Update on new GH-IGF axis genetic defects

ABSTRACT The somatotropic axis is the main hormonal regulator of growth. Growth hormone (GH), also known as somatotropin, and insulin-like growth factor 1 (IGF-1) are the key components of the somatotropic axis. This axis has been studied for a long time and the knowledge of how some molecules could promote or impair hormones production and action has been growing over the last decade. The enhancement of large-scale sequencing techniques has expanded the spectrum of known genes and several other candidate genes that could affect the GH-IGF1-bone pathway. To date, defects in more than forty genes were associated with an impairment of the somatotropic axis. These defects can affect from the secretion of GH to the bioavailability and action of IGF-1. Affected patients present a large heterogeneous group of conditions associated with growth retardation. In this review, we focus on the description of the GH-IGF axis genetic defects reported in the last decade. Arch Endocrinol Metab. 2019;63(6):608-17

Niveles de IGF-1 en la plastía de ligamento cruzado anterior de rodilla empleando aloinjerto vs autoinjerto en pacientes del Hospital Central Militar / IGF-1 levels in anterior cruciate ligament reconstruction using allograft vs autograft in patients at Central Military Hospital

Resumen: Antecedentes: El tratamiento para la lesión del ligamento cruzado anterior (LCA) es la reconstrucción quirúrgica. Se desconoce si el resultado mejora, pues depende del tipo de injerto empleado. El factor de crecimiento semejante a la insulina tipo 1(IGF-1) es un potente estimulante de matriz extracelular y del crecimiento de condrocitos. Material y métodos: Estudio experimental, analítico, prospectivo, longitudinal en pacientes con reconstrucción del LCA en un período comprendido entre los años 2016 y 2017. Se determinó la concentración de IGF-1 en el líquido sinovial de estos pacientes operados con aloinjerto y autoinjerto además de determinar su asociación con la evolución postoperatoria. Para el análisis estadístico, se utilizó ANOVA de dos vías post hoc con la prueba U de Mann-Whitney. Resultados: Dentro del grupo de aloinjerto, se identificó un aumento significativo de IGF-1 a los 90 días del postoperatorio. En el grupo de autoinjerto, se observó un aumento significativo de IGF-1 desde los 30 días de postoperatorio. Se encontró además que el grupo de autoinjerto presentó niveles significativamente más altos de IGF-1 (3.27 ± 0.09 ng/ml) en comparación con el grupo de aloinjerto (2.80 ± 0.11 ng/ml; p < 0.001) a los 90 días después de la colocación del injerto. Discusión: Los niveles de IGF-1 fueron más altos en pacientes con injerto autólogo; la funcionalidad de la rodilla fue clínicamente similar en ambos grupos a los 30 y 90 días.

Abstract: Background: Treatment of ACL injury is surgical reconstruction. It is not known whether the result is better depending on the type of graft used. Insulin-like growth factor type 1(IGF-1) is a powerful stimulant of extracellular matrix and chondrocyte growth. Material and methods: Experimental, analytical, prospective, longitudinal study in patients with ACL reconstruction in a period from 2016 to 2017. The concentration of IGF-1 in synovial fluid of these patients operated with allograft and autograft was determined, its association with postoperative evolution was determined. For statistical analysis, two-way ANOVA with Mann-Whitney post-hoc U was used. Results: A significant increase in IGF-1 was identified in the allograft group at 90 days of postopertory. In the autograft group, a significant increase in IGF-1 was observed from 30 days of postoperative. The autograft group was found to have significantly higher levels of IGF-1 (3.27 ± 0.09 ng/ml) compared to the allograft group (2.80 ± 0.11 ng/ml; p < 0.001) at 90 days after graft placement. Discussion: IGF-1 levels were higher in patients with autologous graft, knee functionality was clinically similar in both groups at 30 and 90 days.

Ramipril can alleviate the accumulation of renal mesangial matrix in rats with diabetic nephropathy by inhibiting insulin-like growth factor-1

Abstract Purpose: To investigate the impact of Ramipril (RAM) on the expressions of insulin-like growth factor-1 (IGF-1) and renal mesangial matrix (RMM) in rats with diabetic nephropathy (DN). Methods: The Sprague Dawley rats were divided into normal control (NC) group (n = 12), DN group (n = 11), and DN+RAM group (n = 12). The ratio of renal weight to body weight (RBT), fasting blood glucose (FBG), HbA1c, 24-h urine protein (TPU), blood urea nitrogen (BUN), creatinine (Cr), renal pathological changes, the levels of IGF-1, fibronectin (FN), type IV collagen (Col-IV), and matrix metalloproteinases (MMP)-2 were compared among the groups. Results: Compared with NC group, the RBT, FBG, HbA1c, TPU, BUN, Cr, and RMM in DN group were significantly increased (P < 0.05), the IGF-1, FN, and Col-IV were significantly upregulated (P < 0.05), while MMP was significantly downregulated (P < 0.05). Compared with DN group, the indexes except for the FBG and HbA1c in DN+RAM group were significantly improved (P < 0.05), among which IGF-1 exhibited significant positive correlation with TPU(r=0.937), FN(r=0.896) and Col-IV(r=0.871), while significant negative correlation with MMP-2 (r=-0.826) (P<0.05). Conclusion: RAM may protect the kidneys by suppressing IGF-1 and mitigating the accumulation of RMM.

Physical training reverses changes in hepatic mitochondrial diameter of Alloxan-induced diabetic rats / Treinamento físico reverte alterações no diâmetro de mitocôndrias hepáticas de ratos diabéticos induzidos pela Aloxana

ABSTRACT Objective To investigate the effects of physical training on metabolic and morphological parameters of diabetic rats. Methods Wistar rats were randomized into four groups: sedentary control, trained control, sedentary diabetic and trained diabetic. Diabetes mellitus was induced by Alloxan (35mg/kg) administration for sedentary diabetic and Trained Diabetic Groups. The exercise protocol consisted of swimming with a load of 2.5% of body weight for 60 minutes per day (5 days per week) for the trained control and Trained Diabetic Groups, during 6 weeks. At the end of the experiment, the rats were sacrificed and blood was collected for determinations of serum glucose, insulin, albumin and total protein. Liver samples were extracted for measurements of glycogen, protein, DNA and mitochondrial diameter determination. Results The sedentary diabetic animals presented decreased body weight, blood insulin, and hepatic glycogen, as well as increased glycemia and mitochondrial diameter. The physical training protocol in diabetic animals was efficient to recovery body weight and liver glycogen, and to decrease the hepatic mitochondrial diameter. Conclusion Physical training ameliorated hepatic metabolism and promoted important morphologic adaptations as mitochondrial diameter in liver of the diabetic rats.

RESUMO Objetivo Investigar os efeitos do treinamento físico nos parâmetros morfológicos e metabólicos de ratos diabéticos. Métodos Ratos Wistar foram randomizados para quatro grupos: controle sedentário, controle treinado, diabético sedentário e diabético treinado. Diabetes mellitus foi induzido por administração de Aloxana (35mg/kg) nos Grupos Diabético Sedentário e diabético treinado. O protocolo de treinamento físico incluiu natação com carga de 2,5% do peso corporal, por 60 minutos por dia (5 dias por semana) para os Grupos Controle Treinado e diabético treinado, durante 6 semanas. Ao final do experimento, os ratos foram sacrificados, e o sangue foi coletado para determinação das concentrações séricas de glicose, insulina, albumina e proteínas totais. Amostras do fígado foram coletadas para determinação do glicogênio, proteínas, DNA e diâmetro mitocondrial. Resultados O Grupo Sedentário Diabético apresentou redução no peso corporal, insulinemia e glicogênio hepático, além de maior glicemia e diâmetro mitocondrial hepático. O protocolo de treinamento físico em animais diabéticos foi eficiente para restaurar o peso corporal e o glicogênio hepático, além de reduzir o diâmetro mitocondrial hepático. Conclusão O treinamento físico melhorou o metabolismo hepático e promoveu importantes adaptações morfológicas, como no diâmetro mitocondrial no fígado de animais diabéticos.

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

ABSTRACT Objective: 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.

Loss of Ovarian Function Results in Increased Loss of Skeletal Muscle in Arthritic Rats / Perda da função ovariana resulta em perda de músculo esquelético aumentada em ratos artríticos

Objective We studied the effects of loss of ovarian function (ovariectomy) onmuscle mass of gastrocnemius and themRNA levels of IGF-1, atrogin-1, MuRF-1, andmyostatin in an experimental model of rheumatoid arthritis in rats. Methods We randomly allocated 24 female Wistar rats (9 weeks, 195.3±17.4 grams) into four groups: control (CT-Sham; n = 6); rheumatoid arthritis (RA; n = 6); ovariectomy without rheumatoid arthritis (OV; n = 6); ovariectomy with rheumatoid arthritis (RAOV; n = 6). We performed the ovariectomy (OV and RAOV) or Sham (CTSham or RA) procedures at the same time, fifteen days before the rheumatoid arthritis induction. The RA and RAOV groups were immunized and then were injected with Met- BSA in the tibiotarsal joint. After 15 days of intra-articular injections the animals were euthanized. We evaluated the external manifestations of rheumatoid arthritis (perimeter joint) as well as animal weight, and food intake throughout the study. We also analyzed the cross-sectional areas (CSA) of gastrocnemius muscle fibers in 200 fibers (H&E method). In the gastrocnemius muscle, we analyzed mRNA expression by quantitative real time PCR followed by the Livak method (ΔΔCT). Results The rheumatoid arthritis induced reduction in CSA of gastrocnemius muscle fibers. The RAOV group showed a lower CSA of gastrocnemius muscle fibers compared to RA and CT-Sham groups. Skeletal muscle IGF-1 mRNA increased in arthritics and ovariectomized rats. The increased IGF-1 mRNA was higher in OV groups than in the RA and RAOV groups. Antrogin-1 mRNA also increased in the gastrocnemius muscle of arthritic and ovariectomized rats. However, the increased atrogin-1 mRNA was higher in RAOV groups than in the RA and OV groups. Gastrocnemius muscle MuRF-1 mRNA increased in the OVand RAOVgroups, but not in the RA and Shamgroups. However, the RAOV group showed higher MuRF-1 mRNA than the OV group. The myostatin gene expression was similar in all groups. Conclusion Loss of ovarian function results in increased loss of skeletal musclerelated ubiquitin ligases atrogin-1 and MuRF-1 in arthritic rats.

Objetivo Foram estudados os efeitos da perda da função ovariana (ovariectomia) sobre músculo esquelético e os níveis de RNAm de IGF-1, atrogina-1, MuRF-1, e de miostatina em modelo experimental de artrite reumatóide em ratos. Métodos 24 ratos Wistar (9 semanas, 195,3±17,4 gramas) foram distribuídos aleatoriamente em quatro grupos: controle (CT-Sham, n = 6); artrite reumatóide (RA, n = 6); ovariectomia sem artrite reumatóide (OV; n = 6); ovariectomia com artrite reumatóide (RAOV; n = 6). Os procedimentos da ovariectomia (OV e RAOV) ou simulação da ovariectomia (CT-Shamou RA) foramrealizados aomesmo tempo, quinze dias antes da indução da artrite reumatóide. Os grupos RA e RAOV foramimunizados e, em seguida, foram injetados com Met-BSA na articulação tibiotársica. Após 15 dias das injeções intra-articulares, os animais foram eutanasiados. Foram avaliadas as manifestações externas da artrite reumatóide (perimetria articular), bem como o peso dos animais e a ingestão de alimentos ao longo do estudo. Além disso, as áreas de secção transversa (CSA) do músculo gastrocnêmio foram analisadas em 200 fibras (método H & E). No músculo gastrocnêmio, a expressão de RNAm foi analisada por PCR quantitativo em tempo real, seguido pelo método Livak (ΔΔCT). Resultados A artrite reumatoide reduziu a CSA das fibras do músculo gastrocnêmio. O grupo RAOV mostrou uma CSA menor nas fibras do músculo gastrocnêmio em comparação com os grupos RA e CT-Sham. O RNAm do IGF-1 do músculo esquelético aumentou nos ratos artríticos e ovariectomizados. O RNAm do IGF-1 foi maior nos grupos OV do que nos grupos RA e RAOV. A expressão de antrogina-1 também aumentou no músculo gastrocnêmio dos ratos artríticos e ovariectomizados. No entanto, o aumento do RNAm da atrogina-1 foi maior no grupo RAOV do que nos grupos RA e OV. O RNAm da MuRF-1 aumentou nos grupos OV e RAOV, mas não nos grupos RA e CT-Sham. Porém, o grupo RAOV apresentou maior expressão gênica de MuRF-1 do que o grupo OV. A expressão do gene da miostatina foi semelhante em todos os grupos. Conclusão A perda de função ovariana resulta em perda de músculo esquelético associado às ubiquitina-ligases atrogina-1 e MuRF-1 em ratos artríticos.

Type 2 Diabetes Mellitus and Its Association with the Risk of Pancreatic Carcinogenesis: A Review / 대한소화기학회지

The prevalence of diabetes mellitus (DM) and associated diseases such as cancers are substantially increasing worldwide. About 80% of the patients with pancreatic cancer have glucose metabolism alterations. This suggests an association between type 2 DM and pancreatic cancer risk and progression. There are hypotheses that show metabolic links between the diseases, due to insulin resistance, hyperglycemia, hyperinsulinemia, low grade chronic inflammation, and alteration in the insulin-insulin-like growth factor axis. The use of diabetes medications can influence the extent of carcinogenesis of the pancreas. This study briefly reviews recent literature on investigation of metabolic link of type 2 DM, risk of carcinogenesis of the pancreas and their association, as well as the current understanding of metabolic pathways implicated in metabolism and cellular growth. The main finding of this review, although there are discrepancies, is that according to most research long-term DM does not raise the risk of pancreatic cancer. The longest duration of DM may reflect hypoinsulinemia due to treatment for hyperglycemia, but recent onset diabetes was associated with increased risk for pancreatic cancer due to hyperinsulinemia and hyperglycemia. In conclusion, the review demonstrates that type 2 DM and the duration of diabetes pose a risk for pancreatic carcinogenesis, and that there is biological link between the diseases.

Cotransfected human chondrocytes: over-expression of IGF-I and SOX9 enhances the synthesis of cartilage matrix components collagen-II and glycosaminoglycans

Damage to cartilage causes a loss of type II collagen (Col-II) and glycosaminoglycans (GAG). To restore the original cartilage architecture, cell factors that stimulate Col-II and GAG production are needed. Insulin-like growth factor I (IGF-I) and transcription factor SOX9are essential for the synthesis of cartilage matrix, chondrocyte proliferation, and phenotype maintenance. We evaluated the combined effect of IGF-I and SOX9 transgene expression on Col-II and GAG production by cultured human articular chondrocytes. Transient transfection and cotransfection were performed using two mammalian expression plasmids (pCMV-SPORT6), one for each transgene. At day 9 post-transfection, the chondrocytes that were over-expressing IGF-I/SOX9 showed 2-fold increased mRNA expression of the Col-II gene, as well as a 57% increase in Col-II protein, whereas type I collagen expression (Col-I) was decreased by 59.3% compared with controls. The production of GAG by these cells increased significantly compared with the controls at day 9 (3.3- vs 1.8-times, an increase of almost 83%). Thus, IGF-I/SOX9 cotransfected chondrocytes may be useful for cell-based articular cartilage therapies.

Epidemiology of coronary artery bypass grafting at the Hospital Beneficência Portuguesa, São Paulo / Epidemiologia da cirurgia de revascularização miocárdica do Hospital Beneficência Portuguesa de São Paulo

Introduction: The knowledge of the prevalence of risk factors and comorbidities, as well as the evolution and complications in patients undergoing coronary artery bypass graft allows comparison between institutions and evidence of changes in the profile of patients and postoperative evolution over time. Objective: To profile (risk factors and comorbidities) and clinical outcome (complications) in patients undergoing coronary artery bypass graft in a national institution of great surgical volume. Methods: A retrospective cohort study of patients undergoing coronary artery bypass graft in the hospital Beneficência Portuguesa de São Paulo, from July 2009 to July 2010. Results: We included 3,010 patients, mean age of 62.2 years and 69.9% male. 83.8% of patients were hypertensive, 36.6% diabetic, 44.5% had dyslipidemia, 15.3% were smokers, 65.7% were overweight/obese, 29.3% had a family history of coronary heart disease. The expected mortality calculated by logistic EuroSCORE was 2.7%. The isolated CABG occurred in 89.3% and 11.9% surgery was performed without cardiopulmonary bypass. The most common complication was cardiac arrhythmia (18.7%), especially acute atrial fibrillation (14.3%). Pneumonia occurred in 6.2% of patients, acute renal failure in 4.4%, mediastinites in 2.1%, stroke in 1.8% and AMI in 1.2%. The in-hospital mortality was 5.4% and in isolated coronary artery bypass graft was 3.5%. The average hospital stay was 11 days with a median of eight days (3-244 days). Conclusion: The profile of patients undergoing coronary artery bypass graft surgery in this study is similar to other published studies. .

Introdução: O conhecimento da prevalência dos fatores de risco e comorbidades, bem como a evolução com complicações nos pacientes submetidos à cirurgia de revascularização miocárdica, permite a comparação entre instituições e a comprovação de modificações no perfil de pacientes e na evolução pós-operatória ao longo do tempo. Objetivo: Conhecer o perfil (fatores de risco e comorbidades) e a evolução clínica (complicações) nos pacientes submetidos à cirurgia de revascularização miocárdica em uma instituição nacional de grande volume cirúrgico. Métodos: Estudo de coorte retrospectivo de pacientes submetidos ao procedimento de cirurgia de revascularização miocárdica no Hospital Beneficência Portuguesa de São Paulo, no período de julho de 2009 a julho de 2010. Resultados: Foram incluídos 3010 pacientes, com idade média de 62,2 anos e 69,9% do sexo masculino. 82,8% dos pacientes eram hipertensos, 36,6% diabéticos, 44,5% dislipidêmicos, 15,3% tabagistas, 65,7% com sobrepeso/obesidade e 29,3% tinham antecedentes familiares de doença coronária. A mortalidade média esperada calculada pelo EuroSCORE logístico foi de 2,7%. A cirurgia de revascularização miocárdica isolada ocorreu em 89,3% e em 11,9% foi realizada cirurgia sem circulação extracorpórea. A complicação mais comum foi arritmia cardíaca (18,7%), especialmente a fibrilação atrial aguda (14,3%). Pneumonia ocorreu em 6,2% dos pacientes, lesão renal aguda em 4,4%, mediastinite em 2,1%, acidente vascular encefálico em 1,8% e infarto agudo do miocárdio em 1,2%. A mortalidade intra-hospitalar foi de 5,4% e na cirurgia de revascularização miocárdica isolada foi de 3,5%. O tempo de permanência hospitalar médio foi de 11 dias, com mediana de oito dias (3 - 244 dias). Conclusão: O perfil dos pacientes submetidos à cirurgia de revascularização miocárdica neste estudo assemelha-se ao de outros estudos publicados. .

Signaling Pathways in Insulin- and IGF-I Mediated Oocyte Maturation in Lower Vertebrates.

The endocrine control of oocyte maturation in fish and amphibians has proved to be a valuable model for investigating the rapid and non-genomic steroid actions at the cell surface. Considerable progress has made over the last decade in elucidating signaling pathways in steroid-induced oocyte maturation. In addition to steroids, various growth factors have also been reported to be involved in this process and progress being made to elucidate their mechanism of actions. Exposure of fully-grown oocytes to steroids or growth factors (insulin/IGFs) initiates various signaling cascade, leading to formation and activation of maturation-promoting factor (MPF), a key enzyme that catalyzes entry into M-phase of meiosis I and II. Whereas the function of MPF in promoting oocyte maturation is ubiquitous, there are differences in signaling pathways between steroids- and growth factors-induced oocyte maturation in amphibian and fish. Here, we have reviewed the recent advances on the signaling pathways in insulin- and IGF-I-induced oocyte maturation in these two groups of non-mammalian vertebrates. New findings demonstrating the involvement of PI3 kinase and MAP kinase in induction of oocyte maturation by insulin and IGF-I are presented.

Estudo do papel do Fator de Crescimento Semelhante à Insulina-I (IGF-I) na modulação funcional de macrófagos infectados pelo Mycobacterium leprae / Study of the role of growth factor insulin-like (IGF-I) in the functional modulation of macrophages infected with Mycobacterium leprae

Fagócitos mononucleares são as células-alvo para micobactérias patogênicas que geralmente requerem um ambiente intracelular adequado para sua sobrevivência e replicação. Mycobacterium leprae, o agente etiológico da Hanseníase, é capaz de subverter mecanismos microbicidas de macrófagos e sobreviver e replicar no interior dessas células. Contudo o mecanismo molecular envolvido na modulação da célula hospedeira, não étotalmente compreendido. O presente estudo mostrou o potencial papel exercido pelo IGF-I na patogênese causada pelo M. leprae. Foi demonstrado que o M. leprae induz a expressão do fator de crescimento semelhante a insulina (IGF-I), em macrófagos RAW 264.7. Curiosamente, apenas quando as células foram tratadas com anticorpo neutralizante para o receptor do tipo I de IGF-I (IGF-1R) o M. leprae foi capaz de regular positivamente a expressão da enzima óxido nítrico sintase induzível (iNOS) em macrófagos RAW 264.7 ou ativar o promotor de iNOS em células transfectadas com a construção contendo gene repórter da luciferase sob o controle do promotor de iNOSO bloqueio da sinalização de IGF-I reduziu a viabilidade intracelular do M. leprae determinada por qPCR. As células RAW 264.7 pré-tratadas com IGF-I apresentaram uma redução significativa da atividade do promotor iNOS em resposta ao Mycobacterium bovis BCG, Mycobacterium smegmatis e consequentemente um aumento na viabilidade intracelular monitorada através de contagem de Unidades Formadoras de Colônia (CFU). Outro fato é que IGF-I foi capaz de atenuar a ativação de macrófagos mediada por IFN-gama medida através da expressão de iNOS e da quantificação da fosforilação de Ativador de transcrição e de transdução de sinal (pSTAT1). Além disso, o IGF-I foi capaz de induzir aumento de PGE2 em macrófagos, um eicosanoide previamente implicado na persistência micobacteriana no hospedeiro...

Mononuclear phagocytes are targeted cells for pathogenic mycobacteria thatgenerally require afavorable intracellular environment in wich they survive and replicate. Mycobacterium leprae, the etiologic agent of leprosy, is able to subvert macrophage microbicidal mechanisms and survive and replicate within these cells. However, the molecular mechanism involved in pathogen driven host cellmodulation is not fully understood. The present study investigated the potential role of insulin-like growth factor-I (IGF-I) in M. leprae pathogenesis. We showed that M.leprae induces IGF-I expression in RAW 264.7 macrophages in a dose-dependent manner. Notably, only when cells were treated with a neutralizing antibody to IGFtype 1 receptor (IGF-1R), M. leprae infection was able to upregulate inducible nitricoxide sintase (iNOS) expression in RAW cells or to activate the iNOS promoter incells transfected with the iNOS-luciferase reporter construct. . The blockage ofIGF-I signaling also decreased the intracellular M. leprae viability as measured byqPCR. Moreover, RAW cells pre-treated with IGF-I showed a significant reduction in iNOS promoter activity in response to Mycobacterium bovis BCG and Mycobacterium smegmatis with subsequent increase in bacterial intracellular survival as accessed by colony-forming unit counts (CFU). Of note, IGF-I was able to attenuate interferon gamma (IFN-gama ) activating effects on macrophages asacessed by iNOS expression and quantification of phosphorylated SignalTransducers and Activators of Transcription 1 (p-STAT1). Additionally, IGF-I was able to induce PGE2 secretion in murine macrophages, an eicosanoid previously implicated in mycobacterial persistence in the host. Finally, immunohistochemicalanalysis of skin lesions of lepromatous leprosy (LL) patients revealed an abundantexpression of IGF-I by highly infected foamy macrophages...

Efficacy of Short-Term Growth Hormone Treatment in Prepubertal Children with Idiopathic Short Stature

PURPOSE: It has been reported that daily recombinant human growth hormone (GH) treatment showed beneficial effects on growth in prepubertal children with idiopathic short stature (ISS). The present study aimed to validate the GH (Eutropin(R)) effect on growth promotion and safety after short-term GH treatment. MATERIALS AND METHODS: This study was an open-label, multicenter, interventional study conducted at nine university hospitals in Korea between 2008 and 2009. Thirty six prepubertal children with ISS were enrolled in this study to receive 6-month GH treatment. Yearly growth rate, height standard deviation score (SDS), and adverse events were investigated during treatment. RESULTS: After 26 weeks of GH treatment, the height velocity significantly increased by 6.36+/-3.36 cm/year (p<0.001). The lower end of one-sided 95% confidence interval was 5.22 cm/year, far greater than the predefined effect size. The gain in height SDS at week 26 was 0.57+/-0.27 (p<0.0001). Bone age significantly increased after GH treatment, however, bone maturation rate (bone age for chronological age) showed limited advancement. This 26-week GH treatment was effective in increasing serum levels of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 from baseline (p<0.0001). Eutropin was well tolerated and there were no withdrawals due to adverse events. No clinically significant changes in laboratory values were observed. CONCLUSION: This 6-month daily GH treatment in children with ISS demonstrated increased height velocity, improved height SDS, and increased IGF-I and IGFBP-3 levels with a favorable safety profile.

Electrolyzed-reduced water increases resistance to oxidative stress, fertility, and lifespan via insulin/IGF-1-like signal in C. elegans

Electrolyzed-reduced water (ERW) scavenges reactive oxygen species and is a powerful anti-oxidant. A positive correlation between oxidative stress and aging has been proved in many model organisms. In Caenorhabditis elegans, many long-lived mutants showed reduced fertility as a trade off against longevity phenotype. We aimed to study the effect of ERW on oxidative stress, fertility and lifespan of C. elegans. We also investigated the genetic pathway involved in the effect of ERW on resistance to oxidative stress and lifespan. We compared lifespan and fertility of worms in media prepared with distilled water and ERW. ERW significantly extended lifespan and increased the number of progeny produced. Then the effect of ERW on resistance to oxidative stress and lifespan of long-lived mutants was determined. ERW increased resistance to oxidative stress and lifespan of eat-2, a genetic model of dietary restriction, but had no effect on those of age-1, which is involved in insulin/insulin-like growth factor (IGF)-1-like signal. In addition, knockdown of daf-16, the downstream mediator of insulin/IGF-1-like signal, completely prevented the effect of ERW on lifespan. These findings suggest that ERW can extend lifespan without accompanying reduced fertility and modulate resistance to oxidative stress and lifespan via insulin/IGF-1-like signal in C. elegans.

Valores de referência para níveis séricos do fator de crescimento semelhante à insulina tipo I (IGF-I) numa população adulta do Estado do Rio de Janeiro, Brasil / Reference ranges for serum levels of insulin-like growth Factor I (IGF-I) in an adult population of Rio de Janeiro State, Brazil

O nível sérico do Fator de crescimento semelhante à insulina tipo I (IGF-I) é fundamental para auxiliar no dignóstico e controle terapêutico dos transtornos relacionados à secreção do Hormônio de Crescimento (GH), bem como no diagnóstico e seguimento de outras doenças. Estabelecer valores de referência para as dosagens séricas de IGF-I por um ensaio imunoquimioluminométrico (ICMA), utilizando o sistema automatizado Immulite 2000/Diagnostic Products Corporation (DPC), e por um ensaio imunoradiométrico (IRMA), utilizando o kit comercial ACTIVE IGF-I/Diagnostic System Laboratories (DSL)-5600, numa população brasileira adulta da cidade do Rio de Janeiro. Este estudo, aprovado pelo Comitê de Ética do Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti, Rio de Janeiro, Brasil, incluiu amostras de 484 indivíduos saudáveis (251 homens e 233 mulheres) com idades entre 18 e 70 anos. As amostras foram estudadas por ICMA- Immulite 2000/DPC and IRMA- ACTIVE IGF-I/DSL-5600. Para análise dos dados foram utilizados modelos específicos para idade e sexo, após transformação dos dados de IGF-I. Foi observada uma lenta diminuição dos níveis de IGF-I com a idade usando ambos os ensaios. Os níveis de IGF-I foram signicativamente (p=0,0181) mais elevados em mulheres do que em homens, quando as amostras foram analisadas usando ICMA. Não houve diferença significativa dos níveis de IGF-I entre homens e mulheres quando as amostras foram analisadas usando IRMA. Este estudo estabeleceu valores de referência de IGF-I específicos para idade e sexo, determinados com o sistema automatizado ICMA-Immulite 2000/DPC, e valores de referência de IGF-I específicos para idade, determinados com o kit comercial IRMA- ACTIVE IGF-I/DSL-5600, em uma população adulta brasileira, da cidade do Rio de Janeiro

Serum level of insulin-like growth factor I (IGF-I) is fundamental in order to aid in the diagnosis and follow-up of growth hormone (GH)-related disorders, as well as in the diagnosis and follow-up of other diseases. The aim of this investigation was to determine reference values for IGF-I using an automated immunochemiluminometric assay (ICMA) system Immulite 2000/Diagnostic Products Corporation (DPC); and an immunoradiometric assay (IRMA), using the commercial kit ACTIVE IGF-I/Diagnostic System Laboratories (DSL)-5600, in an adult Brazilian population of Rio de Janeiro city. The study, approved by the Ethical Committee of the Instituto Estadual de Hematologia Arthur de Siqueira Cavalcanti, Rio de Janeiro, Brazil, included samples of blood taken from 484 healthy subjects (251men, 233 women) aged from 18 up to 70. The samples were analyzed by ICMA- Immulite 2000/DPC and IRMA- ACTIVE IGF-I/DSL-5600. For statistical analysis, age and sex-specific models were fitted after transformation of IGF-I values. In adulthood, a slow age-dependent decrease was found, using both assays. IGF-I in women were significantly (p=0,0181) higher than in men when samples were analayzed using ICMA.There was no significant difference between men and women IGF-I values when samples were analayzed using IRMA. The present study established age- and sex specific IGF-I reference values, determined with the automated system: ICMA-Immulite 2000/DPC and age-specific IGF-I reference values determined with the IRMA- ACTIVE IGF-I/DSL-5600, in an adult Brazilian population of Rio de Janeiro city

Resistance exercise improves hippocampus-dependent memory

It has been demonstrated that resistance exercise improves cognitive functions in humans. Thus, an animal model that mimics this phenomenon can be an important tool for studying the underlying neurophysiological mechanisms. Here, we tested if an animal model for resistance exercise was able to improve the performance in a hippocampus-dependent memory task. In addition, we also evaluated the level of insulin-like growth factor 1/insulin growth factor receptor (IGF-1/IGF-1R), which plays pleiotropic roles in the nervous system. Adult male Wistar rats were divided into three groups (N = 10 for each group): control, SHAM, and resistance exercise (RES). The RES group was submitted to 8 weeks of progressive resistance exercise in a vertical ladder apparatus, while the SHAM group was left in the same apparatus without exercising. Analysis of a cross-sectional area of the flexor digitorum longus muscle indicated that this training period was sufficient to cause muscle fiber hypertrophy. In a step-through passive avoidance task (PA), the RES group presented a longer latency than the other groups on the test day. We also observed an increase of 43 and 94% for systemic and hippocampal IGF-1 concentration, respectively, in the RES group compared to the others. A positive correlation was established between PA performance and systemic IGF-1 (r = 0.46, P < 0.05). Taken together, our data indicate that resistance exercise improves the hippocampus-dependent memory task with a concomitant increase of IGF-1 level in the rat model. This model can be further explored to better understand the effects of resistance exercise on brain functions.

Inhibition of cytohesin-1 by siRNA leads to reduced IGFR signaling in prostate cancer

To explore how cytohesin-1 (CYTH-1) small interfering RNA (siRNA) influences the insulin-like growth factor receptor (IGFR)-associated signal transduction in prostate cancer, we transfected human prostate cancer PC-3 cell lines with liposome-encapsulatedCYTH-1 siRNA in serum-free medium and exposed the cells to 100 nM IGF-1. The mRNA and protein levels of the signal molecules involved in the IGFR signaling pathways were determined by real-time PCR and detected by Western blotting. The relative mRNA levels of CYTH-1, c-Myc, cyclinD1 and IGF-1R (CYTH-1 siRNA group vs scrambled siRNA group) were 0.26 vs 0.97, 0.34 vs 1.06, 0.10 vs 0.95, and 0.27 vs 0.41 (P < 0.05 for all), respectively. The relative protein levels of CYTH-1, pIGF-1R, pIRS1, pAkt1, pErk1, c-Myc, and cyclinD1 (CYTH-1 siRNA group vsscrambled siRNA group) were 0.10 vs 1.00 (30 min), 0.10 vs 0.98 (30 min), 0.04 vs 0.50 (30 min), 0.10 vs 1.00 (30 min), 0.10 vs 1.00 (30 min), 0.13 vs 0.85 (5 h), and 0.08 vs 0.80 (7 h), respectively. The tyrosine kinase activity of IGF-1R was associated with CYTH-1. The proliferative activity of PC-3 cells transfected with CYTH-1 siRNA was significantly lower than that of cells transfected with scrambled siRNA at 48 h (40.5 vs87.6 percent, P < 0.05) and at 72 h (34.5 vs 93.5 percent, P < 0.05). In conclusion, the interference of siRNA with cytohesin-1 leads to reduced IGFR signaling in prostate cancer; therefore, CYTH-1 might serve as a new molecular target for the treatment of prostate cancer.

Evaluation of IGF-I levels and serum protein profiles of diabetic cats and dogs

In this study, we measured the insulin-like growth factor (IGF)-I levels and evaluated the serum protein profiles of diabetic, insulin-treated, and healthy cats and dogs. The total IGF-I concentrations were 33.74 +/- 3.4 ng/mL for normal, 25.8 +/- 4.5 ng/mL for diabetic, and 180.4 +/- 31.4 ng/mL for insulin-treated cats. IGF-I concentrations were 46.4 +/- 6.6 ng/mL for normal, 25.1 +/- 4.1 ng/mL for diabetic, and 303.0 +/- 61.3 ng/mL for insulin-treated dogs. Total serum protein profiles were analyzed by SDS-PAGE. Fourteen bands ranging from 25 to 240 kDa in size were observed for cats, and 17 bands ranging from 25 to 289 kDa were observed for dogs. The densities of the bands differed among control, diabetic, and insulin-treated animals. In conclusion, we found that serum protein profiles and IGF-I concentrations were altered in both diabetic and insulin-treated animals. When judiciously interpreted in the light of other clinical and laboratory data, the techniques used in our study provide a valuable modality for measuring the severity of diabetes mellitus in dogs and cats.

Physical growth in children with reflux nephropathy with normal or mildly impaired renal function.

Ten children aged 11 months to 10 years (means 5.7 years) with reflux nephropathy, vesicoureteric reflux (VUR) and normal or mildly impaired renal function having GFR more than 50 ml/min/1.72 m2, were included in the study. The hematological and biochemical parameters were within normal limits. Height standard deviation score (HZ score) was reduced at entry and, decreased further during follow-up (-2.2 and -2.6 at 0 and 12 months, respectively). Weight for height index (WHI) improved significantly (p=0.0004) during follow-up. The basal and stimulated peak growth hormone levels of these patients were found to be elevated, 18.53 ± 11.36 μg/L and 34.20 ± 5.86 μg/L, respectively. The IGF-1 levels were low ranging from 45.00 to 84.40 ng/dl (mean ± SD 61.54 ± 10.21 ng/dl) compared to 51.80 to 247.50 ng/dl (mean ± SD111.20 ± 70.24 ng/dl) in age and sex matched controls, indicating partial insensitivity to growth hormone.

Growth hormone secretion in response to glucagon stimulation test in healthy middle-aged men / Secreção do hormônio do crescimento em resposta ao teste de estímulo com glucagon em homens saudáveis de meia-idade

OBJECTIVE: To investigate the growth hormone (GH) response to glucagon stimulation test (GST) in a population of healthy men over 50 years old in comparison to insulin tolerance test (ITT), analysis of the spontaneous 24-hour GH profile and insulin-like growth factor 1 (IGF-I). METHODS: 27 healthy men aged between 51 and 65 years were tested. RESULTS: Using non-parametric correlation analysis, a positive correlation between GH peak after GST and mean IGF-I (r = 0.528; p = 0.005) was found, as well with GH peak in 24-hour profile (r = 0.494; p = 0.009). No correlation was found comparing GH peak after ITT with the same parameters. Ten subjects presented GH peak of less than 3.0 μg/L after GST, none confirmed in ITT. CONCLUSIONS: GH peak response to GST was lower than ITT, but it showed a positive correlation with mean IGF-I and also with GH peak in 24-hour profile. However, GST should not be used to differentiate organic growth hormone deficiency (GDH) from the expected decline on GH secretion due to aging.

OBJETIVO: Investigar a resposta do hormônio do crescimento (GH) ao teste de estímulo com glucagon (GST) numa população de homens saudáveis acima dos 50 anos de idade, em comparação ao teste de tolerância à insulina (ITT), além da análise do perfil de secreção espontânea de GH nas 24 horas e fator de crescimento semelhante à insulina (IGF-I) basal. MÉTODOS: 27 homens, com idades entre 51 e 65 anos, foram submetidos aos testes. RESULTADOS: Utilizando análise de correlação não paramétrica, encontrou-se correlação positiva entre o pico de GH pós-GST e a média de IGF-I (r = 0,528; p = 0,005), e também com o pico espontâneo do GH no perfil de 24 horas (r = 0,494; p = 0,009). Não houve correlação do pico de GH pós-ITT com os mesmos parâmetros. Dez indivíduos apresentaram pico de GH após GST inferior a 3,0 μg/L, sem confirmação no ITT. CONCLUSÕES: O pico de GH pós-GST foi menor do que o obtido pós-ITT, porém demonstrou correlação positiva com a média de IGF-I e o pico de GH na secreção espontânea de 24 horas. Entretanto, o GST não demonstrou ser um bom teste para distinguir entre deficiência de hormônio de crescimento (DGH) e somatopausa.