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1.
Cell Physiol Biochem ; 52(6): 1398-1411, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075190

RESUMO

BACKGROUND/AIMS: Visfatin is known to act as a mediator in several metabolic disorders, such as obesity, diabetes, and cardiovascular diseases. This study aimed to investigate the effect of visfatin on the adhesion of THP-1 monocytes to human vascular endothelial cells and the underlying mechanism. METHODS: Monocytes adhesion to endothelial cells was determined by using fluorescence-labeled monocytes. ICAM-1 and VCAM-1 expression in endothelial cells were measured by western blotting. Production of reactive oxygen species (ROS) was measured by using a fluorescent dye. The amounts of nuclear factor-kappa B (NF-κB) and phosphorylation of inhibitory factor of NF-κB (IκB) were determined by using western blot analysis. The translocation of NF-κB from the cytoplasm to the nucleus was determined by using immunofluorescence. RESULTS: Here we showed that visfatin significantly caused the upregulation of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells, as well as enhanced monocyte adhesion to endothelial cells. Moreover, we found that inhibition of PI3K, Akt, and p38 MAPK activation significantly prevented visfatin-enhanced expression of ICAM-1 and VCAM-1 and monocyte adhesion to endothelial cells. Visfatin enhanced ROS production and IKK/NF-кB activation and then led to upregulation of ICAM-1 and VCAM-1 and enhanced monocyte adhesion to endothelial cells. These effects were also p38/PI3K/Akt-dependent. CONCLUSION: These results demonstrated that visfatin promoted monocyte-endothelial cell adhesion by increasing ICAM-1 and VCAM-1 expression via the activation of p38/PI3K/Akt signaling and downstream ROS production and IKK/NF-кB activation.


Assuntos
Adesão Celular/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Monócitos/citologia , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
J Chin Med Assoc ; 81(10): 884-891, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30017812

RESUMO

BACKGROUND: The aim of this study was to identify genotypic and phenotypic cardiovascular metabolic risk factors, and to establish risk models of diseases, including diabetes mellitus, cardiovascular disease, stroke, kidney dysfunction and psychiatric disorders, in Taiwanese adults. METHODS: In 2009, a community-based cohort study was initiated in the Shipai area of the Shilin and Beitou districts in Taipei. Residents were randomly sampled by age (young adults: 35-44 years and middle-aged adults: 45-55 years) and urbanization (rural and urban). Residents who agreed to participate were scheduled to receive examinations (physical and blood) and answer questionnaires. A ten-year follow-up is anticipated. Metabolic syndrome (MetS) was defined based on the Adult Treatment Panel III guidelines, and individuals with only one or two of the five MetS components was identified for prevention target. RESULTS: The response rate of the 9000 invited residents was 10.1%. After screening, 906 participants were enrolled. While 31.0% (281) had no MetS components, 29.1% (264) had only one, and 22.0% (199) had two. MetS with at least three components was diagnosed in 17.9% (162) of the cohort. Concerning gender difference, 25.4% of men and 13.2% of women had MetS (p < 0.001). The percentage of MetS was higher in middle-aged participants than in young adults (20.5% versus 13.4%, p = 0.008). Forty-six percent of participants had central obesity. After adjusting for gender, age, and urbanization, the central obesity odds ratio for MetS was 23.7, with a 95% confidence internal of 13.1-42.7. CONCLUSION: Our preliminary results revealed a high MetS percentage among young and middle-aged adults in Taiwan, with central obesity being a particularly urgent prevention target. The research design and operational protocol of this cohort study may stimulate more research in the future.


Assuntos
Doenças Cardiovasculares/etiologia , Síndrome Metabólica/etiologia , Projetos de Pesquisa , Adulto , Fatores Etários , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Fatores de Risco
3.
BMC Pediatr ; 18(1): 80, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29471797

RESUMO

BACKGROUND: Improvements in insulin resistance and pancreatic ß-cell function have been shown following exercise in adults with obesity; however, few adolescent-based studies have been conducted. This study examined the impact of exercise training on body fat and insulin sensitivity and secretion in overweight and obese adolescents. METHODS: The effects of a 12-week exercise program on the parameters of adiposity and glucose homeostasis were investigated in 47 overweight and obese male adolescents. RESULTS: After the exercise training program, body weight, body mass index, waist circumference, and body fat were significantly decreased (P < 0.001). Improvements in insulin sensitivity (HOMA-IR: 1.40 vs. 0.86, P < 0.001) and the disposition index (5.84 vs. 12.77, P < 0.001) were also observed. Compared to baseline, oral glucose tolerance tests showed reduced glucose and insulin levels at all time points following the exercise training (all P < 0.001). Subgroup analysis of overweight and obese adolescents with abnormal glucose tolerance revealed that there was no difference in plasma glucose levels as compared to the lean group. CONCLUSIONS: A 12-week exercise training is effective in reducing body fat and improving insulin sensitivity and secretion. In addition, the benefits of the exercise intervention were even experienced by those with impaired glucose tolerance.


Assuntos
Adiposidade/fisiologia , Terapia por Exercício/métodos , Exercício/psicologia , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Obesidade Pediátrica/terapia , Adolescente , Biomarcadores/sangue , Glicemia/metabolismo , Exercício/fisiologia , Homeostase , Humanos , Masculino , Obesidade Pediátrica/sangue , Obesidade Pediátrica/fisiopatologia , Taiwan , Resultado do Tratamento
4.
Proteomics ; 17(1-2)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27928909

RESUMO

Over activity of cannabinoid receptor type 1 (CB1R) plays a key role in increasing the incidence of obesity-induced non-alcoholic fatty liver disease. Tissue proteome analysis has been applied to investigate the bioinformatics regarding the mode of action and therapeutic mechanism. The aim of this study was to explore the potential pathways altered with CB1R in obesity-induced fatty liver. Male C57BL/6 mice were fed either a standard chow diet (STD) or a high-fat diet (HFD) with or without 1-week treatment of CB1R inverse agonist AM251 at 5 mg/kg. Then, liver tissues were harvested for 2DE analysis and protein profiles were identified by using MALDI-MS. Results showed that eight of significantly altered protein spots at the level of changes > twofold were overlapped among the three groups, naming major urinary protein 1, ATP synthase subunit ß, glucosamine-fructose-6-phosphate aminotransferase 1, zine finger protein 2, s-adenosylmethionine synthase isoform type-1, isocitrate dehydrogenase subunit α, epoxide hydrolase 2 and 60S acidic ribosomal protein P0. These identified proteins were involved in glucose/lipid metabolic process, xenobiotic metabolic system, and ATP synthesized process in mitochondria. Based on the findings, we speculated that CB1R blockade might exert its anti-metabolic disorder effect via improvement of mitochondrial function in hepatic steatosis in HFD condition.


Assuntos
Biomarcadores/sangue , Antagonistas de Receptores de Canabinoides/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/sangue , Piperidinas/uso terapêutico , Proteômica/métodos , Pirazóis/uso terapêutico , Receptores de Canabinoides/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo
5.
Am J Med Sci ; 351(5): 492-8, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27140708

RESUMO

OBJECTIVE: The association between ankle brachial index (ABI) and outcomes in diabetic subjects is controversial. The purpose of this study was to evaluate whether the ABI is more strongly associated with cardiovascular outcomes comparing with non-high-density lipoprotein cholesterol (non-HDL-c). RESEARCH DESIGN AND METHODS: A total of 452 type 2 diabetic subjects followed up for a mean of 5.8 years were grouped by ABI (<0.9 versus ≥0.9) and non-HDL-c (<100mg/dL versus ≥100mg/dL). Primary outcomes were composite events including all-cause mortality, hospitalization for coronary artery disease, stroke, revascularization, amputation and diabetic foot, and the secondary end point was all-cause mortality. RESULTS: Intergroup differences in percentage of men, duration of diabetes, hemoglobin A1c, total cholesterol, low-density lipoprotein cholesterol, triglycerides and estimated glomerular filtration rate were significant. A total of 64 composite events and 17 deaths were recorded. A higher number of composite events occurred in the group with abnormal ABI but optimal non-HDL-c than in those with suboptimal non-HDL-c but normal ABI (29% versus 11%, P < 0.05). A similar trend was observed in all-cause mortality (11% versus 1%, P < 0.05). The ABI was the dominant risk factor for both end points after adjusting other factors (for composite events, hazard ratio = 0.02, 95% CI: 0.00-0.10, P < 0.001 and for all-cause mortality, hazard ratio = 0.01, 95% CI: 0.00-0.28, P = 0.006). CONCLUSIONS: The ABI was more strongly associated with outcomes in diabetes than non-HDL-c. The ABI should be routinely screened in diabetes even without symptom.


Assuntos
Índice Tornozelo-Braço , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Colesterol/sangue , Diabetes Mellitus Tipo 2/complicações , Técnicas de Diagnóstico Cardiovascular/instrumentação , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taiwan
6.
Int J Mol Med ; 37(3): 743-54, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26847930

RESUMO

Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA­IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/metabolismo , Resistência à Insulina/fisiologia , Obesidade/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Agonistas de Receptores de Canabinoides/farmacologia , Citrato (si)-Sintase/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 Relacionado a NF-E2/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia
7.
Obesity (Silver Spring) ; 24(3): 643-53, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26833777

RESUMO

OBJECTIVE: The aim of this study was to investigate the regulatory mechanism of endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, on adipogenesis in vitro and in vivo. METHODS: 3T3-L1 preadipocytes were used to explore the mechanisms mediating ET-1 actions on preadipocyte proliferation and adipocyte differentiation. To investigate the in vivo effect of ET-1, male Sprague-Dawley rats were infused with ET-1 or saline for 4 weeks via intraperitoneally implanted osmotic pumps, and the fat pad weight and adipocyte size of adipose tissues were measured. RESULTS: ET-1 stimulated preadipocyte proliferation and increased the cell number at the mitotic clonal expansion stage of adipocyte differentiation via the endothelin A receptor (ETAR) and activation of the protein kinase C (PKC) pathway. ET-1, via ETAR, inhibited adipocyte differentiation partially through an ERK-dependent pathway. Furthermore, no significant difference in the body weight and fat pad weight was observed in either ET-1- or saline-infused rats. Compared with saline-infused rats, the adipocyte cell number was significantly increased but the adipocyte size was significantly decreased in ET-1-infused rats. CONCLUSIONS: Chronic ET-1 infusion increased the number of small adipocytes without the change of white adipose tissue mass in rats, which were associated with ET-1-stimulated preadipocyte proliferation, but not ET-1-suppressed adipocyte differentiation.


Assuntos
Adipócitos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Endotelina-1/farmacologia , Hiperplasia/etiologia , Receptor de Endotelina A/efeitos dos fármacos , Células 3T3-L1/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotelina-1/metabolismo , Hiperplasia/metabolismo , Masculino , Camundongos , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/metabolismo
8.
Clin Chim Acta ; 453: 197-202, 2016 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-26552040

RESUMO

BACKGROUND: We determined effects of bariatric weight loss surgery on serum tartrate-resistant acid phosphatase 5a (TRACP 5a), inflammatory cytokines and glucose homeostasis in severely obese Chinese adults. METHODS: Severely obese adults undergoing bariatric surgery were recruited. Anthropometry, insulin resistance (IR), inflammatory markers and serum TRACP 5a were measured at baseline and 3, 6 and 12months postoperatively. RESULTS: Data of 93 patients, including 69 non-diabetic (non-DM group) and 24 diabetic (DM group), were analyzed. Anthropometry decreased significantly at 3months postoperatively in both groups; low-density lipoprotein cholesterol decreased obviously at 3, 6 and 12months in non-DM group, while improving significantly at 6 and 12months in DM group. Homeostasis model assessment for IR (HOMA-IR) improved significantly at 3, 6 and 12months in non-DM group and 12months in DM group. In DM group, C-reactive protein (CRP) decreased significantly at 3months postoperatively and inflammatory markers interleukin-6 (IL-6) and TRACP 5a improved at 6months postoperatively; in non-DM group, serum TRACP 5a decreased obviously at 12months postoperatively without significant changes in CRP and IL-6. CONCLUSION: Weight reduction by bariatric surgery decreases anthropometry, IR, lipids and inflammatory markers in severely obese Chinese adults.


Assuntos
Fosfatase Ácida/sangue , Grupo com Ancestrais do Continente Asiático , Cirurgia Bariátrica , Glicemia/metabolismo , Citocinas/sangue , Isoenzimas/sangue , Obesidade/sangue , Obesidade/cirurgia , Adulto , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/sangue , Resistência à Insulina , Lipídeos/sangue , Masculino , Fosfatase Ácida Resistente a Tartarato , Perda de Peso
9.
Shock ; 45(4): 460-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26536203

RESUMO

BACKGROUND: Visfatin is produced in and secreted from adipocytes. Increased circulating visfatin level is observed in obese subjects. Previous studies demonstrated that visfatin was involved in obesity-related cardiovascular diseases. AIMS: This study aims to explore the regulatory effects of adipokine visfatin on foam cell formation, a key step in the development of atherosclerosis. METHODS: Effect of visfatin on protein and mRNA expression of scavenger receptor and ATP binding cassette transporter in RAW264.7 macrophages were measured by western blotting and real-time RT-PCR. To confirm the influence of visfatin-regulated scavenger receptor and ATP binding cassette transporter to foam cell formation, the visfatin-caused changes of ox-LDL uptake, cholesterol efflux, and foam cell formation were determined. RESULTS: Visfatin significantly increased the expression of CD36 and scavenger receptor A (SRA), decreased the expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), and had no effect on the expression of SR-B1. Visfatin increased oxidized-LDL (ox-LDL) uptake and decreased cholesterol efflux, which increased foam cell formation. The PI3K inhibitor LY294002 blocked the effect of visfatin on the protein and mRNA expression levels of CD36, SRA, and ABCG1 and ox-LDL uptake and cholesterol efflux. The ERK inhibitor PD98059 also prevented visfatin-induced ABCA1 instability and subsequently decreased cholesterol efflux. CONCLUSIONS: Visfatin upregulated CD36 and SRA expression and downregulated ABCA1 and ABCG1 expression, subsequently increased ox-LDL uptake and decreased cholesterol efflux, and finally promoted foam cell formation via the PI3K- and ERK-dependent pathways.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/biossíntese , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Antígenos CD36/biossíntese , Citocinas/metabolismo , Células Espumosas/metabolismo , Regulação da Expressão Gênica , Nicotinamida Fosforribosiltransferase/metabolismo , Receptores Depuradores/biossíntese , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Células Espumosas/patologia , Sistema de Sinalização das MAP Quinases , Camundongos
10.
Biochem Biophys Res Commun ; 460(3): 497-503, 2015 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-25824048

RESUMO

Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose-diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ETAR during insulin resistance, ETAR expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ETAR expression, but not ETBR, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ETAR pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ETAR/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ETAR are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ETAR expression, and ET-1-induced mitogenic actions in aortic VSMCs.


Assuntos
Aterosclerose/etiologia , Endotelina-1/fisiologia , Hipertensão/etiologia , Resistência à Insulina , Animais , Aterosclerose/fisiopatologia , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Endotelina-1/metabolismo , Hipertensão/fisiopatologia , Insulina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley
11.
Biochem Biophys Res Commun ; 460(4): 1063-8, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25843798

RESUMO

Hepatic insulin resistance (HIR) is a metabolic abnormality characterized by increased gluconeogenesis which usually contributes from an elevation of free fatty acids. Cannabinoid receptor type 1 (CB1R) and major urinary protein 1 (MUP1) are thought to play pivotal roles in mitochondrial dysfunction, liver steatosis and insulin resistance. The aim of this study was to explore the role of MUP1 in CB1R-mediated HIR through the dysregulation of mitochondrial function in AML12 mouse hepatocytes challenged with high concentration of free fatty acids (HFFA). Firstly we observed that treatment of AM251, a selective CB1R antagonist, obviously reversed the HFFA-induced reduction of MUP1 protein expression both in vivo and in vitro. Additionally, our results revealed that AM251 also reverted HFFA-mediated decrease of the mRNA level of mitochondrial biogenesis-related factors, mtDNA amount, ATP production, mitochondrial respiratory complexes-I and -III, and mitochondrial membrane potential, thus consequently might correlate with a parallel reduction of ROS production. Meanwhile, AM251 attenuated HFFA-induced impairment of insulin signaling phosphorylation and elevation of phosphoenolpyrvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), two key enzymes of gluconeogenesis. Silence of MUP1 gene abolished the inhibitory effect of AM251 on HFFA-mediated elevation of PEPCK and G6Pase expression, whereas the suppression of insulin signaling and mRNA level of mitochondrial biogenesis-related factors were only partially recovered. Altogether, these findings suggest that the anti-HIR effect of AM251 via improvement of mitochondrial functions might occur in a MUP1-dependent manner.


Assuntos
Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Resistência à Insulina , Fígado/metabolismo , Proteínas/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Western Blotting , Dieta Hiperlipídica , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Piperidinas/farmacologia , Proteínas/genética , Pirazóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor CB1 de Canabinoide/antagonistas & inibidores
12.
Diabetes Res Clin Pract ; 108(2): 316-22, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25726334

RESUMO

AIMS: Peripheral arterial disease (PAD) could be an additional risk factor for the clinical outcomes in different populations. The purpose of this study was to evaluate the influence of PAD on patients with diabetic kidney disease. METHODS: 362 persons with type 2 diabetes were followed-up for a mean 4.8 years grouped by ankle brachial index (ABI) (<0.9 vs. ≧0.9) and albuminuria (with or without). Primary and secondary outcomes were composite events (all-cause mortality, hospitalization for coronary artery disease, stroke, re-vascularization, amputation, and diabetic foot) and all-cause mortality. RESULTS: Inter-group differences in duration of diabetes, glycated hemoglobin, creatinine, and estimated glomerular filtration rate were significant. During the follow-up period, 53 composite events were recorded (14.7%) and 13 (3.5%) individuals died. Subjects with albuminuria plus ABI<0.9 had higher risk of composite events than those with albuminuria but normal ABI (p<0.05). The only trend difference between the two groups was in all-cause mortality. Albuminuria plus ABI <0.9 was associated with risk of composite events (hazard ratio [HR] 4.20, 95% confidence interval [CI] 1.77-9.92, p=0.001) and all-cause mortality (HR 17.77, 95% CI 1.93-162.20, p=0.011). CONCLUSIONS: PAD might be an additional risk factor for adverse outcomes in patients with diabetic kidney disease. Further prospective data are required to validate this conclusion.


Assuntos
Índice Tornozelo-Braço , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Idoso , Albuminúria/complicações , Albuminúria/diagnóstico , Albuminúria/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/complicações , Prognóstico , Estudos Retrospectivos , Fatores de Risco
13.
Intern Med ; 53(21): 2425-31, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25365999

RESUMO

OBJECTIVE: Patients with type 2 diabetes mellitus (T2DM) and peripheral arterial disease are classified as having very high cardiovascular risks. We therefore sought to determine whether assessments of the ankle brachial index (ABI) and brachial ankle pulse wave velocity (baPWV) together exhibited a superior association with the outcomes of T2DM. METHODS: A retrospective analysis of patients receiving ABI and baPWV during the period 2005-2007 was performed. Patients A total of 452 subjects were enrolled and followed-up for a mean 5.8 years after being grouped according to the ABI (<0.9 vs. ≥0.9) and baPWV (<1,700 cm/s vs. ≥1,700 cm/s). RESULTS: The outcomes were all-cause mortality and composite events (all-cause mortality, hospitalization for coronary artery disease, stroke, re-vascularization, amputation and diabetic foot). Inter-group differences in the smoking rate, duration of diabetes, systolic and pulse blood pressure, anti-platelet drugs, estimated glomerular filtration rate, and urine albumin excretion were significant. During the follow-up period, 17 (3.7%) individuals died and composite events were recorded in 64 cases (14.1%). A low ABI plus high baPWV was found be associated with poor outcomes compared with a normal ABI plus low baPWV (p<0.001). Meanwhile, a low ABI plus high baPWV was associated with an increased risk of all-cause mortality [hazard ratio (HR) 17.01, 95% confidence interval (CI) 1.57-183.73, p=0.019] and composite events (HR 8.53, 95% CI 3.31-21.99, p<0.001). CONCLUSION: In this study, the outcomes of patients with a low ABI plus high baPWV were the worst, while the subjects with a low ABI plus low baPWV or normal ABI exhibited similar outcomes. Therefore, the ABI plus baPWV exhibits a better association with the outcomes of T2DM.


Assuntos
Índice Tornozelo-Braço , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/complicações , Doença Arterial Periférica/complicações , Análise de Onda de Pulso , Idoso , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/mortalidade , Angiopatias Diabéticas/fisiopatologia , Feminino , Seguimentos , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/fisiopatologia , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia
15.
Biochem Biophys Res Commun ; 451(2): 263-9, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-25088996

RESUMO

Endothelin-1 (ET-1) is the most potent vasoconstrictor by binding to endothelin receptors (ETAR) in vascular smooth muscle cells (VSMCs). The complex of angiotensin II (Ang II) and Ang II type one receptor (AT1R) acts as a transient constrictor of VSMCs. The synergistic effect of ET-1 and Ang II on blood pressure has been observed in rats; however, the underlying mechanism remains unclear. We hypothesize that Ang II leads to enhancing ET-1-mediated vasoconstriction through the activation of endothelin receptor in VSMCs. The ET-1-induced vasoconstriction, ET-1 binding, and endothelin receptor expression were explored in the isolated endothelium-denuded aortae and A-10 VSMCs. Ang II pretreatment enhanced ET-1-induced vasoconstriction and ET-1 binding to the aorta. Ang II enhanced ETAR expression, but not ETBR, in aorta and increased ET-1 binding, mainly to ETAR in A-10 VSMCs. Moreover, Ang II-enhanced ETAR expression was blunted and ET-1 binding was reduced by AT1R antagonism or by inhibitors of PKC or ERK individually. In conclusion, Ang II enhances ET-1-induced vasoconstriction by upregulating ETAR expression and ET-1/ETAR binding, which may be because of the AngII/Ang II receptor pathways and the activation of PKC or ERK. These findings suggest the synergistic effect of Ang II and ET-1 on the pathogenic development of hypertension.


Assuntos
Angiotensina II/metabolismo , Endotelina-1/metabolismo , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Vasoconstrição/fisiologia , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Linhagem Celular , Imidazóis/farmacologia , Losartan/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteína Quinase C/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Vasoconstrição/efeitos dos fármacos
16.
Diabetes Res Clin Pract ; 102(1): 16-24, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23993469

RESUMO

AIM: To compare the efficacy and safety of acarbose plus metformin fixed-dose combination (FDC) versus acarbose monotherapy for type 2 diabetes (T2D). METHODS: Eligible T2D patients undergoing treatment with diet control only or oral antidiabetic medications were run-in on acarbose 50mg thrice-daily for 4 weeks, then randomised either to continue this monotherapy, or to acarbose 50mg plus metformin hydrochloride 500mg FDC (acarbose/metformin FDC), each thrice-daily for 16 weeks. RESULTS: Acarbose/metformin FDC therapy significantly reduced HbA1c, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) from baseline (all p<0.0001) with superior efficacy compared with acarbose monotherapy (between-group differences; HbA1c -1.35%; FPG -29.5mg/dl; PPG -41.6mg/dl; all p<0.0001). Proportionally more patients treated with acarbose/metformin FDC achieved HbA1c <7.0% (47.8% vs. 10.7%, p<0.0001). Both treatments reduced bodyweight (p<0.0001), with a significant between-group difference (-0.6kg, p<0.01) favouring acarbose/metformin FDC. Hypoglycaemia was not reported with either treatment, and the incidence of other adverse events did not differ significantly between the groups. CONCLUSIONS: Compared with acarbose monotherapy, acarbose/metformin FDC has superior antihyperglycaemic efficacy, brings proportionally more T2D patients to HbA1c goal, and further reduces bodyweight. Acarbose/metformin FDC is well-tolerated without significant risk of hypoglycaemia and is a potentially advantageous therapy for T2D.


Assuntos
Acarbose/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/administração & dosagem , Adulto , Idoso , Glicemia/metabolismo , Peso Corporal , Combinação de Medicamentos , Feminino , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Growth Factors ; 31(2): 66-73, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23452315

RESUMO

We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Cronoterapia Farmacológica , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/farmacologia , Resistência à Insulina , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Técnica Clamp de Glucose , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Masculino , Octreotida/administração & dosagem , Octreotida/sangue , Octreotida/farmacologia
18.
Diabetes Res Clin Pract ; 98(1): 61-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22704126

RESUMO

Type 2 diabetes mellitus is a global health issue. Patients with poor glycemic control often suffer from cardiovascular, cerebrovascular, neuropathic, and nephropathic complications as well as other chronic conditions. Therapeutic guidelines recommend that diabetic patients should maintain their HbA(1c) level below a certain target in order to minimize the risk of developing complications. However, hypoglycemia is recognized as a major impediment to the adequate control of type 2 diabetes. Hypoglycemia can manifest symptoms of varying degrees of severity. Moreover, an association between hypoglycemia and cardiovascular morbidity and mortality has been reported. Here, we present a post hoc Taiwan subgroup analysis of these data collected in the RECAP-DM study to indicate probably more emphasis and concern on hypoglycemia in type 2 diabetic patients in Taiwan. In this analysis, we found no significant difference was observed in treatment-related satisfaction between Taiwanese patients with or without hypoglycemia. Another finding of our study further shows that varying order of hypoglycemic symptoms or severity has no effect on patients' assessment of health-related quality of life scores. We need to pay more attention to this issue because of its enduring impact on compliance and concerns about hypoglycemia in type 2 diabetic patients. Nevertheless, socio-demographic characteristics are also important factors influencing glycemic control and patients' health-related quality of life. Future interventions and therapeutic algorithms should emphasize the probable patients' unawareness or neglect on hypoglycemia in diabetic patients.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Hemoglobina A Glicada/metabolismo , Hipoglicemia/sangue , Ásia , Automonitorização da Glicemia , Comorbidade , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Ilhas do Pacífico , Cooperação do Paciente , Qualidade da Assistência à Saúde , Medição de Risco , Taiwan , Resultado do Tratamento
20.
Curr Med Res Opin ; 27(8): 1645-51, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21699369

RESUMO

OBJECTIVE: To assess the efficacy, safety, and tolerability of a combination of 10 mg ezetimibe and 20 mg simvastatin in Taiwanese patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: A prospective, open-label, multi-center, hospital-based cohort study was conducted to evaluate the efficacy, safety, and tolerability of a single tablet combination of ezetimibe/simvastatin for the treatment of hypercholesterolemia. Taiwanese adults without low-density lipoprotein cholesterol (LDL-C) goal achievement, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines, were treated with ezetimibe/simvastatin once daily for 6 weeks. The primary endpoint was the percentage of patients achieving LDL-C treatment goals after 6 weeks of treatment. Secondary endpoints included percentage change from baseline of LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglyceride. Safety and tolerability were assessed via clinical and laboratory examinations. The clinicaltrial.gov identifier of this study was NCT00654628. RESULTS: In total, 173 patients with a mean age of 57.9 ± 10.4 years were included. Of these, 57.8% were female and the average body mass index was 25.5 ± 3.4 kg/m(2). After 6 weeks of treatment, the great majority of the patients had reached their treatment goals (90.4% for LDL-C; 87% for TC; and 59% for TG). LDL-C levels were significantly reduced from 156.8 ± 30.8 mg/dL at baseline to 75.9 ± 25.4 mg/dL (51.4%, P < 0.0001) after only 6 weeks of therapy. Forty-nine adverse events (AEs), including one non-drug related serious AE, were reported. For non-serious AEs, the most common reported AEs during the entire study period were myalgia and upper respiratory infection (both n = 7). Nine patients dropped out of the study, reportedly due to AEs. CONCLUSIONS: A single tablet combination of 10 mg ezetimibe and 20 mg simvastatin in Taiwanese patients with hypercholesterolemia provided high LDL-C goal attainment rates and resulted in significant reductions in LDL-C.


Assuntos
Anticolesterolemiantes/administração & dosagem , Azetidinas/administração & dosagem , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia , Sinvastatina/administração & dosagem , Triglicerídeos/sangue , Adulto , Idoso , Anticolesterolemiantes/efeitos adversos , Azetidinas/efeitos adversos , Combinação de Medicamentos , Ezetimiba , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Sinvastatina/efeitos adversos , Taiwan , Fatores de Tempo
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