RESUMO
PURPOSE: Poor sleep quality has been reported to be a risk factor for cardiovascular disease, diabetes, and metabolic syndrome, as well as mental disorders including depression and anxiety. However, few studies have investigated the association between sleep quality and diet in young males. We aimed to assess this association, adjusting for psychological factors. METHODS: In this study, a total of 124 male Japanese students were analyzed. Sleep quality, diet, and psychological symptoms were assessed using self-reported questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), brief-type self-administered diet history questionnaire (BDHQ), 12-item General Health Questionnaire (GHQ12), and State-Trait Anxiety Inventory (STAI) A-Trait scale. RESULTS: Among participants, 40% exhibited a PSQI total score ≥ 6, indicating poor sleep quality. Poor sleep quality was associated with poor mental health status and higher levels of anxiety. After adjusting for covariates including these psychological factors, poor sleep quality was significantly associated with low intakes of fat, beta-carotene, retinol, alpha-tocopherol, vitamin K, vitamin B1, daidzein, genistein, and iron. Poor sleep quality was also associated with low intake of pulses, fat and oil, as well as high intakes of sugar-sweetened beverages. CONCLUSIONS: Our findings demonstrated that sleep quality among young Japanese males was associated with specific dietary features, independently of psychological status, which may help to elucidate the mechanisms underlying the link between sleep and sleep-related diseases.
Assuntos
Dieta/estatística & dados numéricos , Transtornos do Sono-Vigília/epidemiologia , Adulto , Ansiedade/epidemiologia , Comorbidade , Humanos , Japão/epidemiologia , Masculino , Adulto JovemRESUMO
Chronic hyperglycemia has deleterious effects on pancreatic ß-cell function, a process known as glucotoxicity. This study examined whether chronic high glucose (CHG) induces cellular hypoxia in rat INS-1 ß cells, and whether hyperoxia (35% O2) can reverse glucotoxicity-induced inhibition of insulin secretion. CHG (33.3 mm, 96 h) reduced insulin secretion, and down-regulated insulin and pancreatic duodenal homeobox factor 1 gene expression. CHG also increased intracellular pimonidazole-protein adducts, a marker for hypoxia. CHG also enhanced hypoxia-inducible factor 1α (HIF-1α) protein expression and its DNA-binding activity, which was accompanied by a decrease in mRNA expression of glucose transporter 2 (GLUT2), glucokinase and uncoupling protein-2 and an increase in mRNA expression of GLUT1 and pyruvate dehydrogenase kinase 1. Hyperoxia restored the decrease in insulin secretion and the gene expression except for GLUT2, and suppressed intracellular hypoxia and HIF-1α activation. These results suggest that glucotoxicity may cause ß-cell hypoxia. Hyperoxia might prevent glucotoxicity-induced ß-cell dysfunction and improve insulin secretion.
Assuntos
Glucose/efeitos adversos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Oxigênio/metabolismo , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Proteínas de Drosophila/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucoquinase/genética , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 2/genética , Proteínas de Homeodomínio/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Secreção de Insulina , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Nitroimidazóis/farmacologia , Ratos , Transativadores/genética , Proteína Desacopladora 2RESUMO
The aim of this study was to investigate the genetic background of familial clustering of diabetes using genome-wide linkage analysis combined with exome sequencing. We recruited a Japanese family with a 3-generation history of diabetes. The family comprised 16 members, 13 having been diagnosed with diabetes. Nine members had been diagnosed before the age of 40. Linkage analysis was performed assuming an autosomal dominant model. Linkage regions were observed on chromosomes 4q34, 5q11-q13, and 12p11-q22 and the logarithm of odds (LOD) scores were 1.80. To identify the susceptibility variants, we performed exome sequencing of an affected family member. We predicted that the familial clustering of diabetes is caused by a rare non-synonymous variant, and focused our analysis on non-synonymous variants absent in dbSNP131. Exome sequencing identified 10 such variants in the linkage regions, 7 of which were concordant with the affection status in the family. One hundred five normal subjects and 67 lean diabetes subjects were genotyped for the 7 variants; the only variant found to be significantly more frequent in the diabetes subjects than in the normal subjects was the N1072K variant of the early endosome antigen 1 (EEA1) gene (0 in normal subjects and 4 in diabetes subjects, p=0.022). We therefore propose that the N1072K variant of the EEA1 gene is a candidate mutation for susceptibility to diabetes in the Japanese population.
Assuntos
Diabetes Mellitus Tipo 2/genética , Exoma/genética , Ligação Genética , Mutação , Proteínas de Transporte Vesicular/genética , Diabetes Mellitus Tipo 2/patologia , Predisposição Genética para Doença , Genoma Humano , Humanos , Linhagem , Análise de Sequência de DNARESUMO
The aim of this study was to investigate the effects of increased dietary protein in daily-life settings in Japan for 6 months on the activities of daily living (ADL) in adults aged 75 or older at nutritional risk. The study was an open-label, exploratory, randomized controlled trial conducted at seven hospitals in Japan. The study participants were adults aged 75 or older who were hospitalized for treatable cancer, pneumonia, fractures, and/or urinary-tract infection at nutritional risk. The primary outcome was change in grip strength, skeletal muscle, and ADL indices (Barthel index, Lawton score). One hundred sixty-nine patients were randomly assigned to the intensive care (IC) or standard care (SC) group; the protein intake goals (g/kgw/day) were 1.5 for IC and 1.0 for SC. There was a significant improvement in grip strength only in the IC group (1.1 kg: 95% CI 0.1 to 2.1) (p = 0.02). While the skeletal muscle index and ADL indices were not significantly improved in either group, the improvement ratio tended to be greater in the IC group. There was no decrease in renal function in either group. Thus, intervention of increased dietary protein in daily-life settings for 6 months in adults aged 75 or older with treatable cancer, pneumonia, fractures, and/or urinary-tract infection and at nutritional risk may be effective in ameliorating loss of muscle strength.
Assuntos
Atividades Cotidianas , Fraturas Ósseas , Humanos , Adulto , Proteínas Alimentares , Projetos de Pesquisa , Cuidados CríticosRESUMO
BACKGROUND: The purpose of this study is to clarify the correlations between the expression of membrane-bound estrogen receptor-α (mERα) and epidermal growth factor receptor (EGFR) mutation and clinicopathological factors, especially in relation to the prognosis, in patients with lung adenocarcinoma. METHODS: We conducted a retrospective review of the data of 51 lung adenocarcinoma patients with tumors measuring less than 3 cm in diameter. Immunohistochemical staining for mERα expression and detection of the EGFR mutation status were performed. RESULTS: Among the 51 patients, the tumors in 15 showed both mERα expression and EGFR mutation. ("double positive") Significant associations between "double positive" and vascular invasion, vascular endothelial growth factor expression, and Ki-67 expression were observed. A multivariate analysis revealed that only "double positive" was an independent risk factor influencing the recurrence-free survival. CONCLUSIONS: Presence of mERα expression together with EGFR mutation was found to be an independent prognostic factor for survival in patients with lung adenocarcinoma, suggesting cross-talk between mERα and EGFR mutation.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Receptores ErbB/genética , Receptor alfa de Estrogênio/metabolismo , Neoplasias Pulmonares/metabolismo , Mutação , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Feminino , Seguimentos , Marcadores Genéticos , Humanos , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVES: The mitochondrial uncoupling proteins UCP2 and UCP3 are implicated in energy metabolism and regulation of reactive oxygen species, which are closely involved in autonomic nervous system function. Heart rate variability (HRV) reflects cardiac autonomic regulation and has been used to evaluate dysfunction of the autonomic nervous system in hypertension and cardiovascular diseases. We examined the association between polymorphisms in the UCP2 and UCP3 genes and HRV in healthy young Japanese men. METHODS: The 45 bp insertion/deletion polymorphism in exon8 of UCP2 and the -55C/T polymorphism in the UCP3 promoter region were genotyped (n = 255). Cardiac autonomic function was evaluated by power spectral analysis of HRV during supine rest and in a standing position. Low-frequency (<0.15 Hz) and high-frequency (>0.15 Hz) components of HRV were quantified by frequency domain analysis. RESULTS: The I/I genotype of the UCP2 45 bp insertion/deletion polymorphism was associated with relatively higher blood pressure and HRV sympathetic indices (low frequency percentage and low frequency:high frequency ratio) at supine rest. For the -55C/T polymorphism of UCP3, individuals carrying the -55T allele had significantly lower HRV sympathetic indices, but higher HRV parasympathetic indices (high frequency and high frequency percentage), than carriers of the C/C genotype at standing. Both UCP2 and UCP3 polymorphisms were significantly associated with a third-degree family history of hypertension, diabetes, and obesity. Additionally, carriers of the UCP2 45 bp I allele -UCP3 -55C/C combined genotype had the lowest HRV sympathetic and the highest HRV parasympathetic indices at standing among the combined genotypes. CONCLUSION: UCP2 and UCP3 polymorphisms were associated with HRV in young and healthy states, suggesting a significant relationship between autonomic cardiovascular regulation and UCP2/UCP3 polymorphisms.
Assuntos
Vias Autônomas/fisiologia , Frequência Cardíaca/genética , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Adolescente , Adulto , Povo Asiático , Humanos , Mutação INDEL , Japão , Masculino , Polimorfismo Genético , Regiões Promotoras Genéticas , Proteína Desacopladora 2 , Proteína Desacopladora 3 , Adulto JovemRESUMO
1. Dipeptidyl peptidase IV (DPP-IV) is a new drug target in the treatment of Type 2 diabetes. Dipeptidyl peptidase IV enzyme activity is significantly altered in Type 2 diabetic patients with hyperglycaemia, but the underlying molecular mechanisms remain unclear. 2. The first aim of the present study was to clarify whether glucose regulates DPP-IV enzyme activity. To address this, DPP-IV gene expression and enzyme activity were measured in Caco2 cells cultured in the presence of low (2.5 mmol/L) or high (16.7 mmol/L) concentrations of glucose. We observed that high glucose inhibited DPP-IV gene expression and enzyme activity. 3. The second aim of the present study was to investigate whether hepatocyte nuclear factor (HNF)-1alpha contributes to glucose regulation of DPP-IV gene expression. To explore this question, associations between the gene expression of DPP-IV and HNF-1alpha were examined in Caco-2 cells cultured in the presence of low (2.5 mmol/L) or high (16.7 mmol/L) glucose. We found that the pattern of glucose-regulated DPP-IV gene expression is similar to that of HNF-1alpha. Moreover, to elucidate whether glucose regulation of DPP-IV gene expression is affected when HNF-1alpha is inhibited, we produced two stable cell lines in which a dominant-negative mutant HNF-1alphaR271G or basic vectors were stably expressed. We found that glucose regulation of DPP-IV gene expression was compromised in HNF-1alphaR271G cells, but was well maintained in basic vector cells. 4. These results suggest that glucose regulation of DPP-IV gene expression is mediated by HNF-1alpha.
Assuntos
Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Glucose/fisiologia , Fator 1-alfa Nuclear de Hepatócito/fisiologia , Mucosa Intestinal/enzimologia , Células CACO-2 , Dipeptidil Peptidase 4/biossíntese , Humanos , Mucosa Intestinal/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
A 78-year-old male was admitted to our hospital complaining of anorexia. Endoscopy revealed gastric cancer with pyloric stenosis and MRI showed multiple metastasis of thoracic vertebral body. Blood examinations showed DIC and CEA was 118.3 ng/mL. Sternum bone marrow biopsy revealed poorly-differentiated adenocarcinoma. Chemotherapy with sequential therapy consisting of MTX and 5-FU (MTX 150 mg/body, 5-FU 1,000 mg/body) was performed in addition to anti-DIC therapy. After 3 courses, DIC was resolved. Then, we changed the chemotherapy regimen to S-1/ paclitaxel (S-1 60 mg/body, PTX 60 mg/body). After 2 courses, the primary tumor was remarkably reduced and CEA decreased to within normal limits. After discharge, the patient has been undergoing chemotherapy on an outpatient basis.
Assuntos
Neoplasias da Medula Óssea/tratamento farmacológico , Carcinoma/tratamento farmacológico , Coagulação Intravascular Disseminada/complicações , Fluoruracila/uso terapêutico , Metotrexato/análogos & derivados , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Neoplasias da Medula Óssea/sangue , Neoplasias da Medula Óssea/secundário , Neoplasias da Medula Óssea/cirurgia , Antígeno Carcinoembrionário/sangue , Carcinoma/sangue , Carcinoma/secundário , Carcinoma/cirurgia , Humanos , Masculino , Metotrexato/uso terapêutico , Neoplasias Gástricas/sangue , Neoplasias Gástricas/complicaçõesRESUMO
BACKGROUND: The beta1- and beta2-adrenergic receptors (ARs) coexist in the human heart and control sympathetic responses. Several functional genetic variations in the beta-AR genes (ADRB1 or ADRB2) have been identified and implicated as causes of hypertension and cardiovascular disease. We assessed the relationship between 4 representative genetic polymorphisms of beta-AR (Ser49Gly and Arg389Gly in beta1-AR, Arg16Gly and Gln27Glu in beta2-AR) and autonomic nervous system (ANS) function in healthy young Japanese males. METHODS: One hundred forty-nine subjects were genotyped for each beta-AR polymorphism and underwent evaluation of ANS function by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. The low-frequency (LF; <0.15 Hz) and high-frequency (HF; >0.15 Hz) components of HRV were quantified by frequency domain analysis and expressed in absolute and normalized units. RESULTS: The beta2-AR Arg16 homozygous group had a significantly lower diastolic and mean blood pressure than the Gly16 group in both Arg16Gly individual and Gln27Glu polymorphism combined diplotype-based analyses. In a supine rest position, subjects homozygous for the beta2-AR Arg16 allele had significantly lower HRV sympathetic indices (LF [%] and LF/HF ratio) but higher HRV parasympathetic indices (HF [%]) than the Gly16 allele carriers. Meanwhile, the beta2-AR Glu27 allele was significantly associated with higher HRV LF power than were Gln27 homozygous subjects. In the analysis of gene-gene interaction, the effects of the beta2-AR Arg16 homozygotes on HRV were more apparent in the presence of the beta1-AR Gly389 allele. No independent associations were observed between the beta1-AR Ser49Gly or Arg389Gly genotypes and HRV indices. CONCLUSIONS: The Arg16Gly polymorphism of the beta2-AR is related to the modulation of sympathovagal balance, and beta2-AR Glu27 allele carriers potentially have increased autonomic activity. Thus, beta-AR genotype-related differences in basic receptor function cause phenotypic differences in cardiac ANS function.
Assuntos
Povo Asiático/genética , Sistema Nervoso Autônomo/fisiologia , Coração/fisiologia , Polimorfismo Genético/fisiologia , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genética , Adolescente , Adulto , Arginina/genética , Eletrocardiografia , Frequência do Gene , Genótipo , Glicina/genética , Frequência Cardíaca/fisiologia , Humanos , Desequilíbrio de Ligação , Masculino , Postura/fisiologia , Sistema Nervoso Simpático/fisiologiaRESUMO
Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Obesidade/genética , Obesidade/fisiopatologia , Polimorfismo Genético/genética , Receptores Adrenérgicos/genética , Animais , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/fisiologia , HumanosRESUMO
CONTEXT: The renin-angiotensin system (RAS) interacts with the autonomic nervous system (ANS) in the regulation of blood pressure and cardiovascular function. Several genetic polymorphisms in the RAS have been identified and have been implicated as a cause of hypertension and cardiovascular disease. OBJECTIVE: The aim of the present study was to evaluate the relation between genetic polymorphisms of the RAS (M235T of AGT gene, insertion/deletion of ACE gene, A1166C of AT1R gene, and A1675G of AT2R gene) and ANS function. SUBJECTS: One hundred forty-nine young healthy Japanese males were genotyped for each RAS polymorphism. MAIN OUTCOME MEASURES: ANS function was evaluated by power spectral analysis of heart rate variability (HRV) during supine rest and in a standing position. RESULTS: In a supine position, subjects homozygous for the AGT 235T allele had a higher HRV sympathetic index than 235M allele carriers, whereas the orthostatic change in this index was relatively blunted in AGT 235TT carriers. In the analysis of gene-gene interaction, these effects of the AGT 235T homozygotes on HRV sympathetic index were more apparent in the presence of the ACE D allele. Meanwhile, the AT1R 1166C allele was significantly associated with higher HRV low-frequency power and sympathetic index in a standing position. These data suggest that the AGT M235T polymorphism is associated with sympathetic predominance at rest, and AT1R 1166C allele carriers have potentially increased sympathetic response. CONCLUSIONS: Cardiac autonomic function can be modulated by genetic variation in the RAS even in young and healthy states.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Variação Genética , Sistema Renina-Angiotensina/genética , Adolescente , Adulto , Angiotensinogênio/genética , Povo Asiático , Frequência do Gene , Saúde , Humanos , Masculino , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genéticaRESUMO
Hepatocyte nuclear factor (HNF)-1alpha and HNF-1beta are concerned in sucrase-isomaltase (SI) gene expression, and directly bind two sites (SIF2, SIF3) of the promoter of the SI gene. However, it is not completely clear that HNF-1alpha and HNF-1beta play a role in regulation of SI gene expression. To clarify mechanisms of SI gene expression regulated by HNF-1alpha and HNF-1beta, we established four stable cell lines based on enterocyte-like cell line Caco-2, in which wild HNF-1alpha or wild HNF-1beta, or else mutant HNF-1alphaT539fsdelC or mutant HNF-1betaR177X was overexpressed. In the HNF-1alphaT539fsdelC cells and HNF-1betaR177X cells, but not in the wild HNF-1alpha cells and wild HNF-1beta cells, SI gene expression and enzyme activity were significantly diminished compared with that in Caco-2 cells. Moreover, to clarify whether or not stable cell differentiation was influenced by overexpression of these transgenes, alkaline phosphatase (ALP) gene expression and enzyme activity were measured. There were no changes in ALP gene expression or enzyme activity in these cells. These observations suggest that mutant HNF-1alphaT539fsdelC and mutant HNF-1betaR177X inhibits SI gene at the transcriptional level, resulting in decreased SI enzyme activity in Caco-2 cells. We propose that both HNF-1alpha and HNF-1beta would contribute to constitutive expression of the SI gene in the differentiated state in Caco-2 cells.
Assuntos
Expressão Gênica/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-beta Nuclear de Hepatócito/genética , Complexo Sacarase-Isomaltase/genética , Fosfatase Alcalina/metabolismo , Células CACO-2 , Genoma Humano/genética , Humanos , Mutação/genética , RNA Mensageiro/genéticaRESUMO
OBJECTIVE: To investigate the characteristics of isolated impaired glucose tolerance (IGT) and isolated impaired fasting glucose (IFG), we analyzed the factors responsible for elevation of 2-hour postchallenge plasma glucose (2 h PG) and fasting plasma glucose (FPG) levels. METHODS: We investigated the relationship between 2 h PG and FPG levels who underwent 75 g OGTT in 5620 Japanese subjects at initial examination for medical check-up. We compared clinical characteristics between isolated IGT and isolated IFG and analyzed the relationships of 2 h PG and FPG with clinical characteristics, the indices of insulin secretory capacity, and insulin sensitivity. RESULTS: In a comparison between isolated IGT and isolated IFG, insulinogenic index was lower in isolated IGT than that of isolated IFG (0.43 ± 0.34 versus 0.50 ± 0.47, resp.; p < 0.01). ISI composite was lower in isolated IFG than that of isolated IGT (6.87 ± 3.38 versus 7.98 ± 4.03, resp.; p < 0.0001). In isolated IGT group, insulinogenic index showed a significant correlation with 2 h PG (r = -0.245, p < 0.0001) and had the strongest correlation with 2 h PG (ß = -0.290). In isolated IFG group, ISI composite showed a significant correlation with FPG (r = -0.162, p < 0.0001) and had the strongest correlation with FPG (ß = -0.214). CONCLUSIONS: We have elucidated that decreased early-phase insulin secretion is the most important factor responsible for elevation of 2 h PG levels in isolated IGT subjects, and decreased insulin sensitivity is the most important factor responsible for elevation of FPG levels in isolated IFG subjects.
Assuntos
Glicemia/metabolismo , Jejum/sangue , Intolerância à Glucose/sangue , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Intolerância à Glucose/diagnóstico , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Secreção de Insulina , Japão , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
BACKGROUND: The 52-week monotherapy with the dipeptidyl peptidase-4 inhibitor sitagliptin and the sulphonylurea glimepiride on early-phase insulin secretion in Japanese patients with type 2 diabetes mellitus (T2DM) is not known. METHODS: A randomized, parallel-group, open-label trial was conducted at 18 centers between February, 2011 and March, 2013. 171 outpatients with T2DM were recruited and randomly assigned to glimepiride or sitagliptin by minimization. Doses of glimepiride (0.25-1.0 mg/day) and sitagliptin (25-100 mg/day) were adjusted for hemoglobin A1c (HbA1c) > 6.9 %. Analyses were performed on full analysis set (FAS) of randomized subjects taking medications as allocated, and underwent 75 g oral glucose tolerance test (OGTTs) before and after treatment. The primary outcome was insulinogenic index to quantify early-phase insulin secretion after treatment, which was evaluated by analysis of covariance (ANCOVA). RESULTS: Of 171 enrolled subjects, 68 in the sitagliptin group and 65 in the glimepiride group were included in the FAS (mean age, 64 years; baseline (HbA1c), 7.4 %). The primary outcome revealed a significantly higher insulinogenic index in the sitagliptin group than that in the glimepiride group (p = 0.036). Sitagliptin also reduced plasma glucose levels at 60 and 120 min during OGTT compared with glimepiride, while achieving a similar improvement in HbA1c during treatment. Body weight did not change in either of the two groups, and one case of hypoglycemia was observed in the glimepiride group. CONCLUSIONS: Sitagliptin shows better effects on insulinogenic index after 52-week treatment compared with glimepiride in Japanese patients with T2DM. Trial registration University hospital Medical Information Network (UMIN) Clinical Trials Registry, No.00004791.
RESUMO
BACKGROUND: The T allele of the C825T polymorphism of the G protein beta3 subunit gene (GNB3) is reported to be associated with increased intracellular signal transduction and the prevalence of essential hypertension. Because the two major receptors in the autonomic nervous system (ANS), the adrenergic and muscarinic acetylcholine receptors, are G protein-coupled receptors, it was expected that the GNB3 C825T polymorphism was associated with ANS function. In the present study, we have investigated the association of this polymorphism with ANS in young, healthy Japanese male individuals. METHODS: A total of 94 young, healthy subjects underwent the genotyping for the GNB3 C825T polymorphism and electrocardiogram R-R interval power spectral analysis in supine rest and standing positions. RESULTS: There were no significant differences among genotypes in any of the characteristics investigated (body mass index, blood pressure, plasma glucose, insulin, lipids, and family history of hypertension, diabetes, or obesity). However, in power spectral analysis of heart rate variability, the very-low-frequency component when standing was higher in TT carriers than in CC carriers, and TT and CT carriers had a significantly higher sympathetic nervous system (SNS) index and lower parasympathetic nervous system (PNS) index when standing than CC carriers. In addition, we found that TT carriers showed no chronological variations in either SNS or PNS index after postural change. CONCLUSIONS: These observations suggested that GNB3 C825T polymorphism is associated with ANS in youth. These findings raise the possibility that individuals who are T allele carriers are at increased risk for developing hypertension in relation to ANS function.
Assuntos
Povo Asiático/genética , Sistema Nervoso Autônomo/fisiologia , Proteínas Heterotriméricas de Ligação ao GTP/genética , Polimorfismo Genético , Adulto , Alelos , Citosina , Eletrocardiografia , Frequência do Gene , Frequência Cardíaca/fisiologia , Heterozigoto , Humanos , Masculino , Sistema Nervoso Parassimpático/fisiologia , Postura/fisiologia , Valores de Referência , Sistema Nervoso Simpático/fisiologia , TiminaRESUMO
In this study, we investigated the effects of endocrine disrupters bisphenol A (BPA) and nonylphenol (NP) on insulin secretion from rat pancreatic islets. Following acute exposure to BPA and NP, neither BPA nor NP (0.1, 1, 10, 100 and 1000 microg/l) affected insulin secretion in concentrations of 16.7 mM glucose. However, insulin secretion following long-term exposure to BPA or NP for 24 h in 16.7 mM glucose was significantly higher than without exposure. To determine whether increased insulin secretion resulting from long-term exposure to BPA and NP is induced via intracellular estrogen receptors, we blocked the cytosolic/nuclear estrogen receptors, using actinomycin-D (Act-D), an inhibitor of RNA synthesis, and ICI 182,780 (ICI), an estrogen receptor inhibitor. Following long-term exposure to BPA (10 microg/l) or NP (10 microg/l), Act-D or ICI treatment eliminated the facilitation of insulin secretion. In conclusion, we have demonstrated for the first time that long-term exposure to endocrine disrupters, such as BPA and NP, promotes in vitro insulin secretion from the pancreatic islets, via cytosolic/nuclear estrogen receptors.
Assuntos
Estradiol/análogos & derivados , Estrogênios não Esteroides/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Fenóis/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Animais , Compostos Benzidrílicos , Dactinomicina/farmacologia , Relação Dose-Resposta a Droga , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Fulvestranto , Glucose/metabolismo , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: Isolated postchallenge hyperglycemia (IPH), defined as fasting plasma glucose (FPG) level <7.0 mmol/l and 2-h plasma glucose (PG) level >/=11.1 mmol/l, is a subtype of early-stage diabetes. This study evaluates the metabolic profiles of insulin secretion and insulin sensitivity in IPH to clarify the factors responsible for development of this form of type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted cross-sectional analysis of 231 Japanese men aged 20-70 years. The subjects were classified into the following three groups, based on the results of a 75-g oral glucose tolerance test (OGTT): 1) normal glucose tolerance (NGT), defined as FPG level <6.1 mmol/l and 2-h PG level <7.8 mmol/l (n = 89); 2) impaired glucose tolerance (IGT), defined as FPG level <7.0 mmol/l and 2-h PG level of 7.8-11.1 mmol/l (n = 94); and 3) IPH (n = 48). We compared the three groups for insulin secretion (insulinogenic index) and insulin sensitivity (index of insulin resistance using homeostasis model assessment [HOMA-IR]). RESULTS: The insulinogenic index in IPH was the lowest of the three groups (P < 0.001 versus NGT). The HOMA-IR in the IGT and IPH groups were significantly higher than in the NGT group (P < 0.001), but both were similar. By linear regression analysis, the insulinogenic index rather than fasting insulin or HOMA-IR was the more significant factor in the 2-h PG level in IGT and IPH. CONCLUSIONS: Subjects with IPH exhibited distinctly impaired early-phase insulin secretion and only mild insulin resistance, indicating that reduced insulin secretion is the primary determinant of deterioration from NGT to IGT and IPH in development of type 2 diabetes in these subjects.
Assuntos
Glicemia/metabolismo , Teste de Tolerância a Glucose/métodos , Hiperglicemia/sangue , Adulto , Idoso , Povo Asiático , Estudos Transversais , Diabetes Mellitus/genética , Família , Jejum , Hemoglobinas Glicadas/análise , Glicosúria , Humanos , Insulina/sangue , Japão , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Valores de Referência , Análise de RegressãoRESUMO
While renal cell carcinoma frequently metastasizes to the lung, solitary pleural metastasis without lung involvement is extremely rare. A 69-year-old man was admitted to our hospital with a solitary pleural metastasis 6 years after surgery for renal cell carcinoma. Needle biopsy was performed, and the tumor was diagnosed as a metastasis of renal cell carcinoma. The pleural tumor was surgically resected. The patient received interferon-α as postoperative therapy. He has been alive for 9 years without recurrence. Only 11 cases of solitary pleural metastasis have been reported thus far, and of these, 7 involved a large amount of pleural effusion resulting in a poor prognosis. This is the first reported case of solitary pleural metastasis from renal cell carcinoma, which was curatively resected, as indicated by long-term survival.
RESUMO
The immune microenvironment of primary tumors has been reported to be a prognostic factor. We previously reported that the tumor-infiltrating regulatory T cell (Treg) count was positively correlated with the intratumoral cyclooxygenase-2 (COX-2) expression level and was associated with a poor survival among patients with non-small cell lung cancer (NSCLC). Recently, numerous single nucleotide polymorphisms (SNPs) in the COX-2 gene have been identified, and these SNPs may contribute to differential gene expression and enzyme activity levels. However, whether COX-2 genetic variants influence the functions of COX-2 in NSCLC remains unclear. Eighty NSCLC patients who underwent a complete resection at our institute were enrolled. We extracted DNA from the peripheral blood and identified five different COX-2 SNPs. The correlations between the COX-2 SNPs and the expression levels of COX-2, Tregs and Ki-67 were studied. The prognostic significance of the COX-2 SNPs was also evaluated. COX-2 SNPs were not correlated with the expression of COX-2. However, for the COX-2 -1195G/A polymorphism, the AA genotype group had a significantly higher Treg score. Furthermore, the AA group had a significantly higher Treg score regardless of the COX-2 expression level. The COX-2 -1195AA genotype group tended to have a shorter disease-free survival period than the GA/GG group. In conclusion, the COX-2 -1195G/A polymorphism influences the infiltration of Tregs into NSCLC, and the COX-2 SNP factor may be a prognostic factor reflecting Treg infiltration in NSCLC.
Assuntos
Adenocarcinoma/enzimologia , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Ciclo-Oxigenase 2/genética , Neoplasias Pulmonares/enzimologia , Linfócitos T Reguladores/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Expressão Gênica , Estudos de Associação Genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
INTRODUCTION: Several cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown. METHODS: This study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis. RESULTS: We demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a. CONCLUSION: In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.