-like Growth Factor-1 Levels Research Articles

The Role of Insulin-Like Growth Factor 1 in Delirium: A Systematic Review and Meta-Analysis

Background: The relationship between delirium and low levels of insulin-like growth factor 1 (IGF-1) is contradictory and uncertain. We hypothesised that low levels of IGF-1 are a predisposing factor for delirium in medical and abdominal surgical cohorts, in contrast to other surgical cohorts. Aims: Systematic review and meta-analysis investigating the association between peripheral levels of IGF-1 and delirium in medical and surgical patients to explore if there are distinct patterns of associations by using subgroup meta-analysis. Methods: PubMed, Scopus, CINAHL, Cochrane, and Embase databases were searched. Inclusion criteria were prospective studies in medical and surgical populations and available data. The following were collected: the setting (surgical/medical), the type (orthopaedic surgery, abdominal, cardiovascular, or medical), the number of participants, mean age, the number of delirious patients, scale/criteria for delirium, IGF-1 levels, and MMSE. Results: Thirteen studies were included and analysed. Low levels of IGF-1 are significantly associated with delirium in abdominal surgical samples and medical samples but not in the other surgical samples. Age, cognition, and the setting (medical vs. surgical) do not have any significant effect on the differences in IGF-1 levels between those with and without delirium. Discussion: Delirium in acute medical and abdominal surgery is triggered by low IGF-1 which may reflect chronic conditions like frailty/cachexia/sarcopenia, while in other surgeries perhaps from an inflammatory process. Conclusions: Low peripheral levels of IGF-1 are a predisposing factor for delirium only in acute medical and abdominal surgery. More studies are needed to confirm and to explore further this finding.

Влияние полиморфизма rs9939609 гена FTO на прибавку массы тела при беременности, уровни лептина и ИПФР-1 в грудном молоке и рост младенцев на грудном вскармливании

The search for possible ways of early prevention of obesity is an urgent task. Previous studies have provided evidence of the association of breast milk (BM) hormones with growth in young children. However, information on the influence of the mother’s genetic predisposition to obesity and her weight gain during pregnancy on their level is limited. Objective. To assess the effect of the rs9939609 polymorphism in the maternal FTO gene on body weight gain during pregnancy, the levels of leptin and insulin-like growth factor-1 (IGF-1) in BM, as well as the dynamics of the physical development of exclusively breastfed children. Patients and methods. The study involved 103 healthy women aged (M ± m) 32.2 ± 0.5 years, with a BMI of 19.8 ± 2.8 kg/m2 and their children living in Smolensk. Mothers gave informed consent to participate in the study. BM was taken on days 10–14, at 1 and 3 months of lactation. Levels of leptin and IGF-1 were determined in the morning midstream portion of BM serum by ELISA. Anthropometric data of children were assessed at birth, at 1 and 3 months of life using the WHO Anthro software (2009) by calculating the Z-scores of “weight-for-age” (WAZ) and “length-for-age” (LAZ). The women were genotyped for rs9939609 by real-time PCR. Results. Mothers with the TT genotype (frequency of occurrence – 62%) had higher body weight gain during pregnancy than carriers of the AT (22%) and AA (16%) genotypes, as well as significantly higher leptin and lower IGF-1 levels in BM during the entire observation period. Their infants had significantly lower WAZ at birth and at 1 month and LAZ at 3 months of life than children born to mothers with the AA and AT genotypes. Conclusion. Lower parameters of the physical development of infants born to mothers with the TT genotype of the rs9939609 polymorphism in the FTO gene can be explained by their low genetic predisposition to obesity. However, we cannot exclude the existence of an additional mechanism of growth restriction due to the influence of BM hormones on it, i.e., a reduced level of IGF-1 and the anorexigenic effect of an increased level of leptin, probably associated with a higher BMI and weight gain in mothers with the TT genotype over the period of pregnancy. Key words: anthropometry, breast milk, insulin-like growth factor-1, leptin, rs9939609 polymorphism, pregnancy weight gain

Insulin-Like Growth Factor -1 (IGF-1) and Glucose Dysregulation in Young Adult Patients with β-Thalassemia Major: Causality or Potential Link?

Insulin-like growth factor-1 (IGF-1) has been shown to lower blood glucose through stimulating glucose transport to fat and muscle and inhibiting hepatic glucose output. Although previous cross-sectional reports reported an association between low circulating concentrations of IGF-1 and glucose dysregulation (GD), its role is still debated. The present retrospective study was designed to assess the circulating IGF-1 levels in β-thalassemia major (β -TM) patients with normal oral glucose tolerance test (NGT-OGTT) and (GD) referred for an endocrine evaluation to explore the potential link between low IGF-1 and GD. Our study included 34 young adult patients with β-TM; 12 patients with NGT after OGTT, 7 with impaired glucose tolerance (IGT), 9 with impaired fasting glucose (IFG) plus IGT, and 6 patients with β-TM-related diabetes mellitus (β-TM- DM). Twenty-two β-TM patients with GD or β-TM- DM and 1 patient with NGT had IGF-1 levels below the 2.5th percentile. Correlation of IGF-1 with fasting plasma glucose, HOMA-IR (homeostatic model assessment for insulin resistance) and OGIS (oral glucose insulin sensitivity) was found. Moreover, a negative correlation was documented between ALT and the Insulinogenic Index (IGI) and a positive correlation between serum ferritin and PG 2-h after OGTT. This study reports for the first time an association between low levels of IGF-1 and GD in β-TM patients. Despite some limitations, our study can serve to generate proposals for more convenient and efficient methods to identify and treat early GD in patients with β-TM, and to conduct more extensive studies. www.actabiomedica.it).

Association Between Insulin-Like Growth Factor-1 and Social Cognition in Huntington's Disease.

Insulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure. To investigate the association of IGF-1 levels with social cognition and brain structure in Huntington's disease (HD). We evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume-based voxel-based morphometry and surface-based cortical thickness pipeline. We analyzed the association of IGF-1 levels with social cognition and brain structure using adjusted regression analysis. Social cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P=0.02), and with lower IGF-1 levels (P=0.04). In neuroimaging analyses, lower IGF-1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). In HD, abnormal IGF-1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition.

Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects; a Japanese single-center, retrospective-study

Insulin like growth factor-1 (IGF-1) plays important roles in metabolic functions, especially in adulthood. Additionally, obese subjects are reportedly predisposed to having low absolute IGF-1 levels. However, the prevalence and clinical characteristics of obese subjects with low IGF-1 levels are unknown. We examined 64 obese subjects with a body mass index (BMI) ≥ 35 kg/m2, with no history of endocrinological disorders, receiving inpatient care. IGF-1 levels were interpreted based on the IGF-1 standard deviation score (SDS) clinically used and standardized by age and sex (low IGF-1 group; ≤ − 2.0 SDS and standard IGF-1 group; − 2.0 < and < + 2.0 SDS). Notably, 26.6% of the subjects had low IGF-1. Body fat mass and percentage, but not BMI, were significantly higher in the low than in the standard IGF-1 group. Furthermore, natural log-transformed high-sensitivity C-reactive protein, and the frequencies of dyslipidemia and hyperuricemia were higher in the low IGF-1 group. Moreover, among the subjects without diabetes, fasting glucose levels were significantly higher in the low IGF-1 group. Stepwise variable selection procedure revealed body fat percentage to be a parameter most strongly associated with low IGF-1. Thus, low IGF-1 levels may be an important marker of adiposity-associated metabolic disorders in obese patients.

Insulin-like growth factor 1 and the hormonal mediation of sibling rivalry

In altricial animals, young are completely dependent on parents for provisioning. The ability to outcompete siblings to receive parental provisioning has clear fitness benefits, and may be mediated by hormones that influence growth. We analyzed the effects of insulin-like growth factor 1 (IGF-1) on body size, growth, and sibling rivalry in eastern bluebirds (Sialia sialis). To determine whether IGF-1 is upregulated in response to the competitive environment, we manipulated brood sizes and examined the effect on IGF-1 levels, nestling body size, growth rate, and behavior. In a separate experiment, we injected nestlings with exogenous IGF-1 to study its impacts on body size, growth rate, and sibling competition. Brood size manipulation did not influence endogenous IGF-1 levels, but male nestlings with higher IGF-1 levels early in the nestling period tended to have greater mass gain than males with lower IGF-1 levels. Nestlings with higher IGF-1 levels also tended to be fed more frequently by parents. In the injection experiment, IGF-1 injected individuals tended to be heavier than vehicle injected young by the end of the nestling period, which suggests that IGF-1 can influence mass gain in bluebirds. IGF-1 has been proposed to be a mediator of life-history strategies and post-hatching behavior. Our results suggest that although bluebird nestlings do not adaptively elevate IGF-1 in response to the presence or number of siblings, IGF-1 may influence growth during the nestling period. These findings shed light on sibling competition, life history strategies, and the hormones that underlie them.

Acute effects of low load resistance training with blood flow restriction on serum growth hormone, insulin-like growth factor-1, and testosterone in patients with mild to moderate unilateral knee osteoarthritis

ObjectiveTo investigate the acute effects of blood flow restriction (BFR) with single-leg low load resistance exercise and high load resistance exercise on serum insulin-like growth factor-1 (IGF-1), growth hormone (GH), and testosterone in patients with unilateral knee osteoarthritis (OA). MethodsThis study recruited 18 postmenopausal female patients with mild to moderate unilateral knee OA, which was then followed by randomly conducting three resistance exercise protocols by drawing lots: 1. A 30% 1-repetition maximum (1-RM) resistance exercise with BFR of 70% arterial occlusive pressure (AOP) (BFR group); 2. A 70% 1-RM resistance exercise without BFR (RES group); 3. A 30% 1-RM resistance exercise without BFR (CON group). Blood lactate (BLA) and muscle growth related hormone levels were tested at 4-time points: before exercise, immediately after exercise, 15 min after exercise, and 30 min after exercise. ResultsThere was no statistical difference between the indexes in each group before exercise, but the different exercise had different effects on each index and also an interactive effect (P < 0.05). The increase of rating of perceived exertion in the BFR and RES groups, which were of similar magnitude, was greater compared to the levels in the CON group (P < 0.05). Post-exercise BLA levels were lower in the CON group in comparison to the BFR and RES groups (P < 0.05). Rather than the RES group, GH levels of the BFR group were also significantly higher than the CON group (P < 0.05) at 15 min post-exercise. At post- and 15 min after exercise, the CON group recorded significantly lower IGF-1 levels compared to the BFR and RES groups (P < 0.05). At post- and 15 min after exercise, the CON group (P < 0.05) reflected the lowest testosterone levels, followed by the RES group (P < 0.05), and the highest in the BFR group (P < 0.05). ConclusionsMyogenesis-related hormones in women with unilateral knee OA could be increased by high load resistance exercise and low load resistance exercise with BFR on unaffected limb.

Low-Plasma Insulin-Like Growth Factor-1 Associates With Increased Mortality in Chronic Kidney Disease Patients With Reduced Muscle Strength

Chronic kidney disease (CKD) leads to metabolic and nutritional abnormalities including resistance to insulin-like growth factor-1 (IGF-1) action, and reduced muscle mass and strength. Low IGF-1 as well as low hand-grip muscle strength (HGS) are independent predictors of increased mortality in CKD patients. In 685 patients (CKD Stage 3-5, median age 58years; 62% men), baseline measurements of IGF-1, HGS, subjective global assessment (SGA), lean body mass index (LBMI), and metabolic and inflammatory biomarkers potentially linked to IGF-1 were analyzed in relation to mortality during 5years of follow-up. We compared survival in 4 groups with high or low (cut-offs defined by receiver operating characteristic curve analysis) levels of IGF-1 and HGS. Patients with low IGF-1 were older; had lower BMI, HGS, and LBMI, were more likely to have diabetes, cardiovascular disease (CVD), and malnutrition (SGA >1); and had high-sensitivity C-reactive protein levels. During 5years of follow-up, 208 patients died. The mortality rate was highest among patients with Low IGF-1+Low HGS. In competing-risk regression analysis, Low IGF-1+Low HGS was independently associated with 2.8 times higher all-cause mortality risk than Low IGF-1+High HGS, after adjusting for Framingham's CVD risk score, presence of CVD, SGA, dialysis status, high-sensitivity C-reactive protein, albumin, LBMI, and sample time in freezer. Low IGF-1 was associated with increased all-cause mortality in patients who also had low HGS but not in those with high HGS, suggesting that the association of IGF-1 with survival in CKD patients depends on nutritional status.

Relationship between growth hormone deficiency and nonalcoholic fatty liver disease in patients with pituitary stalk interruption syndrome.

Pituitary stalk interruption syndrome (PSIS), characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary, and an ectopic posterior pituitary, can lead to congenital combined pituitary hormone deficiency. There is a high prevalence of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD), in this population. To investigate the characteristics of NAFLD in Chinese adult patients with PSIS and its association with growth hormone deficiency. Retrospective cross-sectional study in a tertiary referral center of China. Adult patients with PSIS diagnosed, followed up between September 2019 and August 2021, were consecutively enrolled. Abdominal ultrasonography images were evaluated and noninvasive fibrosis scores were determined to assess the severity of NAFLD. Anthropometric, clinical, and biochemical parameters were compared between patients with and without NAFLD. Logistic regression was performed to assess the independent effects of insulin-like growth factor-1 (IGF-1) on NAFLD. A total of 93 patients (77 men, 16 women, mean age: 29.6 ± 7.1 years) were included. The prevalence of NAFLD and advanced fibrosis/cirrhosis was 50.5% and 4.3%, respectively. Insufficient hormone therapy and prominent metabolic disorders, including central obesity, dyslipidemia, insulin resistance, and metabolic syndrome, were more common in the NAFLD (+) group. After adjusting for multiple variables, IGF-1 &lt;-2 standard deviation score (SDS) was found to be associated with an increased prevalence of NAFLD (odds ratio [OR]: 4.92, 95% confidence interval [CI]: 1.21-24.55, p = .035). Per 1 SDS increase in IGF-1 was associated with a 27% lower risk of NAFLD (OR: 0.73, 95% CI: 0.52-0.97, p = .042). NAFLD is a frequent comorbidity among Chinese adult patients with PSIS and is strongly associated with lower IGF-1 levels. Timely and appropriate hormone replacement, particularly growth hormone may contribute to decreasing the risk of NAFLD in these patients.

Vitamin D, insulin-like growth factor-1, and stunting in children with transfusion-dependent thalassemia

Background Transfusion-dependent thalassemia (TDT) has a major impact on a child’s growth and is associated with stunting, risk of vitamin D deficiency, and decreased insulin-like growth factor-1 (IGF-1). To date, the relationship between vitamin D levels and stunting in TDT remains unclear. Futhermore, the role of vitamin D and IGF-1 in mediating stunting in TDT patients is still unknown. &#x0D; Objective To investigate the relationship between stunting and vitamin D as well as IGF-1 levels in children with TDT.&#x0D; Methods This cross-sectional study involved 50 TDT children aged 5 to 18 years, included consecutively from the Pediatric Hemato-oncology Outpatient Clinic, Dr. Soetomo Hospital, Surabaya, East Java. Subjects were divided into two groups: stunted (S) and not stunted (NS). Vitamin D and IGF-1 were evaluated by antibody competitive immunoassay and sandwich-enzyme-linked immunosorbent assay (ELISA), respectively. Age, sex, and duration of repeated transfusion were analyzed as confounding factors.&#x0D; Results Median IGF-1 levels were 91.43 (13.67-192.86) ng/mL and 161.53 (17.99-363.01) ng/mL in the S and NS groups, respectively (P=0.011). Mean vitamin D levels were 20 (+ 5.71) ng/mL and 20.46 (5.25) ng/mL in the S and NS groups, respectively (P=0.765). The correlation coefficient (r) of vitamin D and IGF-I levels was not significant. Multivariate analysis showed that low IGF-1 levels, male, and longer duration of repeated transfusions were associated with stunting in children with TDT. &#x0D; Conclusion Low IGF-1 level is associated with stunting in children with TDT. Vitamin D is not significantly associated with either stunting or IGF-1 in children with TDT.

Interrelationships among growth hormone, thyroid function, and endocrine-disrupting chemicals on the susceptibility to attention-deficit/hyperactivity disorder.

Abnormal growth hormones and thyroid function may be linked to pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Phthalates and bisphenol-A (BPA), two endocrine-disrupting chemicals (EDCs), may affect the human endocrine system. In this study, we aimed to perform a comprehensive investigation of whether growth hormone, thyroid function, and EDCs exhibited differential levels between ADHD patients and healthy controls. In total, 144 children with ADHD and 70 healthy control subjects were enrolled. Their endocrine systems were evaluated using the serum levels of insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and Free T4. The urinary levels of EDCs, including monoethyl phthalate (MEP), mono-methyl phthalate (MMP), monoethylhexyl phthalate (MEHP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), and BPA, were also examined. Patients with ADHD had lower IGF-1 levels than healthy controls (p = 0.003), but we observed no significant difference in IGFBP-3, TSH, T3, T4, or Free T4. Compared to the control group, patients with ADHD demonstrated higher MEHP levels (p = 0.043), MnBP (p = 0.033), and MBzP (p = 0.040). Furthermore, MEHP levels (p < 0.001) and BPA levels (p = 0.041) were negatively correlated with IGF-1 levels, while IGF-1 levels were negatively correlated with principal components consisting of ADHD clinical symptoms and neuropsychological performance variables. We suggest that MEHP exposure may be associated with decreased serum levels of IGF-1 and increased risk of ADHD. The mechanism underlying this association may be important for protecting children from environmental chemicals that adversely affect neurodevelopment.

Linear growth response to growth hormone therapy in underweight versus normal weight short children

Introduction Physiologically, growth hormone (GH) increases lean body mass and has a lipolytic function. However, long-term changes in weight status during GH treatment, as a function of pretreatment weight status have not previously been reported in large data sets. Aim To identify the growth response to GH therapy in those who were before treatment underweight versus normal weight short children. Patients and methods A retrospective study, we studied the auxologic data of 78 short, prepubertal children [height standard deviation score (HtSDS) less than −2 SDS below the mean for age and sex] with normal GH secretion [idiopathic short stature (ISS)]. Two groups were identified according to their pretreatment body mass index standard deviation score (BMISDS). Nineteen children were underweight (BMISDS &lt; −2) and 59 children had normal BMISDS (&gt;−2). All children received daily subcutaneous dose of GH (0.03–0.05 mg/kg/day) to keep their insulin-like growth factor-1 (IGF-1) level between 0 and 2 SD for 2 years. Results Before GH treatment, the underweight ISS group had significantly lower IGF-1 level versus the normal weight group with IGF-1 SD −1.633±0.766 SD versus −0.749±1.197 SD, respectively. Age and HtSDS did not differ among the two underweight and normal weight groups. Treatment with GH for 2 years was associated with a significant increase in the BMISDS in the underweight group (BMISDS increased by 0.45 SD) from −2.063±0.344 before treatment with GH versus −1.633±0.766 after treatment but not in the normal weight group. The HtSDS increased significantly in both groups after GH therapy, but the increase was greater in children with normal weight versus those with underweight as the increment in HtSDS was 0.42 and 0.374 SD, respectively. The difference of HtSDS from mid-parental HtSDS in low BMI versus normal BMI groups was −0.91 and −1.212 SD, respectively Conclusions GH therapy for 2 years significantly increased the IGF-1 level and improved BMISDS and HtSDS in underweight children with ISS. The BMISDS was better in the underweight group, but their HtSDS was less compared with the normal weight group.

Low bone mass in Noonan syndrome children correlates with decreased muscle mass and low IGF-1 levels.

Although musculoskeletal abnormalities have long been described in patients with Noonan syndrome (NS), only a few studies have investigated the bone status of these patients. The aim of this retrospective observational study was to describe the bone health of children with NS. Thirty-five patients with a genetically confirmed diagnosis of NS were enrolled. We analyzed the axial skeleton (lumbar spine) using dual energy X-ray absorptiometry and the appendicular skeleton (hand) with the BoneXpert system. Bone metabolism markers, including mineral homeostasis parameters, serum 25-hydroxy vitamin D (25-OHD) levels and markers of bone formation and resorption were also reported. Compared to the general population, axial and appendicular bone mass was significantly decreased in children with NS (p<0.0001). Serum 25-OHD levels were low in about half of the patients and were negatively correlated with age (r=-0.52; p<0.0001). Patients with NS exhibited reduced bone formation marker levels and increased bone resorption marker levels (p<0.0001). No gender difference or genotype-phenotype correlations were found for the different bone parameters. Muscle mass and, to a lesser extent, serum insulin-like growth factor 1 (IGF-1) levels were independent predictors of whole-body bone mineral content (p<0.0001 for both parameters; adjusted R2=0.97). In conclusion, bone mass is reduced in children with NS and correlates with decreased muscle mass and low serum IGF-1 levels. These data justify addressing all potential threats to bone health including sufficient calcium and vitamin D intake, regular physical exercise, and hormone replacement therapy.

Associations of Serum Insulin-Like Growth Factor 1 with New Cardiovascular Events and Subsequent Death in Hemodialysis Patients: The DREAM Cohort.

Aim: Patients with chronic kidney disease (CKD) have elevated risk of death from cardiovascular disease (CVD). A low serum insulin-like growth factor 1 (IGF-1) level is known to predict higher risk for all-cause mortality in incident dialysis patients, although it is unknown whether IGF-1 predicts cardiovascular outcomes. Methods: This was a prospective cohort study of maintenance hemodialysis patients followed up for 5 years. Serum IGF-1 levels were measured at baseline, and patients were divided into IGF-1 tertiles. The key outcomes were all-cause mortality, a composite of new CVD, and death after new CVD events. Additional outcomes were hospitalization for infection and subsequent death. Association was analyzed using Cox proportional hazards models. Results: In the 516 patients that were analyzed, we identified 106 all-cause deaths, 190 new CVD events, and 61 subsequent deaths. In addition, there were 169 hospitalizations for infection and 47 subsequent deaths. The risk of all-cause death was the highest in the lowest IGF-1 tertile, and this association remained significant in multivariable-adjusted models. Regarding CVD outcomes, IGF-1 was not associated with new CVD events but significantly associated with subsequent death in adjusted models. Similarly, IGF-1 was not an independent predictor of hospitalization for infection, but it predicted subsequent death. Conclusions: A low IGF-1 level was not a significant predictor of new CVD events but an independent predictor of subsequent death in hemodialysis patients. Since similar associations with infection outcomes were observed, IGF-1 may be a biomarker of fragility or frailty in this population.

A low serum IGF-1 is correlated with sarcopenia in subjects with type 1 diabetes mellitus: Findings from a post-hoc analysis of the iDIAMOND study

AimOur previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM. MethodsThis cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study. ResultsThe z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p < 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM. ConclusionsA low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM.

The antagonistic pleiotropy of insulin-like growth factor 1.

While insulin‐like growth factor‐1 (IGF‐1) is a well‐established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF‐1 levels and clinical disease. We examined prospective associations of serum IGF‐1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns: First, IGF‐1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF‐1 are protected from disease, while older individuals with high IGF‐1 are at increased risk for incident disease or death. Second, the association between IGF‐1 and risk is generally U‐shaped, indicating that both high and low levels of IGF‐1 may be detrimental. With the exception of a more uniformly positive relationship between IGF‐1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age‐associated diseases. These data suggest that IGF‐1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.

The Correlation Between Iron Overload and Endocrine Function in Adult Transfusion-Dependent Beta-Thalassemia Patients with Growth Retardation.

BackgroundIron overload is a major problem in patients with transfusion-dependent beta-thalassemia (TDT). Reports on the correlation between iron overload and endocrine function with growth retardation in such a population in Indonesia have not been established. Therefore, this study aims to obtain a profile of iron load and endocrine function of adult transfusion dependent beta-thalassemia patients and their correlation with growth retardation.MethodsA cross-sectional study was performed, involving adult homozygous and HbE beta-thalassemia patients receiving blood transfusions at the Cipto Mangunkusumo Hospital, Jakarta. Iron overload was represented by serum ferritin (FS) and transferrin saturation (TS), while the endocrine function was examined by the Thyroid Stimulating Hormone-sensitive (TSHs), free T4 (fT4), and insulin-like growth factor-1 (IGF-1). The results were analyzed using bivariate analysis plus Pearson and Spearman correlation tests.ResultsIn general, 58 subjects were selected from 224 adult transfusion dependent beta- thalassemia patients, consisting of 31 males (53.4%) and 27 females (46.6%). Furthermore, their median age was 21 (18–24) years, while the subclinical hypothyroid proportion was 32.7% and low IGF-1 levels were detected in 79.3% of the total population. There was a weak negative correlation between FS and fT4 (Spearman rho=−0.361; p=0.003), as well as IGF-1 (Spearman rho=−0.313; p=0.008), but FS and TSHs had no correlation (Spearman rho=0.074; p=0.29). Also, there was no correlation between ST with TSHs (Spearman rho=0.003; p=0.492), fT4 (Spearman rho=0.018; p=0.448), and IGF-1 (Spearman rho=−0.142; p=0.143).ConclusionBased on serum ferritin, iron overload is discovered to have a negative correlation with free T4 and insulin-like growth factor-1.

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.

Genetic deletion of the ghrelin receptor (GHSR) impairs growth and blunts endocrine response to fasting in Ghsr-IRES-Cre mice

ObjectiveThe orexigenic hormone ghrelin exerts its physiological effects by binding to and activating the growth hormone secretagogue receptor (GHSR). The recent development of a Ghsr-IRES-Cre knock-in mouse line has enabled to genetically access GHSR-expressing neurons. Inserting a Cre construct using a knock-in strategy, even when following an upstream internal ribosome entry site (IRES) can, however, interfere with expression of a targeted gene, with consequences for the phenotype emerging. This study aimed to phenotype, both physically and metabolically, heterozygous and homozygous Ghsr-IRES-Cre mice, with a view to discovering the extent to which the ghrelin signalling system remains functional in these mice. MethodsWe assessed feeding and arcuate nucleus (Arc) Fos activation in wild-type, heterozygous and homozygous Ghsr-IRES-Cre mice in response to peripherally-administered ghrelin. We also characterised their developmental and growth phenotypes, as well as their metabolic responses upon an overnight fast. ResultsInsertion of the IRES-Cre cassette into the 3′-untranslated region of the Ghsr gene led to a gene-dosage GHSR depletion in the Arc. Whereas heterozygotes remained ghrelin-responsive and more closely resembled wild-types, ghrelin had reduced orexigenic efficacy and failed to induce Arc Fos expression in homozygous littermates. Homozygotes had a lower body weight accompanied by a shorter body length, less fat tissue content, altered bone parameters, and lower insulin-like growth factor-1 levels compared to wild-type and heterozygous littermates. Moreover, both heterozygous and homozygous Ghsr-IRES-Cre mice lacked the usual fasting-induced rise in growth hormone (GH) and displayed an exaggerated drop in blood glucose and insulin compared to wild-types. Unexpectedly, fasting acyl-ghrelin levels were allele-dependently increased. ConclusionsOur data suggest that (i) heterozygous but not homozygous Ghsr-IRES-Cre mice retain the usual responsiveness to administered ghrelin, (ii) the impact of fasting on GH release and glucose homeostasis is altered even when only one copy of the Ghsr gene is non-functional (as in heterozygous Ghsr-IRES-Cre mice) and (iii) homozygous Ghsr-IRES-Cre mice exhibit growth retardation. Of the many transgenic models of suppressed ghrelin signalling, Ghsr-IRES-Cre mice emerge as best representing the full breadth of the expected phenotype with respect to body weight, growth, and metabolic parameters.

Adherence to growth hormone therapy guidelines in a real-world French cohort of adult patients with growth hormone deficiency

ObjectiveUsing real-world data from patients with growth hormone deficiency (GHD), we evaluated whether clinical practice in France adheres to international guidelines regarding somatropin dose adjustment, and assessed the long-term effectiveness and safety of somatropin. MethodsData were obtained from a national prospective systematic longitudinal routine follow-up programme of naive/non-naive adults with childhood-onset (CO) or adult-onset (AO) GHD treated with Norditropin® (Novo Nordisk A/S). ResultsBetween 2003 and 2006, 331 treatment-naive and non-naive adults with severe GHD were enrolled and followed for a median duration of approximately 5 years; 328 patients were available for analysis. At baseline, mean patient age was 39.2 years; median standard deviation score (SDS) for insulin-like growth factor−1 (IGF-1) level was −2.2 in naive patients, subsequently fluctuating between −0.1 and +0.3 SDS during the study period. Mean GH doses ranged between 0.25 and 0.51mg/day (naive patients) and 0.39 and 0.46mg/day (non-naive patients). Despite generally receiving a higher somatropin dose, women (naive/non-naive) tended to have lower IGF-1 levels than men. Median somatropin dose was consistently higher in patients with CO-GHD than patients with AO-GHD. Extreme IGF-1 values (<–2 or >+2 SDS) were not systematically accompanied by somatropin dose adjustments. Waist circumference improved in approximately one third of patients, at a mean 3.5 years. Somatropin was well tolerated; there were no cardiovascular or cerebrovascular events during the 5-year analysis period. ConclusionCurrent clinical practice of physicians in France follows international guidelines regarding somatropin dose adjustment in adults with GHD. However, dose adjustments are not always sufficient, notably in women, and treatment effects may have been delayed due to low somatropin dose (Clinical trial registration NCT01580605).