Serum Insulin-like Growth factor-I Levels Research Articles

Mediating Effect of Insulin-Like Growth Factor-I Underlying the Link Between Vitamin D and Gestational Diabetes Mellitus.

Vitamin D was well-known to be associated with gestational diabetes mellitus (GDM). Insulin-like growth factor-I (IGF-I) has been linked to vitamin D and GDM, respectively. We hypothesize that changes in IGF-I metabolism induced by 25(OH)D3 might contribute to GDM. Therefore, we investigated the independent and combined relationships of serum 25(OH)D3 and IGF-I concentrations with GDM risk, and the mediation effect of IGF-I on 25(OH)D3. A total of 278 pregnant women (including 125 cases and 153 controls) were recruited in our current study. Maternal serum 25(OH)D3 and IGF-I were measured in the second trimester. Logistic regression models were used to estimate the associations of 25(OH)D3 and IGF-I concentrations with the risk of GDM. Mediation analyses were used to explore the mediation effect of IGF-I on the association between 25(OH)D3 and the risk of GDM. After adjusted for the confounded factors, both the third and fourth quartile of 25(OH)D3 decreased the risk of GDM (OR = 0.226; 95% CI, 0.103-0.494; OR = 0.109; 95% CI, 0.045-0.265, respectively) compared to the first quartile of 25(OH)D3. However, the third and fourth quartile of serum IGF-I (OR = 5.174; 95% CI, 2.287-11.705; OR = 12.784; 95% CI, 5.292-30.879, respectively) increased the risk of GDM compared to the first quartile of serum IGF-I. Mediation analyses suggested that 19.62% of the associations between 25(OH)D3 and GDM might be mediated by IGF-I. The lower concentration of serum 25(OH)D3 or higher IGF-I in the second trimester was associated with an increased risk of GDM. The serum IGF-I level might be a potential mediator between 25(OH)D3 and GDM.

Stunting and wasting in neurological Wilson disease: Role of copper, zinc, and insulin-like growth factor-I.

Copper (Cu) and zinc (Zn) are important trace elements for the growth and development of children. In Wilson disease (WD), impaired Cu metabolism may affect growth. This study was conducted to evaluate the height and weight of children with neurological WD and correlate these with serum Cu, Zn, and insulin-like growth factor-I (IGF-I). This prospective cohort study was conducted in a tertiary care teaching institute. Children with neurologic WD were included. The height, weight, and body-mass index of each child were measured and categorized according to the revised national growth chart. Serum Cu, Zn, calcium, alkaline phosphatase, albumin, thyroid-stimulating hormone, and urinary-Cu were measured. Serum IGF-1 was measured by enzyme-linked immunosorbent assay. The relationship between height and weight with trace elements and IGF was analyzed using parametric or non-parametric tests. There were 52 children (5-18 years) with neurologic WD. Thirty-six (69.2%) children had normal height, 12 (23.1%) were tall, and 4 (7.7%) were stunted. Forty-six (88.5%) children had normal weight and six (11.5%) children were underweight. IGF-1 correlated with height, weight, duration of treatment, and serum Zn level. About 15.4% of children had stunting and/or wasting, which was associated with low levels of serum IGF-I, Zn, and calcium. Stunting and/or wasting occurs in 15.4% of children with neurologic WD and is associated with reduced serum IGF-I, Zn, and calcium concentration. Adjunctive Zn and calcium treatment may help in achieving normal growth.

INFLUENCE OF INSULIN-LIKE GROWTH FACTOR-I LEVELS ON THE COURSE OF ACUTE MYOCARDIAL INFARCTION: review

Over the last many years, cardiovascular disease has reached epidemic proportions among chronic noncommunicable diseases worldwide. According to the latest tendencies, cardiovascular diseases play the leading role in the formation of current negative health and demographic trends in Ukraine and all over the world: they significantly affect the main health indicators: morbidity, mortality, disability, life expectancy and quality of life. If we take the last 20 years, we can see that the prevalence of CVDs among the Ukrainian population has tripled, and the mortality rate from them has risen by 40%. Review was analysed serum level insulin-like growth factor-I (IGF-I) in patients with acute myocardial infarction and his role in left ventricular remodelling was established. The scientific data regarding the neurohumoral component of acute myocardial infarction pathogenesis have been expanded by increasing levels of the angiogenesis marker IGF-I, which can be explained by his properties as markers of the acute phase of inflammation. An analysis of the relationship between troponin I and IGF-I, a marker of myocardial damage, showed a direct relationship, indicating an increase in troponin I concentration with rising serum IGF-I levels. This indicates that the activity of the angiogenesis marker IGF-I may be associated with the severity and depth of myocardial damage.

Essential Amino Acid Intake Is Required for Sustaining Serum Insulin-like Growth Factor-I Levels but Is Not Necessarily Needed for Body Growth.

Essential amino acids (EAAs) are those that cannot be synthesized enough to meet organismal demand; therefore, it is believed that they must be taken from the diet for optimal growth. The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system is also considered significant for growth regulation in mammals. This study aimed to evaluate the relative contributions of protein nutrition and the GH/IGF-I system to body growth regulation. Experiments using rodents and hepatocyte-derived cell lines subjected to EAA deficiency showed that a reduction in the serum EAA concentration hinders Igf1 transcription in the liver in a cell-autonomous manner, thereby decreasing serum IGF-I levels. Remarkably, when the serum IGF-I level of mice on a low-protein diet was restored by the recombinant IGF-I infusion, the body growth was mostly rescued, although the mice were still deficient in EAA intake. Meanwhile, the GH signal activation and subsequent Igf1 transcription were also dramatically diminished by EAA deprivation in the cell culture model. Altogether, we demonstrate that EAAs are not strictly necessary for animal growth as building blocks but are required as IGF-I-tropic cues. The results will bring a paradigm shift regarding the definition of “essential” amino acids.

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.

The relation of fat tissue hormones and some galactopoietic hormones with milk yield in Holstein and Simmental cows

The present study was conducted to investigate the physiological changes in leptin, adiponectin, and ghrelin hormones, which are effective in the regulation of energy metabolism, and the galactopoietic hormones including growth hormone (GH), insulin, insulin-like growth factor-I (IGF-I), cortisol, thyroid stimulating hormone (TSH) and thyroxine (T4 ) levels, which are also effective in the regulation of metabolic activities and their correlation with milk yield levels in Holstein and Simmental cows with low, medium, and high milk yield. Holstein (n = 30) and Simmental cows (n = 30) with low, medium, and high milk yield were used. Cows were divided into 6 groups with 10 animals in each group, and body condition scores (BCS) were determined. Serum GH, insulin, IGF-I, cortisol, TSH, T4 , leptin, adiponectin, and ghrelin levels were measured. GH level increased in both breeds (p < 0.05). As a result, in cases when the energy requirement increases during lactation without reaching a critical point, the GH, cortisol, and ghrelin hormone levels increase, while the plasma T4 level decreases and insulin, IGF-I, TSH, leptin, and adiponectin levels remain unchanged. An interaction between leptin, adiponectin, and ghrelin and galactopoietic hormones was noted.

Thyroid-related ophthalmopathy development in concurrence with growth hormone administration

BackgroundThyroid stimulating hormone (TSH) receptor and local infiltrate lymphocytes have been considered as major pathological factors for developing thyroid-related ophthalmopathy. Overexpression of insulin-like growth factor-I (IGF-I) receptor has emerged as a promising therapeutic target for refractory patients. However, the relationship between activation of growth hormone (GH)/IGF-I receptor signaling and development or exacerbation of thyroid ophthalmopathy has not been elucidated. Herein we describe a case that provides further clarification into the association between thyroid-related ophthalmopathy and GH/IGF-I receptor signaling.Case presentationA 62-year-old Japanese female diagnosed with thyroid-related ophthalmopathy was admitted to Kurume University Hospital. She had received daily administration of GH subcutaneously for severe GH deficiency; however, serum IGF-I levels were greater than + 2 standard deviation based on her age and sex. She exhibited mild thyrotoxicosis and elevation in levels of TSH-stimulating antibody. Discontinuation of GH administration attenuated the clinical activity scores of her thyroid-related ophthalmopathy. Additionally, concomitant use of glucocorticoid and radiation therapies resulted in further improvement of thyroid-related ophthalmopathy. The glucocorticoid administration was reduced sequentially, followed by successful termination. Thereafter, the patient did not undergo recurrence of thyroid-related ophthalmopathy and maintained serum IGF-I levels within normal physiological levels.ConclusionsWe describe here a case in which development of thyroid-related ophthalmopathy occurred upon initiation of GH administration. GH/IGF-I signaling was highlighted as a risk factor of developing thyroid-related ophthalmopathy. Additionally, aberrant TSH receptor expression was suggested to be a primary pathophysiological mechanism within the development of thyroid-related ophthalmopathy. Physicians should be aware of the risks incurred via GH administration, especially for patients of advanced age, for induction of thyroid-related ophthalmopathy.

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.

Effect of Growth Hormone on Neuropsychological Outcomes and Quality of Life of Patients with Traumatic Brain Injury: A Systematic Review.

One of the most devastating chronic consequences of traumatic brain injury (TBI) is cognitive impairment. One of the possible underlying causes is growth hormone deficiency (GHD) caused by TBI-induced hypopituitarism. Currently, TBI patients are not routinely screened for pituitary function, and there are no standard therapies when GHD is diagnosed. Further, the possible positive effects of GH replacement on cognitive function and quality of life after TBI are not well established. We aimed to assess the current knowledge regarding the effect of GH therapy on cognitive function and quality of life after TBI. We performed a literature search in PubMed, Embase, and Central® databases from inception to October 2019. We extracted data on each term of severity (mild-moderate-severe) of TBI with and without GHD, time since injury, parameters of growth hormone treatment (dosing, length), and cognitive outcomes in terms of verbal and non-verbal memory, and executive, emotional, and motor functions, and performed a meta-analysis on the results of a digit span test assessing working memory. We identified 12 studies (containing two randomized controlled trials) with 264 mild-to-moderate-to-severe TBI patients (Glasgow Coma Score [GCS] varied between 6 and 15) with (n = 255) or without (n = 9) GHD who received GH therapy. GH was administered subcutaneously in gradually increasing doses, monitoring serum insulin-like growth factor-I (IGF-I) level. After TBI, regardless of GCS, 6-12 months of GH therapy, started in the chronic phase post-TBI, induced a moderate improvement in processing speed and memory capacities, decreased the severity of depression, and led to a marked improvement in quality of life. Limitations include the relatively low number of patients involved and the divergent neuropsychological tests used. These results indicate the need for further multi-centric controlled studies to substantiate the use of GH replacement therapy as a potential tool to alleviate TBI-related cognitive impairment and improve quality of life.

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.

A Mediterranean Dietary Intervention in Female Carriers of BRCA Mutations: Results from an Italian Prospective Randomized Controlled Trial.

Simple SummaryUnmet clinical needs in women with deleterious mutations in the BRCA1/2 genes include lifestyle recommendations as adjuvant support and risk-reducing options. Insulin-like growth factor I (IGF-I), body weight and metabolic markers of insulin resistance may affect BRCA penetrance. Therefore, we conducted a multicenter prospective two-armed randomized controlled trial to investigate whether a Mediterranean dietary intervention with moderate protein restriction reduced IGF-I and other metabolic modulators of BRCA penetrance. Out of 502 randomized women with deleterious BRCA1/2 mutations, 416 (216 in the intervention group and 200 in the control group) concluded the six-month dietary intervention and participated in the final examinations. Women in the intervention group significantly lowered serum levels of IGF-I, weight, waist circumference, hip circumference, total cholesterol and triglycerides with respect to the control group. Our findings suggest that a Mediterranean diet with moderate protein restriction is effective in reducing potential modulators of BRCA penetrance.Background: Women carriers of BRCA1/2 mutations face a high lifetime risk (penetrance) of developing breast and/or ovarian cancer. Insulin-like growth factor I (IGF-I), body weight and markers of insulin resistance affect BRCA penetrance. We conducted a multicenter prospective two-armed (1:1) randomized controlled trial (NCT03066856) to investigate whether a Mediterranean dietary intervention with moderate protein restriction reduces IGF-I and other metabolic modulators of BRCA penetrance. Methods: BRCA carriers, with or without a previous cancer, aged 18–70 years and without metastases were randomly assigned to an active dietary intervention group (IG) or to a control group (CG). The primary endpoint of the intervention was the IGF-I reduction. Results: 416 women (216 in the IG and 200 in the CG) concluded the six-month dietary intervention. The IG showed significantly lowered serum levels of IGF-I (−11.3 ng/mL versus −1.3 ng/mL, p = 0.02), weight (−1.5 Kg versus −0.5 Kg, p < 0.001), waist circumference (−2 cm versus −0.7 cm, p = 0.01), hip circumference (−1.6 cm versus −0.5 cm, p = 0.01), total cholesterol (−10.2 mg/dL versus −3.6 mg/dL, p = 0.04) and triglycerides (−8.7 mg/dL versus + 5.5 mg/dL, p = 0.01) with respect to the CG. Conclusions: A Mediterranean dietary intervention with moderate protein restriction is effective in reducing IGF-I and other potential modulators of BRCA penetrance.

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.

Delirium, insulin-like growth factor I, growth hormone in older inpatients.

BACKGROUNDDelirium is a common disorder in elderly medical inpatients with serious adverse outcomes and is characterized by sudden onset, disturbance in attention, awareness, consciousness and cognition, and often with behavioural disturbances. Central to understanding delirium, is understanding mechanisms by which body and brain wellbeing are linked and in particular how brain responses to bodily homeostatic stress is mediated. A number of studies have investigated the relationship between insulin-like growth factor I (IGF-I) and delirium in medically ill hospitalised patients with conflicting results. However, none have investigated growth hormone (GH) which is related to IGF-I via negative feedback.AIMTo investigate the relationship between serum levels of IGF-I and GH, and the occurrence of delirium.METHODSProspective, longitudinal, observational study. Consecutive elderly inpatients (aged 70+), were assessed twice weekly with Montreal cognitive assessment (MoCA), Confusion assessment method (CAM), Acute Physiology and Chronic Health Evaluation II. Delirium was defined using CAM. Previous history of dementia was evaluated with the Informant Questionnaire on Cognitive Decline in the Elderly. IGF-I and GH levels were estimated with the ELISA method. Generalized estimating equations (GEE) model was applied for the first five assessments to analyze those longitudinal data.RESULTSThe sample consisted of 198 participants (mean age 80.63 ± 6.81; range 70-97). Of these 92 (46.5%) were females. Eighty six (43.4%) were identified with a history of dementia. Incident or prevalent delirium during hospitalisation was identified with CAM in 40 participants (20.2%). Evaluation of missing values with Little's MCAR test indicated that they were missing completely at random (MCAR χ2 = 12.24, u: 9, P = 0.20). Using GEE for the analysis we found that low MoCA scores, low levels of IGF-I and high levels of GH were significantly associated with any delirium (prevalence, incident, or fluctuating , during the study period (Wald χ2 = 12.231; u: 1, P < 0.001, Wald χ2 = 7.196, u: 1, P = 0.007, Wald χ2 = 6.210; : u: 1, P = 0.013 respectively).CONCLUSIONThe results show that low levels of IGF-I, high levels of GH and low scores in cognition are independently associated with the occurrence of any delirium during the hospitalisation of medically ill older people. The results of the study supports the hypothesis that deficits in the immunoreactivity of the brain (low cerebral reserve) may be associated with delirium.

Associations between Maternal and Fetal Levels of Total Adiponectin, High Molecular Weight Adiponectin, Selected Somatomedins, and Birth Weight of Infants of Smoking and Non-Smoking Mothers.

The aim of the study was to determine the relationships between maternal smoking, total adiponectin, high molecular weight adiponectin (HMW adiponectin), selected somatomedins, and the birth weight of newborns. A total of 78 women with a healthy, singleton pregnancy, 41 active smokers and 37 non-smokers, and their offspring were studied. Total and HMW adiponectin, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1) and 2 (IGFBP-2) were determined in maternal and cord blood by enzyme-link immunosorbent assay. Serum levels of total and HMW adiponectin were lower in smokers compared to the tobacco abstinent in both the mothers (p = 0.013; p = 0.006) and the infants (p = 0.001; p = 0.047). In smoking women and their children, serum concentrations of IGF-I were significantly lower (p = 0.014; p = 0.042), IGFBP-1 significantly higher (p = 0.009; p = 0.039), and IGFBP-2 did not differ from that observed in the non-smoking group. In multivariate analysis performed on the whole group of mothers, the highest impact of serum cotinine and IGFBP-2 levels were indicated for adiponectin and cotinine and the number of cigarettes/day for HMW adiponectin concentration. In correlation analysis estimated separately for smokers and non-smokers, neonatal birth weight was positively associated with total and HMW adiponectin concentrations in umbilical cord blood. Birth weight was also inversely associated with IGFBP-1 and positively correlated with IGF-I levels in maternal serum as well as in cord blood (r = −0.317, p = 0.005; r = −0.294, p = 0.004; r = 0.245, p = 0.031; r = 0.271, p = 0.009, respectively). The present study showed the levels of total and HMW adiponectin in umbilical cord blood may have a significant effect on fetal development. Both IGF-I and IGFBP-1 concentrations also play an essential role in fetal growth, which is an important predictor of birth weight. Cigarette smoking during pregnancy negatively affected adiponectin and the insulin growth factor profile in the serum of women and the cord blood and may be the reason for the lower birth weight of the smokers newborns compared with the nonsmokers offspring.

Phenotypic and genotypic features of a large kindred with a germline AIP variant.

Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved. To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant. The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants. We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin-like growth factor-I (IGF-I) levels in all family members were above the mean for age and sex (IGF-I SDS: +0.6 [CI95% +0.4-0.9], P<.01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons. This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.

MON-311 Glucose Metabolism in Acromegaly Patients Resistant to First Generation Somatostatin Receptor Ligands Treated with Pegvisomant And/Or Pasireotide Lar

Introduction: Acromegaly (Acro) is a systemic disease characterized by high growth hormone (GH) and insulin like growth factor-I (IGF-I), insulin resistance, glucose intolerance (IGT) and higher diabetes mellitus (DM) risk in 15% - 38% of patients (pts). Moreover, different medical therapies of Acro are reported to have variable effects on glucose metabolism. An association between blood glucose (BG) and serum IGF-I levels in patients with DM and Acro has been suggested, while IGF-I levels and hemoglobin A1c (HbA1c) correlation is still controversial because of the multifactorial influence.Study aim: to investigate glucose metabolism in pts with Acro resistant to 1st gen somatostatin receptor ligands (SRLs) treated with Pegvisomant (Peg) or Pasireotide LAR (Pasi). Patients and Methods: Retrospective, international, multicenter study; consecutive pts enrolled according to following inclusion criteria for at least 6 consecutive months: (1) resistant to 1st gen SRLs, (2) treated with Pasi or Peg for active Acro. Patients with concomitant treatments with known action on glucose metabolism were excluded, with the exception of glucocorticoid replacement for central hypoadrenalism. Results: 72 pts with active Acro, mean age at study entry 37 ±15 yrs, 47 females (65.3%). 28 (38.9%) pts were treated with Pasi and 44 pts with Peg (61.1%). Peg was monotherapy in 18 pts (40.9%) and in combo with first generation SRLs for 26 pts (59.1%). The number of pts with IGT and DM2 was superimposable between the 2 groups (Pasi and Peg). In Pasi group, 19 pts had Acro control (67.9%); glucose metabolism worsened in 16 pts (57.1%). Worsening of glucose metabolism occurred most frequently in pts with persistently active Acro (62.5%) and in pts with higher BG and HbA1c values at study start. Similarly, HbA1c was higher in pts with active Acro, although HbA1c worsened during Pasi treatment both in euglycemic and IGT at study entry, regardless of Acro control. In Peg group, 31 pts reached Acro control (73%); glucose metabolism worsened in 12 (27.3%) but improved in 5 pts (11.4%). All pts who experienced glucose metabolism improvement had controlled Acro, regardless of the use of a combo with first generation SRL. Among the 13 pts with active Acro after Peg, BG worsened in 5 cases (38.4%). Moreover, we found that pts with worsening BG control had higher HbA1c (p=0.03) and required higher Peg doses (mean ±SD 25 ±10 mg/day; p=0.04). Patients with higher HbA1c had higher IGF-I, both at study entry and at study end and were treated with higher Peg dose (mean 25 mg/day). Conclusion: Impaired glucose metabolism was more frequent after Pasireotide treatment and in patients of both Pasireotide and Pegvisomant groups with altered pre-treatment glucose and persistently active disease. Therefore, in such acromegaly patients close monitoring of glucose status is recommended during treatment.

Patients with Alzheimer's Disease Have Increased Levels of Insulin-like Growth Factor-I in Serum but not in Cerebrospinal Fluid.

Insulin-like growth factor-I (IGF-I) is important for amyloid-β (Aβ) metabolism, and also interacts with the brain vasculature. In previous IGF-I studies, it has not been evaluated whether Alzheimer's disease (AD) patients had vascular comorbidities. A cross-sectional study of 40 consecutive non-diabetic AD patients and 36 healthy controls. We measured IGF-I in serum and cerebrospinal fluid (CSF) and also serum insulin. Mixed forms of AD and vascular dementia were excluded. After adjustment for covariates including age, serum IGF-I level was higher in the AD group than in the controls, whereas CSF IGF-I and serum insulin were unchanged. Binary logistic regression confirmed that high serum IGF-I was associated with increased prevalence of AD [adjusted Odds Ratio (OR) = 1.83, 95% confidence interval (CI): 1.005-3.32 per standard deviation (SD) increase in serum IGF-I]. This association was more robust after exclusion of patients receiving treatment with acetylcholinesterase inhibitors or N-methyl D-aspartate (NMDA) receptor antagonists (OR = 2.23, 95 % CI: 1.10-4.48). In the total study population (n = 76) as well in the AD group (n = 40), serum IGF-I correlated negatively with CSF Aβ1-42, and CSF IGF-I correlated positively with CSF/serum albumin ratio, CSF total tau, and CSF phosphorylated tau. In AD patients without major brain vascular comorbidities, serum but not CSF levels of IGF-I were increased after correction for covariates. This association was strengthened by exclusion of patients receiving medical treatment. Overall, the results support the notion of IGF-I resistance in mild AD dementia.

Relationship between Levels of Pre-Stroke Physical Activity and Post-Stroke Serum Insulin-Like Growth Factor I.

Physical activity (PA) and insulin-like growth factor I (IGF-I) have beneficial effects for patients who have suffered an ischemic stroke (stroke). However, the relationship between the levels of PA and IGF-I after stroke has not been explored in detail. We investigated the pre-stroke PA level in relation to the post-stroke serum IGF-I (s-IGF-I) level, at baseline and at 3 months after the index stroke, and calculated the change that occurred between these two time-points (ΔIGF-I). Patients (N = 380; 63.4% males; mean age, 54.7 years) with data on 1-year leisure-time pre-stroke PA and post-stroke s-IGF-I levels were included from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Pre-stroke, leisure-time PA was self-reported as PA1–4, with PA1 representing sedentary and PA2–4 indicating progressively higher PA levels. Associations between s-IGF-I and PA were evaluated by multiple linear regressions with PA1 as the reference and adjustments being made for sex, age, history of previous stroke or myocardial infarctions, cardiovascular risk factors, and stroke severity. PA correlated with baseline s-IGF-I and ΔIGF-I, but not with the 3-month s-IGF-I. In the linear regressions, there were corresponding associations that remained as a tendency (baseline s-IGF-I, p = 0.06) or as a significant effect (ΔIGF-I, p = 0.03) after all the adjustments. Specifically, for each unit of PA, ΔIGF-I increased by 9.7 (95% CI 1,1−18.4) ng/mL after full adjustment. This supports the notion that pre-stroke PA is independently related to ΔIGF-I.

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.

Hormonal Dynamics Effect of Serum Insulin-Like Growth Factor I and Cortisol/Dehydroepiandrosterone Sulfate Ratio on Symptom Severity of Major Depressive Disorder.

Insulin-like growth factor I (IGF-I) is a neurotrophic factor produced by the hypothalamic-pituitary-somatotropic axis and is considered a potential contributor to the pathology of major depressive disorder (MDD). Although it is known that the hypothalamic-pituitary-adrenal axis and cortisol are involved in the pathology of MDD, the association with dehydroepiandrosterone sulfate (DHEAS) remains unclear. The current study sought to clarify the relationship between these hormones and the pathology of MDD. Subjects were 91 Japanese patients with a diagnosis of MDD. Serum IGF-I, cortisol, and DHEAS were measured. Samples were taken before breakfast after overnight fasting. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAM-D). Subjects included 59 men and 32 women with an average age of 44.1 ± 13.1 years (mean ± SD). The blood IGF-I level was 152.0 ± 50.0 ng/mL, the cortisol level was 10.1 ± 4.6, and the DHEAS level was 201.3 ± 112.7 μg/dL. The mean HAM-D score was 13.9 ± 9.0. Serum IGF-I levels were not correlated with cortisol. Higher IGF-I, cortisol, and cortisol/DHEAS ratios were associated with higher HAM-D scores (adjusted R = 0.240, P < 0.001), and higher IGF-I and cortisol were associated with higher melancholic or suicide subscores (adjusted R = 0.200, P < 0.001; adjusted R = 0.273, P < 0.001). Our findings suggest that hormonal dysregulation of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-somatotropic axes may be related to the symptom severity of MDD, melancholia, and suicide-related factors.