Basal Insulin-like Growth Factor Research Articles

Are Proteins Such as MMP2, IGF1, IL-13, and IL-1ra Valuable as Markers of Fitness Status in Racehorses? A Pilot Study

In a recent study, in which more than a thousand racehorses were evaluated, three potential blood markers were selected. It was concluded that insulin-like growth factor 1 (IGF1), interleukin-1 receptor antagonist (IL-1ra), and matrix metalloproteinase 2 (MMP2) may enable the early detection of horses at risk of injuries. However, in other studies, it was suggested that cytokine concentrations indicate the athlete’s status better than mRNA expression in blood cells. Thus, the purpose of this study was to evaluate changes in IGF1, MMP-2, and novel markers such as interleukin-13 (IL-13) after exercise in horses at different fitness levels as well as after different intensities of exercise. ELISA tests were performed on thirty-one racehorses [n = 31], who were divided into an inexperienced [beginner] group [n = 20] and an experienced [advanced] group [n = 6]. In addition, differences between race and training session were evaluated to see the influence of different intensities of exercise. Blood samples were taken before and after exercise. The basal IGF1 concentration was lower in an inexperienced group (p < 0.01) as well as IL-13 (p < 0.05) in comparison to the experienced group. There were no differences between pre- and post-exercise samples, changes in multiples or between training, and racing exercises. In conclusion, the basal values of some cytokines may appear to be more beneficial in forecasting horse fitness level.

Effect of insulin-like growth factor system on luteinising angiogenesis.

Preovulatory follicle growth and the luteal transition requires intense angiogenesis. This enables progesterone production to increase sufficiently to support a pregnancy. Inadequate follicular or luteal vascularisation can lead to reduced ovarian function and thus compromise fertility. Insulin-like growth factor 1 (IGF1) and IGF2 regulate multiple ovarian processes and are key links between an animal's reproductive and metabolic status. This study investigated the role that the IGF system plays in regulating luteinising follicular endothelial cell (EC) networks and progesterone production in vitro. Bovine luteinising follicular angiogenesis cultures were treated with 1) LR3-IGF1 (10 or 100ng/ml) under basal and angiogenic-stimulated conditions or 2) IGF1 receptor inhibitor (picropodophyllin (PPP); 1µM) in the presence or absence of LR3-IGF1, IGF2, or combined LR3-IGF1+IGF2 (10ng/ml). EC networks were quantified by von Willebrand factor immunohistochemistry. Progesterone production was analysed by ELISA and cell proliferation was determined by MTT assay. LR3-IGF1 had limited effects on EC growth parameters, whilst PPP (p<0.001) markedly reduced EC growth parameters (by 60-70%). Cell proliferation was slightly increased (by 3-5%) by LR3-IGF1 (p<0.001). LR3-IGF1 had variable effects on progesterone production, whilst PPP reduced progesterone concentration (p<0.001) with or without LR3-IGF1 or IGF2 alone or in combination. IGF1 was detected in cell conditioned media and was increased by LH (50ng/ml) (p<0.001). In conclusion, exogenous IGF1 and IGF2 had minimal effects on luteinising follicular angiogenesis and progesterone production, but the inhibitory effect of the IGFR1 inhibitor (PPP) suggests that IGF1 receptor signalling is critical for the development of EC networks and progesterone production in luteinising follicular cells.

Factors associated with therapeutic response in acromegaly diagnosed in the elderly in Spain.

ContextSome reports suggest that acromegaly in elderly patients has a more benign clinical behavior and could have a better response to first-generation long-acting somatostatin receptor ligands (SRL). However, there is no specific therapeutic protocol for this special subgroup of patients.ObjectiveThis study aimed at identifying predictors of response to SRL in elderly patients.DesignMulticentric retrospective nationwide study of patients diagnosed with acromegaly at or over the age of 65 years.ResultsOne-hundred and eighteen patients (34 men, 84 women, mean age at diagnosis 71.7 ± 5.4 years old) were included. Basal insulin-like growth factor type 1 (IGF-1) above the upper limit of normal (ULN) and growth hormone (GH) levels (mean ± SD) were 2.7 ± 1.4 and 11.0 ± 11.9 ng/ml, respectively. The mean maximal tumor diameter was 12.3 ± 6.4 mm, and up to 68.6% were macroadenoma. Seventy-two out of 118 patients (61.0%) underwent surgery as primary treatment. One-third of patients required first-line medical treatment due to a rejection of surgical treatment or non-suitability because of high surgical risk. After first-line surgery, 45/72 (63.9%) were in disease remission, and 16/34 (46.7%) of those treated with SRL had controlled disease. Patients with basal GH at diagnosis ≤6 ng/ml had lower IGF-1 levels and had smaller tumors, and more patients in this group reached control with SRL (72.7% vs. 33.3%; p < 0.04) [OR: 21.3, IC: 95% (2.4–91.1)], while male patients had a worse response [OR: 0.09, IC 95% (0.01–0.75)]. The predictive model curve obtained for SRL response showed an AUC of 0.82 CI (0.71–0.94).ConclusionsThe most frequent phenotype in newly diagnosed acromegaly in the elderly includes small adenomas and moderately high IGF-1 levels. GH at diagnosis ≤6 ng/ml and female gender, but not age per se, were associated with a greater chance of response to SRL.

Chronic, acute and protocol-dependent effects of exercise on psycho-physiological health during long-term isolation and confinement

Exercise could prevent physical and psychological deteriorations, especially during pandemic times of lock-down scenarios and social isolation. But to meet both, the common exercise protocols require optimization based on holistic investigations and with respect to underlying processes. This study aimed to explore individual chronic and acute effects of continuous and interval running exercise on physical and cognitive performance, mood, and affect and underlying neurophysiological factors during a terrestrial simulated space mission. Six volunteers (three females) were isolated for 120 days. Accompanying exercise training consisted of a continuous and interval running protocol in a cross-over design. Incremental stage tests on a treadmill were done frequently to test physical performance. Actigraphy was used to monitor physical activity level. Cognitive performance, mood (MoodMeter®), affect (PANAS), brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), vascular-endothelial growth factor (VEGF), and saliva cortisol were investigated prior to, four times during, and after isolation, pre- and post-exercise on two separate days, respectively. As a chronic effect, physical performance increased (and IGF-1 tended) in the course of isolation and training until the end of isolation. Subjective mood and affect state, as well as cognitive performance, basal BDNF and VEGF levels, were well-preserved across the intervention. No acute effects of exercise were detected, besides slower reaction time after exercise in two out of nine cognitive tests, testing sensorimotor speed and memory of complex figures. Consistently higher basal IGF-1 concentrations and faster reaction time in the psychomotor vigilance test were found for the continuous compared to the interval running protocol. The results suggest that 120 days of isolation and confinement can be undergone without cognitive and mental deteriorations. Regular, individual aerobic running training supporting physical fitness is hypothesized to play an important role in this regard. Continuous running exercise seems to trigger higher IGF-1 levels and vigilance compared to interval running. Systematic and prolonged investigations and larger sample size are required to follow up on exercise-protocol specific differences in order to optimize the exercise intervention for long-term psycho-physiological health and well-being.

Resistance to first-generation somatostatin receptor ligands does not impair the results of gamma knife radiosurgery in acromegaly.

Gamma knife radiosurgery (GKRS) has proven to be an effective adjuvant treatment for patients with acromegaly. We performed the present study to investigate, which would be the outcome of GKRS, independently on the response to somatostatin receptor ligand (SRL). Retrospective, observational study. Ninety-six patients with active acromegaly were included. The cumulative probability of normalisation of insulin-like growth factor 1 (IGF-1) levels after GKRS was assessed by the Kaplan-Meier method. The association of several clinical characteristics with GKRS outcomes was explored with the use of a Cox proportional-hazard model with the relative hazard ratioand 95% confidence interval (CI). Resistance to SRLoccurred in 39 of the 96 patients (40.6%). After GKRS, patients resistant to SRL had a 5- and 10-year probability of remission of 40.7% (95% CI: 23.7%-57.7%) and 75.9% (95% CI: 57.9%-93.9%), respectively. Patients responding to SRL had a 5- and 10-year probability of remission of 46.8% (95% CI: 32.2%-61.4%) and 58.1% (95% CI: 41.5%-74.7%), respectively. The difference was not significant (p = .48 by the log-rank test). Multivariate Cox analysis confirmed that the only independent variables associated with GKRS outcome were basal growth hormone (GH; p = .001) and IGF-1 multiple of the upper limit of normal levels before GKRS (p = .013). We demonstrate for the first time that the responsiveness to SRL has no effect on the probability to obtain remission of acromegaly after GKRS. The remission of disease occurred more frequently in patients who had lower GH and IGF-1 levels before GKRS.

The Prevalence of Cancer and Its Relation to Disease Activity in Patients With Acromegaly: Two Centers' Experience

ObjectiveAcromegaly is characterized by increased serum concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Although animal studies have demonstrated a relationship between these hormones and cancer risk, the results of human studies evaluating cancer prevalence in acromegaly are inconsistent. We aimed to investigate the prevalence of malignant neoplasms in patients with acromegaly. MethodsCancer risk was evaluated in a cohort of 280 patients (male/female: 120/160; mean age: 50.93 ± 12.07 years) with acromegaly. Patients were categorized into 2 groups according to the presence or absence of cancer. Standard incidence ratios were calculated as compared to the general population. ResultsFrom 280 patients, cancer was diagnosed in 19 (6.8%) patients; 9 (47%) of them had thyroid cancer, which was the most common cancer type. Standard incidence ratios of all cancers were 0.8 (95% CI, 0.5-1.1) and 1.0 (95% CI, 0.8-1.3) in men and women, respectively. Compared to patients without cancer, the current age was higher in patients with cancer (59 [49-65] to 51 [42-59], P = .027). In contrast, the age at diagnosis was similar in both groups. Not only was the time to diagnosis and disease duration similar in both groups but also the basal and current GH and IGF-1 levels. The prevalence of active disease was also similar between the groups (32% to 23%, P = .394). ConclusionOur findings were not consistent with the studies suggesting that patients with acromegaly encounter an increased cancer risk. Furthermore, there were similar basal and current GH and IGF-1 levels in patients with acromegaly, both with and without cancer.

Surgical and Pharmacological Outcomes in Acromegaly: Real-Life Data From the Mexican Acromegaly Registry.

Acromegaly registries constitute a valuable source of therapeutic outcome information in real-life. The objective of this work is to analyze surgical and pharmacological outcomes in the Mexican Acromegaly Registry (MAR). Data were extracted from the MAR informatic platform. Surgical remission was defined by a postoperative postglucose (GH) of less than 1 ng/mL and an insulin-like growth factor 1 (IGF-1) of less than 1.2 × upper limit of normal (ULN). Pharmacological remission was defined by a basal GH of less than 1 ng/mL and an IGF-1 of less than 1.2 × ULN. A total of 650 surgical outcomes were analyzed (94.6% transsphenoidal). Surgical remission was achieved in 40.15%, whereas 44.15% remained biochemically active. Persistently active disease after surgery was significantly associated with harboring an invasive macroadenoma, a basal GH of greater than 10 ng/mL, and/or an IGF-1 of greater than 2 × ULN at diagnosis on bivariate and multivariate analysis. The outcome of monotherapy with first-generation somatostatin analogs (SSAs) was evaluated in 267 patients (adjunctive in 65%), of whom 28.4% achieved remission. Persistently active disease was significantly associated with harboring an invasive macroadenoma as well as with pretreatment basal GH and IGF-1 levels of greater than 10 ng/mL and greater than 2 × ULN, respectively, on bivariate and multivariate analysis. Combined therapy with SSA and cabergoline was analyzed in 100 patients, of whom 19% achieved remission and 44% remained active; in this subset of patients, only a pretreatment IGF-1 of greater than 2 × ULN was significantly associated with persistent disease activity. Surgical and pharmacological outcomes in acromegaly are highly dependent on tumor size/invasiveness as well as on the degree of hypersomatotropinemia.

Somatotropic Axis and Obesity: Is There Any Role for the Mediterranean Diet?

Obesity is associated with reduced spontaneous and stimulated growth hormone (GH) secretion and basal insulin-like growth factor I (IGF-1) levels—which in turn is associated with increased prevalence of cardiovascular risk factors. The aim of this study was to investigate: (1) the association of somatotropic axis with cardiometabolic status; (2) the association of somatotropic axis with the Mediterranean diet and nutritional pattern in people with obesity. Cross-sectional observational study was carried out in 200 adult women, aged 36.98 ± 11.10 years with severe obesity (body mass index—BMI of 45.19 ± 6.30 kg/m2). The adherence to the Mediterranean diet and the total calorie intake was assessed. Anthropometric measurements, body composition and biochemical profile were determined along with Growth Hormone (GH)/Insulin like Growth Factor 1 (IGF-1) axis and insulin resistance (homeostatic model assessment for insulin resistance—HoMA-IR). The enrolled subjects were compared after being divided according to GH peak response and according to IGF-1 standard deviation scores (SDS). Derangements of GH peak were detected in 61.5% of studied patients while IGF-1 deficiency was detected in 71% of the population. Both blunted GH peak response and IGF-1 SDS were indicators of derangements of somatotropic axis and were associated with comparable results in terms of cardiometabolic sequelae. Both GH peak and IGF-1 levels were inversely associated with anthropometric and metabolic parameters. The adherence to the Mediterranean diet predicts GH peak response. Fatty liver index (FLI), fat mass (FM) and phase angle (PhA) were predictive factors of GH peak response as well. In conclusion derangements of somatotropic axis is associated with a worse cardiometabolic profile in people with obesity. A high adherence to the Mediterranean diet—and in particular protein intake—was associated with a better GH status.

Associations Between Circulating Basal BDNF, IGF-1 and Physical Fitness

Exercise-induced increase in circulating insulin-like growth factor 1 (IGF-1) levels might stimulate brain-derived neurotrophic factor (BDNF) expression. Thus, circulating IGF-1 can travel from the periphery to the brain and there stimulate the expression of BDNF and facilitate long-lasting changes in neural activity. It has been shown that chronic training leads to upregulation of basal levels of both BDNF and IGF-1. Several longitudinal studies have also shown that aerobic exercise acutely elevates circulating BDNF levels in humans. PURPOSE: To investigate associations of peripheral BDNF and IGF-1 with several physical fitness components at rest. METHODS: 792 adults (26±6 yr) men participated. BDNF and IGF-1 concentrations were analyzed from venous blood samples using an ELISA Assay (Human BDNF ELISA kit, ScienCell Research laboratories, San Diego, California) and Dynex DS 2 ELISA processing system (Dynex Technologies, Chantilly, Virginia). Cardiorespiratory fitness (VO2max) was determined using an indirect graded cycle ergometer test until exhaustion. Bilateral maximal isometric leg (MVCleg) and arm extension forces (MVCarm) were measured using dynamometers. Muscular endurance tests consisted of repeated 1-min push-ups and sit-ups, while standing long jump assessed muscular power. RESULTS: The mean±SD BDNF and IGF-1 concentrations were 15.20±3.96 ng/ml, 25.0±6.9nmol/l, respectively, while VO2max was 41.1±8.8ml/kg/min, MVCleg 3394±933N, MVCarm 871±216N, push-ups 28±14reps/min, sit-ups 35±12reps/min, standing long jump 227±26cm. BDNF and IGF-1 correlated weakly with each other (r=-0.146, p=0.003). Linear regression analysis (adjusted for age, smoking and education) revealed that associations between BDNF and physical fitness were weak for VO2max (β=-0.077, p=0.006) and muscle fitness (β=-0.077, p=0.895). This was also the case for IGF-1. CONCLUSIONS: The associations between peripheral BDNF, IGF-1 and physical fitness components were weak or non-existent at rest in the present cross-sectional design. Thus, it seems that only exercise-induced elevated values of BDNF and IGF-1 may associate with each other and physical fitness components. Therefore, their interactions should be investigated in future studies during acute and / or chronic exercises.

Influence of nutrition on somatotropic axis: Milk consumption in adult individuals with moderate-severe obesity

Nutrition is the major environmental factor that influences the risk of developing pathologies, such as obesity. Although a number of recent reviews pinpoint a protective effects of milk on body weight and obesity related co-morbidities, an inaccurate estimate of milk might contribute to hamper its beneficial effects on health outcomes. Seven-day food records provide prospective food intake data, reducing recall bias and providing extra details about specific food items. Milk intake stimulates the somatotropic axis at multiple levels by increasing both growth hormone (GH) and insulin-like growth factor-1 (IGF-1) secretion. On the other hand, obesity is associated with reduced spontaneous and stimulated GH secretion and basal IGF-1 levels. Aim of this study was to evaluate the milk consumption by using the 7-days food record in obese individuals and to investigate the association between milk intake and GH secretory status in these subjects. Cross-sectional observational study carried out on 281 adult individuals (200 women and 81 men, aged 18-74 years) with moderate-severe obesity (BMI 35.2-69.4kg/m2). Baseline milk intake data were collected using a 7 day food record. Anthropometric measurements and biochemical profile were determined. The GH/IGF-1 axis was evaluated by peak GH response after GHRH+ARGININE and IGF-1 standard deviation score (SDS). The majority of individuals (72.2%) reported consuming milk; 250mL low-fat milk was the most frequently serving of milk consumed, while no subjects reported to consume whole milk. Milk consumers vs no milk consumers presented the better anthropometric measurements and metabolic profile. At the bivariate proportional odds ratio model, after adjusting for BMI, age and gender, milk consumption was associated the better GH status (OR=0.60; p<0.001). Among milk consumers, subjects consuming 250mL reduced-fat milk vs 250mL low-fat milk presented the better anthropometric measurements and metabolic profile. At the bivariate proportional odds ratio model, after adjusting for BMI, age and gender, the consume of 250mL reduced-fat milk was associated better GH status (OR=0.54; p=0.003). A novel positive association between milk consumption, GH status, and metabolic profile in obese individuals was evidenced. Regardless of the pathogenetic mechanisms, this novel association might be relevant in a context where commonly obese individuals skip breakfast, and suggests the need of a growing cooperation between Nutritionists and Endocrinologists in the management of the obese patients.

Prospective multicenter cohort study of estrogen and insulin-like growth factor system in BRCA mutation carriers.

Major clinical characteristics of BRCA1/2-related cancers include association with estrogen and metabolic consequences. We aimed to evaluate serum estradiol (E2) and insulin-like growth factor 1 (IGF-1) levels as a marker of insulin resistance in BRCA1/2 mutation carriers and high-risk, BRCA-negative controls. Eligible cancer-free women (age 18-42 with regular menstrual cycles) who had been screened for BRCA1/2 mutations between 2005 and 2013 completed a questionnaire and underwent a single blood draw. E2 was measured with radioimmunoassay, and IGF-1 was measured with enzyme-linked immunosorbent assay. Eighty-six women participated (44 carriers and 42 non-carriers) in this study. BRCA mutation carriers were significantly younger than non-carriers (p=0.0002). Age-adjusted basal (menstrual cycle days 2-5) serum E2 level was not significantly different between BRCA mutation carriers and non-carriers (30.4 vs. 24.7pg/mL, p=0.07). BRCA mutation carriers have significantly lower age-adjusted serum IGF-1 levels compared to non-carriers (89.7 vs. 112.6ng/mL, p<0.001). In women with BRCA mutations, the risk of having low serum IGF-1 level (IGF-1: ≤85ng/mL) was 10.7 times as great as that of women without BRCA mutations (95% CI 2.5, 46.2). There was a significant inverse association between basal E2 and IGF-1 levels in BRCA mutation carriers after adjusting age and BMI (p=0.03). IGF-1 level is significantly lower in cancer-free BRCA mutation carriers versus BRCA-negative controls, and there is a potential association between E2 and IGF-1 in cancer-free BRCA mutation carriers. Our findings may instigate future studies evaluating the role of both E2 and IGF-1 in BRCA mutation carriers.

Predictive value of serum insulin-like growth factor-1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. Insulin-like growth factor-1 (IGF-1) levels reflect hepatic function and are inversely correlated with the severity of background chronic liver disease. This study evaluated whether basal serum IGF-1 levels can predict prognosis of HCC patients according to different risks of disease progression. A total of 89 patients with hepatocellular carcinoma (HCC) were recruited in 3 groups: Group I, 30 HCC patients receiving sorafinib; Group II, 30 HCC patients with best supportive care; and Group III include 29 patients undergoing transcatheter arterial chemoembolization (TACE). All patients were investigated for serum levels of AST, ALP, Bb, Cr, BUN, AFP and IGF-I. Patients with disease control had significantly higher baseline IGF-1 levels 210 (185-232.5) ng/mL (p value<0.01) than did patients without disease control. Low basal IGF-1 levels were associated with advanced HCC, such as multiple tumors and advanced stage, and low IGF-1 levels predicted shorter TTP and overall survival in patients treated with TACE. The levels of serum IGF-1, expressed as continuous values, may be helpful for accurately assessing hepatic function and the prognostic stratification of patients with HCC.

Managing the Child with Severe Primary Insulin-Like Growth Factor-1 Deficiency (IGFD): IGFD Diagnosis and Management

Growth failure associated with severe primary insulin-like growth factor 1 (IGF-1) deficiency (SPIGFD), a condition defined as basal IGF-1 standard deviation score (SDS) less than or equal to −3 and height SDS less than or equal to −3 in a child with normal or elevated levels of growth hormone, can be successfully treated with the recombinant human IGF-1 mecasermin. In this review, we describe the most safe and effective way to use mecasermin in the treatment of patients with SPIGFD, including how to initiate dosing, key side effects, and how to monitor treatment. Finally, mention of how to reinitiate therapy is made, given the recent drug shortage with mecasermin.

Muscle strength and body composition during the transition phase in patients treated with recombinant GH to final height.

We assessed body composition and muscle strength during the transition phase in 18 growth hormone (GH) deficient males treated with recombinant GH to final height and 18 controls. According to peak-stimulated GH and basal insulin-like growth factor-1 (IGF-1) during the transition phase, patients were subdivided into GH deficient (GHD-TP, n=9) and GH sufficient (GHS-TP, n=9) groups. Assessments included lean and fat body mass and bone mineral density (BMD), all measured by dual-energy X-ray absorptiometry, and dynamic knee muscle strength, assessed by isokinetic dynamometer. Total body and lumbar spine BMD and muscle strength were lower in GHD-TP patients when compared with GHS-TP and controls (all p<0.05), whereas lean and fat body mass were lower in both GHD-TP and GHS-TP patients when compared with controls (p<0.05). These findings suggest that administration of recombinant GH to final height is not sufficient to provide normal body composition and muscle strength in young male patients with GH deficiency.

Growth hormone/insulin-like growth factor-1 axis: a possible non-nutritional factor for growth retardation in children with cerebral palsy

To assess growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis as a possible non-nutritional factor for growth retardation in children with cerebral palsy (CP). A case-control study was conducted at a tertiary university hospital. Thirty children with CP (seven children with normal growth [CP-N] and 23 with retarded growth [CP-R]), 30 children with protein energy malnutrition (PEM), and 30 healthy children (REF group) underwent an assessment of growth parameters, serum IGF-1, basal GH, and peak GH after stimulation with insulin. PEM patients had higher basal GH levels than CP-N, CP-R and REF groups (p = 0.026, p < 0.001, and p < 0.001 respectively). After insulin stimulation, CP-N, CP-R, and PEM patients had lower GH levels compared to the REF group (p = 0.04, p = 0.007, and p = 0.036 respectively). IGF-1 levels were lower in CP-R group compared to CP-N and REF groups (p = 0.037 and p < 0.001 respectively), and in PEM group compared to CP-N and REF groups (p < 0.001 and p < 0.001 respectively). CP-R patients failed to demonstrate the same high basal GH response as PEM patients, and responded inadequately to the insulin stimulation test, but they had IGF-1 levels comparable to those of PEM patients. On the other hand, CP-N patients behaved as controls regarding their basal GH and IGF-1 levels, but failed to respond adequately to the insulin stimulation test. The PEM group presented high basal GH and low IGF-1 levels. These findings suggest that non-nutritional factors contribute to growth retardation in CP children.

Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs

To determine the effects of hypothyroidism on insulin sensitivity, glucose tolerance, and concentrations of hormones counter-regulatory to insulin in dogs. 8 anestrous mixed-breed bitches with experimentally induced hypothyroidism and 8 euthyroid control dogs. The insulin-modified frequently sampled IV glucose tolerance test and minimal model analysis were used to determine basal plasma insulin and glucose concentrations, acute insulin response to glucose, insulin sensitivity, glucose effectiveness, and disposition index. Growth hormone response was assessed by stimulation and suppression tests. Additionally, basal serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations and urine cortisol-to-creatinine concentration ratios were measured and dual energy x-ray absorptiometry was performed to evaluate body composition. Insulin sensitivity was lower in the hypothyroid group than in the euthyroid group, whereas acute insulin response to glucose was higher. Glucose effectiveness and disposition index were not different between groups. Basal serum GH and IGF-1 concentrations as well as abdominal fat content were high in hypothyroid dogs, but urine cortisol-to-creatinine concentration ratios were unchanged. Hypothyroidism appeared to negatively affect glucose homeostasis by inducing insulin resistance, but overall glucose tolerance was maintained by increased insulin secretion in hypothyroid dogs. Possible factors affecting insulin sensitivity are high serum GH and IGF-1 concentrations and an increase in abdominal fat. In dogs with diseases involving impaired insulin secretion such as diabetes mellitus, concurrent hypothyroidism can have important clinical implications.

The effects of long-term growth hormone and insulin-like growth factor-1 exposure on the development of cardiovascular, cerebrovascular and metabolic co-morbidities in treated patients with acromegaly

Acromegaly is characterized by the hypersecretion of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). This leads to an increased cardiovascular, cerebrovascular and metabolic morbidity resulting in excess mortality. There is controversy over which biomarker, GH or IGF-1, better predicts this increased morbidity and mortality. The relationship between the cumulative exposure to GH and IGF-1 with co-morbidities in acromegaly has not previously been reported. To investigate the relationship between the cumulative exposure to GH and IGF-1 with cardiovascular, cerebrovascular and metabolic co-morbidities. Records of 116 acromegalic patients were retrospectively examined. Cardiovascular and cerebrovascular histories, serum GH and IGF-1, fasting glucose and oral glucose tolerance test results, were reviewed for the duration of follow-up. IGF-1 index was calculated by dividing each serum IGF-1 value by the upper limit of reference range for IGF-1. GH and IGF-1 burdens were calculated for each patient by multiplying known disease duration (in years) by mean level of basal GH or IGF-1 index recorded during the patients' entire follow-up. Patients with abnormal glucose tolerance had a significantly higher mean GH burden compared with euglycaemic patients (P = 0·005). Ischaemic heart disease was also associated with a higher GH burden (P = 0·009) whereas cerebrovascular disease and cardiomyopathy were associated with a significantly higher mean IGF-1 burden (P = 0·018, P = 0·011 respectively). This study identifies associations of raised GH and IGF-1 burden with cardiovascular, cerebrovascular and metabolic complications of acromegaly. Results from this study therefore suggest that consideration of the overall level of GH and IGF-1 exposure may provide important information for the management and surveillance of patients with treated acromegaly.

Phosphorylated Insulin-Like Growth Factor 1 Receptor is Implicated in Resistance to the Cytostatic Effect of Gefitinib in Colorectal Cancer Cells

IntroductionThe ability of certain cancer cells to maintain signaling via the phosphoinositide-3-kinase/Akt and/or Ras/mitogen-activated protein kinase (MAPK) pathways has been repeatedly involved in resistance to epidermal growth factor receptor (EGFR) inhibition. DiscussionWe investigated the potential mechanisms of the uncoupling of EGFR from its downstream signals in colorectal cancer (CRC) cells. Alternative growth factor receptors and regulation of downstream pathways in different gefitinib-responsive cell lines were determined. Basal insulin-like growth factor receptor-1β (IGFR-1β) phosphorylation was undetectable or present at very low levels in highly gefitinib-responsive cell lines and was present at strikingly high levels in less responsive cell lines. Further analysis of cell lines representing the most sensitive (Lovo), moderately sensitive (HT29), and most resistant (HCT116) strains was treated with an IGFR-1 inhibitor (AG1024), gefitinib, or both, revealing that elevated IGFR-1β phosphorylation can compensate for the loss of EGFR signaling function. Increased insulin-like growth factor II expression induced by gefitinib or heterodimerization of EGFR and IGFR-1β may trigger IGFR-1β signal transduction via activation of Akt and MAPK. In addition, high levels of EGFR and IGFR-1β phosphorylation were detected in CRC tumor tissue. We also showed that gefitinib- and/or AG1024-induced cytostatic effects could be mediated by glycogen synthase kinase-3β (GSK-3β) activation. Our data suggest that the crosstalk between EGFR and IGFR-1β signaling are likely to contribute to resistance of CRC cells to gefitinib and that measurement of GSK-3β activation may present a potential biomarker for evaluating the antitumor efficacy of receptor tyrosine kinase inhibition.

Responses of serum neurotrophic factors to exercise in pregnant and postpartum women

It was recently shown in humans that exercise affects the neurotrophic factors known to function as neurogenesis regulators. No data related to exercise and pregnancy, however, is yet available. Thus, we investigated the effects of acute exercise on pregnant women during late pregnancy and women postpartum, on the serum concentration of the brain-derived neurotrophic factor (BDNF), the insulin-like growth factor 1 (IGF-1), the vascular endothelial growth factor (VEGF), prolactin (PRL) and cortisol (COR). Twenty women with uncomplicated pregnancies underwent a graded submaximal exercise test during pregnancy (weeks 32-36 of gestation; T(1)) and postpartum (10-12 weeks after childbirth; T(2)). On two of these test days the women carried out an intensifying exercise test (25 W steps) on a cycle ergometer until a heart rate of 150 bpm was reached. Blood samples were taken in the rest period before beginning the exercise, immediately at the end of the exercise and after recovery periods of 5 and 10 min, respectively. Basal maternal IGF-1, PRL and COR were found to be higher during T(1) (p<.01), while the BDNF was higher during T(2) (p=.00). VEGF was not detectable in the serum of the pregnant women. During T(2), VEGF, which was found to be within the normal range before exercise, was at a higher level after exercise (p<.01). Exercise increased the BDNF and IGF-1 during T(1) and T(2) (p<.01). This study also shows that exercise increases the serum concentrations of IGF-1 and BDNF during pregnancy and postpartum as well as VEGF postpartum. Thus, exercise might be a beneficial lifestyle factor with therapeutic/public health implications i.e. with regard to maternal mood and cognitive performance.

A Patient with Thyrotropinoma Cosecreting Growth Hormone and Follicle-Stimulating Hormone with Low α-Glycoprotein: A New Subentity?

Thyrotropinomas are rare pituitary tumors. In 25 percent of cases there is autonomous secretion of a second pituitary hormone, adding to the clinical complexity. We report a patient with thyrotropin (TSH)-dependant hyperthyroidism along with growth hormone (GH) and follicle-stimulating hormone (FSH) hypersecretion but low alpha-glycoprotein (alpha-subunit) concentrations, a hitherto unique constellation of findings. A 67-year-old Scottish lady presented with longstanding ankle edema, paroxysmal atrial fibrillation, uncontrolled hypertension, fine tremors, warm peripheries, and agitation. Initial findings were a small goiter, elevated serum TSH of 7.37 mU/L (normal range, 0.30-6.0 mU/L), a free-thyroxine concentration of 34.9 pmol/L (normal range, 9.0-24.0 pmol/L), a flat TSH response to TSH-releasing hormone, and serum alpha-subunit of 3.1 IU/L (normal, <3.0 IU/L). There was no evidence of an abnormal thyroid hormone beta receptor by genotyping. Serum FSH was 56.8 U/L, but the luteinizing hormone (LH) was 23.6 U/L (postmenopausal FSH and LH reference ranges both >30 U/L) Basal insulin-like growth factor I was elevated to 487 microg/L with the concomitant serum GH being 14.1 mU/L, and subsequent serum GH values 30 minutes after 75 g oral glucose being 19.1 mU/L and 150 minutes later being 13.7 mU/L. An magnetic resonance imaging pituitary revealed a macroadenoma. Pituitary adenomectomy was performed with the histology confirming a pituitary adenoma, and the immunohistochemistry staining showed positive reactivity for FSH with scattered cells staining for GH and TSH. Staining for other anterior pituitary hormones was negative. After pituitary surgery she became clinically and biochemically euthyroid, the serum IFG-1 became normal, but the pattern of serum FSH and LH did not change. This case of plurihormonal thyrotropinoma is unique in having hypersecretion of TSH, GH, and FSH with low alpha-subunit. Such a combination may represent a new subentity of TSHomas.