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BACKGROUND AND OBJECTIVES: Barley mixed rice, "Mugi gohan," is traditionally eaten with yam paste in Japan. Both ingredients contain dietary fiber and reportedly reduce postprandial hyperglycemia. However, evidence supporting the benefits of combining barley mixed rice with yam paste is limited. In this study, we evaluated whether ingesting a combination of barley mixed rice and yam paste affected postprandial blood glucose concentration and insulin secretion. METHODS AND STUDY DESIGN: This study followed an open-label, randomized controlled crossover design, following the unified protocol of the Japanese Association for the Study of Glycemic Index. Fourteen healthy subjects each consumed four different test meals: white rice only, white rice with yam paste, barley mixed rice, and barley mixed rice with yam paste. We measured their postprandial blood glucose and insulin concentrations after every meal, and we calculated the area under curve for glucose and insulin. RESULTS: Participants had significantly reduced area under curve for glucose and insulin after eating barley mixed rice with yam paste compared to when they ate white rice only. Participants had similar area under curve for glucose and insulin after eating barley mixed rice only, or eating white rice with yam paste. Participants had lower blood glucose concentrations 15 min after eating barley mixed rice only, whilst eating white rice with yam paste did not maintain lower blood glucose after 15 min. CONCLUSIONS: Eating barley mixed rice with yam paste decreases postprandial blood glucose concentrations and reduces insulin secretion.
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Glucemia , Dioscorea , Hordeum , Secreción de Insulina , Oryza , Adulto , Humanos , Estudios Cruzados , Pueblos del Este de Asia , Ingestión de Alimentos , Insulina , Comidas , Periodo PosprandialRESUMEN
BACKGROUND: The expressions of genes related to lipid metabolism are decreased in adipocytes with insulin resistance. In this study, we examined the effects of fatty acids on the reduced expressions and histone acetylation of lipid metabolism-related genes in 3T3-L1 adipocytes treated with insulin resistance induced by tumor necrosis factor (TNF)-α. METHODS: Short-, medium-, and long-chain fatty acid were co-administered with TNF-α in 3T3-L1 adipocytes. Then, mRNA expressions and histone acetylation of genes involved in lipid metabolism were determined using mRNA microarrays, qRT-PCR, and chromatin immunoprecipitation assays. RESULTS: We found in microarray and subsequent qRT-PCR analyses that the expression levels of several lipid metabolism-related genes, including Gpd1, Cidec, and Cyp4b1, were reduced by TNF-α treatment and restored by co-treatment with a short-chain fatty acid (C4: butyric acid) and medium-chain fatty acids (C8: caprylic acid and C10: capric acid). The pathway analysis of the microarray showed that capric acid enhanced mRNA levels of genes in the PPAR signaling pathway and adipogenesis genes in the TNF-α-treated adipocytes. Histone acetylation around Cidec and Gpd1 genes were also reduced by TNF-α treatment and recovered by co-administration with short- and medium-chain fatty acids. GENERAL SIGNIFICANCE: Medium- and short-chain fatty acids induce the expressions of Cidec and Gpd1, which are lipid metabolism-related genes in insulin-resistant adipocytes, by promoting histone acetylation around these genes.
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Studies indicate that induction of metabolic gene expression by nutrient intake, and in response to subsequently secreted hormones, is regulated by transcription factors binding to cis-elements and associated changes of epigenetic memories (histone modifications and DNA methylation) located in promoter and enhancer regions. Carbohydrate intake-mediated induction of metabolic gene expression is regulated by histone acetylation and the histone acetylation reader bromodomain-containing protein 4 (BRD4) on the gene body region, which corresponds to the transcribed region of the gene. In this review, we introduce carbohydrate-responsive metabolic gene regulation by (i) transcription factors and epigenetic memory in promoter/enhancer regions (promoter/enhancer-based epigenetics), and (ii) histone acetylation and BRD4 in the gene body region (gene body-based epigenetics). Expression of carbohydrate-responsive metabolic genes related to nutrient digestion and absorption, fat synthesis, inflammation in the small intestine, liver and white adipose tissue, and in monocytic/macrophage-like cells are regulated by various transcription factors. The expression of these metabolic genes are also regulated by transcription elongation via histone acetylation and BRD4 in the gene body region. Additionally, the expression of genes related to fat synthesis, and the levels of acetylated histones and BRD4 in fat synthesis-related genes, are downregulated in white adipocytes under insulin resistant and/or diabetic conditions. In contrast, expression of carbohydrate-responsive metabolic genes and/or histone acetylation and BRD4 binding in the gene body region of these genes, are upregulated in the small intestine, liver, and peripheral leukocytes (innate leukocytes) under insulin resistant and/or diabetic conditions. In conclusion, histone acetylation and BRD4 binding in the gene body region as well as transcription factor binding in promoter/enhancer regions regulate the expression of carbohydrate-responsive metabolic genes in many metabolic organs. Insulin resistant and diabetic conditions induce the development of metabolic diseases, including type 2 diabetes, by reducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in white adipose tissue and by inducing the expression of BRD4-targeted carbohydrate-responsive metabolic genes in the liver, small intestine, and innate leukocytes including monocytes/macrophages and neutrophils.
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BACKGROUND AND OBJECTIVES: We demonstrated that the mRNA induction of S100s in rat peripheral leukocytes by severe hyperglycemia was reduced by inhibiting postprandial hyperglycemia. Here, we compared inflammatory gene expression in peripheral leukocytes between type 2 diabetes mellitus (T2DM) patients undergoing dietary therapy alone and healthy volunteers, and between T2DM patients undergoing dietary therapy alone and those undergoing such therapy in combination with drug therapy using the α-glucosidase inhibitor miglitol. METHODS: T2DM patients who had undertaken dietary therapy alone or in combination with drug therapy using miglitol for ≥ 8 weeks and healthy volunteers were subjected to a meal tolerance test and glucose concentration, neutrophil elastase concentration, and mRNA expression analyses of peripheral leukocytes by microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) immediately before and 180 min after a meal. RESULTS: Blood glucose concentrations 60 min after a meal were lower in T2DM patients with dietary + miglitol therapy than in those with dietary therapy alone. Neutrophil elastase concentrations at 60 and 120 min after a meal were lower in T2DM patients with dietary + miglitol therapy than in those with dietary therapy alone. Expression levels of S100A8 in a fasting state and S100A6, S100A8, and S100A9 180 min after a meal were higher in T2DM patients with dietary therapy alone than in healthy volunteers. Expression levels of S100A12 in a fasting state and 180 min after a meal were higher in T2DM patients with dietary therapy alone than in T2DM patients with dietary + miglitol therapy. CONCLUSIONS: S100 genes were more highly expressed in T2DM patients with dietary therapy than in healthy volunteers.
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Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/dietoterapia , Leucocitos/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Adulto , Anciano , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ayuno/sangre , Femenino , Regulación de la Expresión Génica , Hospitales Universitarios , Humanos , Hipoglucemiantes/uso terapéutico , Inflamación/genética , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Mensajero/análisisRESUMEN
Our previous study demonstrated that the transfection of a short hairpin (sh)RNA targeting bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family of proteins, into 3T3-L1 cells, a white adipocyte-like cell line, reduced the expression of insulin sensitivity genes, such as Adipoq, Fabp4, Lpl, Slc2a4 and Dgat1, and that BRD4 directly bound to the Adipoq, Slc2a4 and Lpl genes. In the present study, we aimed to identify other target genes of BRD4 by microarray analysis of Brd4 shRNA- and control shRNA-transfected cells. We found that the expression of many genes related to fat metabolism, and particularly those involved in fat accumulation in the glycolytic pathway, tricarboxylic acid cycle, and triacylglycerol synthesis, such as Dgat2, Gpd1, Acsl1, Pnpla2, Pgkfb3, Pcx, Fasn, Acacb and Cidec, was reduced by Brd4 shRNA transfection 2 and 8 days after the end of adipocyte differentiation. The binding of BRD4 at the 2-day and histone acetylation at the 8-day time point, in the vicinity of the Dgat2, Gpd1, Acsl1 and Cidec genes, was also reduced by Brd4 shRNA transduction. Treatment with low doses (10-100 nM) of the BET family inhibitor (+)-JQ-1 for 2, 4 or 8 days also reduced the expression of Dgat2, Gpd1, Fasn, Acab, Acsl1, Pnpla2 and Cidec in 3T3-L1 white adipocyte-like cells. These results indicate that BRD4 regulates the expression of numerous genes involved in lipid accumulation at the transcriptional level in a white adipocyte-like cell line.
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Adipocitos Blancos/metabolismo , Metabolismo de los Lípidos/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética , Células 3T3-L1 , Acetilación , Adipocitos Blancos/efectos de los fármacos , Animales , Azepinas/farmacología , Cromatina/metabolismo , Perfilación de la Expresión Génica , Histonas/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Unión Proteica , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacos , Triazoles/farmacologíaRESUMEN
OBJECTIVE: Foods reducing postprandial hyperglycemia could suppress the postprandial blood glucose response after the next meal (a "second-meal" effect). However, the second-meal effect of refined barley flour bread has not been evaluated. The aim of this study is to determine whether consumption of refined barley flour bread reduces postprandial glucose concentrations after this and the subsequent meal. METHODS: We enrolled 23 healthy young Japanese adults and conducted a randomized, double-blind, placebo-controlled, crossover study. The participants consumed refined barley flour bread containing 2.5 g ß-glucan or refined wheat flour bread in a first meal, then consumed three rice balls as a second meal. Their postprandial blood glucose concentrations were measured 0, 15, 30, 45, 60, 90, and 120 min after both meals. Participants with fasting glucose concentrations above the diagnostic threshold for diabetes were excluded. RESULTS: The blood glucose concentration 30 min after the first meal was significantly lower (P < 0.05) if refined barley flour bread (7.1 ± 1.0 mmol/L) rather than refined wheat flour bread (7.7 ± 1.2 mmol/L) was consumed. Significantly lower glucose concentrations after the second meal measured at 60 (P < 0.05, barley flour bread: 8.7 ± 1.8 mmol/L, wheat flour bread: 9.3 ± 1.7 mmol/L) and 90 min (P < 0.01, barley flour bread: 7.8 ± 1.4 mmol/L, wheat flour bread: 8.8 ± 2.1 mmol/L) were lower in participants who had previously consumed the refined barley flour bread. CONCLUSIONS: Consumption of bread made with refined barley flour lowers postprandial blood glucose concentration after this and a subsequent meal compared with the consumption of refined wheat flour bread in healthy young Japanese adults.
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Glucemia/análisis , Pan/análisis , Harina/análisis , Hordeum , Comidas/fisiología , Triticum , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Japón , Masculino , Periodo Posprandial , Adulto Joven , beta-Glucanos/análisisRESUMEN
We recently reported that a treatment with tauroursodeoxycholic acid (TUDCA), a secondary bile acid, improved developmentally-deteriorated hepatic steatosis in an undernourishment (UN, 40% caloric restriction) in utero mouse model after a postnatal high-fat diet (HFD). We performed a microarray analysis and focused on two genes (Cidea and Cidec) because they are enhancers of lipid droplet (LD) sizes in hepatocytes and showed the greatest up-regulation in expression by UN that were completely recovered by TUDCA, concomitant with parallel changes in LD sizes. TUDCA remodeled developmentally-induced histone modifications (dimethylation of H3K4, H3K27, or H3K36), but not DNA methylation, around the Cidea and Cidec genes in UN pups only. Changes in these histone modifications may contribute to the markedly down-regulated expression of Cidea and Cidec genes in UN pups, which was observed in the alleviation of hepatic fat deposition, even under HFD. These results provide an insight into the future of precision medicine for developmentally-programmed hepatic steatosis by targeting histone modifications.
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Proteínas Reguladoras de la Apoptosis/genética , Hígado Graso/genética , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Código de Histonas/efectos de los fármacos , Procesamiento Proteico-Postraduccional , Proteínas/genética , Ácido Tauroquenodesoxicólico/farmacología , Animales , Colagogos y Coleréticos/farmacología , Dieta Alta en Grasa/efectos adversos , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Lipoprotein lipase (LPL) is the rate-controlling enzyme for the accumulation of triacylglycerol into adipocytes, which acts by digesting it into glycerol and fatty acids. In this study, we found that treatment with (+)-JQ1, an inhibitor of the bromodomain and extra-terminal (BET) family proteins, for 4 days from the end of stimulation to induce adipocyte differentiation reduced binding of BRD4, a BET family member, within the gene body of Lpl. This eventually downregulated the expression of Lpl in 3T3-L1 adipocytes. Longer treatment for 8 days reduced the acetylation of histones H3 and H4 within the gene body of Lpl and subsequent Lpl expression. Lpl expression in mesenteric adipose tissues was lower in Brd4+/- heterozygous mice at 14 days after birth than in wild-type mice at the same age. Furthermore, treatment with an inducer of insulin resistance, tumor necrosis factor-α, reduced BRD4 binding and histone acetylation in the gene body of Lpl and its expression. These results indicate that transcriptional elongation of Lpl controlled by BRD4 may be associated with adipocyte differentiation, and that its suppression is potentially associated with insulin resistance of adipocytes.
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Adipocitos/citología , Diferenciación Celular/genética , Epigénesis Genética , Resistencia a la Insulina/genética , Lipoproteína Lipasa/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Células 3T3-L1 , Acetilación/efectos de los fármacos , Adipocitos/efectos de los fármacos , Tejido Adiposo/citología , Tejido Adiposo/efectos de los fármacos , Animales , Azepinas/farmacología , Diferenciación Celular/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/genética , Heterocigoto , Histonas/metabolismo , Ratones , Triazoles/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Epigenetic memories are acquired information included in the chromatin or DNA such as methylation and histone modifications. Recent studies suggest that epigenetic memories determine the types of differentiated cells in each tissue. Moreover, the development of metabolic diseases induced by environmental factors during development is controlled by epigenetic regulation rather than the genetic regulation such as DNA sequence-dependent transcriptional regulation. In general, the demethylation of CpG islands induces histone acetylation, associated changes from heterochromatin to euchromatin, and enhances transcriptional activation. Under the classical model of epigenetics, these changes are induced by the binding of transcriptional factors to cis-elements located on promoter/enhancer regions and the associated binding of histone acetyl-transferase and the transcription initiation complex. This model is dependent on epigenetics in the promoter/enhancer region and is used to explain the induction of genes by lipophilic nutrients such as vitamin A, vitamin D, and unsaturated fatty acid metabolites. However, recent studies have demonstrated that epigenetics in the gene body (transcribed region) also regulate transcription. This novel model postulates that histone acetylation and bromodomain-containing protein 4, which contains two bromodomains to bind acetylated histones, on the gene body enhance transcriptional elongation. Gene expression alterations induced by carbohydrate signals and changes to energy balance in the body accompanied by the intake of major nutrients are also regulated by this model. In this section, we introduce these epigenetic regulations and their relationship with nutrient intake and discuss the link between epigenetic regulation and the development of metabolic diseases.
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Epigénesis Genética/fisiología , Regulación de la Expresión Génica , Interacción Gen-Ambiente , Modelos Genéticos , Fenómenos Fisiológicos de la Nutrición , Animales , Metilación de ADN , Humanos , Regiones Promotoras GenéticasRESUMEN
We previously reported that induction of the adipocyte-specific gene adiponectin (Adipoq) during 3T3-L1 adipocyte differentiation is closely associated with epigenetic memory histone H3 acetylation on the transcribed region of the gene. We used 3T3-L1 adipocytes and Brd4 heterozygous mice to investigate whether the induction of Adipoq during adipocyte differentiation is regulated by histone acetylation and the binding protein bromodomain containing 4 (BRD4) on the transcribed region. Depletion of BRD4 by shRNA and inhibition by (+)-JQ1, an inhibitor of BET family proteins including BRD4, reduced Adipoq expression and lipid droplet accumulation in 3T3-L1 adipocytes. Additionally, the depletion and inhibition of BRD4 reduced the expression of many insulin sensitivity-related genes, including genes related to lipid droplet accumulation in adipocytes. BRD4 depletion reduced P-TEFb recruitment and histone acetylation on the transcribed region of the Adipoq gene. The expression levels of Adipoq and fatty acid synthesis-related genes and the circulating ADIPOQ protein level were lower in Brd4 heterozygous mice than in wild-type mice at 21 days after birth. These findings indicate that BRD4 regulates the Adipoq gene by recruiting P-TEFb onto acetylated histones in the transcribed region of the gene and regulates adipocyte differentiation by regulating the expression of genes related to insulin sensitivity.
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Adiponectina/biosíntesis , Proteínas Nucleares/metabolismo , Factor B de Elongación Transcripcional Positiva/metabolismo , Factores de Transcripción/metabolismo , Activación Transcripcional , Células 3T3-L1 , Animales , RatonesRESUMEN
Environmental stressors during developmental stages are hypothesized to increase the risk of developing metabolic diseases such as obesity, type 2 diabetes, hypertension, and psychiatric diseases during later life. This theory is known as the Developmental Origins of Health and Disease (DOHaD). Recent studies suggest that accumulation of environmental stress, including those during developmental stages, is internalized as acquired information designated as "epigenetic memory." This epigenetic memory is generally indicated as DNA methylation and histone modifications in the chromatin. In general, the demethylation of CpG islands induces histone acetylation and associated changes from heterochromatin to euchromatin, and enhances transcriptional activation. These changes are induced by the binding of transcriptional factors to cis-elements located on promoter and enhancer regions and the associated binding of histone acetyl-transferase and the transcription initiation complex. Recent studies have demonstrated novel epigenetic modifications that regulate transcription elongation steps by activating histone acetylation and bromodomain-containing protein 4, which contains two bromodomains to bind acetylated histones, on the gene body (transcribed region). Gene expression alterations induced by carbohydrate signals and by changes in energy balance in the body are regulated by this model. In addition, induction of many metabolic genes, which are induced or reduced in adulthood by malnutrition during developmental stages, by intake of major nutrients, or development of lifestyle diseases in adulthood, are targeted by these novel epigenetic changes. In the present review, we introduce epigenetic regulations and the relationship with nutrient intake, and discuss links between epigenetic regulation and the development of metabolic diseases according to DOHaD.
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Diabetes Mellitus Tipo 2/genética , Ambiente , Epigénesis Genética , Conducta Alimentaria/psicología , Histonas/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Acetilación , Proteínas de Ciclo Celular , Cromatina/química , Cromatina/metabolismo , Islas de CpG , Metilación de ADN , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Elementos de Facilitación Genéticos , Salud Ambiental , Regulación del Desarrollo de la Expresión Génica , Histonas/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismoRESUMEN
Metformin, α-glucosidase inhibitors (α-GIs), and dipeptidyl peptidase 4 inhibitors (DPP-4Is) reduce hyperglycemia without excessive insulin secretion, and enhance postprandial plasma concentration of glucagon-like peptide-1 (GLP-1) in type-2 diabetes mellitus (T2DM) patients. We assessed add-on therapeutic effects of DPP-4I anagliptin in Japanese T2DM patients treated with metformin, an α-GI miglitol, or both drugs on postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of the appetite-suppressing hormone leptin. Forty-two Japanese T2DM patients with inadequately controlled disease (HbA1c: 6.5%-8.0%) treated with metformin (n=14), miglitol (n=14) or a combination of the two drugs (n=14) received additional treatment with anagliptin (100mg, p.o., b.i.d.) for 52 weeks. We assessed glycemic control, postprandial responses of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), and on plasma concentration of leptin in those patients. Add-on therapy with anagliptin for 52 weeks improved glycemic control and increased the area under the curve of biologically active GLP-1 concentration without altering obesity indicators. Total GIP concentration at 52 weeks was reduced by add-on therapy in groups treated with miglitol compared with those treated with metformin. Add-on therapy reduced leptin concentrations. Add-on therapy with anagliptin in Japanese T2DM patients treated with metformin and miglitol for 52 weeks improved glycemic control and enhanced postprandial concentrations of active GLP-1/total GIP, and reduce the leptin concentration.
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1-Desoxinojirimicina/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Pirimidinas/uso terapéutico , 1-Desoxinojirimicina/farmacología , 1-Desoxinojirimicina/uso terapéutico , Anciano , Glucemia , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada , Femenino , Polipéptido Inhibidor Gástrico/sangre , Péptido 1 Similar al Glucagón/sangre , Humanos , Hipoglucemiantes/farmacología , Leptina/sangre , Masculino , Metformina/farmacología , Persona de Mediana Edad , Pirimidinas/farmacología , Resultado del TratamientoRESUMEN
Prader-Willi syndrome (PWS) is a congenital neurodevelopmental disorder caused by loss of function of paternally expressed genes on chromosome 15 due to paternal deletion of 15q11-q13, maternal uniparental disomy for chromosome 15, or an imprinting mutation. We previously developed a DNA methylation-based PCR assay to identify each of these three genetic causes of PWS. The assay enables straightforward and rapid diagnosis during infancy and therefore allows early intervention such as nutritional management, physical therapy, or growth hormone treatment to prevent PWS patients from complications such as obesity and type 2 diabetes. It is known that various environmental factors induce epigenomic changes during the perinatal period, which increase the risk of adult diseases such as type 2 diabetes and intellectual disabilities. Therefore, a similar preemptive approach as used in PWS would also be applicable to acquired disorders and would make use of environmentally-introduced "epigenomic signatures" to aid development of early intervention strategies that take advantage of "epigenomic reversibility".
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Neurodevelopmental disorders (NDs) are currently thought to be caused by either genetic defects or various environmental factors. Recent studies have demonstrated that congenital NDs can result not only from changes in DNA sequence in neuronal genes but also from changes to the secondary epigenomic modifications of DNA and histone proteins. Thus, epigenomic assays, as well as genomic assays, are currently performed for diagnosis of the congenital NDs. It is recently known that the epigenomic modifications can be altered by various environmental factors, which potentially cause acquired NDs. Furthermore these alterations can potentially be restored taking advantage of use of reversibility in epigenomics. Therefore, epigenome-based early diagnosis and subsequent intervention, by using drugs that restore epigenomic alterations, will open up a new era of preemptive medicine for congenital and acquired NDs.
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Acarbose, an α-glucosidase inhibitor, leads to the production of hydrogen gas, which reduces oxidative stress. In this study, we examined the effects of a single dose of acarbose immediately before a test meal on postprandial hydrogen gas in breath and peripheral blood interleukin (IL)-1ß mRNA expression in Japanese type 2 diabetic patients. Sixteen Japanese patients (14 men, 2 women) participated in this study. The mean±standard deviation age, hemoglobin A1c and body mass index were 52.1±15.4 years, 10.2±2.0%, and 27.7±8.0kg/m(2), respectively. The patients were admitted into our hospital for 2 days and underwent test meals at breakfast without (day 1) or with acarbose (day 2). We performed continuous glucose monitoring and measured hydrogen gas levels in breath, and peripheral blood IL-1ß mRNA levels before (0min) and after the test meal (hydrogen gas: 60, 120, 180, and 300min; IL-1ß: 180min). The induction of hydrogen gas production and the reduction in peripheral blood IL-1ß mRNA after the test meal were not significant between days 1 (without acarbose) and 2 (with acarbose). However, the changes in total hydrogen gas production from day 1 to day 2 were closely and inversely associated with the changes in peripheral blood IL-1ß mRNA levels. Our results suggest that an increase in hydrogen gas production is inversely associated with a reduction of the peripheral blood IL-1ß mRNA level after a single dose of acarbose in Japanese type 2 diabetic patients.
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Acarbosa/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hidrógeno/metabolismo , Interleucina-1beta/sangre , Interleucina-1beta/genética , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Acarbosa/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
It is known that insulin resistance in skeletal muscle induces subsequent metabolic diseases such as metabolic syndrome (MetS). However, which genes are altered in the skeletal muscle by development of insulin resistance in animal models has not been examined. In this study, we performed microarray and subsequent real-time RT-PCR analyses using total RNA extracted from the gastrocnemius muscle of the MetS model, spontaneously hypertensive corpulent congenic (SHR/NDmc-cp) rats, and control Wistar Kyoto (WKY) rats. SHR/NDmc-cp rats displayed overt insulin resistance relative to WKY rats. The expression of many genes related to fatty acid oxidation was higher in SHR/NDmc-cp rats than in WKY rats. Among 18 upregulated genes, putative peroxisome proliferator responsive elements were found in the upstream region of 15 genes. The protein expression of ACOX2, an upregulated gene, and peroxisome proliferator-activated receptor (PPAR) G1, but not of PPARG2, PPARA or PPARD, was higher in the gastrocnemius muscle of SHR/NDmc-cp rats than that in WKY rats. These results suggest that insulin resistance in the MetS model, SHR/NDmc-cp rats, is positively associated with the expression of fatty acid oxidation-related genes, which are presumably PPARs' targets, in skeletal muscle.
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Ácidos Grasos/metabolismo , Resistencia a la Insulina/genética , Insulina/metabolismo , Síndrome Metabólico/genética , Músculo Esquelético/metabolismo , Oxidorreductasas/genética , Receptores Activados del Proliferador del Peroxisoma/genética , Animales , Modelos Animales de Enfermedad , Glucosa/metabolismo , Hipertensión/genética , Hipertensión/metabolismo , Masculino , Síndrome Metabólico/metabolismo , Oxidación-Reducción , Oxidorreductasas/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Regulación hacia ArribaRESUMEN
BACKGROUND AND OBJECTIVES: In this study we examined the effects of switching α-glucosidase inhibitors (α-GI) from acarbose or voglibose to miglitol on glucose fluctuations and circulating concentrations of cardiovascular disease risk factors, such as soluble adhesion molecules (sE-selectin, sICAM-1 and sVCAM-1), a chemokine monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor-1, and fatty acid-binding protein 4, in type 2 diabetic patients for 3 months. METHODS: We enrolled 47 Japanese patients with type 2 diabetes, with HbA1c levels with 7.26 ± 0.5 % (mean ± standard deviation), and who were treated with the highest approved dose of acarbose (100 mg/meal) or voglibose (0.3 mg/meal) in combination with insulin or sulfonylurea. Patients' prior α-GIs were switched to a medium dose of miglitol (50 mg/meal), and the new treatments were maintained for 3 months. Thirty-five patients who completed the 3-month study and provided serum samples were analyzed. RESULTS: The switch to miglitol for 3 months did not affect HbA1c, fasting glucose, triglycerides, total-cholesterol or C-reactive protein levels, or result in any adverse events. Glucose fluctuations were significantly improved by the change in treatment (M-value: 10.54 ± 4.32 to 8.36 ± 2.54), while serum protein concentrations of MCP-1 (525.04 ± 288.06-428.11 ± 163.78 pg/mL) and sE-selectin (18.65 ± 9.77-14.50 ± 6.26 ng/mL) were suppressed. CONCLUSION: Our results suggest that switching from acarbose or voglibose to miglitol for 3 months suppressed glucose fluctuations and serum protein levels of MCP-1 and sE-selectin in type 2 diabetic Japanese patients, with fewer adverse effects.
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1-Desoxinojirimicina/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , 1-Desoxinojirimicina/administración & dosificación , 1-Desoxinojirimicina/farmacología , 1-Desoxinojirimicina/uso terapéutico , Acarbosa/farmacología , Acarbosa/uso terapéutico , Anciano , Pueblo Asiatico , Glucemia/efectos de los fármacos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Quimiocina CCL2/sangre , Quimioterapia Combinada , Selectina E/sangre , Femenino , Inhibidores de Glicósido Hidrolasas/administración & dosificación , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Inositol/análogos & derivados , Inositol/farmacología , Inositol/uso terapéutico , Insulina/administración & dosificación , Insulina/uso terapéutico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Neurodevelopmental disorders, such as autism, are complex entities that can be caused by biological and social factors. In a subset of patients with congenital neurodevelopmental disorders, clear diagnosis can be achieved using DNA sequence-based analysis to identify changes in the DNA sequence (genetic variation). However, it has recently become clear that changes to the secondary modifications of DNA and histone structures (epigenetic variation) can also cause neurodevelopmental disorders via alteration of neural gene function. Moreover, it has recently been demonstrated that epigenetic modifications are more susceptible to alterations induced by environmental factors than are DNA sequences, and that some drugs commonly used reverse mental-stress induced alterations to histone modifications in neural genes. Therefore, application of diagnostic assays to detect epigenetic alterations will provide new insight into the characterization and treatment of neurodevelopmental disorders.
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Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/etiología , Epigénesis Genética , Epigenómica , Animales , Metilación de ADN , Epigenómica/métodos , Femenino , Histonas/metabolismo , Humanos , MasculinoRESUMEN
Ectopic adipose tissue in skeletal muscle is implicated in the development of insulin resistance, which is frequently induced by abnormal dietary habits such as excessive eating and a high-fat diet. However, the characteristics of ectopic adipocytes are unknown. In this study, we investigated the characteristics of ectopic adipocytes in the skeletal muscle of spontaneously hypertensive corpulent congenic (SHR/NDmc-cp) rats as a model of insulin resistance from excessive eating. SHR/NDmc-cp rats displayed overt insulin resistance with high plasma glucose, insulin, and triacylglycerol concentrations relative to control Wistar-Kyoto (WKY) rats. In contrast, streptozotocin (STZ)-treated WKY rats had high glucose but low insulin concentrations. Ectopic adipocytes were found around blood vessels in the gastrocnemius in SHR/NDmc-cp rats. Areas of perivascular adipocytes and protein expression of resistin were greater in SHR/NDmc-cp rats than in control and STZ-treated WKY rats. The level of the phosphorylated (active) form of endothelial nitric oxide synthase in the gastrocnemius was lower in SHR/NDmc-cp rats than in the other groups. Insulin-resistant SHR/NDmc-cp rats showed enlarged perivascular adipocytes and greater endothelial cell dysfunction in the gastrocnemius.
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Adipocitos/citología , Células Endoteliales/citología , Resistencia a la Insulina , Músculo Esquelético/metabolismo , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Dieta Alta en Grasa/efectos adversos , Insulina/sangre , Masculino , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Estreptozocina/administración & dosificación , Estreptozocina/efectos adversos , Triglicéridos/sangreRESUMEN
OBJECTIVE: Faster eating and elevated circulating activity of alanine aminotransferase (ALT), a marker for liver injury, are risk factors for the development of obesity and type 2 diabetes mellitus, and their complications. The aim of this study was to examine the association between self-reported eating rate and circulating ALT activity in apparently healthy middle-aged Japanese women. METHODS: We conducted a cross-sectional study of 900 apparently healthy women ages 40 to 64 y (mean ± SD, 53.1 ± 7.1 y) who participated in health check-ups in Japan. We analyzed their clinical serum parameters and lifestyle factors, including self-reported eating rate. Associations between liver injury markers (ALT, γ-glutamyl transpeptidase [GTP], and aspartate aminotransferase [AST]), other clinical parameters and lifestyle factors were analyzed using Tukey's multiple range test following analysis of variance and analysis of covariance for three groups, divided by self-reported eating rates. The associations between self-reported faster eating and ALT activity and lifestyle factors were analyzed by multivariate logistic regression analyses. RESULTS: ALT activity, but not γ-GTP or AST activities, was higher in participants who reported relatively fast/very fast eating than in those who reported medium eating after adjusting for age, alcohol intake, energy intake, smoking, and physical activity. The odds ratio of eating rate for ALT activity in T3 (18-128 U/L) compared with T1 (3-12 U/L) was 1.67 (P < 0.01), but the association disappeared after adjustment for body mass index (BMI). CONCLUSIONS: ALT activity is positively associated with faster eating, but is dependent on BMI in middle-aged, apparently healthy Japanese women.