Low Insulin-like Growth factor-I Research Articles

Evaluation of Insulin-Like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia

Introduction: Preeclampsia (PE) is a serious pregnancy-induced disease characterized by hypertension, proteinuria and other systemic disorders after 20 weeks of gestation and is a leading cause of maternal and fetal morbidity and mortality. The main pathological characteristics of preeclampsia are poor trophoblast cell invasion and uterine spiral artery remodeling dysfunction caused by placenta ischemia and oxidative stress. Nowadays, preeclampsia is considered to be the results of the interactions of genetic and environmental factors. However, its accurate pathogenesis remains unknown. It was considered IGF-1 might be involved in the pathogenesis of preeclampsia. As is known, the behaviors of cells, the formation of placenta and the growth of fetus are widely regulated by insulin-like growth factor 1 (IGF-1). Several studies have shown that IGF-1 was significantly reduced in preeclampsia. Objectives: To assess the role of Insulin like Growth Factor-I (IGF-I) as a Predictor of Preeclampsia. Materials and Methods: It was a prospective cohort study conducted in General Obstetrics and Gynaecology Unit OPD, Dhaka Medical College Hospital from January, 2020 to December, 2020. Pregnant women between 8 weeks to 15 weeks were enrolled for study after fulfilling selection criteria. Serum concentration of Insulin like growth factor-I (IGF-I) was assessed with cut off value of IGF-I 175.9 ng/ml. The value above 175.9 ng/ml was categorized as normal IGF-I and value below 175.9 ng/ml was categorized as low IGF-I. The patients who had value above 175.9 ng/ml were grouped as A. The value below 175.9 ng/ml was grouped as B. Then they were followed up monthly upto 28 weeks, two weekly upto 36 weeks, weekly upto delivery and puerperium for development of preeclampsia or not. All information was recorded in data collection sheet. Data were analyzed by SPSS-23. Data were compared and correlated among groups and presented by tables and figures. Result: Maternal serum concentration .....

Characteristics and treatment outcomes of micromegaly - acromegaly with apparently normal basal GH: A retrospective study and literature review.

Objective. Micromegaly describes a subgroup of patients with clinically evident acromegaly and elevated insulin-like growth factor I (IGF-I) with apparently normal basal growth hormone (bGH) and often a glucose-suppressed growth hormone (GH) of <1 ng/mL at diagnosis. It is controversial whether this condition is a distinct clinical entity or a classic acromegaly in early stages. The aim of the present article was to characterize the prevalence, clinical and biochemical characteristics, and therapeutic outcomes of micromegaly. Methods. A retrospective study of patients with an acromegaly followed ≥1 year at a tertiary center from 1995 to 2019. Patients without IGF-I or GH measurements at diagnosis were excluded. At diagnosis, bGH was considered normal if <2 ng/mL. Results. From 74 patients with acromegaly, 6 (8.1%) had normal bGH levels. There was no difference in the gender distribution, median diagnostic delay, and follow-up time between patients with normal bGH and elevated bGH. Patients with normal bGH were significantly older at time of the first acromegalic manifestation and diagnosis they had significantly lower nadir post-glucose GH and IGF-I levels, and tended to have a higher prevalence of obesity than patients with the elevated bGH. The frequency of acromegalic symptoms, signs, and other comorbidities than obesity was similar between groups. Five patients (83.3%) with normal bGH presented microadenomas. Post-operative remission and outcomes at last visit were comparable between patients with or without normal bGH. Conclusions. Normal bGH acromegaly is relatively uncommon in our patients. These patients showed differentiating characteristics from the classical acromegaly with elevated bGH. Further studies are needed to extend the knowledge about its clinical behavior, therapeutic outcomes, morbidity, and mortality.

BMI and Contraceptives Affect New Age-, Sex-, and Puberty-adjusted IGF-I and IGFBP-3 Reference Ranges Across Life Span.

Various clinical factors influencing serum levels of insulin-like growth factor I (IGF-I) and its binding protein 3 (IGFBP-3) are not entirely consistently described. We asked whether body mass index (BMI), contraceptive drugs (CDs), and hormone replacement therapy (HRT) have potential effects on data for interpreting new age-, sex-, and puberty-adjusted reference ranges for IGF-I and IGFBP-3 serum levels. Subjects were mainly participants from 2 population-based cohort studies: the LIFE Child study of children and adolescents and the LIFE Adult study. We investigated 9400 serum samples from more than 7000 healthy and 1278 obese subjects between 3 months and 81 years old. Associations between IGF-I or IGFBP-3, measured with a new electrochemiluminescence immunoassay, and the predictors BMI and CDs were estimated using hierarchical linear modeling. During infancy, obese children had up to 1 SD score (SDS) higher mean predicted IGF-I values, converging with levels of normal-weight subjects up to 13 years old. Between 20 and 40 years of age, obesity was related to up to -0.5 lower IGF-I SDS values than the predicted values. Obesity had less impact on IGFBP-3. Estrogen- and progestin-based CDs, but not HRT, decreased IGF-I and increased IGFBP-3 (P < 0.01) in adolescents (β IGF-I = -0.45, β IGFBP-3 = 0.94) and adults (β IGF-I = -0.43, β IGFBP-3 = 1.12). Conversely, progestin-based CDs were significantly positive associated with IGF-I (β IGF-I =0.82). BMI and CDs must be considered when assessing and interpreting the clinical relevance of IGF-I and IGFBP-3 measurements.

Pleiotropic Effect of Hormone Insulin-Like Growth Factor-I in Immune Response and Pathogenesis in Leishmaniases.

Leishmaniases are diseases caused by several Leishmania species, and many factors contribute to the development of the infection. Because the adaptive immune response does not fully explain the outcome of Leishmania infection and considering that the initial events are crucial in the establishment of the infection, we investigated one of the growth factors, the insulin-like growth factor-I (IGF-I), found in circulation and produced by different cells including macrophages and present in the skin where the parasite is inoculated. Here, we review the role of IGF-I in leishmaniasis experimental models and human patients. IGF-I induces the growth of different Leishmania species in vitro and alters the disease outcome increasing the parasite load and lesion size, especially in L. major- and L. amazonensis-infected mouse leishmaniasis. IGF-I affects the parasite interacting with the IGF-I receptor present on Leishmania. During Leishmania-macrophage interaction, IGF-I acts on the arginine metabolic pathway, resulting in polyamine production both in macrophages and Leishmania. IGF-I and cytokines interact with reciprocal influences on their expression. IL-4 is a hallmark of susceptibility to L. major in murine leishmaniasis, but we observed that IGF-I operates astoundingly as an effector element of the IL-4. Approaching human leishmaniasis, patients with mucosal, disseminated, and visceral diseases presented surprisingly low IGF-I serum levels, suggesting diverse effects than parasite growth. We observed that low IGF-I levels might contribute to the inflammatory response persistence and delayed lesion healing in human cutaneous leishmaniasis and the anemia development in visceral leishmaniasis. We must highlight the complexity of infection revealed depending on the Leishmania species and the parasite's developmental stages. Because IGF-I exerts pleiotropic effects on the biology of interaction and disease pathogenesis, IGF-I turns up as an attractive tool to explore biological and pathogenic processes underlying infection development. IGF-I pleiotropic effects open further the possibility of approaching IGF-I as a therapeutical target.

Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia).

We performed a cross-sectional study on anthropometric and laboratory characteristics of inhabitants of Rampasasa (Flores, Indonesia). Adults were categorised according to ancestry into three groups: pygmoid (P/P, offspring of pygmoid parents, n=8), mixed pygmoid (P/N, offspring of pygmoid and non-pygmoid parents, n=12) and non-pygmoid (N/N, n=10). Children (n=28) were P/N. Measurements included height, weight, sitting height, arm span, head circumference, haematological analysis and serum albumin, calcium, vitamin D, insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3). Pubertal stage and bone age was assessed in children. Anthropometric data were expressed as standard deviation score (SDS) for age. IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio were expressed as SDS for age, bone age and pubertal stage. Mean height SDS showed a gradient from P/P (-4.0) via P/N (-3.2) to N/N (-2.3) (-3.4,-3.1 and-2.2 adjusted for age-associated shrinking). Sitting height and head circumference showed similar gradients. Serum IGF-I SDS was similar among groups (approximately-1 SDS). IGFBP-3 SDS tended toward a gradient from P/P (-1.9) via P/N (-1.5) to N/N (-1.1), but IGF-I/IGFBP-3 ratio was normal in all groups. In P/P and P/N, mean head circumference SDS was >2SD greater than mean height SDS. Children showed a progressive growth failure and bone age delay, delayed female pubertal onset and an initial low serum IGF-I, normal IGFBP-3 and low IGF-I/IGFBP-3 ratio. P/P showed proportionate short stature with relative macrocephaly and relatively low IGFBP-3; P/N presented an intermediate pattern. P/N children were progressively short, showed delayed skeletal maturation, delayed puberty in girls and low IGF-I and IGF-I/IGFBP-3.

Patients with low IGF-I after curative surgery for Cushing's syndrome have an adverse long-term outcome of hypercortisolism-induced myopathy.

Glucocorticoid excess leads to muscle atrophy and weakness in patients with endogenous Cushing's syndrome. Insulin-like growth factor I (IGF-I) is known to have protective effects on muscle loss. We hypothesized that individual serum IGF-I concentrations might be predictive for long-term myopathy outcome in Cushing's syndrome. In a prospective longitudinal study of 31 patients with florid Cushing's syndrome, we analyzed IGF-I and IGF binding protein 3 (IGFBP 3) concentrations at the time of diagnosis and following surgical remission over a period of up to 3 years. We assessed muscle strength by grip strength measurements using a hand grip dynamometer and muscle mass by bio-impedance measurements. Individual serum IGF-I concentrations in the postoperative phase were strongly predictive of long-term grip strength outcome (rs = 0.696, P ≤ 0.001). Also, lower IGF-I concentrations were associated with a lower muscle mass after 3 years (rs = 0.404, P = 0.033). While patients with high IGF-I s.d. scores (SDS; >1.4) showed an improvement in grip strength within the follow-up period (P = 0.009), patients with lower IGF-I SDS (≤-0.4) had a worse outcome with persisting muscle dysfunction. In contrast, preoperative IGF-I concentrations during the florid phase of Cushing's syndrome did not predict long-term muscle function outcome (rs = 0.285, P = 0.127). Lower individual IGF-I concentrations 6 months after curative surgery for Cushing's syndrome are associated with adverse long-term myopathy outcome and IGF-I might be essential for muscle regeneration in the early phase after correction of hypercortisolism.

Cord Blood IGF-I, Proinsulin, Leptin, HMW Adiponectin, and Ghrelin in Short or Skinny Small-for-Gestational-Age Infants.

Small-for-gestational-age (SGA) is an indicator of poor fetal growth "programming" an elevated risk of type 2 diabetes in adulthood. Little is known about early-life endocrine characteristics in SGA subtypes. Stunting (short) and wasting (skinny) are considered distinct SGA phenotypes in neonatal prognosis. This work aimed to assess whether SGA infants with stunting or wasting have similar alterations in neonatal endocrine metabolic health biomarkers. This was a nested case-control study based on the 3D (Design, Develop, and Discover) birth cohort in Canada. The study subjects were 146 SGA (birth weight < 10th percentile) and 155 optimal-for-gestational age (OGA, 25th-75th percentiles) infants. Stunting was defined as birth length less than the 10th percentile, and wasting as body mass index less than the 10th percentile for sex and gestational age, respectively. Main outcome measures included cord plasma concentrations of insulin-like growth factor I (IGF-I), proinsulin, leptin, high-molecular-weight (HMW) adiponectin, and ghrelin. Comparing to OGA infants adjusted for maternal and neonatal characteristics, SGA infants with either stunting only or wasting only had lower cord plasma IGF-I and leptin concentrations. HMW adiponectin concentrations were lower in SGA infants with wasting only (P = .004), but similar in SGA infants with stunting only (P = .816). Only SGA infants with both stunting and wasting had substantially lower proinsulin (P < .001) and higher ghrelin concentrations (P < .001) than OGA infants. This study is the first to demonstrate that SGA infants with wasting only are characterized by low HMW adiponectin concentrations, whereas those with stunting only are not. SGA with both stunting and wasting are characterized by low proinsulin and high ghrelin concentrations.

IGF-I/IGFBP3/ALS Deficiency in Sarcopenia: Low GHBP Suggests GH Resistance in a Subgroup of Geriatric Patients.

Definition of etiological subgroups of sarcopenia may help to develop targeted treatments. insulin like growth factor-I (IGF-I), Insulinlike growth factor binding protein 3 (IGFBP3), and acid labile subunit (ALS) build a ternary complex that mediates growth hormone (GH) effects on peripheral organs, such as muscle. Low GH binding protein (GHBP) as a marker of GH receptor number would hint toward GH resistance. We aimed to analyze the association of IGF-I, IGFBP3, and ALS with sarcopenia. A total of 131 consecutively recruited patients of a geriatric ward were included in a single-center cross-sectional analysis; the nonsarcopenic patients served as controls. Measures included sarcopenia status by hand-grip strength measurement and Skeletal Muscle Index (SMI); IGF-I, IGFBP3, ALS, GH, GHBP; body mass index (BMI); Activity of Daily Living (ADL); Mini-Mental State Examination (MMSE); routine laboratory parameters; and statistical regression modeling. Compared with controls, sarcopenic patients did not differ regarding age, sex, ADL, MMSE, C-reactive protein, glomerular filtration rate, and albumin serum concentrations. However, sarcopenic patients had significantly lower IGF-I, IGFBP3, and ALS. IGF-I and ALS associated significantly with sarcopenia and low hand-grip strength, even after adjustment for age, sex, BMI, and albumin, but not with low SMI. GHBP serum was low in sarcopenic patients, but normal in geriatric patients without sarcopenia. Over 60% of patients with IGF-I/ALS deficiency patients showed GH resistance. Our data suggest that in geriatric patients, low IGF-I/IGFBP3/ALS could be evaluated for causative connection of the sarcopenia spectrum. Low GHBP points toward potential GH resistance as one possible explanation of this deficiency.

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance.

Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation—ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.

Somatotropic-Testicular Axis: A crosstalk between GH/IGF-I and gonadal hormones during development, transition, and adult age.

The hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-somatotropic (HPS) axes are strongly interconnected. Interactions between these axes are complex and poorly understood. These interactions are characterized by redundancies in reciprocal influences at each level of regulation and the combination of endocrine and paracrine effects that change during development. To comprehensively review the crosstalk between the HPG and HPS axes and related pathological and clinical aspects during various life stages of male subjects. A thorough search of publications available in PubMed was performed using proper keywords. Molecular studies confirmed the expressions of growth hormone (GH) and insulin-like growth factor-I (IGF-I) receptors on the HPG axis and reproductive organs, indicating a possible interaction between HPS and HPG axes at various levels. Insulin growth factors participate in sexual differentiation during fetal development, indicating that normal HPS axis activity is required for proper testicular development. IGF-I contributes to correct testicular position during minipuberty, determines linear growth during childhood, and promotes puberty onset and pace through gonadotropin-releasing hormone activation. IGF-I levels are high during transition age, even when linear growth is almost complete, suggesting its role in reproductive tract maturation. Patients with GH deficiency (GHD) and insensitivity (GHI) exhibit delayed puberty and impaired genital development; replacement therapy in such patients induces proper pubertal development. In adults, few studies have suggested that lower IGF-I levels are associated with impaired sperm parameters. The role of GH-IGF-I in testicular development remains largely unexplored. However, it is important to evaluate gonadic development in children with GHD. Additionally, HPS axis function should be evaluated in children with urogenital malformation or gonadal development alterations. Correct diagnosis and prompt therapeutic intervention are needed for healthy puberty, attainment of complete gonadal development during transition age, and fertility potential in adulthood.

Insights from the clinical phenotype of subjects with Laron syndrome in Ecuador.

The Ecuadorian cohort of subjects with LS has taught us valuable lessons since the late 80's. We have learned about migration of Sephardic Jews to our country, their isolation in remote hamlets and further inbreeding. These geographical, historical and social determinants induced dissemination of a growth hormone (GH) receptor mutation which widely occurred in those almost inaccessible villages. Consequently, the world's largest Laron syndrome (LS) cohort emerged in Loja and El Oro, two of the southern provinces of Ecuador. We have been fortunate to study these patients since 1987. New clinical features derived from GH insensitivity, their growth patterns as well as treatment with exogenous insulin-like growth factor I (IGF-I) have been reported. Novel biochemical characteristics in the field of GH insensitivity, IGFs, IGF binding proteins (BP) and their clinical correlates have also been described. In the last few years, studies on the morbidity and mortality of Ecuadorian LS adults surprisingly demonstrated that despite obesity, they had lower incidence of diabetes and cancer than their relatives. These events were linked to their metabolic phenotype of elevated but ineffective GH concentrations and low circulating IGF-I and IGFBP-3. It was also noted that absent GH counter-regulation induces a decrease in insulin resistance (IR), which results in low but highly efficient insulin levels which properly handle metabolic substrates. We propose that the combination of low IGF-I signaling, decreased IR, and efficient serum insulin concentrations are reasonable explanations for the diminished incidence of diabetes and cancer in these subjects.

Current concepts of the diagnosis of adult growth hormone deficiency

In adults, growth hormone (GH) deficiency is associated with increased visceral adiposity, decreased lean body mass, bone mineral density and exercise capacity, dyslipidemia, insulin resistance, increased cardiometabolic and fracture risk, and impaired quality of life. The aim of the present article is to review the diagnosis of GH deficiency in adults. To avoid overdiagnosis of GH deficiency, it is critical to evaluate only patients at risk for pituitary dysfunction, including those who have had sellar masses, pituitary surgery, radiation therapy, traumatic brain injury, subarachnoid hemorrhage or childhood onset GH deficiency. Evaluation for GH deficiency should be undertaken after testing and replacement of other pituitary hormone deficits. Since GH secretion is pulsatile, measuring serum GH levels randomly is not helpful in establishing the diagnosis of GH deficiency. Serum insulin-like growth factor I (IGF-I) levels lack substantial diurnal variation but also lack sufficient sensitivity and specificity in the diagnosis of GH deficiency in adults. However, adults with multiple (≥3) additional pituitary hormone deficiencies, risk factors for hypopituitarism and low serum IGF-I levels are very likely to be GH deficient. In most cases, the diagnosis of GH deficiency requires stimulation testing. These tests involve the administration of a pharmacologic agent that normally stimulates GH release from pituitary somatotrophs, including insulin, glucagon, growth hormone releasing hormone-arginine or macimorelin, followed by sampling of serum specimens at regular intervals for GH assay. Patients with a peak GH level that is below a predetermined cutpoint are classified as GH deficient. A systematic approach to the diagnosis of GH deficiency is essential in order to accurately identify adults who may benefit from GH replacement.

Strong Positive Correlation between TSH and Ghrelin in Euthyroid Non-Growth Hormone-Deficient Children with Short Stature.

The growth processes in children depend on the proper functioning of some hormones and growth factors. Recently, a positive correlation between ghrelin and TSH (thyroid stimulating hormone) in patients with hyper- and hypothyroidism was proved. Moreover, in hypothyroid rats with high ghrelin concentration, growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion was suppressed. We analyzed these relationships in euthyroid prepubertal children with idiopathic short stature (ISS). The analysis comprised concentration of ghrelin, GH in stimulating tests and during the night, as well as IGF-I, TSH, free thyroxine (FT4) and free triiodothyronine (FT3) in 85 children with ISS (36 girls, 49 boys) aged 9.65 ± 3.02 years (mean ± SD). A strong positive correlation between ghrelin and TSH was confirmed (r = +0.44, p < 0.05). A higher ghrelin but lower nocturnal GH and lower IGF-I were observed in children with higher normal TSH concentration than those in children with lower normal TSH. Interestingly, alterations of TSH level were without any impact on FT4 and FT3 concentrations. Summing up, in ISS prepubertal euthyroid children, ghrelin and TSH secretion are closely related. On the other hand, the higher the TSH, the lower the nocturnal GH and IGF-I levels. The contribution of the above findings in deterioration of growth processes requires further studies.

Ocular findings and growth in 5-year-old preterm children born to mothers with preeclampsia.

To evaluate growth, blood pressure and ophthalmological status in preschool children born preterm to mothers with preeclampsia. In a prospective cohort study, 78 children (34 girls) born preterm without retinopathy of prematurity were examined regarding length/height, weight, head circumference and insulin-like growth factor I (IGF-I) at birth and at 5years of age. At 5years, IGF-binding protein 3 and blood pressure were also measured. A detailed ophthalmological examination including ocular dimensions, fundus morphology, visual fields, visual evoked potentials and perceptual visual dysfunction was performed. Children born to preeclamptic mothers (n=24) were compared to children with non-preeclamptic mothers (n=54). Children exposed to preeclampsia had lower weight (p=0.0002, mean difference -1.46, 95% CI -2.09; -0.83), length (p=0.013, -1.10, 95% CI -1.92; -0.23) and IGF-I levels (p=0.0002, -26.0, 95% CI -36.0; -16.1) at birth compared to non-exposed children. At 5years of age, the preeclamptic group had larger optic cup areas (p=0.0006, 0.32, 95% CI 0.15; 0.46, in right eye, p=0.049, 0.18, 95% CI 0.001; 0.35, in left eye). There was no significant difference between the groups regarding other ophthalmological findings or blood pressure. Children with reduced eye motility had lower neonatal IGF-I levels (p=0.033, 15.5, 95% CI 1.1; 30.3). Preeclampsia was shown to affect growth and IGF-I levels, confirming previous studies. Children exposed to preeclampsia were shown to have larger optic cup areas. Furthermore, lower neonatal IGF-I levels were seen in preterm children with reduced eye motility at 5years of age.

Relation of IGF-I with subclinical cardiovascular markers including intima-media thickness, left ventricular mass index and NT-proBNP.

Several studies revealed relations between low or high insulin-like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms behind these associations are still unknown. The study aimed to explore the relations between IGF-I and changes in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ventricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Longitudinal data of the population-based cohort Study of Health in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on echocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular confounders were performed. Statistical analyses demonstrated relations between low baseline IGF-I levels (beta for ΔIMT per s.d. increase -0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta -0.045 (0.012)) and a long-term IMT increase. No associations between IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline IGF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio with an increase in NT-proBNP were found. The study detected significant relations between IGF-I and long-term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities.

Serum level of insulin-like growth factor-I in type 2 diabetic patients: impact of obesity.

Background Insulin-like growth factor-I (IGF-I) is homologous to proinsulin and possesses glucose reducing activity. The association between the level of IGF-I and diabetes has been highlighted. However, this association is controversial due to the influence of different factors including obesity. The aim of the study was to evaluate serum level of IGF-I in type 2 diabetic patients compared to control subjects. Materials and methods A cross-sectional study involving 100 participants was conducted. Serum levels of IGF-I were measured using enzyme-linked immunosorbent assay (ELISA) and the fasting plasma glucose (FPG) levels were measured using the glucose oxidase method. Results IGF-I levels in the diabetic patients were significantly lower than in non-diabetic control subjects (105.13 ± 6.34 vs. 159.96 ± 9.62 ng/mL, p < 0.0001). Among the diabetic group, there was no significant difference in IGF-I levels between obese diabetic patients and non-obese diabetic patients, p = 0.18. Similarly, among the non-diabetic group, a non-significant difference was found in IGF-I levels between obese non-diabetic and non-obese non-diabetic subjects, p = 0.156. However, among the obese group, obese diabetic patients had significantly lower IGF-I serum levels compared to obese non-diabetic subjects (112.07 ± 7.97 vs. 147.07 ± 13.05 ng/mL, p = 0.02). Furthermore, among the non-obese group, the non-obese diabetic patients had significantly lower IGF-I serum levels compared to the non-obese non-diabetic subjects (91.66 ± 9.93 vs. 171.86 ± 13.86 ng/mL, p < 0.0001). No significant associations were observed between IGF-I level and any of the age, gender, body mass index (BMI), FPG levels, or the duration of diabetes. Conclusions Type 2 diabetes mellitus is associated with lower levels of IGF-I regardless to the presence or absence of obesity.

Growth patterns, metabolic indicators and osteoarticular status in the Lusitano horse: A longitudinal study.

Development of a healthy musculoskeletal system is of high concern for horse breeders and users. A longitudinal field study was performed in order to: (i) evaluate growth patterns and long-term changes on bone quality, bone metabolism, growth factors and metabolic variables in the Lusitano horse; and (ii) retrospectively assess whether these changes were related with radiographic findings regarding osteochondrosis-like lesions (OC) at the onset of training. Thirty-four Lusitano foals born and raised at four stud-farms, were periodically weighed (BW), and measured (withers height-WH) from birth to 36 months of age. On the same days, blood samples were collected for determination of osteocalcin, bone alkaline phosphatase, insulin-like growth factor I (IGF-I), leptin, insulin, glucose, parathyroid hormone (PTH), calcium, phosphorus and magnesium plasma concentrations, and quantitative ultrasound measurements were performed on the right third metacarpal bone (McIII). At the end of the study horses underwent radiographic examination of the four fetlocks, hocks and stifles. According to their radiographic status (OC negative vs. OC positive), Richards growth function was adjusted to BW and WH data. Instantaneous BW and WH growth rates (BW IADG and WH IADG) were calculated for each foal, from the resolution of the first derivative of growth models for seven age-classes. The presence of radiographic findings compatible with OC at the onset of training was associated with changes in BW and WH growth rates. Positive horses presented higher BW IADG from six to 18 months of age and lower WH IADG before 45 days of age (P<0.001). Speed of sound measurements (SOS), bone markers, growth factors and other metabolic variables change markedly with age (P<0.01). OC positive horses tended to have lower SOS values at the lateral region of McIII, lower IGF-I, and higher insulin and PTH concentrations (P<0.1). This study provides indirect evidence that monitoring foals’ growth during the first year of life may be of assistance in managing the occurrence of OC. Further studies with a higher number of animals and a controlled feed intake should be pursued.

SAT-LB076 T2-Signal Intensity, SST Receptor Expression and First-Generation Somatostatin Analogues Efficacy Predict Hormone and Tumor Responses to Pasireotide in Acromegaly

Background: Previous studies indicate that PAS-LAR can achieve control of insulin-like growth factor I (IGF-I) levels and may reduce tumor size, however a subset of acromegaly patients responds poorly. T2-signal intensity, somatostatin receptor (SST) subtype 2 and 5 expression, and the response to first-generation somatostatin receptor ligands (SRLs) are recognized predictors of therapy response. Valid prediction of the response to PAS-LAR can alter treatment stratification. Aim: To analyze T2-signal intensity and SST receptor expression in relation to the hormone and tumor response during PAS-LAR treatment, and to determine to what extent this equals SRLs responsiveness. Methods: We included 45 patients initially receiving SRLs, followed by a combination therapy including pegvisomant, and finally treated with PAS-LAR. The hormone response to PAS-LAR was evaluated using IGF-I (x ULN) levels at 24 weeks. T2-weighted MRI signal intensity of the adenoma was visually assessed and quantified by region of interest measurement. A tumor volume change of ≥25% from baseline was considered significant. SST receptor expression in adenomas was evaluated in 13 out of 45 patients using a validated immunoreactivity score (IRS). The clinical characteristics and the hormone and tumor response to PAS-LAR were assessed using multivariable regressions. Results: Patients with the lowest percentage IGF-I (x ULN) reduction during SRLs also showed weak IGF-I (x ULN) control during PAS-LAR and, however, more significant tumor shrinkage (r=0.41, p=0.006; p=0.036). Lower IGF-I (x ULN) levels during PAS-LAR were associated with higher T2-signal intensity and less significant tumor shrinkage (ß=-0.29, p=0.045; ß=0.34, p=0.035). With regards to tumor response, adenoma volume at baseline was associated with higher random GH levels at diagnosis and greater absolute tumor shrinkage during PAS-LAR (ß=69, p=0.0018; ß=1.05, p=0.020). Significant tumor shrinkage was associated with female patients, higher IGF-I (x ULN) levels during PAS-LAR and borderline significant with non-hypointense adenomas at baseline (OR=6.35, 95% CI=1.42-36.4; OR=13.2, 95% CI=2.14-129.1; OR=5.97, 95% CI=0.91-65.5 respectively). Lower IGF-I (x ULN) levels after PAS-LAR correlated with higher (r=-0.68, p=0.011; r=-0.52, p=0.083), while significant tumor shrinkage correlated with lower SST2 levels as well as SST2/SST5 ratio expression (p=0.040; p=0.024). Conclusions: Patients not responding to somatostatin analogs with particularly large adenomas, low SST2 receptor expression and higher T2-signal intensity are more prone to show tumor shrinkage during PAS-LAR than patients with high SST2 receptor expression and T2-hypointense adenomas. Surprisingly, tumor shrinkage is not accompanied by lower IGF-I (x ULN) levels, which are associated with a high SST2 receptor expression and a higher T2-signal intensity. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

OR16-4 The Growth Hormone Axis in Relation to Muscle Weakness in the ICU: Effect of Early Macronutrient Deficit

Background: The activity of the growth hormone (GH) axis is altered by critical illness. In the acute phase, GH resistance, as reflected by increased GH and decreased insulin-like growth factor-I (IGF-I), mimics fasting-induced changes in health. Although early full feeding in ICU has long been assumed to prevent muscle wasting and weakness, the EPaNIC RCT observed fewer complications and faster recovery with accepting the macronutrient deficit in the first ICU week, as compared with early full feeding, including less acquired muscle weakness [1,2]. We previously observed that accepting the early macronutrient deficit attenuated rather than aggravated the rise in GH as compared with early full feeding [3]. We have now further characterized its impact on the GH axis, in relation to the risk of acquiring muscle weakness in ICU. Methods: This was a preplanned sub-analysis of the EPaNIC RCT. For 10 matched patients per group, serum GH was quantified every 10 min between 9 PM and 6 AM, followed by deconvolution analyses to estimate GH secretion. For 564 patients per group, matched for baseline characteristics, and for all patients investigated for muscle weakness (n=600), serum IGF-I, IGF binding protein 3 (IGFBP3) and IGFBP1 were measured upon ICU admission, at day 4 (if still in ICU), and on the last ICU day (LD). Matched healthy subjects (n=65) were included as controls. Groups were compared with Wilcoxon test or repeated-measures ANOVA. Associations between changes in concentrations from baseline to day 4 or LD for patients with shorter ICU stay (d4/LD) and risk of muscle weakness were assessed with nominal logistic regression analysis, adjusted for baseline risk factors, baseline hormone concentrations and randomization. Results: Upon ICU admission, patients revealed low IGF-I and IGFBP3 and high IGFBP1 as compared with controls (p<0.001). Tolerating an early macronutrient deficit in ICU decreased basal (non-pulsatile) GH secretion (p=0.005) without affecting pulsatile GH secretion. From admission to d4/LD IGF-I and IGFBP3 increased, whereas IGFBP1 decreased (all p<0.001) in the fully fed group. Compared to full feeding, tolerating the early macronutrient deficit prevented the rise in IGF-I (p<0.001), did not affect IGFBP3 and attenuated the decrease in IGFBP1 (p<0.001). A stronger rise in GH and IGF-I from admission to d4/LD was independently associated with a lower risk of acquiring muscle weakness (OR (95%CI) per ng/ml change 0.88 (0.81-0.96) for GH, p=0.001; 0.98 (0.97-0.99) for IGF-I, p=0.002). Conclusion: Tolerating the early macronutrient deficit suppresses basal but not pulsatile GH secretion and alters IGF-I bioavailability during critical illness. These effects may counteract the protection of the intervention against the development of muscle weakness. 1. Casaer et al. N Engl J Med 2011;365:506-17 2. Hermans et al. Lancet Respir Med 2013;1:621-9 3. Van Dyck et al. ENDO 2018;SUN601

Idiopathic short stature and growth hormone sensitivity in prepubertal children.

We compared growth hormone sensitivity to an insulin-like growth factor I (IGF-I) generation test in children with idiopathic short stature (ISS) and of normal stature (NS) across the birthweight range. Forty-six prepubertal children (~7.1years) born at term were studied: ISS (n=23; 74% boys) and NS (n=23; 57% boys). Children underwent a modified IGF-I generation test with recombinant human growth hormone (rhGH; 0.05mg/kg/d) over four consecutive days. Hormonal concentrations were measured at baseline and day 5. Children with idiopathic short stature were 1.90 SDS lighter (P<0.0001) but had 4.5% more body fat (P=0.0007) than NS children. Overall, decreasing birthweight SDS across the normal range (-1.9 to +1.5 SDS) was associated with lower percentageIGF-I response to rhGH stimulation in univariable (r=0.45; P=0.002) and multivariable models (β=24.6; P=0.006). Plasma IGF-I concentrations rose in both groups with rhGH stimulation (P<0.0001). GHBP levels (P=0.002) were suppressed in ISS children (-19%; P=0.029) but increased among NS children (+18%; P=0.028), with contrasting responses also observed for leptin and IGFBP-1. Further, the increase in insulin concentrations in response to rhGH stimulation was ~3-fold greater in NS children (142% vs 50%; P=0.006). A progressive decrease in birthweight SDS was associated with a reduction in GH sensitivity in both NS and ISS children. Thus, the lower IGF-I response to rhGH stimulation in association with decreasing birthweight indicates that the ISS children at the lower end of the birthweight spectrum may have partial GH resistance, which may contribute to their poorer growth.