Altered IGF-I activity and accelerated bone elongation in growth plates precedes excess weight gain in a mouse model of juvenile obesity

Nearly one-third of children in the United States are overweight or obese by their pre-teens. Tall stature and accelerated bone elongation are characteristic features of childhood obesity, which co-occur with conditions such as limb bowing, slipped epiphyses, and fractures. Obese children paradoxically have normal circulating IGF-I, the major growth-stimulating hormone. Here we describe and validate a mouse model of excess dietary fat to examine mechanisms of growth acceleration in obesity. We used in vivo multiphoton imaging and immunostaining to test the hypothesis that high-fat diet increases IGF-I activity and alters growth plate structure before the onset of obesity. We tracked bone and body growth in male and female C57BL/6 mice (N = 114) on high-fat (60% kcal fat) or control (10% kcal fat) diets from weaning (3-weeks) to skeletal maturity (12-weeks). Tibial and tail elongation rates increased after brief (1-2 week) high-fat diet exposure without altering serum IGF-I. Femoral bone density and growth plate size were increased, but growth plates were disorganized in not-yet-obese high-fat diet mice. Multiphoton imaging revealed more IGF-I in the vasculature surrounding growth plates of high-fat diet mice, and increased uptake when vascular levels peaked. High-fat diet growth plates had more activated IGF-I receptors and fewer inhibitory binding proteins, suggesting increased IGF-I bioavailability in growth plates. These results, which parallel pediatric growth patterns, highlight the fundamental role of diet in the earliest stages of developing obesity-related skeletal complications and validate the utility of the model for future studies aimed at determining mechanisms of diet-enhanced bone lengthening.

INSULIN-LIKE GROWTH FACTOR 1: CARDIOVASCULAR MORBIDITY PROGNOSIS

The paper is a review devoted to insulin-like growth factor 1 and its role in the development, progression, and prognosis of cardiovascular diseases. IGF-I is one of the important regulatory proteins involved in both adaptation and maladjustment. The purpose of the review is to critically analyze the results of association between IGF-1 and cardiovascular disease. In general, we analyzed 100 literature sources; however, 49 of them were excluded, since the processes under consideration were not described there in detail or included an assessment of correlation between IGF-1 and metabolic parameters. IGF-I regulatory function is to control the synthesis and degradation of proteins, provide a mitogenic effect, and influence apoptosis. IGF-1 plays a leading role in the protection of cardiomyocytes from apoptosis both in vitro and in vivo. IGF-1 is involved in angiogenesis and development of atherosclerosis; it induces the growth of endothelial cells activating vascular endothelial growth factor. An increase in IGF-1 level accompanies arterial hypertension; a decrease in IGF-1 concentration is associated with an increased risk of coronary heart disease, stroke, and heart failure.IGF-1 concentration in ACS is associated with the syndrome outcome; a decrease in IGF-1 levels in patients with myocardial infarction (less than 150 nm/ml) is an unfavorable prognostic factor for six-month mortality after acute coronary pathology. Low IGF-1 level is an independent predictor of vascular accidents in hypertensive patients. Decreased IGF-1 level in patients with cardiovascular disease is associated with a higher risk of atrial fibrillation. The results obtained indicate the advisability of using the IGF-1 concentration as a prognostic marker of cardiovascular diseases. Key words: insulin-like growth factor, arterial hypertension, acute coronary syndrome, apoptosis, cardiovascular diseases, remodeling. Статья представляет собой обзор исследований, посвященных изучению роли инсулиноподобного фактора роста-1 в развитии, прогрессировании, прогнозе кардиоваскулярных заболеваний. IGF-I является одним из важных регуляторных белков, участвующих в процессах как адаптации, так и дезадаптации. Цель обзора – провести критический анализ результатов исследований взаимосвязи IGF-1 и сердечно-сосудистых заболеваний. Проанализировано 100 источников литературы, из них 49 источников исключены, так как интересующие процессы не были подробно описаны или включали оценку взаимосвязей IGF-1 с метаболическими параметрами. Регуляторная функция IGF-I заключается в регуляции синтеза и распада белков, оказании митогенного эффекта, влиянии на апоптоз. IGF-I играет ведущую роль в защите кардиомиоцитов от апоптоза как in vitro, так и in vivo. IGF-I принимает участие в развитии атеросклероза и в ангиогенезе, он индуцирует рост эндотелиальных клеток, участвуя в активации фактора роста эндотелия сосудов. Повышение уровня IGF-I сопровождает артериальную гипертензию, уменьшение концентрации IGF-I ассоциируется с повышенным риском развития ишемической болезни сердца, инсульта и сердечной недостаточности. Концентрация IGF-I при ОКС связана с исходом данного синдрома, снижение уровней IGF-I у пациентов с инфарктом миокарда (менее 150 нм/мл) является неблагоприятным прогностическим фактором полугодовой летальности после острой коронарной патологии. Низкий уровень IGF-1 – это независимый предиктор развития сосудистых катастроф у пациентов с артериальной гипертензией. Снижение уровня IGF-1 у пациентов с кардиоваскулярной патологией связано с более высоким риском развития фибрилляции предсердий. Полученные результаты свидетельствуют о целесообразности использования концентрации IGF-1 как прогностического маркера кардиоваскулярных заболеваний. Ключевые слова: инсулиноподобный фактор роста, артериальная гипертензия, острый коронарный синдром, апоптоз, сердечно-сосудистые заболевания, ремоделирование.

A Role for ER-Beta in the Effects of Low-Density Lipoprotein Cholesterol and 27-Hydroxycholesterol on Breast Cancer Progression: Involvement of the IGF Signalling Pathway?

Cholesterol—in particular, high levels of low-density lipoprotein (LDL) and its metabolite, 27-hydroxycholesterol (27-OHC)—is correlated with increases in the risks of breast cancer and obesity. Although the high expression of LDL/27-OHC has been reported in breast cancer, its effects and mechanism of action remain to be fully elucidated. In this study, we found that the effects of LDL on cell proliferation were mediated by the activation of the cytochrome P450 enzyme, sterol 27 hydroxylase, and cholesterol 27-hydroxylase (CYP27A1) in both ER-α-positive and ER-α-negative breast cancer cells. We found that treatment with 27-OHC only increased cell growth in oestrogen receptor-α (ER-α)-positive breast cancer cells in an ER-α-dependent manner, but, interestingly, the effects of 27-OHC on cell migration and invasion were independent of ER-α. Using ER-α-negative MDA-MB-231 cells, we found that 27-OHC similarly promoted cell invasion and migration, and this was mediated by oestrogen receptor β (ER-β). These results suggest that 27-OHC promotes breast cancer cell proliferation in ER-α-positive breast cancer cells via ER-α, but migration and invasion are mediated via ER-β in ER-α positive and negative cell lines. The addition of LDL/27OHC increased the production of IGF-I and the abundance of IGF-IR in TNBC. We further found that modulating ER-β using an agonist or antagonist increased or decreased, respectively, levels of the IGF-I and EGF receptors in TNBC. The inhibition of the insulin-like growth factor receptor blocked the effects of cholesterol on cell growth and the migration of TNBC. Using TCGA and METABRIC microarray expression data from invasive breast cancer carcinomas, we also observed that higher levels of ER-beta were associated with higher levels of IGF-IR. Thus, this study shows novel evidence that ER-β is central to the effects of LDL/27OHC on invasion, migration, and the IGF and EGF axes. Our data suggest that targeting ER-β in TNBC could be an alternative approach for downregulating IGF/EGF signalling and controlling the impact of LDL in breast cancer patients.

Effective GH replacement with once-weekly somapacitan vs daily GH in children with GHD: 3-year results from REAL 3

Context Current GH therapy requires daily injections, which can be burdensome. Somapacitan is a long-acting GH derivative in development for treatment of GH deficiency (GHD). Objective Evaluate the efficacy, safety, and tolerability of once-weekly somapacitan after 3 years of treatment. Design A multicenter, randomized, controlled, phase 2 study comparing somapacitan and once-daily GH for 156 weeks (NCT02616562). Setting Twenty-nine sites in 11 countries. Patients Fifty-nine children with GHD randomized (1:1:1:1) and exposed to treatment. Fifty-three children completed the 3-year period. Interventions Patients received somapacitan (0.04 [n=14], 0.08 [n=15] or 0.16 [n=14] mg/kg/week) or daily GH (n=14) (0.034 mg/kg/day, equivalent to 0.238 mg/kg/week) subcutaneously during the first year, after which all patients on somapacitan received 0.16 mg/kg/week. Main Outcome Measures Height velocity (HV) at year 3; changes from baseline in height standard deviation score (HSDS), HVSDS and IGF-I SDS. Results The estimated treatment difference (95% CI) in HV for somapacitan 0.16/0.16 mg/kg/week versus daily GH at year 3 was 0.8 cm/year (−0.4; 2.1). Change in HVSDS from baseline to year 3 was comparable between somapacitan 0.16/0.16 mg/kg/week, the pooled somapacitan groups, and daily GH. A gradual increase in HSDS from baseline was observed for all groups. At year 3, mean HSDS was similar for the pooled somapacitan groups and daily GH. Change from baseline to year 3 in mean IGF-I SDS was similar across treatments. Conclusions Once-weekly somapacitan in children with GHD showed sustained efficacy over 3 years in all assessed height-based outcomes with similar safety and tolerability to daily GH.

A MATURAÇÃO OOCITÁRIA IN VITRO PARA PREVENIR A SÍNDROME DA HIPERESTIMULAÇÃO OVARIANA

Introdução: Anos atrás, padronizou-se utilizar protocolos de hiperestimulação medicamentosa controlada para captar oócitos, porém a estimulação ovariana não é isenta de riscos. A síndrome da hiperestimulação ovariana (SHO) é a resposta exagerada dos ovários às gonadotrofinas. Divide-se em quatro graus: leve, moderada, grave e crítica. Devido grande quantidade folicular o líquido acumulado nos ovários aumenta a permeabilidade capilar, resultando no efluxo de líquido intravascular para o espaço intersticial. Consequências são alterações hemodinâmicas, de hemoconcentração, líquido nos pulmões, insuficiência renal, trombose e morte. No Brasil é estimado três óbitos a cada 100 mil tratamentos. A maturação in vitro (MIV) apresenta uma alternativa aos tratamentos que utilizam gonadotrofinas, por ser o cultivo in vitro de oócitos imaturos. Objetivo: Esse trabalho busca reunir informações para responder se a MIV tem se mostrado boa alternativa aos tratamentos de reprodução humana assistida objetivando-se prevenir a SHO. Materiais e Métodos: Realizou-se revisão bibliográfica em revistas acadêmicas, comparando dados. Resultados: Respostas das células de mamíferas à MIV: Certo estudo realizado em 1975 utilizando progesterona no meio de cultivo obteve resultado negativo em sua pesquisa, assim como uma pesquisa em 1998 ao utilizar FSH/LH. Utilizando fluido folicular, em 1991, o resultado obtido foi satisfatório. Ao utilizar estrogênio + soro bovino em 1994 o resultado concluiu-se indiferente. Em 1998 e 2000, foi observado resultado positivo ao usar FSH/LH nos estudos. Trazendo nova perspectiva, em 1998 foi proposto o uso de insulina do fluido folicular in vivo + fator de crescimento insulina símile – I + IGF-I obtendo resultados positivos. Em 2017 inúmeros pesquisadores apoiaram o uso de TCM 199 + SSS + FSH + hCG recombinante + estradiol + insulina + FGF alegando ser o maior avanço até a atualidade. Conclusão: O desenvolvimento oocitário adequado demanda sincronia entre a maturação nuclear e citoplasmática. A partir do pensamento contemporâneo de não repetir expressamente o que ocorre in vivo, alguns grupos de pesquisadores sugerem a adição de agentes farmacológicos ao meio de cultivo para evitar a maturação nuclear precoce. A MIV tem demonstrado ser uma alternativa viável para casos com probabilidade de desenvolver complicações da SHO. É inegável a necessidade de mais estudos na área.

Effect of diabetes mellitus on levels of insulin-like growth factors and their carrier proteins in Guerin’s carcinoma and it’s perifocal tissue in rats

Purpose of the study. Diabetes mellitus (DM) is considered an independent risk factor for higher cancer incidence and death rates. The system of insulin-like growth factors and their carrier proteins (IGF and IGFBP) and hyperglycemia create favorable conditions for the proliferation and metastasis of cancer cells.Materials and methods. Outbred male and female rats were divided into groups (n = 8 each): controls - with Guerin's carcinoma; main group - Guerin's carcinoma growing in presence of DM. Experimental DM was reproduces in animals by the single intraperitoneal alloxan injection (150 mg/kg body weight). After 10 days of the carcinoma growth, levels of IGF and IGFBP in the tumor and in it's perifocal area were measured using ELISA.Results. DM in females upregulated levels of glucose both in the tumor and in perifocal tissues by 1.8 (p < 0.05) and 8.1 times, respectively, but caused opposite changes in IGF-I - it's increase by 6.3 times in the tumor and decrease by 3.2 times in the perifocal area; as a result, such tumors with small primary nodes were more "aggressive" and actively metastasized. In males, induced DM downregulated levels of glucose, IGF-II and IGFBP2 in the carcinoma by 8.4, 3.1 and 1.7 (p < 0.05) times, respectively, and increased levels of IGF-I and IGFBP2 by 1.4 and 1.3 times (p < 0.05) in the perifocal area without changing glucose levels; as a result, tumor volumes exceeded the values in the standard growth, without metastasizing into visceral organs.Conclusion. We revealed gender differences in changing levels of glucose and IGF both in the tumor and in it's perifocal tissue in rats with Guerin's carcinoma growing in presence of DM; these differences could determine different tumor growth dynamics in male and female rats.

Impacts of Metformin on Local Ovarian Cell Tissue of Rats with Polycystic Ovary Syndrome and Intestinal Flora Under Aerobic Exercise

In order to explore the possible treatment mechanism of metformin on the local ovarian cell tissue of rats with polycystic ovary syndrome (PCOS), 35 female clean sterile rats were selected as the research objects in this study, and randomly divided a PCOS model group (PCOS MG) (25 rats) and a control group (CG) (10 rats). After the modelling was completed, 5 rats were randomly selected to evaluate the modelling effect. When the success rate was higher than 80%, the remaining model rats were divided into two groups randomly, namely the (PCOS MG) (10 rats) and the treatment group (TG) (10 rats). Hematoxylin-eosin (HE) staining was performed on ovarian tissue of the rat, and the ovarian tissue structure was observed under light microscope. Immunohistochemistry was used to detect the distribution and expression levels of tumour necrosis factor-α (TNF-α), insulin-like growth factor-I (IGF-I), and connective tissue growth factor (CTGF) on the ovaries of rats in each group. It was found by observing the vaginal smear under the microscope that the rats in the (PCOS MG) had lost the regular estrous cycle, suggesting that there was no ovulation. The expression levels of TNF-α and CTGF in rats in the (PCOS MG) were greatly higher than those in the CG (P < 0.05); compared with the (PCOS MG), the expression levels of TNF-α and CTGF in the TG were decreased observably (P < 0.05). IGF-I was mainly expressed in granulosa cells (GCs) and follicular membrane cells (FMCs) of the ovarian tissue. The expression level of IGF-I in ovarian GCs in rats in the (PCOS MG) was significantly higher than that in the CG (P < 0.05). The expression level of IGF-I in GCs in the TG was lower significantly than that in the (PCOS MG) (P < 0.05). By comparing with rats in the CG, the rats in the (PCOS MG) had obviously decreased Actinobacteria and Betaproteobacteria in the intestinal tract, and the proportion of Firmicutes in the intestine was significantly increased; the amount of butyric acid in the faeces of rats with aerobic exercise was obviously higher than that in the (PCOS MG), because exercise increased the proportion of intestinal butyric acid-producing bacteria. Conclusion: metformin combined with aerobic exercise can treat the PCOS by regulating serum hormone levels and the expression levels of TNF-α, IGF-I, and CTGF.

Sugar Intake and Cancer: A Literature Review

ABSTRACTBackground: Cancer is the second leading cause of death after heart disease globally (total death 9.6 million). Cancer prevalence is increasing in Indonesia from 1.4 per 1000 people in 2013 to 1.79 per 1000 people in 2018. Diet is linked with cancer prognosis, particularly carbohydrate intake which stimulates insulin signals that can be potent mitogens.Purpose: This literature review aims to examine sugar intake and cancer incidence.Method: This literature review (traditional review) using the keywords “cancer”,” sugar”, “carbohydrate”, “insulin” and “hyperinsulinemia” in the Sciencedirect database and Google search engine. The inclusion criteria were peer-review articles or documents from credible national and international institutions, the literature uses English or Bahasa (Indonesian Language). The exclusion criteria were that the literature had similar content or redundant with other literature.Result: Sugar increases insulin resistance which enhances the levels of bioactive IGF-I that contribute to raising the risk of cancer. Prolonged hyperinsulinemia reduces the production of growth-promoting factors such as IGFBP-1 and IGFBP-2 which normally bind to and inhibit the action of IGF-I with resultant increases in the levels of free, bio-active IGF-I, and concomitant changes in the cellular environment that favor cancer development, proliferation, and metastatic cancer cells.Conclusion: The mechanism of insulin and IGF-1 stimulate and accelerate cancer cell proliferation may explain the relationship between sugar intake and cancer incidence. Adopting a balanced diet, changing or decreasing sugar intake with healthier food coupled with increased physical activity reduces the risk of cancer.

Different Effects of Soy and Whey on Linear Bone Growth and Growth Pattern in Young Male Sprague-Dawley Rats

The aim of this investigation was to determine the better protein for supporting optimal linear growth, as the exact composition and benefits of specific dietary proteins in supporting linear growth is unknown. In the current study, we compared the effect of soy and whey proteins, both proteins contain all essential amino acids and are considered the best proteins in their categories. Young male rats were subjected to multiple feeding protocols using iso-energetic diets containing soy or whey as the sole protein source. The rats were allowed to eat ad libitum for 11, 24, or 74 days in the first set of experiments, and the soy group was pair-fed to the whey group in the second set. The differences in weight gain, food consumption, and humeri length of the soy group that were greater at the beginning of the ad libitum experiments lessened over time. Pair-fed experiments revealed that the increased weight and humeri length resulted from the differences in food consumption. However, other parameters were protein specific. Bone quality, which was better in the soy group at 24 days, was matched by the whey group and even surpassed that of the soy group in the long-term experiment, with a significantly greater bone mineral density, cortical thickness, and growth plate. Although in the short term the levels of insulin like growth factor (IGF)-I were similar between the groups, IGF-I increased with age in the whey group, and the levels at the long-term experiment were significantly higher compared to the soy group. Furthermore, using the pair fed setup made it clear that when the difference in food consumption were no longer playing part, whey was more efficient in increasing IGF-I. There were no indications of metabolic sequelae. Although the use of soy is gaining in popularity as a sustainable protein, our findings indicate a better effect of whey on linear growth by leading to slower growth with better-organized epiphyseal growth plates and bone quality.