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1.
Nutrients ; 12(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31935821

RESUMO

While human milk composition is characterised by marked dynamicity, we are far from having a clear picture of what factors drive this variation. Hormones in human milk are known to vary according to specific maternal phenotypes, but limited evidence shows the infant also has a role in determining milk composition. The present study aimed to investigate the interplay between maternal and infant characteristics in relation to human milk hormonal profile. In total, 501 human milk samples from mothers recruited in the Finnish STEPS cohort study (Steps to the healthy development) were analysed. Pre-pregnancy and pregnancy maternal data, socioeconomic status and infant characteristics at birth were collated. Leptin, adiponectin, insulin-like growth factor-1 and cyclic Glycine-Proline in milk were measured. Multivariate analysis of variance (MANOVA) and linear regression were utilised for statistical analysis. Sex-specific interactions with maternal factors were observed, as the infant sex mediated associations between gestational diabetes and milk adiponectin (p = 0.031), birth-mode and total protein (p = 0.003), maternal education and insulin-like growth factor-1: cyclic Glycine-Proline ratio (p = 0.035). Our results suggest that changes in human milk composition are associated with interactions between maternal and infant characteristics and pathophysiological factors. Future work should expand on these findings and further explore the link between hormonal profiles in human milk and infant outcomes.

2.
Nutr Metab Cardiovasc Dis ; 30(2): 339-346, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31753784

RESUMO

BACKGROUND AND AIMS: Insulin-like growth factor (IGF)-1 deficiency is associated with a range of metabolic disorders. Cyclic glycine-proline (cGP) is a natural nutrient and regulates the amount of active IGF-1 in plasma. Plasma cGP decreases in hypertensive women whereas increases in obese women, suggesting its involvement in cardio-metabolic function. We therefore examined the effects of cGP on metabolic profiles and blood pressure in high-fat diet (HFD)-induced obese male rats. METHODS: Male rats were fed either a HFD or a standard chow diet (STD) ad-libitum from 3 to 15 weeks of age. Rats were administered either saline or cGP from 11 to 15 weeks of age. At 14 weeks of age, systolic-blood pressure (SBP) was measured by tail-cuff plethysmography and body composition quantified by DEXA. Blood and retroperitoneal fat tissues were collected. Plasma concentrations of insulin, IGF-1, IGF binding protein (IGFBP)-3 and cGP were evaluated using ELISA and HPLC-MS respectively. RESULTS: Compared to STD, HFD feeding increased SBP, total fat mass and fat/lean ratio, retroperitoneal fat weight, fasting plasma insulin and cGP concentrations whereas decreased plasma IGF-1 and IGFBP-3 concentrations. Administration of cGP reduced SBP and retroperitoneal fat weight, but had no effect on body composition and plasma insulin concentrations. CONCLUSION: HFD-associated decreases in IGFBP-3 and increases in cGP represent an autocrine response to normalize IGF-1 function through improving the amount of bioavailable IGF-1 in the circulation of obese male rats. The beneficial effects of cGP on SBP and retroperitoneal fat mass may suggest a therapeutic potential for cGP in HFD-associated cardio-metabolic complications.

3.
Genomics ; 112(1): 151-162, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095996

RESUMO

Cancer cell lines often have large structural variants (SVs) that evolve over time. There are many reported differences in large scale SVs between HL-60 and HL-60/S4, two cell lines derived from the same acute myeloid leukemia sample. However, the stability and variability of inter- and intra-chromosomal structural variants between different sources of the same cell line is unknown. Here, we used Hi-C and RNA-seq to identify and compare large SVs in HL-60 and HL-60/S4 cell lines. Comparisons with previously published karyotypes identified novel SVs in both cell lines. Hi-C was used to characterize the known expansion centered on the MYC locus. The MYC expansion was integrated into known locations in HL-60/S4, and a novel location (chr4) in HL-60. The HL-60 cell line has more within-line structural variation than the HL-60/S4 derivative cell line. Collectively we demonstrate the usefulness of Hi-C and with RNA-seq data for the identification and characterization of SVs.

4.
Curr Dev Nutr ; 3(11): nzz115, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31720556

RESUMO

Background: Nondairy beverages, produced from soy, rice, oat, almond, or coconut, are increasingly being used as alternatives to dairy milk, with the perception that they are healthier and/or more sustainable products than dairy products. Objective: The aim of this study was to compare the effects of supplementing either bovine milk, soy, or almond-based beverages to young, growing rats fed an intact-protein diet or a diet that had protein substituted with amino acids (AA-diet). Methods: Three-week-old male Sprague-Dawley rats were randomly assigned to 5 groups (n = 10/group) and fed ad libitum for 4 wk. Two control groups were fed either standard AIN-93G food [20% casein (CN) protein] or AIN-93G with amino acids (AAs) equivalent to CN protein, and water to drink. Three treatment groups were fed AIN-93G AA and supplemented with either bovine ultra-heat treatment (UHT) milk or soy or almond UHT beverages. Rat weight gain and food intakes were recorded. During week 4, body composition was assessed using DEXA to determine lean soft tissue, fat, and bone mass. At trial end, bone biomechanical properties and blood plasma mineral concentrations were measured. Results: At the end of the trial, animals supplemented with almond beverage were lightest (P > 0.05), with higher plasma calcium concentrations (P > 0.05) and lower bone mineral content (BMC) and bone density (P > 0.05) than animals supplemented with milk or soy beverage. Soy-supplemented animals had similar BMC and bone density compared with milk-supplemented animals, although the soy group gained most weight (P > 0.05) and had the highest fat:lean ratio (P > 0.05) compared with other groups. Conclusions: In the model tested, supplementing rats with bovine UHT milk and soy UHT beverage provided favorable bone health outcomes. Conversely, almond UHT beverage was not an effective supplement and could be detrimental to bone mineralization and strength outcomes.

5.
Mol Nutr Food Res ; : e1900770, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31738006

RESUMO

SCOPE: Glucose intolerance during pregnancy is associated with short- and long-term maternal and offspring health consequences. In young male mice, knockout of the major pro-inflammatory mediator interleukin-1-receptor-1 (IL1R1) protects against high-fat diet (HFD)-induced glucose intolerance and metabolic dysfunction. This phenotype has not been examined during pregnancy. The hypothesis that IL1R1 depletion will protect females against HFD-induced glucose intolerance and metabolic dysfunction before, during, and post pregnancy is tested. METHODS AND RESULTS: C57BL/6J control and IL1R1 knockout (IL1R1-/- ) mice are randomized to either a control diet (10% kcal from fat) or HFD (45% kcal from fat), and three distinct cohorts are established: nulliparous, pregnant, and postpartum females. Contrary to the authors' hypothesis, it is found that IL1R1-/- does not protect against glucose intolerance in nulliparous or pregnant females, and while control HFD animals see a resolution of glucose tolerance postpartum, IL-1R1-/- mice remain impaired. These effects are accompanied by adipocyte hypertrophy, hyperleptinemia, and increased adipose tissue inflammatory gene expression. Maternal genotype differentially affects fetal growth in male and female fetuses, demonstrating sexual dimorphism in this genotype prior to birth. CONCLUSIONS: These findings suggest that IL1R1 signaling is important for normal metabolic functioning in females, during and outside of pregnancy.

6.
Sci Rep ; 9(1): 14343, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586132

RESUMO

Research in human lactation is a growing field. However, difficulties in studying human milk originate from the dynamicity of its composition. Using standardized collection protocols is mandatory to minimize variation and warrant comparability of findings across different studies. Yet, information on the feasibility of collecting human milk with standardized procedures, especially in neonatal units, are lacking. The present study aims to report on the feasibility and difficulties to collect human milk according to a standardized protocol, during early lactation from women who gave birth to preterm infants. Human milk was collected from 129 mothers of moderate- to late-preterm infants according to two variations of a standard protocol which differed for number of collection time-points. Collection rates and adherence to the sampling protocol were evaluated together with reason for missed collection. Collection of ≥1 sample was successful for 80% of the mothers. However adherence to the standard protocol was overall low (36% and 27%). Collection rates were different between the two protocol variations (73% against 92%, p ≤ 0.001). Amongst the reason for missed collection, low milk supply was the most recurrent (40%). Our findings show that while collecting human milk in neonatal units is achievable, obtaining standard and comparable samples results challenging.

7.
Curr Diab Rep ; 19(9): 73, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31368026

RESUMO

PURPOSE OF REVIEW: Gestational diabetes mellitus (GDM) is a common pregnancy complication that has short- and long-term health implications for both the mother and child. While lifestyle modifications, insulin therapy, and oral agents such as metformin are effective, they can be difficult to adhere to, and there remain concerns over long-term effects of oral agents on the infant. Further, GDM has no proven preventive strategies, which could be more effective than treatment postdiagnosis. Nutritional supplements are an appealing, potentially safer, and better tolerated alternative to pharmaceuticals to treat and/or prevent GDM. Here, we review the existing evidence for nutritional supplementation for treatment and prevention of GDM. RECENT FINDINGS: There is limited evidence that myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics might be beneficial for the prevention or treatment of GDM. There are very few studies for each nutrient, and the existing studies tend to have few participants. Where multiple studies of a nutrient exist, often those studies were conducted within the same country, limiting the generalizability of the findings, or alternatively there was no consensus across findings. There is limited evidence that nutritional supplementation of myo-inositol, vitamins D and B6, magnesium, selenium, zinc, fatty acids, and probiotics could improve glycemic control or prevent GDM. Our understanding is constrained by the small number of studies, small sample sizes in most studies, and by lack of consistency across findings. Further large, high-quality, randomized controlled trials are required to determine the efficacy of nutritional supplements to treat or prevent GDM.

8.
G3 (Bethesda) ; 9(8): 2775-2786, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263060

RESUMO

Tumor necrosis factor alpha (TNF-α) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF-α are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF-α treatment has been investigated as part of a combined therapy for acute myeloid leukemia due to its modifying effects on all-trans retinoic acid (ATRA) mediated differentiation into granulocytes. To investigate the interaction between cellular differentiation and TNF-α, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-α. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF-α treatment compared to the undifferentiated promyelocytes. The observed TNF-α responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF-α treated promyelocytes, and downregulated in TNF-α treated granulocytes. This is consistent with TNF-α induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, we found evidence that TNF-α treatment of granulocytes shifts the transcriptome toward that of a macrophage. We conclude that TNF-α treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF-α promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF-α stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.


Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Genes cdc , Leucemia Promielocítica Aguda/genética , Fator de Necrose Tumoral alfa/farmacologia , Biomarcadores , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Células HL-60 , Humanos , Transcriptoma
9.
Neuropeptides ; 76: 101935, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146894

RESUMO

Childhood metabolic disorders are associated with insulin-like growth factor (IGF)-1 deficiency, which can adversely affect brain development and function. As a neuropeptide, cyclic glycine-proline (cGP) improves IGF-1 function in brain and regulates IGF-1 bioavailability in plasma. Whether such a regulatory process mediates the neurotrophic effects of cGP remains unknown. This study examined the effects cGP treatment on synaptic expression and their association with IGF-1, IGF binding protein (IGFBP)-2 and cGP concentrations in the brain of rats with high fat diet (HFD)-induced obesity. Male rats received either a HFD or a standard chow diet (STD) from weaning and were then treated with either saline or cGP from 11 to 15 weeks of age. The concentrations of cGP, IGF-1 and IGFBP-2 were measured in the brain tissues using ELISA and HPLC-MS. The expressions of synaptic markers were evaluated in the hippocampus, hypothalamus and striatum using immunohistochemical staining. Compared to the STD group, IGF-1 and IGFBP-2, but not cGP concentrations, were lower in the HFD groups. The expression of hippocampal synaptophysin, glutamate receptor-1, GFAP and striatal tyrosine-hydroxylase were also reduced in the HFD groups. While treatment did not alter tissue IGF-1, cGP administration that increased the concentration of cGP in brain tissues, normalized the expression of synaptophysin, GFAP and tyrosine-hydroxylase, but not glutamate receptor-1. IGF-1 concentration in brain tissues correlated with the expression of all synaptic markers. HFD feeding reduced synaptic expression and tissue IGF-1 in brains which were closely associated, thus suggesting IGF-1 in the brain is largely bioavailable. Without increasing IGF-1 in the brain, administration of cGP normalized synaptic expression, possibly be mediated through increasing bioavailable IGF-1, but further studies are required to confirm this.


Assuntos
Obesidade/metabolismo , Peptídeos Cíclicos/administração & dosagem , Sinaptofisina/metabolismo , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Ratos Sprague-Dawley
10.
Adv Exp Med Biol ; 1134: 59-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30919332

RESUMO

Early epidemiology studies in humans have and continue to offer valuable insight into the Developmental Origins of Health and Disease (DOHaD) hypothesis, which emphasises the importance of early-life nutritional and environmental changes on the increased risk of metabolic and reproductive disease in later life. Human studies are limited and constrained by a range of factors which do not apply to preclinical research. Animal models therefore offer a unique opportunity to fully investigate the mechanisms associated with developmental programming, helping to elucidate the developmental processes which influence reproductive diseases, and highlight potential biomarkers which can be translated back to the human condition. This review covers the use and limitations of a number of animal models frequently utilised in developmental programming investigations, with an emphasis on dietary manipulations which can lead to reproductive dysfunction in offspring.


Assuntos
Dieta , Infertilidade Feminina/etiologia , Desnutrição/complicações , Estado Nutricional , Reprodução , Animais , Modelos Animais de Doenças , Feminino , Humanos
11.
Front Genet ; 9: 535, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524468

RESUMO

Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D.

12.
BMC Biol ; 16(1): 142, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30477489

RESUMO

BACKGROUND: Mammalian cells are flexible and can rapidly change shape when they contract, adhere, or migrate. The nucleus must be stiff enough to withstand cytoskeletal forces, but flexible enough to remodel as the cell changes shape. This is particularly important for cells migrating through confined spaces, where the nuclear shape must change in order to fit through a constriction. This occurs many times in the life cycle of a neutrophil, which must protect its chromatin from damage and disruption associated with migration. Here we characterized the effects of constricted migration in neutrophil-like cells. RESULTS: Total RNA sequencing identified that migration of neutrophil-like cells through 5- or 14-µm pores was associated with changes in the transcript levels of inflammation and chemotaxis-related genes when compared to unmigrated cells. Differentially expressed transcripts specific to migration with constriction were enriched for groups of genes associated with cytoskeletal remodeling. Hi-C was used to capture the genome organization in control and migrated cells. Limited switching was observed between the active (A) and inactive (B) compartments after migration. However, global depletion of short-range contacts was observed following migration with constriction compared to migration without constriction. Regions with disrupted contacts, TADs, and compartments were enriched for inactive chromatin. CONCLUSION: Short-range genome organization is preferentially altered in inactive chromatin, possibly protecting transcriptionally active contacts from the disruptive effects of migration with constriction. This is consistent with current hypotheses implicating heterochromatin as the mechanoresponsive form of chromatin. Further investigation concerning the contribution of heterochromatin to stiffness, flexibility, and protection of nuclear function will be important for understanding cell migration in relation to human health and disease.


Assuntos
Núcleo Celular/química , Cromatina/química , Neutrófilos/química , Células HL-60 , Humanos
13.
Pharmacol Res ; 137: 122-134, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30292428

RESUMO

Fetal growth restriction (FGR) is associated with an increased risk of hypertension, insulin resistance, obesity and cardiovascular disease in adulthood. Currently there are no effective treatments to reverse the course of FGR. This study used the eNOS knockout mouse (eNOS-/-), a model of FGR, to determine the ability of sildenafil, a potential new treatment for FGR, to improve cardiovascular and metabolic outcomes in adult offspring following a complicated pregnancy. Pregnant eNOS-/- and C57BL/6J control dams were randomised to sildenafil treatment (0.2 mg/ml in drinking water) or placebo at day 12.5 of gestation until birth. After weaning, male offspring were randomised to either a high fat (HFD; 45% kcal from fat) or normal chow diet (ND), and raised to either postnatal day 90 or 150. Growth and body composition, glucose tolerance, insulin resistance, systolic blood pressure and vascular function were analysed at both time-points. eNOS-/- offspring were significantly smaller than their C57BL/6J controls at weaning and P90 (p < 0.01); at P150 they were a similar weight. Total adipose tissue deposition at P90 was significantly increased only in eNOS-/- mice fed a HFD (p < 0.001). At P150 both C57BL/6J and eNOS-/- offspring fed a HFD demonstrated significant adipose tissue deposition (p < 0.01), regardless of maternal treatment. Both diet and maternal sildenafil treatment had a significant effect on glucose tolerance. Glucose tolerance was significantly impaired in eNOS-/- mice fed a HFD (p < 0.01); this was significant in offspring from both sildenafil and vehicle treated mothers at P90 and P150. Glucose tolerance was also impaired in C57BL/6J mice fed a HFD at both P90 and P150 (p < 0.01), but only in those also exposed to sildenafil. In these C57BL/6J mice, sildenafil was associated with impaired insulin sensitivity at P90 (p = 0.020) but increased insulin resistance at P150 (p = 0.019). Exposure to sildenafil was associated with a significant increase in systolic blood pressure in eNOS-/- mice compared with their C57BL/6J diet controls at P150 (p < 0.05). Exposure to sildenafil had differing effects on vascular function in mesenteric arteries; it increased vasodilation in response to ACh in C57BL/6J mice, but was associated with a more constrictive phenotype in eNOS-/- mice. eNOS-/- mice demonstrate a number of impaired outcomes consistent with programmed cardiometabolic disease, particularly when faced with the 'second hit' of a HFD. Exposure to sildenafil treatment during pregnancy did not increase fetal growth or significantly improve adult metabolic or cardiac outcomes. Maternal sildenafil treatment was, however, associated with small impairments in glucose handling and an increase in blood pressure. This study highlights the importance of understanding the long-term effects of treatment during pregnancy in offspring from both complicated and healthy control pregnancies.


Assuntos
Retardo do Crescimento Fetal/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/genética , Citrato de Sildenafila/uso terapêutico , Adiposidade/efeitos dos fármacos , Animais , Glicemia/análise , Pressão Sanguínea , Dieta Hiperlipídica , Feminino , Insulina/sangue , Masculino , Troca Materno-Fetal , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez
14.
Int J Mol Sci ; 19(11)2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30373146

RESUMO

Gestational diabetes mellitus (GDM) is a serious pregnancy complication, in which women without previously diagnosed diabetes develop chronic hyperglycemia during gestation. In most cases, this hyperglycemia is the result of impaired glucose tolerance due to pancreatic ß-cell dysfunction on a background of chronic insulin resistance. Risk factors for GDM include overweight and obesity, advanced maternal age, and a family history or any form of diabetes. Consequences of GDM include increased risk of maternal cardiovascular disease and type 2 diabetes and macrosomia and birth complications in the infant. There is also a longer-term risk of obesity, type 2 diabetes, and cardiovascular disease in the child. GDM affects approximately 16.5% of pregnancies worldwide, and this number is set to increase with the escalating obesity epidemic. While several management strategies exist-including insulin and lifestyle interventions-there is not yet a cure or an efficacious prevention strategy. One reason for this is that the molecular mechanisms underlying GDM are poorly defined. This review discusses what is known about the pathophysiology of GDM, and where there are gaps in the literature that warrant further exploration.


Assuntos
Diabetes Gestacional/fisiopatologia , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/etiologia , Diabetes Gestacional/metabolismo , Feminino , Glucose/metabolismo , Humanos , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Leptina/metabolismo , Estresse Oxidativo , Gravidez , Fatores de Risco
15.
Nutrients ; 10(9)2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30200404

RESUMO

Male and female infants respond differentially to environmental stimuli, with different growth and neurodevelopmental trajectories. Male infants are more likely to be disadvantaged when subjected to adversity and show a higher risk of perinatal complications. However, the underlying causes of this sex-bias are not well defined and optimising the early life nutritional care may be necessary to minimise the "male disadvantage" that may be experienced early in life. Experimental models have demonstrated that animal milk composition differs according to offspring sex, suggesting that the tailoring of early life nutrition may be one mechanism to maximise health protection and development to infants of both sexes. However, evidence for a sex-specificity in human milk composition is limited and conflicting, with studies documenting higher milk energy content for either male or female infants. These data show sex differences, however, there has been limited compositional analysis of the current data nor strategies proposed for how sex-specific compositional differences in early life nutrition may be used to improve infant health. The present narrative review highlights that an improved understanding of sex-specific human milk composition is essential for promoting optimal infant growth and development.


Assuntos
Aleitamento Materno , Desenvolvimento Infantil , Fenômenos Fisiológicos da Nutrição do Lactente , Leite Humano/metabolismo , Estado Nutricional , Valor Nutritivo , Fatores Etários , Animais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fatores Sexuais
16.
Mol Cell Endocrinol ; 477: 70-80, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29913182

RESUMO

Type 1 diabetes mellitus (T1D) is a complex autoimmune disorder characterised by loss of the insulin-producing pancreatic beta cells in genetically predisposed individuals, ultimately resulting in insulin deficiency and hyperglycaemia. T1D is most common among children and young adults, and the incidence is on the rise across the world. The aetiology of T1D is hypothesized to involve genetic and environmental factors that result in the T-cell mediated destruction of pancreatic beta cells. There is a strong genetic risk to T1D; with genome-wide association studies (GWAS) identifying over 60 susceptibility regions within the human genome which are marked by single nucleotide polymorphisms (SNPs). Here, we review what is currently known about the genetics of T1D. We argue that advancing our understanding of the aetiology and pathogenesis of T1D will require the integration of genome biology (omics-data) with GWAS data, thereby making it possible to elucidate the putative gene regulatory networks modulated by disease-associated SNPs. This approach has a potential to revolutionize clinical management of T1D in an era of precision medicine.


Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Autoimunidade/genética , Variação Genética , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos
17.
Endocrinology ; 159(5): 2186-2198, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659791

RESUMO

Growth hormone (GH), an endocrine hormone, primarily secreted from the anterior pituitary, stimulates growth, cell reproduction, and regeneration and is a major regulator of postnatal growth. Humans have two GH genes that encode two versions of GH proteins: a pituitary version (GH-N/GH1) and a placental GH-variant (GH-V/GH2), which are expressed in the syncytiotrophoblast and extravillous trophoblast cells of the placenta. During pregnancy, GH-V replaces GH-N in the maternal circulation at mid-late gestation as the major circulating form of GH. This remarkable change in spatial and temporal GH secretion patterns is proposed to play a role in mediating maternal adaptations to pregnancy. GH-V is associated with fetal growth, and its circulating concentrations have been investigated across a range of pregnancy complications. However, progress in this area has been hindered by a lack of readily accessible and reliable assays for measurement of GH-V. This review will discuss the potential roles of GH-V in normal and pathological pregnancies and will touch on the assays used to quantify this hormone.


Assuntos
Hormônio do Crescimento/metabolismo , Hormônios Placentários/metabolismo , Complicações na Gravidez/metabolismo , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Gestacional/metabolismo , Síndrome de Down/metabolismo , Feminino , Retardo do Crescimento Fetal/metabolismo , Macrossomia Fetal/metabolismo , Doença Trofoblástica Gestacional/metabolismo , Humanos , Gravidez , Gravidez em Diabéticas/metabolismo , Gravidez Ectópica/metabolismo , Isoformas de Proteínas , Síndrome da Trissomía do Cromossomo 18/metabolismo
18.
Front Nutr ; 5: 1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29564328

RESUMO

Maternal high-fat or high-salt diets can independently program adverse cardiometabolic outcomes in offspring. However, there is a paucity of evidence examining their effects in combination on metabolic function in adult offspring. Female Sprague Dawley rats were randomly assigned to either: control (CD; 10% kcal from fat, 1% NaCl), high-salt (SD; 10% kcal from fat, 4% NaCl), high-fat (HF; 45% kcal from fat, 1% NaCl) or high-fat and salt (HFSD; 45% kcal from fat, 4% NaCl) diets 21 days prior to mating and throughout pregnancy and lactation. Male offspring were weaned onto a standard chow diet and were culled on postnatal day 130 for plasma and tissue collection. Adipocyte histology and adipose tissue, liver, and gut gene expression were examined in adult male offspring. HF offspring had significantly greater body weight, impaired insulin sensitivity and hyperleptinemia compared to CD offspring, but these increases were blunted in HFSD offspring. HF offspring had moderate adipocyte hypertrophy and increased expression of the pre-adipocyte marker Dlk1. There was a significant effect of maternal salt with increased hepatic expression of Dgat1 and Igfb2. Gut expression of inflammatory (Il1r1, Tnfα, Il6, and Il6r) and renin-angiotensin system (Agtr1a, Agtr1b) markers was significantly reduced in HFSD offspring compared to HF offspring. Therefore, salt mitigates some adverse offspring outcomes associated with a maternal HF diet, which may be mediated by altered adipose tissue morphology and gut inflammatory and renin-angiotensin regulation.

19.
Methods Mol Biol ; 1735: 145-163, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29380311

RESUMO

Any effective strategy to tackle the global obesity and rising noncommunicable disease epidemic requires an in-depth understanding of the mechanisms that underlie these conditions that manifest as a consequence of complex gene-environment interactions. In this context, it is now well established that alterations in the early life environment, including suboptimal nutrition, can result in an increased risk for a range of metabolic, cardiovascular, and behavioral disorders in later life, a process preferentially termed developmental programming. To date, most of the mechanistic knowledge around the processes underpinning development programming has been derived from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. This review will cover the utility of small animal models in developmental programming, the limitations of such models, and potential future directions that are required to fully maximize information derived from preclinical models in order to effectively translate to clinical use.


Assuntos
Deficiências do Desenvolvimento/etiologia , Desenvolvimento Fetal/fisiologia , Animais , Deficiências do Desenvolvimento/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Predisposição Genética para Doença , Humanos , Desnutrição/complicações , Desnutrição/metabolismo , Modelos Animais , Hipernutrição/complicações , Hipernutrição/metabolismo , Roedores , Fatores Sexuais
20.
Hormones (Athens) ; 16(3): 282-290, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29278514

RESUMO

OBJECTIVE: To investigate whether maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF binding proteins (IGFBP) 1 and 3 were altered in pregnancies complicated by gestational diabetes mellitus (GDM). METHOD: In a nested case-control study, GDM cases (n=28) and matched controls (n=28) were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Maternal serum hormone concentrations at 20 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: There was no significant difference in maternal serum GH-V concentration in the GDM group compared to the control group (1.64 ± 0.11 ng/ml vs. 1.38 ± 0.10 ng/ml, p=0.079). However, GDM cases who delivered large for gestational age (LGA) babies had significantly higher serum GH-V concentrations compared to non-diabetic control cases. Maternal IGF-1 concentrations in GDM pregnancies were significantly higher than in controls (275.7 ± 11.5 ng/ml vs. 218.5 ± 11.1 ng/ml, p <0.001). Maternal IGFBP-1 concentrations were significantly lower in GDM pregnancies than in controls (41.04 ± 3.42 ng/ml vs. 67.58 ± 6.17 ng/ml, p <0.001). There were no significant differences in serum IGF-2 and IGFBP-3 concentrations between groups. CONCLUSION: Concentrations of IGF-1 and IGFBP-1 in maternal serum were altered in GDM pregnancies compared to controls, suggesting that the IGF axis plays a role in the development of this condition. GH-V may be associated with macrosomia as increased maternal GH-V was observed in GDM cases who delivered LGA babies.


Assuntos
Diabetes Gestacional/sangue , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Placentário/sangue , Segundo Trimestre da Gravidez/sangue , Somatomedinas/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Gravidez
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