Insulin-like Growth factor-I Levels Research Articles

The Effect of Capsaicin on IGF-I and IGF-IR Expression in Ovarian Granulosa Cells

Capsaicin (trans-8-methyl-N-vanillyl-6-noneadamide) is a pungent ingredient in red peppers from the Capsicum family. Insulin-like growth factor-I (IGF-I) is expressed in granulosa cells and has an important role in ovarian development. However, there are no data about the IGF-I expression in ovarian granulosa cells after capsaicin treatment. The aim of this study was to investigate the expression of IGF-I and its receptor (insulin-like growth factor-I receptor [IGF-IR]) in primary rat ovarian granulosa cells after low and high doses of capsaicin treatment. For this, granulosa cells were isolated and cultured from ovaries of 30-day-old female Sprague-Dawley rats. Granulosa cell plates were divided into four groups as cell control (C), vehicle control (V), and 50 μM and 150 μM capsaicin groups. In experimental groups, granulosa cells were exposed to capsaicin for 24 hours and immunocytochemistry was performed afterwards using anti-IGF-I and anti-IGF-IR antibodies. Both IGF-I and IGF-IR expressions were found to be significantly increased in parallel to the capsaicin doses. Elevated levels of IGF-I may be a risk factor for ovarian development. Because of the crucial role of IGF-I in ovary development, capsaicin treatment can be effective on follicular development and/or disorders characterized by high IGF-I levels.

Mechanisms of putative IGF-I receptor resistance in active acromegaly

Acromegaly is a disease characterized by overproduction of growth hormone (GH). As a consequence of excessive GH secretion, circulating insulin-like growth factor-I (IGF-I) is elevated in active (untreated) acromegaly. IGF-I is often used as a marker of disease activity and growth hormone status in acromegaly. Although IGF-I can directly improve insulin sensitivity and glucose uptake in muscles, the excessive GH secretion in active acromegaly frequently leads to insulin resistance, glucose intolerance and even diabetes. In this review evidence will be discussed that in active acromegaly chronically elevated IGF-I, insulin and soluble Klotho (S-Klotho) levels play a pathophysiological role in the development of IGF-I receptor (IGF-IR) resistance. It is postulated that as soon as circulating IGF-I, insulin and S-Klotho rise above a certain level the IGF-IR becomes relatively resistant to actions of IGF-I. The development of a degree of IGF-IR resistance for metabolic actions may help to explain why in active acromegaly diabetogenic effects of GH predominate and are not completely counteracted and neutralized by elevated circulating levels of IGF-I. Further studies are necessary in order to support this hypothesis.

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.

Growth, stress and non-specific immune responses of turbot (Scophthalmus maximus) larvae exposed to different light spectra

The welfare of farmed fish is an important issue in aquaculture. There is particular concern regarding ambient light in culture systems. In the current study, turbot (Scophthalmus maximus) larvae were exposed to four different light spectra: full spectrum (LDF), blue (LDB, peak at 450 nm), orange (LDO, peak at 595 nm) and red (LDR, peak at 629 nm) from the embryo stage to 60 days post hatching (dph). During this time, the growth and immune response of the turbot were evaluated. Whole fish tissue samples were collected and weighed. mRNA expression levels of insulin-like growth factor-I (IGF-I), heat shock protein 70 (HSP70), glutathione S-transferase (GST), catalase (CAT), metallothionein (MT), lysozyme (LZM), cathepsin D (CTSD), cathepsin F (CTSF) and the enzyme activity of superoxide dismutase (SOD), CAT, and peroxidase (POD) were measured at 10, 20, 30, 40, 50, and 60 dph. The results showed that LDB had a positive effect on the growth of turbot larvae at 20, 40, 50 and 60 dph, while this effect was not significant at 10 and 30 dph. Levels of IGF-I mRNA also showed a similar tendency, indicating the crucial interaction between IGF-I and somatic growth. The effect of light spectrum on the stress response of turbot larvae was stage specific. At 10 dph, prior to metamorphosis, long wavelengths could induce a stress response in turbot larvae. At 20 dph, metamorphosis began and no significant stress response was observed in larvae exposed to different light spectra; however, LDO significantly up-regulated SOD, CAT, POD and LZM activity. Metamorphosis continued until 56 dph. From 20 to 60 dph long wavelengths (LDR and LDO) resulted in a stress response characterized by high mRNA expression levels of HSP70, GST, CAT, MT, LZM, CTSD and CTSF. SOD, CAT, POD and LZM activities were inhibited, indicating increased enzyme consumption to maintain homeostasis. Overall, our results suggested that LDF should be used in turbot culture systems prior to metamorphosis and LDB should be used after metamorphosis. These findings are in keeping with the changes in light spectra experienced by turbot larvae undergoing metamorphosis in the wild.

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.

Insulin-Like Growth Factor I (IGF-I); cytoprotective effects, idea of replacement therapy in the healthy elderly subjects

Insulin-like growth factor-I (IGF-I) is one of the important molecule that has driven great interest in gerontology. The connection between IGF-I and the replacement therapy has been the center for many investigations for the past decade. IGF-I levels decline with age and has been considered to contribute to age-related decline in body activities. As adults age, there is a decline in the concentration of IGF-I. It has been postulated that the declines in both growth hormone (GH) and IGF-I, as it is evident in aged adults, may be associated with increased body fat, reduced muscle strength, decreased bone mass, and reduced lean body mass. This reduction may lead to overall body performance and thus may decrease the quality of life. In the present review, we have viewed the past history of the relevant publications to find a perception that would lead us to come close to the idea of the therapeutic step and provide a view of a possible IGF-I replacement therapy in the healthy elderly subjects. More specifically, this review will summarize and help to understand the effects and benefits of IGF-I system impacting on the aged organ systems. In addition, we aim to discuss the general functional properties of IGF-I and implications of its possible use as a replacement to the healthy elderly subjects and we will emphasis its downfalls and new perceptions.

Influence of the level of insulin-like growth factor-I and endostatin in blood serum on the lipid profile indicators in patients with acute myocardial infarction and obesity

The levels of insulin-like growth factor I and endostatin in the blood serum and their relationship with lipid profile were investigated in patients with acute myocardial infarction and obesity. The object of the study was 105 patients. All patients were divided into two groups: group 1 consisted of patients with AMI and concomitant obesity (n=60), group 2 consisted of AMI patients without obesity (n=45). The control group consisted of 20 practically healthy people. The average age of patients in group 1 was (67.44±1.34) years old, and in group 2 was (66.85±1.72) years old. The content of IGF-I and endostatin was determined by the enzyme immunoassay. To determine IGF-I, an enzyme-linked immunosorbent assay was used using the Human Insulin like growth factor-I ELISA Kit (MEDIAGNOST, Germany). The endostatin level was determined by the enzyme immunoassay using the Endostatin Elisa Kit (BIOMEDICA, Austria). The biochemical study included the determination of the level of TC and HDL, carried out by the peroxidase method using a set of reagents «Cholesterol Liquicolor» from «Human» (Germany) in blood serum stabilized with heparin. The obtained correlations indicate that an increase in the level of endostatin in the blood serum is significantly associated with an increase in the levels of TC, LDL, TG, CA and a decrease in HDL. Also, reliable data were obtained on the feedback between IGF-I and the level of TC, LDL, TG and CA, as well as a direct relationship between the indicators of IGF-I and HDL. The data obtained indicate that endostatin as a marker of angiogenesis is associated with obesity and dyslipidemia, and also indicate the anti-inflammatory and antioxidant properties of IGF-I under conditions of high autoimmune activity.

Diagnosis, treatment and follow-up of patients with acromegaly in a clinical practice setting in Spain: the ACROPRAXIS program Delphi survey

AimThe ACROPRAXIS program aims to describe the management of acromegaly in Spain and provide guidance.MethodsNinety-three endocrinologists were organized into 13 panels to discuss the practical issues in managing acromegaly. Based on the key learnings, an online Delphi survey with 62 statements was performed, so those statements achieving consensus could be used as guidance. Statements were rated on a 9-point scale (9, full agreement; consensus > 66.6% of response in the same tertile).ResultsNinety-two endocrinologists (98.8%) answered two rounds of the survey (mean age 47.6 years; 59.8% women; median 18.5 years of experience). Consensus was achieved for 49 (79%) statements. Diagnosis: The levels of insulin-like growth factor I (IGFI) is the preferred screening test. If IGFI levels 1–1.3 ULN, the test is repeated and growth hormone (GH) after oral glucose tolerance test (OGTT) is assessed. A pituitary magnetic resonance is performed after biochemical diagnosis. Treatment: Surgery is the first treatment choice for patients with microadenoma or macroadenoma with/without optical pathway compression. Pre-surgical somatostatin analogues (SSA) are indicated when surgery is delayed and/or to reduce anaesthesia-associated risks. After unsuccessful surgery, reintervention is performed if the residual tumor is resectable, while if non-resectable, SSA are administered. Follow-up First biochemical and clinical controls are performed 1–3 months after surgery. Disease remission is considered if random GH levels are < 1 µg/L or OGTT is < 1 or ≤ 0.4 µg/L, depending on the assay’s sensitivity.ConclusionCurrent clinical management for acromegaly is homogeneous across Spain and generally follows clinical guidelines.

Associations between serum levels of insulin-like growth factor-I and bone mineral acquisition in pubertal children: a 3-year follow-up study in Hamamatsu, Japan

BackgroundEpidemiological data regarding the association between serum levels of IGF-I and bone mineral acquisition during childhood are scarce. Here, we investigated the association between serum levels of IGF-I and bone status during puberty.MethodsWe analyzed prospective 3-year follow-up data of 254 community-dwelling children who completed both baselines (at age 11.2 years) and follow-up (at age 14.2 years) surveys in Hamamatsu, Japan. Total body (TB) bone area and bone mineral parameters were assessed using dual-energy X-ray absorptiometry.ResultsDuring the 3-year follow-up period, there were significant (P < 0.05) increases in total body less head (TBLH) areal bone mineral density (aBMD), TBLH bone mineral content (BMC), and TB bone area, and a significant decrease in TB bone mineral apparent density (BMAD, volumetric bone mineral density, vBMD). IGF-I levels showed significant positive relationships with TBLH BMC and TBLH aBMD at both baseline and follow-up. TBLH aBMD in boys and TB BMAD in girls at follow-up showed significant increases from the lowest to highest quartiles of baseline IGF-I levels after adjusting for confounding factors. Similarly, changes in TBLH aBMD in boys and TB BMAD in girls during the 3-year follow-up period showed significant increases from the lowest to highest quartiles of baseline IGF-I levels after adjusting for confounding factors.ConclusionsThese results suggest that pubertal children with high levels of serum IGF-I tended to have high bone mineral acquisition later on.

Growth hormone treatment strategies in assisted reproduction for the poor responder patients

The goal of the study was to estimate the efficacy of growth hormone (GH) co-treatment to the antagonist protocol in IVF/ ICSI cycles in poor responders. A prospective observational study involved 75 patients. All patients underwent standard antagonist protocol with or without GH co-treatment. GH additional was given a daily subcutaneous injection of 1.33 mg (equivalent to 4 IU) of GH from day 1 of ovarian stimulation until the day of human chorionic gonadotropin (hCG). Concentrations of GH, insulin-like growth factor I (IGF-I) and IGF binding protein-3 (IGFBP-3) in serum and follicular fluid were analyzed. The GH co-treatment significantly lowered effective dose of gonadotropins, duration of stimulation, IGFBP-3 level in serum and follicular fluid day of oocytes retrieval. The number of oocytes recovered, metaphase II stage (MII) oocytes, 2 pronucleus (2 pn) zygote, good-quality transferred embryos were significantly higher in the GH+ group. Only patients GH+ group became pregnant. Positive correlation was found between IGF-I level in follicular fluid, dynamics of IGFBP-3 level changes during stimulation protocol and number of good-quality transferred embryos in the GH+ group. GH administration in IVF/ICSI cycles for poor responders raises ovarian sensitivity to the gonadotropin exogenous influence, this way, increasing number of high-quality embryos and the probability of pregnancy.

Gene expression and DNA methylation changes in BeWo cells dependent on tumor necrosis factor-α and insulin-like growth factor-I.

Pregnant women with increased insulin resistance, characterized by elevated levels of tumor necrosis factor-alpha (TNF-α) and insulin-like growth factor-I (IGF-I), are at high risk of preeclampsia. We hypothesized that TNF-α and IGF-I affect the placentas and cause pathological changes leading to preeclampsia. To understand the genetic and epigenetic effects of TNF-α and IGF-I on trophoblast cells, gene expression microarray and DNA methylation array of BeWo cells stimulated by TNF-α (100pg/ml, 100ng/ml) and IGF-I (100ng/ml) were conducted. Microarray analysis revealed the differential gene expression patterns in BeWo cells co-stimulated by TNF-α and IGF-I. Enrichment analysis identified the terms associated with NF-kappa B signaling pathways and arachidonic acid cascades such as PTGS2 and PTGER2. DNA methylation array revealed the distinct CpG methylation pattern in BeWo cells stimulated by high-TNF-α and IGF-I, while neither of them showed independent effects. Enrichment analysis identified the terms associated with major histocompatibility complex proteins. Integration of transcriptome and DNA methylome analyses identified three differentially expressed genes with significant DNA methylation change: C3, GP1BA, and NFKBIE, which are all possibly associated with pathogenesis of preeclampsia. In conclusion, co-stimulation of TNF-α and IGF-I induced the genetic and epigenetic changes associated with preeclampsia in BeWo cells. The results suggested that BeWo cells stimulated by TNF-α and IGF-I is a good in vitro model of preeclamptic placenta in pregnancy with increased insulin resistance.

PHYSIOLOGICAL RESPONSE OF BROILER CHICKENS UNDER HEAT STRESS CONDITIONS FOR SOME ORGANIC ANTIOXIDANT ADDITIVES.

One hundred and twenty 1-d old commercial broiler chicks (Cobb) were divided in to four groups with six replicats, to investigate the effect of dietary supplementation with organic chromium (Cr), organic selenium (Se) and Vitamin E (Vit.E) on some physiological and immunological parameters. The first group was the control group, while the second group was fed the basal diet supplemented with organic chromium (0.8 mg/kg diet), the third group was fed the basal diet supplemented with organic selenium (0.3 mg/kg diet) and the fourth group was fed the basal diet supplemented with vitamin E (200 IU/kg diet). Temperature and humidity were recorded daily and the Temperature-Humidity Index (THI) was calculated, which demonstrated that birds were exposed to heat stress throughout the experiment period. The results showed that increasing dietary levels of organic chromium, organic selenium and Vitamin E especially Vitamin E supplementation could improve plasma total protein and globulin (p<0.05) values at 42 DOA. Supplements could significantly (p<0.05) enhance the total antibody titer against Newcastle disease Virus (NDV) either for the primary or secondary response and induce higher expression of heat shock protein 70 (HSP 70). Insulin-like Growth factor-I (IGF-I) level was improved significantly (p<0.05) due to increasing dietary organic chromium levels followed by vitamin E than organic selenium. It could be concluded that the dietary addition of organic chromium (Cr), organic selenium (Se) and Vitamin E (Vit.E) triggered improvements in the physiological and immunological measurements of broilers reared under heat stress conditions

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.

Low plasma level of Iinsulin-like growth factor-I (IGF-I) s a risk factor for multibacillary type of leprosy

Introduction: Leprosy is one of infectious diseases with complex issues. Previous study showed poverty, malnutrition, lack of proper food and nutrient intake, as well as low income. Recently, many studies reported insulin-like growth factor-I (IGF-I) as excellent nutrient marker.Objective: This study aims to prove that low plasma level of insulin-like growth factor-I is a risk factor for multibacillary type of leprosy. Material and methods: This case-control study design involved 38 patients with leprosy subjects as cases and 38 control subjects. The sample collection is done by consecutive sampling and has fulfilled the inclusion and exclusion criteria which matched by age and gender in Dermatology and Venereology Outpatient clinic of Sanglah General Hosptital. The collected data was analyzed using SPSS version 23.0 with Pearson Chi square test to obtain Odds Ratio. Results: This study showed that IGF-I plasma levels in the case group were significantly lower than the control group (p&lt;0.05) with Odds ratio for IGF-I plasma 34.61 (95% CI= 7.17-167.01, p&lt;0.001)Conclusion: Low plasma level of insulin-like growth factor-I is a risk factor for multibacillary type of leprosy.

THE IGF -I IN DIABETIC PATIENTS WITH RESISTANT HYPERTENSION DECREASES INSULIN RESISTANCE BUT IS ASSOCIATED WITH CARDIOVASCULAR TARGET ORGAN DAMAGE

Objective: The insulin-like growth factor-I (IGF-I) is involved in glucose metabolism and may contribute to the accelerated cardiovascular disease. The aim of the study was to assess IGF-I level in diabetic patients with resistant hypertension (RHTN) and to evaluate its association with glucose metabolism and cardiac, renal and brain tissues. Design and method: The study included 19 diabetic patients with RHTN (mean age 58.9 ± 7.6 years, five men, mean office BP (systolic/diastolic) 174.8 ± 20.7/94.6 ± 15mmHg, mean HbA1c 7 ± 0.8%) and 21 age- and sex-matched patients with RHTN without diabetes mellitus (DM). Office BP, echocardiography, kidney and brain MRI, lab tests (IGF-1, plasma glucose and insulin levels, HOMA-index, HbA1c, serum creatinine, serum cystatin, eGFR (MDRD formula) and 24 h microalbuminuria) were performed in all patients. On average, patients were taking 4.2 ± 0.8 antihypertensive drugs. Results: IGF-I level was in the normal range in 18 (95%) patients with DM+RHTN and in 100% of patients with RHTN without DM, one diabetic patient with RHTN had elevated IGF-I levels. The mean IGF-I values in hypertensive patients with DM and those without DM were the same. In diabetic patients with RHTN the IGF-I level was inversely correlated to HOMA-IR index (R = -0.87, P = 0.002), but had a direct correlation with basal glucose level (R = 0.48, P = 0.04). In addition, increase in IGF-I level was associated with both of left ventricular mass (R = 0.49, P = 0.03), and the end-diastolic interventricular septum thickness (R = 0.59, P = 0.008), with decreased renal function (R = 0.64, P = 0.003 for serum creatinine; R = 0.76, p = 0.01 for serum cystatin; R = -0.50, P = 0.03 for eGFR), microalbuminuria level (R = 0.61, P = 0.03), as well as with structural kidney damage (R = -0.67, P = 0.04 for the medulla volume according to kidney MRI) and brain damage (R = 0.89, P = 0.015 for Evans’ index as a MRI- sign of brain atrophy) Conclusions: Most diabetic patients with RHTN have a normal IGF-I level, which does not differ from that in patients with RHT without DM. Although an increase in IGF-I level is associated with a decrease in insulin resistance, our data suggest the possible participation of IGF-I in the development of myocardial hypertrophy, the progression both of chronic kidney disease and brain atrophy.

Combination of treadmill exercise with bone marrow stromal cells transplantation activates protein synthesis-related molecules in soleus muscle of the spinal cord injured rats.

The present study investigated whether treadmill exercise with bone marrow stromal cells (BMSCs) transplantation increase expression level of protein synthesis-related molecules in the soleus muscle after spinal cord injury (SCI). The spinal cord contusion injury was performed at the T9–10 level using the impactor (10 g×25 mm). BMSCs were cultured from femur and tibia of 4-week-old rats and then transplanted directly into the lesion 1-week post injury. The rats in exercise group were walking on treadmill device for 6 days per a week during 6 weeks. Prepared soleus muscles were used for examining mechanisms of protein synthesis after SCI. Myostatin induction level was increased by SCI, but BMSCs engrafting after SCI decreased compared to SCI group. Combination of treadmill exercise with BMSCs showed more potent decrement on myostatin expression. Protein kinase B (Akt) and mammalian target of rapamycin (mTOR) levels were significantly increased in SCI and BMSCs transplantation group compared to SCI group. Combination of treadmill exercise with BMSCs further facilitated expression levels of Akt and mTOR. Insulin-like growth factor-I (IGF-I) and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) induction levels were more increased in SCI and BMSC transplantation group compared to SCI group. Combination of treadmill exercise with BMSCs further increased expression levels of IGF-I and p-CREB, although statistical significance was not appeared. Combining treadmill exercise with BMSCs transplantation might accelerate protein synthesis and hypertrophy in the soleus muscle after SCI through activation of IGF-I/mTOR signaling pathway.

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.

The IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis

BackgroundPatients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab.MethodsThirty-eight patients with active IBD treated with either prednisolone (n = 17) or infliximab (n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects.ResultsFollowing seven days of prednisolone treatment, total and bioactive IGF-I were increased (p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab (p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments.ConclusionIGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected.Trial registrationClinicalTrials.gov: NCT00955123. Date of registration: August 7, 2009 (retrospectively registered).

Chronic adult-onset of growth hormone/IGF-I hypersecretion improves cognitive functions and LTP and promotes neuronal differentiation in adult rats.

Besides their metabolic and endocrine functions, the growth hormone (GH) and its mediated factor, the insulin-like growth factor I (IGF-I), have been implicated in different brain functions, including neurogenesis. Long-lasting elevated GH and IGF-I levels result in non-reversible somatic, endocrine and metabolic morbidities. However, the subcutaneous implantation of the GH-secreting (GH-S) GC cell line in rats leads to the controllable over-secretion of GH and elevated IGF-I levels, allowing the experimental study of their short-term effects on brain functions. Adult rats were implanted with GC cells and checked 10weeks later, when a GH/IGF-I-secreting tumour was already formed. Tumour-bearing rats acquired different operant conditioning tasks faster and better than controls and tumour-resected groups. They also presented better retentions of long-term memories in the passive avoidance test. Experimentally evoked long-term potentiation (LTP) in the hippocampus was also larger and longer lasting in the tumour bearing than in the other groups. Chronic adult-onset of GH/IGF-I hypersecretion caused an acceleration of early progenitors, facilitating a faster neural differentiation, maturation and integration in the dentate gyrus, and increased the complexity of dendritic arbours and spine density of granule neurons. Thus, adult-onset hypersecretion of GH/IGF-I improves neurocognitive functions, long-term memories, experimental LTP and neural differentiation, migration and maturation.

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.