Plasma IGF-I Levels Research Articles

Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone

ObjectiveSomapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys. MethodsPharmacokinetic studies investigating exposure, absorption, clearance, and bioavailability after single intravenous (i.v.) and subcutaneous (s.c.) administration were performed in all species. A dose-response study with five dose levels and a multiple dose pharmacodynamic study with four once weekly doses was performed in hypophysectomised rats to evaluate the effect of somapacitan on growth and IGF-I production. ResultsPharmacokinetic profiles indicated first order absorption from the subcutaneous tissue after s.c. injections for somapacitan in all three species. Apparent terminal half-lives were 5–6h in rats, 10–12h in minipigs, and 17–20h in monkeys.Somapacitan induced a dose-dependent growth in hypophysectomised rats (p<0.001) and an increase in plasma IGF-I levels in rats (p<0.01), minipigs (p<0.01), and cynomolgus monkeys (p<0.05) after single dose administration. Multiple once weekly dosing of somapacitan in hypophysectomised rats induced a step-wise increase in body weight with an initial linear phase the first 3–4days in each dosing interval (p<0.001). ConclusionThe nonclinical pharmacokinetic and pharmacodynamic studies of somapacitan showed similar pharmacokinetic properties, with no absorption-limited elimination, increased clearance and increased and sustained levels of IGF-I in plasma for up to 10days after a single dose administration in all three species.Somapacitan induced a dose-dependent increase in body weight and IGF-I levels in hypophysectomised rats. Multiple dosing of somapacitan in hypophysectomised rats suggested a linear growth for the first 3–4days in each weekly dosing interval, whereas daily hGH dosing showed linear growth for approximately two weeks before reaching a plateau level.

3D Volumetric Measurements of GH Secreting Adenomas Correlate with Baseline Pituitary Function, Initial Surgery Success Rate, and Disease Control.

There is scarce data on the clinical utility of volume measurement for growth hormone (GH)-secreting pituitary adenomas. The current study objective was to assess the association between pituitary adenoma volumes and baseline endocrine evaluation, initial surgical success rate, and disease control among patients with acromegaly. A retrospective cohort study was conducted at a clinical research center including patients with acromegaly due to GH-secreting pituitary adenomas. Baseline hormonal evaluation and adenoma characteristics according to MRI were collected. Volumetric measurements of pituitary adenomas were performed using a semi-automated lesion segmentation and tumor-volume assessment tools. Rates of post-operative medical treatment, radiation therapy, and re-operation were gathered from the patients' medical records. Twenty seven patients (11 females) were included, median age 21.0 years (interquartile range 29 years, range 3-61 years). Patients harboring adenomas with a volume <2 000 mm3 had higher chance to achieve disease remission [94.1% (n=16) vs. 50.0% (n=4), p<0.05]. Adenoma volumes positively correlated with baseline plasma GH levels before and after oral glucose administration, and with plasma IGF-I and PRL levels. Adenoma volume had negative correlation with morning plasma cortisol levels. Finally, patients harboring larger adenomas required 2nd surgery and/or medical treatment more often compared with subjects with smaller adenomas. Accurate 3D volume measurement of GH-secreting pituitary adenomas may be used for the prediction of initial surgery success and for disease control rates among patients with a GH-secreting pituitary adenomas and performs better than standard size assessments.

Utility of baseline serum phosphorus levels for predicting remission in acromegaly patients.

High GH and IGF I levels increase tubular phosphate reabsorption in patients with acromegaly. We aimed to investigate the utility of serum phosphorus levels as an indicator for predicting chance of remission in acromegaly patients. Fifty-one patients (n: 51; F: 24, M: 27) with diagnosis of acromegaly were included in the study. Plasma IGF-1, Phosphorus (P) and nadir GH levels on oral glucose tolerance test (OGTT) at the time of diagnosis were analysed retrospectively. Patients were classified into two groups according to their plasma P levels; P ≤ 4.5mg/dl (Group-1, n: 23, 45.1%), P>4.5mg/dl (Group-2, n: 28, 54.9%). Two groups were compared according to remission status; remission (n: 27) and non-remission (n: 24). Remission was defined with absence of clinical symptoms, normal plasma IGF-1 (adjusted for age and gender) and GH levels (<1 mcg/dl) at least 3 months after initial treatment. Serum P levels decreased significantly after treatment in both groups (p < 0.001). There was a significant correlation between baseline phosphorus levels and remission rates, nadir GH in OGTT, pituitary adenoma size and Ki-67 scores (p = 0.001, r: -0.51; p = 0.01, r: 0.44; p = 0.001, r: 0.52; p = 0.02, r: 0.71, respectively). Mean baseline P levels were significantly higher in patients with non-remission (4.8 vs 4.2, P < 0.001). Logistic regression analysis did not reveal an independent effect on remission with any of these risk factors. High serum P levels may be an indicator for a low likelihood of onset of remission in acromegaly patients. Further studies with wider spectrum are needed to make specific suggestions.

A polymorphism at IGF1 locus is associated with anemia.

In vitro and in vivo studies suggest that IGF-1 has a role in erythropoiesis. There is evidence that the rs35767 C/T polymorphism near IGF1 is associated with plasma IGF-1 levels. We investigated the effect of this polymorphism on hemoglobin (Hb) concentration and anemia. The study group comprised 3286 adult Whites. The rs35767 polymorphism was screened using a TaqMan allelic discrimination assay. The rs35767 polymorphism was not associated with age, gender, BMI, waist circumference, smoking, blood pressure, plasma glucose, HbA1c, type 2 diabetes, HOMA-IR, hsCRP, eGFR, and lipid profile. Erythrocyte sedimentation rate (ESR), fibrinogen, and fasting insulin levels were significantly lower in TT genotype carriers compared with C allele carriers. Hb concentration was significantly higher in carriers of the TT genotype compared with C allele carriers, and a lower proportion of TT carriers had anemia. As compared with TT genotype carriers, those bearing the CC genotype had a 2.4-fold higher risk of anemia (OR 2.40, 95%CI 1.19-4.82), and those with the CT genotype had a 2.0-fold higher risk of anemia (OR 2.06, 95%CI 1.04-4.11). The association remained significant when fasting insulin, eGFR, smoking, diabetes, ACE inhibitors, sartans or diuretics treatments, use of metformin and pioglitazone were added to the model, but its independence was not retained after inclusion of fibrinogen and ESR values into the model. In conclusion, rs35767 TT allele carriers exhibited significantly higher concentrations of Hb, and lower risk of anemia compared with C allele carriers supporting the idea that IGF-1 plays a role in erythropoiesis homeostasis.

Oxygen-sensitive regulation and neuroprotective effects of growth hormone-dependent growth factors during early postnatal development.

Perinatal hypoxia severely disrupts metabolic and somatotrophic development, as well as cerebral maturational programs. Hypoxia-inducible transcription factors (HIFs) represent the most important endogenous adaptive mechanisms to hypoxia, activating a broad spectrum of growth factors that contribute to cell survival and energy homeostasis. To analyze effects of systemic hypoxia and growth hormone (GH) therapy (rhGH) on HIF-dependent growth factors during early postnatal development, we compared protein (using ELISA) and mRNA (using quantitative RT PCR) levels of growth factors in plasma and brain between normoxic and hypoxic mice (8% O2, 6 h; postnatal day 7, P7) at P14. Exposure to hypoxia led to reduced body weight (P < 0.001) and length (P < 0.04) compared with controls and was associated with significantly reduced plasma levels of mouse GH (P < 0.01) and IGF-1 (P < 0.01). RhGH abrogated these hypoxia-induced changes of the GH/IGF-1 axis associated with normalization of weight and length gain until P14 compared with controls. In addition, rhGH treatment increased cerebral IGF-1, IGF-2, IGFBP-2, and erythropoietin mRNA levels, resulting in significantly reduced apoptotic cell death in the hypoxic, developing mouse brain. These data indicate that rhGH may functionally restore hypoxia-induced systemic dysregulation of the GH/IGF-1 axis and induce upregulation of neuroprotective, HIF-dependent growth factors in the hypoxic developing brain.

Insulin, Glucagon and Growth Hormone and CIMT in Glucose Intolerance

Objective: There is an increasing evidence that glucagon and growth hormone (GH)-insulin-like growth factor (IGF) axis may play an important role in glucose metabolism since early stages of glucose intolerance. Carotid intima media thickness is a marker for subclinical atherosclerosis. We aimed to evaluate glucagon, GH and IGF-1 in prediabetic states and their relationship with carotid intima media thickness. Methods: One hundred subjects underwent a 75 gr oral glucose tolerance test and were divided into 4 groups according to their state of glucose tolerance: (i) normal glucose tolerance (NGT)/Controls (n=21), (ii) impaired glucose tolerance (IGT) (n=35), (iii) impaired fasting glucose (IFG) (n=22), (iv) type 2 diabetes mellitus (n=22). Insulin, glucagon and GH were measured at 0, 60 and 120. minutes of OGTT and their area under the curve (AUC) were calculated. Fasting IGF-1 levels and carotid intima media thickness were determined in all participants. Results: AUC for Glucagon was significantly higher in subjects with IGT, IFG and type 2 diabetes mellitus compared to NGT subjects. AUC for GH was significantly higher in subjects with IFG compared to subjects with IGT, type 2 diabetes mellitus and NGT. Plasma IGF-1 levels were significantly lower in subjects with abnormal glucose tolerance. CIMT was significantly higher in IFG group and CIMT was found to be negatively correlated with IGF-1 levels in subjects with IFG. Conclusion: There are pathological alterations of glucagon, GH-IGF-1 and insulin in prediabetic stages. Among these alterations insulin resistance and IGF-1 are associated with CIMT. Further studies needed to investigate the role of treatments targeting insulin sensitivity will have an impact on the association between insulin and early atherogenesis

Concurrent Aerobic and Resistance Training Has Anti-Inflammatory Effects and Increases Both Plasma and Leukocyte Levels of IGF-1 in Late Middle-Aged Type 2 Diabetic Patients.

Type 2 diabetes (T2D) is an age-related chronic disease associated with metabolic dysregulation, chronic inflammation, and activation of peripheral blood mononuclear cells (PBMC). The aim of this study was to assess the effects of a concurrent exercise training program on inflammatory status and metabolic parameters of T2D patients. Sixteen male patients (age range 55–70) were randomly assigned to an intervention group (n = 8), which underwent a concurrent aerobic and resistance training program (3 times a week; 16 weeks), or to a control group, which followed physicians' usual diabetes care advices. Training intervention significantly improved patients' body composition, blood pressure, total cholesterol, and overall fitness level. After training, plasma levels of adipokines leptin (−33.9%) and RBP4 (−21.3%), and proinflammatory markers IL-6 (−25.3%), TNF-α (−19.8%) and MCP-1 (−15.3%) decreased, whereas anabolic hormone IGF-1 level increased (+16.4%). All improvements were significantly greater than those of control patients. Plasma proteomic profile of exercised patients showed a reduction of immunoglobulin K light chain and fibrinogen as well. Training also induced a modulation of IL-6, IGF-1, and IGFBP-3 mRNAs in the PBMCs. These findings confirm that concurrent aerobic and resistance training improves T2D-related metabolic abnormalities and has the potential to reduce the deleterious health effects of diabetes-related inflammation.

Caloric restriction and IGF-I administration promote rabbit fecundity: Possible interrelationships and mechanisms of action

The aim of these in vivo and in vitro studies was to examine the influence of caloric restriction (CR), and the administration of insulin-like growth factor (IGF-I), on rabbit fecundity and to understand the interrelationships between CR and IGF-I, as well as the endocrine and intracellular mechanisms of their effects. Female rabbits were subjected to 50% CR, injections of IGF-I (20 μg/animal/day) and a combination of the two for 10 d before and 2 d after ovulation induced by 25 IU PMSG and 0.25 IU hCG. On the day of ovulation blood samples were collected and analyzed IGF-I, leptin, progesterone (P4) and estradiol (E2) concentrations by RIA. Some animals from each group were killed in their periovulatory period and weighed, as were their ovaries. Granulosa cells isolated from ovaries of does subjected or not to CR were cultured for 2 d with and without IGF-I (100 ng/mL). Accumulation of markers of cell proliferation (PCNA and cyclin B1), apoptosis (bax), MAP/ERK1,2 kinase (MAPK), protein kinase A (PKA) and IGF-I were evaluated by immunocytochemistry. In addition, E2 release by cells isolated from ovaries of animals subjected or not to CR and cultured with and without IGF-I (1, 10, 100, 1000 or 10000 ng/mL) was assessed by RIA. The remaining animals were kept until parturition, when the number of pups was recorded.CR did not affect animal and ovarian weight, but significantly increased the number of pups per litter and plasma levels of IGF-I and decreased plasma leptin and P4, but not E2 concentration. Injections of IGF-I did not influence body and ovarian weights, but increased the number of pups per litter and plasma IGF-I and leptin concentration and reduced plasma E2 but not P4 level. IGF-I administration did not modify the main effects of CR, although it prevented the CR-induced decrease in plasma P4 level.CR reduced accumulation of PCNA, bax, promoted accumulation of cyclin B1 but not of MAPK, PKA or IGF-I within ovarian granulosa cells. Addition of IGF-I to culture medium reduced accumulation of bax, MAPK, and IGF-I and promoted PKA accumulation and E2 release. CR promoted the stimulatory effect of IGF-I on E2 output.Thus, CR can increase rabbit fecundity, probably via changes in IGF-I, leptin and steroid hormones released, which in turn can affect ovarian cell cycle, apoptosis, and response to IGF-I. Furthermore, they demonstrate the stimulatory influence of IGF-I on rabbit fecundity, which was associated with changes in plasma leptin, E2 and ovarian cell apoptosis, PKA, MAPK, IGF-I and E2 release. The promotion of IGF-I output by CR and the ability of IGF-I to mimic/replace but not to modify CR effects on fecundity, plasma IGF-I, and ovarian cell apoptosis suggest that IGF can mediate the action of CR on these reproductive indexes. In contrast, differences in the action of CR and IGF-I on other hormones, ovarian cell proliferation, protein kinases and IGF-I suggest that CR action on these indexes is not mediated by IGF-I. We thus demonstrate that both CR and IGF-I administration can increase rabbit fecundity, and that their effects can be mediated by changes in reproductive hormones, ovarian cell proliferation, apoptosis, and the response of ovarian cells to IGF-I.

Effects of sublethal salinity and temperature levels and their interaction on growth performance and hematological and hormonal levels in tra catfish (Pangasianodon hypophthalmus)

Climate change predictions suggest that the aquatic environment in the Mekong River Delta will change significantly over the next several decades, primarily manifested as higher temperatures with extensive marine incursions. As such, this study was conducted to evaluate the effects of sublethal levels of temperature and salinity and their interaction (TxS) on growth rates and physiological responses of tra catfish (Pangasianodon hypophthalmus), a significant culture species in Vietnam. We aimed to assess the levels of tolerance and acclimation ability when individuals were exposed to simulated predicted conditions of climate change on fish farms in the Mekong Delta in southern Vietnam. Fish were acclimated over an appropriate time frame and then distributed randomly to nine treatment groups across combinations of three temperatures (25, 30, 35 °C) and three salinities (0, 6, 12‰). Results showed that temperature, salinity, and TxS all had significant effects on individual growth rate and feed conversion efficiency, with fish reared at 35 °C and 6‰ salinity displaying the best growth (P < 0.05), while also producing significantly superior FCR values in comparison with the majority of other treatments. Tra catfish were able to acclimate to changes in water temperature and salinity, by increasing their RBC and Hb concentrations. Internal osmotic pressure was salinity-dependent with significantly higher pressure seen when fish were exposed to 12‰ conditions when compared with other treatments, irrespective of temperature. Interaction effects among temperature, salinity, and sampling time were identified for plasma glucose concentration, cortisol, and IGF-1 levels. Glucose, cortisol, and IGF-1 levels increased over the early phase of the experiment, then declined and stabilized for the remainder of the experiment. These results together suggest that moderate increases in water temperature and salinity do not impose a significant stress the tra used in this experiment. Therefore, it appears that the tra catfish industry is unlikely to suffer short-term negative impacts under predicted climate change scenarios, and performance may actually improve in conditions of 35 °C-6‰.

Evaluation of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 Expression Levels in Patients with Chronic Lymphocytic Leukemia.

Objective:Chronic lymphocytic leukemia (CLL) is a disease of nonproliferating and mature-appearing B lymphocytes. Insulin-like growth factor-1 (IGF-1) is a small peptide hormone and has mitogenic and antiapoptotic effects, and insulin-like growth factor binding protein-3 (IGFBP-3) has antiproliferative effects on cells. In this study, we investigated plasma levels of both IGF-1 and IGFBP-3 in patients with CLL compared with controls, and we compared these plasma levels according to prognostic factors.Materials and Methods:Patients with newly diagnosed CLL who were being followed at the Haseki Training and Research Hospital, İstanbul, Turkey, and volunteers were included in this study. Patients were stratified according to the Rai staging system. Statistical analysis was conducted using SPSS 17.0 for Windows.Results:Forty-three patients [16 women (37%) and 27 men (63%)] were enrolled in this study. Twenty-one volunteers (11 women, 10 men) were included in the control group. The median age of the patients was 65±9 years (range: 18-63 years), and subjects in the control group were 68±8 years old (range: 18-63 years). Even though the plasma levels of IGF-1 were higher and those of IGFBP-3 were lower and the ratio of IGF-I/IGFBP-3 was higher in comparison with the control group, these differences were not statistically significant (p>0.05). In the study group, IGF-1 levels appeared to be increased in parallel to more advanced Rai stages. There were no significant differences between the other groups (p=0.105).Conclusion:Plasma IGF-I levels were found higher in patients than in the control group and plasma IGFBP-3 levels were lower; however, neither result was statistically significant. Plasma IGF level increment was observed in concordance with Rai staging. These results prompted us to think that plasma IGF-1 levels in CLL patients are correlated with tumor burden and Rai staging and therefore could be a valuable prognostic factor. Further comprehensive studies are required to support our results.

Evidences for involvement of growth hormone and insulin-like growth factor in ovarian development of starry flounder (Platichthys stellatus).

Although gonadotrophins are major regulators of ovarian function in teleosts and other vertebrates, accumulating evidence indicates that the growth hormone (GH)-insulin-like growth factor (IGF) axis also plays an important role in fish reproduction. As a first step to understand the physiological role of the GH-IGF system in the ovarian development of starry flounder (Platichthys stellatus), the expression profiles of GH and IGF messenger RNAs (mRNAs) and plasma GH, IGF-I, estradiol-17β (E2), and testosterone (T) levels during the ovarian development were investigated. The developmental stages of ovaries were divided into five stages (II, III, IV, V, and VI) by histological analysis. The hepatosomatic index (HSI) and gonadosomatic index (GSI) values increased and peaked at stage IV and stage V, respectively, and then declined at stage VI. Pituitary GH mRNA levels decreased sharply at stage III and raised to top level at stage VI. The hepatic IGF-I mRNA levels ascended to maximum value at stage V and then declined significantly at stage VI. However, the hepatic IGF-II mRNA levels remained stable and increased significantly at stage VI. In contrast, the ovarian IGF-I mRNA levels increased gradually and peaked at stage VI. The ovarian IGF-II mRNA levels were initially stable and increased significantly at stage V until the top level at stage VI. Consistent with the pituitary GH mRNA levels, plasma GH levels reduced sharply at stage III and remained depressed until stage V and then raised remarkably at stage VI. Plasma IGF-I level peaked at stage V and then declined to initial level. Plasma E2 level peaked at stage IV and then dramatically descended to the basal level. Plasma T level peaked at stage V and then declined significantly back to the basal level. Based on statistical analysis, significant positive correlations between hepatic IGF-I mRNA and GSI, ovarian IGF-II mRNA and hepatic IGF-II mRNA, ovarian IGF-I mRNA and ovarian IGF-II mRNA, and plasma IGF-I and plasma T were observed, respectively. These results suggest that the GH-IGF system may be involved in the ovarian development of starry flounder; GH and IGFs appear to play distinct roles in the regulation of the ovarian development in paracrine/autocrine manners. These findings extend our knowledge of the roles of the GH-IGF axis on reproduction regulation in fish.

"Micromegaly": an update on the prevalence of acromegaly with apparently normal GH secretion in the modern era.

Approximately 25% of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but apparently "normal" 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this "normal" GH subpopulation throughout the medical community. A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015. Overall prevalence of acromegalic patients with "normal" GH levels, defined as GH <4.7ng/mL, was 31%. Over time, the percentage of patients with "normal" GH at diagnosis did not decline: 26% from 2001 to 2005, 19% from 2006 to 2010, and 47% from 2011 to 2015. Mean pituitary tumor size was 1.8±0.1cm for the group with elevated GH, and 1.2±0.1cm for the group with "normal" GH (p<0.001). Percent microadenomas was higher in a group with "normal" GH as compared to those with elevated GH (48 vs. 12%, p<0.001), and tumors >2cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14%, p<0.001). Our data show that a substantial percentage of patients with clinical acromegaly have "normal" GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of "micromegaly" and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals.

Low serum Insulin Like Growth Factor - 1 in patients with Stress Urinary Incontinence.

ABSTRACTObjective:SUI, involuntary loss of urine, occurs when intra abdominal pressure exceeds urethral pressure in women. Recent animal study has shown that there are therapeutic effects of Insulin-like growth factors (IGF-1) on stress urinary incontinence in rats with simulated childbirth trauma. IGF-1 is an important mediator of cell growth, differentiation and transformation in various tissues and stimulates fibroblast proliferation and enhances collagen synthesis. The purpose of the current study was to determine the association between IGF-1 levels and SUI.Materials and Methods:All patients were evaluated for SUI and divided into two groups: 116 women with SUI and 76 women without SUI. Diagnosis of SUI was based on the International Consultation on Incontinence Questionnaire-Short Form (ICIQSF). Levels of IGF-1 were measured in serum by enzyme-linked immunosorbent assay. The relationship between IGF-1 levels and SUI in patients was evaluated statisticaly.Results:The mean age of patients wiyh SUI was 49.9±8.6 and 48.7±7.8 in control group. Plasma IGF-1 levels were significantly lower in SUI than in control group (106.5±26.4 and 133.3±37.1ng/mL, respectively, P <0.001). Body mass indexes were higher in women with SUI than women without SUI.Conclusion:In this study lower serum IGF-1 levels were found to be associated with SUI. Serum IGF-1 level appears to be a specific predictor of SUI, and it may be used in early prediction of SUI in female population.

Association of insulin-like growth factor (IGF)-1 gene polymorphisms with plasma levels of IGF-1 and acne severity

Polymorphisms of the insulin-like growth factor (IGF)-1 gene consisting of variable cytosine adenosine repeats in the promoter region may directly influence the expression of IGF-1. We sought to assess the role of IGF-1 gene polymorphisms in determination of plasma IGF-1 levels, acne, and its severity. In this case-control study, 80 patients with acne vulgaris of 4 severity grades as per Global Acne Grading System and 80 age- and gender-matched control subjects without acne were studied. All the study subjects were without any disorder or a history of drug intake likely to affect IGF-1 level within a year before the study inclusion date. IGF-1 polymorphism was determined by polymerase chain reaction and plasma levels of IGF-1 by enzyme-linked immunosorbent assay. Acne severity was assessed by Global Acne Grading System. Mean plasma IGF-1 level in acne cases was significantly higher than in non-acne controls (P=.04). Plasma IGF-1 level positively correlated with severity of acne (P=.01). Individuals homozygous for the 192-base pair (bp) allele had 4.29 times odds risk (95% confidence interval 1.38-13.33) of having acne and a significantly higher mean level of IGF-1 compared with non-192/non-192 participants. Individuals homozygous for the 192-bp allele had 3.08 times odds risk (95% confidence interval 1.15- 8.31) of having higher severity grade of acne compared with non-192/non-192 participants. A relatively small number of participants were studied. Plasma IGF-1 levels positively correlate with severity of acne. The 192/192 homozygotes had higher risk of acne and higher severity grade of acne. Functional studies showing the relationship between IGF-1 promoter level polymorphism and actual gene expression in skin are warranted.

In ovo exposure to monochromatic lights affect posthatch muscle growth and satellite cell proliferation of chicks: role of IGF-1

To study the role of IGF-1 on stimulation with monochromatic light during incubation altering posthatch muscle growth, chicken embryos were exposed to blue light, green light, red light, white light or darkness throughout embryonic period and then were raised in white light conditions upon hatching. Comparing with the other treatment groups, the chicks in green light group had heavier hatching weights, higher muscle indexes and larger muscle fibers. Both in vivo and in vitro studies showed that the number and proliferative activity of satellite cells in green light group were the highest. Plasma IGF-1 level and skeletal muscle IGF-1R mRNA level were higher in green light group. Moreover, exogenous IGF-1 increased the proliferative activity of satellite cell in a dose-dependent fashion. These results suggest that stimulation with monochromatic green light during incubation promoted posthatch muscle growth and satellite cell proliferation of chicks through IGF-1 signaling.

Insulin-like signaling (IIS) responses to temperature, genetic background, and growth variation in garter snakes with divergent life histories

The insulin/insulin-like signaling pathway (IIS) has been shown to mediate life history trade-offs in mammalian model organisms, but the function of this pathway in wild and non-mammalian organisms is understudied. Populations of western terrestrial garter snakes (Thamnophis elegans) around Eagle Lake, California, have evolved variation in growth and maturation rates, mortality senescence rates, and annual reproductive output that partition into two ecotypes: “fast-living” and “slow-living”. Thus, genes associated with the IIS network are good candidates for investigating the mechanisms underlying ecological divergence in this system. We reared neonates from each ecotype for 1.5years under two thermal treatments. We then used qPCR to compare mRNA expression levels in three tissue types (brain, liver, skeletal muscle) for four genes (igf1, igf2, igf1r, igf2r), and we used radioimmunoassay to measure plasma IGF-1 and IGF-2 protein levels. Our results show that, in contrast to most mammalian model systems, igf2 mRNA and protein levels exceed those of igf1 and suggest an important role for igf2 in postnatal growth in reptiles. Thermal rearing treatment and recent growth had greater impacts on IGF levels than genetic background (i.e., ecotype), and the two ecotypes responded similarly. This suggests that observed ecotypic differences in field measures of IGFs may more strongly reflect plastic responses in different environments than evolutionary divergence. Future analyses of additional components of the IIS pathway and sequence divergence between the ecotypes will further illuminate how environmental and genetic factors influence the endocrine system and its role in mediating life history trade-offs.

Evaluation of nucleic acids and plasma IGF1 levels for estimating short-term responses of postsmolt Atlantic salmon (Salmo salar) to food availability

Evaluation of nucleic acids and plasma IGF1 levels for estimating short-term responses of postsmolt Atlantic salmon (Salmo salar) to food availability

One-year GH replacement therapy reduces early cardiac target organ damage (TOD) in adult GHD patients.

Hypopituitarism reduces life expectancy and increases the risk of cardiovascular and cerebrovascular diseases, as well as death. Abnormalities in the cardiovascular system may be independently related to GH deficiency (GHD). The aim of this study was to prospectively investigate coronary flow reserve and diastolic function in GHD adult patients at diagnosis and after 1year of GH replacement therapy. As control group, an age- and sex-matched population was chosen. All patients and controls were non-smokers, non-diabetic, and normotensive, with no history of vascular disease. 14 patients with adult-onset GHD and 17 controls represent the two study groups. Anthropometric data, blood pressure, lipid profile, glycosylated hemoglobin (HbA1c) and IGF-I plasma levels, coronary flow reserve (CFR), and LV diastolic function (evaluated by E/A) were collected in all subjects before and after 12months of GH replacement therapy. Compared with controls, systolic and diastolic blood pressure and LDL cholesterol levels were significantly higher at baseline and return, comparable to controls after 1year of GH replacement (GHRT). GHD patients showed a blunted CFR at baseline (P<0.001) and a significant improvement after GHRT, returning to values comparable with those recorded in the control group. In addition, after therapy a significant (P<0.001) improvement in E/A was recorded. One year of GH therapy improves CFR and E/A in the patient population analyzed, thereby encouraging the early start of GHRT.

Protein intake is associated with plasma insulin‐like growth factor (IGF)1 in postmenopausal women but not in premenopausal women

It has been recently reported that older adults between the ages of 50 and 65 who consumed over 20% of their calories as protein had a 75% increase in overall mortality compared with those consuming low to moderate amounts of protein. This was a cross‐sectional study aimed at: 1) determining the association between protein intake and insulin‐like growth factor (IGF)1 and 2) determining the association between body mass index (BMI) status and age on plasma concentrations of IGF1 in women participating in three independent breast cancer prevention clinical trials (WISER, WISER sister and Minnesota Green Tea Trial (MGTT)). In all three trials, dietary data were collected using the NIH/NCI diet history questionnaire. IGF1 was measured using commercial sandwich enzyme immunoassay kits. Data from the three trials were analyzed separately. Linear regression models were used to examine the association between plasma concentrations of IGF1 and protein intake, BMI status, and age. Protein intake was divided into three categories: low (less than 12% total calories), medium (12–19% of total calories) and high (20% or more total calories). Age was divided into two categories as follows: WISER trial: 18–25 and 26–30 years, WISER sister trial: 18–30 and 31–50 years, MGTT: 50–65 and 65 and older. Data were available from 303, 113, and 935 women in the WISER, WISER sister, and MGTT, respectively. While no associations between protein intake and plasma IGF1 were found in the WISER and WISER sister trials, women in the highest category of protein intake in the green tea trial had significantly higher concentrations of plasma IGF1 (mean ± SE, 97.9 ± 3.1 ng/mL) compared to those in the medium (86.7 ± 1.2 ng/mL, p=.0004) and low (78 ± 3.3 ng/mL, P&lt;0.0001) categories of protein intake, after adjusting for energy intake, animal protein intake, BMI and age. In the WISER trial, the mean plasma IGF1 in women 25–30 years was 358.8 ± 7.7 ng/mL compared with 411.8 ± 9.4 ng/mL in women younger than 25 years (P&lt;0.0001). Similarly, in WISER sister, the mean plasma IGF1 in women 31–50 years was 96.5 ± 3.2 ng/mL compared with 123.5 ± 6 ng/mL in women 18–30 years (P&lt;0.0001). In the MGTT, the mean plasma IGF1 in women older than 65 years was 83.4 ± 1.9 ng/mL compared with 90.5 ± 1.1 ng/mL in women 50–65 years (P=0.0007). We also found that the mean plasma IGF1 of obese women was lower than that of normal weight women in the WISER sister trial (118.9 ± 3.9 ng/mL in normal weight women compared to 94.2 ± 6.2 ng/mL in obese women, P=0.0006) and in the green tea trial (90.7 ± 1.3 ng/mL in normal weight women compared to 81.4 ± 2.4 ng/mL in obese women, P=0.0004). No significant differences in plasma IGF1 concentrations were found between obese and normal weight women in the WISER trial. Our findings indicate that while dietary intake of protein is not associated with plasma IGF1 levels in women younger than 50 years, a significant association exists in women older than 50 years. Similar to previous reports, plasma IGF1 concentrations were lower in older women and in those with higher BMI. Additional research to assess the relationship between amount and type of dietary protein and IGF1 concentrations is needed to better understand how protein intake may affect mortality.Support or Funding InformationThis project was supported by an University of North Florida internal grant received by Dr. Andrea Arikawa.

Essential Role of IGFIR in the Onset of Male Brown Fat Thermogenic Function: Regulation of Glucose Homeostasis by Differential Organ-Specific Insulin Sensitivity.

Brown fat is a thermogenic tissue that generates heat to maintain body temperature in cold environments and dissipate excess energy in response to overfeeding. We have addressed the role of the IGFIR in the brown fat development and function. Mice lacking IGFIR exhibited normal brown adipose tissue/body weight in knockout (KO) vs control mice. However, lack of IGFIR decreased uncoupling protein 1 expression in interscapular brown fat and beige cells in inguinal fat. More importantly, the lack of IGFIR resulted in an impaired cold acclimation. No differences in the total fat volume were found in the KO vs control mice. Epididymal fat showed larger adipocytes but with a lower number of adipocytes in KO vs control mice at age 12 months. In addition, KO mice showed a sustained moderate hyperinsulinemia and hypertriglyceridemia upon time and hepatic insulin insensitivity associated with lipid accumulation, with the outcome of a global insulin resistance. In addition, we found that the expression of uncoupling protein 3 in the skeletal muscle was decreased and its expression was increased in the heart in parallel with the expression of beta-2 adrenergic receptors. Upon nonobesogenic high-fat diet, we found a severe insulin resistance in the liver and in the skeletal muscle, but unchanged insulin sensitivity in the heart. In conclusion, our data suggest that IGFIR it is not an essential growth factor in the brown fat development in the presence of the IR and very high plasma levels of IGF-I, but it is indispensable for full brown fat functionality.