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INTRODUCTION: Despite the serious risks of diabetes with hepatitis C virus (HCV) infection, this preventable comorbidity is rarely a priority for HCV elimination. We aim to examine how a shared care model could eliminate HCV in patients with diabetes (PwD) in primary care. METHODS: There were 27 community-based Diabetes Health Promotion Institutes in each township/city of Changhua, Taiwan. PwD from these institutes from January 2018 to December 2020 were enrolled. HCV screening and treatment were integrated into diabetes structured care through collaboration between diabetes care and HCV care teams. Outcome measures included HCV care continuum indicators. Township/city variation in HCV infection prevalence and care cascades were also examined. RESULTS: Of the 10,684 eligible PwD, 9,984 (93.4%) underwent HCV screening, revealing a 6.18% (n = 617) anti-HCV seroprevalence. Among the 597 eligible seropositive individuals, 507 (84.9%) completed the RNA test, obtaining 71.8% positives. Treatment was initiated by 327 (89.8%) of 364 viremic patients, and 315 (86.5%) completed it, resulting in a final cure rate of 79.4% (n = 289). Overall, with the introduction of antivirals in this cohort, the prevalence of viremic HCV infection dropped from 4.44% to 1.34%, yielding a 69.70% (95% credible interval 63.64%-77.03%) absolute reduction. DISCUSSION: Although HCV prevalence varied, the care cascades achieved consistent results across townships/cities. We have further successfully implemented the model in county-wide hospital-based diabetes clinics, eventually treating 89.6% of the total PwD. A collaborative effort between diabetes care and HCV elimination enhanced the testing and treatment in PwD through an innovative shared care model.
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BACKGROUND: We investigated the association between glucose excursions and the dawn phenomenon, and the effects of oral-glucose lowering drugs on the dawn phenomenon in patients with type 2 diabetes (T2D). METHODS: We conducted a post hoc analysis using data from a previous randomized trial. Patients with T2D on metformin monotherapy were randomized to receive add-on acarbose or glibenclamide for 16 weeks. Ambulatory continuous glucose monitoring (CGM) was conducted before randomization and at the end of the study. Using the CGM data, we assessed glucose excursions as indicated by mean amplitude of glycemic excursions (MAGE). The magnitude of the dawn phenomenon was calculated as the difference between the nocturnal nadir (0:00 to 6:00 a.m.) and prebreakfast glucose level. RESULTS: A total of 50 patients with T2D [mean age 53.5 ± 8.2 years, mean glycated hemoglobin (HbA1c) 8.4 ± 1.2%] were analyzed. There was an independent association between MAGE and the dawn phenomenon [ß coefficient 0.199, 95% confidence interval (CI) 0.074-0.325, p = 0.003]. HbA1c improved significantly after treatment with acarbose or glibenclamide. However, only treatment with acarbose significantly improved glucose excursions. The dawn phenomenon decreased significantly only in patients treated with acarbose (from 35.9 ± 15.7-28.3 ± 16.5 mg/dl, p = 0.037), but not in those treated with glibenclamide (from 35.9 ± 20.6-34.6 ± 17.0 mg/dl, p = 0.776). CONCLUSION: Glucose excursions were independently associated with the dawn phenomenon in patients with T2D on metformin monotherapy. Both glucose excursions and the dawn phenomenon improved after treatment with acarbose, but not after treatment with glibenclamide.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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OBJECTIVE: To investigate the association between diabetes and latent tuberculosis infections (LTBI) in high TB incidence areas. DESIGN: Community-based comparison study. SETTING: Outpatient diabetes clinics at 4 hospitals and 13 health centres in urban and rural townships. A community-based screening programme was used to recruit non-diabetic participants. PARTICIPANTS: A total of 2948 patients with diabetes aged older than 40 years were recruited, and 453 non-diabetic participants from the community were enrolled. PRIMARY AND SECONDARY OUTCOME MEASURES: The interferon-gamma release assay (IGRA) and the tuberculin skin test were used to detect LTBI. The IGRA result was used as a surrogate of LTBI in logistic regression analysis. RESULTS: Diabetes was significantly associated with LTBI (adjusted OR (aOR)=1.59; 95% CI 1.11 to 2.28) and age correlated positively with LTBI. Many subjects with diabetes also had additional risk factors (current smokers (aOR=1.28; 95% CI 0.95 to 1.71), comorbid chronic kidney disease (aOR=1.26; 95% CI 1.03 to 1.55) and history of TB (aOR=2.08; 95% CI 1.19 to 3.63)). The presence of BCG scar was protective (aOR=0.66; 95% CI 0.51 to 0.85). Duration of diabetes and poor glycaemic control were unrelated to the risk of LTBI. CONCLUSION: There was a moderately increased risk of LTBI in patients with diabetes from this high TB incidence area. This finding suggests LTBI screening for the diabetics be combined with other risk factors and comorbidities of TB to better identify high-risk groups and improve the efficacy of targeted screening for LTBI.
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Diabetes Mellitus/epidemiología , Tuberculosis Latente/epidemiología , Adulto , Anciano , Vacuna BCG/uso terapéutico , Estudios de Casos y Controles , Diabetes Mellitus/metabolismo , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Incidencia , Ensayos de Liberación de Interferón gamma , Tuberculosis Latente/diagnóstico , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Fumar/epidemiología , Taiwán/epidemiología , Prueba de Tuberculina , Tuberculosis/prevención & controlRESUMEN
BACKGROUND/PURPOSE: Comprehensive and continuous care is crucial for patients with diabetes. The diabetes pay-for-performance (P4P) program launched by the National Health Insurance (NHI) administration in Taiwan provides a financial incentive to facilitate this goal. In this study, we explored the characteristics of patients in the P4P program between 2005 and 2014. METHODS: Data of patients with diabetes enrolled in the NHI program between 2005 and 2014 were extracted from the NHI research database. Patients were classed as having diabetes if they had three or more outpatient visits within 365 calendar days with an International Classification of Diseases, 9th Revision, Clinical Modification diagnostic code of 250 or hospitalization one or more times with such a diagnosis. The trends of participating in the P4P program were analyzed. RESULTS: Participation rate of the P4P program increased from 12.1% to 19% between 2005 and 2014. Participants were younger and more likely to be female than those not participating in the program. Lower risks of cancer-related mortality, annual mortality and heart failure were seen in patients participating in the P4P program than in those not participating. CONCLUSION: Older, male patients with a high disease severity may be less likely to enroll in the P4P program. Although participation rate is increasing, a broad enrollment is expected.
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Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/terapia , Neoplasias/mortalidad , Reembolso de Incentivo/estadística & datos numéricos , Anciano , Enfermedades Cardiovasculares/mortalidad , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Taiwán/epidemiologíaRESUMEN
To find the associations of circulating cyclophilin A (CyP A) and CD147/EMMPRIN with renal outcomes in type 2 diabetes patients and possible pathogenesis involved. Total 131 patients were recruited since 2004. Glycated hemoglobin, blood glucose and urine albumin-creatinine ratio levels at baseline and every 3 months were measured. Plasma CyP A and CD147 were also measured at baseline. Patients were divided into two groups based upon the median level of the baseline plasma CyP A value: < 93.64 ng/mL (group A, n = 65), ≥ 93.64 ng/mL (group B, n = 66). The estimated glomerular filtration rate was calculated at each follow-up visit. Besides, mitochondrial function assay by cellular mitochondrial energy utility was studied when cells were exposed to glucose or exogenous CyP A or both. Multivariate analysis, using median level (93.64) ng/mL as the cut-off value, revealed that circulating CyP A and CD147 levels at baseline were associated with the baseline estimated glomerular filtration rate (eGFR) (p = .042 and p = .001 separately) in cross-sectional analysis. Longitudinally, higher baseline plasma CyP A level was also correlated to a rapid decline in eGFR (p = .016). The results were also significant when using the continuous plasma CyP A level (p = .003). In cells exposed to glucose, results of oxygen consumption rate (OCR) showed a significant reduction in basal respiration, maximal respiration and ATP production. Depressed OCR further occurred when incubated with both of CyP A and glucose. Plasma CyP A and CD147 can serve as indicators of renal disease progression in type 2 diabetes patients.
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Basigina/sangre , Ciclofilina A/sangre , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Anciano , Animales , Glucemia/análisis , Células Cultivadas , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/metabolismo , Femenino , Humanos , Estudios Longitudinales , Masculino , Ratones , Ratones Transgénicos , Mitocondrias/metabolismoRESUMEN
Probiotics have been reported to ameliorate symptoms of type 2 diabetes mellitus (T2DM) in animal models and human studies. We previously demonstrated that oral administration of Lactobacillus reuteri ADR-3 reduced insulin resistance in high-fructose-fed (HFD) rats. In the present study, we first identified another L. reuteri strain, ADR-1, which displayed anti-diabetes activity that reduced the levels of serum HbA1c and cholesterol and that increased antioxidant proteins in HFD rats. We further performed a randomized, double-blinded, placebo-controlled trial with a total of 68 T2DM patients to examine the beneficial effects of oral consumption of L. reuteri strains ADR-1 and ADR-3 and to investigate the associated changes in intestinal flora using a quantitative PCR method to analyze 16 S rRNA in fecal specimens. Significant reductions in HbA1c and serum cholesterol were observed in participants in the live ADR-1 consumption group (n = 22) after 3 months of intake when compared with those in the placebo group (n = 22). Although there was no significant difference in the HbA1c serum level among participants who consumed heat-killed ADR-3 (n = 24), the systolic blood pressure and mean blood pressure were significantly decreased after 6 months of intake. There was no obvious change in serum inflammatory cytokines or antioxidant proteins in participants after intaking ADR-1 or ADR-3, except for a reduction in IL-1ß in the ADR-3 consumption group after 6 months of intake. With the analysis of fecal microflora, we found that L. reuteri or Bifidobacterium spp. were significantly increased in the ADR-1 and ADR-3 consumption groups, respectively, after 6 months of intake. Interestingly, a significant reduction in HbA1c was observed in the ADR-1 and ADR-3 consumption participants who displayed at least an 8-fold increase in fecal L. reuteri. We also observed that there was a significantly positive correlation between Bifidobacterium spp. and Lactobacillus spp. in participants with increased levels of fecal L. reuteri. In the ADR-1 intake group, the fecal Lactobacillus spp. level displayed a positive correlation with Bifidobacterium spp. but was negatively correlated with Bacteroidetes. The total level of fecal L. reuteri in participants in the ADR-3 consumption group was positively correlated with Firmicutes. In conclusion, L. reuteri strains ADR-1 and ADR-3 have beneficial effects on T2DM patients, and the consumption of different strains of L. reuteri may influence changes in intestinal flora, which may lead to different outcomes after probiotic intake.
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Diabetes Mellitus Tipo 2/terapia , Limosilactobacillus reuteri , Probióticos/uso terapéutico , Adulto , Anciano , Animales , Bifidobacterium , Presión Sanguínea , Colesterol/sangre , Femenino , Microbioma Gastrointestinal , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Ratas , Resultado del TratamientoRESUMEN
BACKGROUND: Cyclophilin A plays a pathogenic role in the development and progression of atherosclerosis, which can be assessed by measuring carotid intima-media thickness. The primary aim of this study was to examine the interaction between plasma Cyclophilin A level and carotid intima-media thickness in patients with acute ischemic stroke. METHOD: Plasma concentration of Cyclophilin A was measured on admission in 66 consecutive patients who had been hospitalized for acute cerebral stroke and in 52 case-control subjects without a history of acute stroke. Subjects in both groups also underwent ultrasound B-mode imaging to measure the mean and maximum intima-media thickness of the carotid artery. Inflammatory biomarkers including high-sensitivity C-reactive protein and fibrinogen were also assessed. RESULTS: We found that the plasma concentration of Cyclophilin A was significantly higher in patients with acute ischemic stroke (p = 0.042). Increased Cyclophilin A was also correlated with carotid intima-media thickness in the patient group (p < 0.001). Among the risk factors for cerebral stroke examined in this study, only hypertension was significantly associated with plasma Cyclophilin A level. CONCLUSION: Increased plasma Cyclophilin A levels might be involved in the pathophysiology of acute ischemic stroke and Cyclophilin A might serve as a biomarker in risk assessment of acute stroke patients.
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Biomarcadores/sangre , Isquemia Encefálica/complicaciones , Ciclofilina A/sangre , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Adulto , Anciano , Análisis de Varianza , Proteína C-Reactiva/metabolismo , Arteria Carótida Común/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Femenino , Humanos , Hipertensión/etiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Accidente Cerebrovascular/complicacionesRESUMEN
Andrographolide is a potent anti-inflammatory agent found in Andrographis paniculata. Endothelin 1 (ET-1) is an endothelium-derived vasoconstrictor with pro-inflammatory properties secreted in response to hypoxia. Mitogen-activated protein kinase phosphatase 5 (MKP-5) is a dual-specificity phosphatase that dephosphorylates threonine and tyrosine residues of MAPKs. We showed previously that hypoxia-induced HIF-1α expression and ET-1 secretion are dependent on p38 MAPK in EA.hy926 cells. Here, we investigate what role MKP-5 plays in andrographolide's inhibition of hypoxia-induced expression of HIF-1α and ET-1. Hypoxic conditions were created using the hypoxia-mimetic agent CoCl2 . Andrographolide enhanced HO-1 and MKP-5 expression and cellular cGMP content in addition to inhibiting hypoxia-induced ROS generation. Concomitantly, the HO-1 byproduct CO and the cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) increased MKP-5 expression, and pretreatment with CO and 8-Br-cGMP inhibited hypoxia-induced HIF-1α and ET-1 expression. Transfection of HO-1 siRNA or pretreatment with the HO-1 inhibitor ZnPP-9 or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific inhibitor of soluble guanylate cyclase, reduced andrographolide-induced MKP-5 expression. Moreover, silencing MKP-5 or treatment with the phosphatase inhibitor vanadate abrogated andrographolide's suppressing hypoxia-induced p38 MAPK activation and HIF-1α expression. The inhibition of hypoxia-induced HIF-1α and ET-1 expression by andrographolide is likely associated with HO-1/CO/cGMP/MKP-5 pathways, which is involved in inhibiting hypoxia-induced p38 MAPK activation.
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Antiinflamatorios/farmacología , Monóxido de Carbono/metabolismo , GMP Cíclico/metabolismo , Diterpenos/farmacología , Fosfatasas de Especificidad Dual/metabolismo , Endotelina-1/metabolismo , Hemo-Oxigenasa 1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Hipoxia de la Célula , Línea Celular , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacología , Humanos , Tionucleótidos/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Increased intercellular reactive oxygen species (ROS) levels are the major cause of podocyte injury with proteinuria. Caveolin1 (CAV1) is an essential protein component of caveolae. CAV1 participates in signal transduction and endocytic trafficking. Recent research has indicated that CAV1 regulates oxidative stressinduced pathways. The present study used hydrogen peroxide (H2O2) at nontoxic concentrations to elevate the level of ROS in E11 podocytes. Treatment with 500 and 1,000 µM H2O2 for 1 h significantly reduced CAV1 expression levels. Simultaneously, the treatment significantly reduced the expression of the antioxidant enzymes glutaminecysteine ligase catalytic subunit, superoxide dismutase 2 and catalase. To determine the role of CAV1 in mediating oxidative stress, E11 podocytes were administered antenapediaCAV1 (APCAV1) peptide for 48 h. The APCAV1 treatment enhanced CAV1 expression and inhibited cyclophilin A expression, thus reducing ROSinduced inflammation. Moreover, CAV1 protected against H2O2induced oxidative stress responses by enhancing the expression of antioxidant enzymes. Furthermore, CAV1 attenuated H2O2induced changes oxidative phosphorylation, and the expression of optic atrophy 1 and translocase of the inner membrane 23, as well as preserving mitochondrial function. CAV1 treatment significantly suppressed apoptosis, as indicated by a higher Bcell lymphoma 2/BCL2associated X protein ratio. Therefore, enhancing the expression of CAV1 may be an important therapeutic consideration in treating podocyte injury.
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Caveolina 1/metabolismo , Peróxido de Hidrógeno/farmacología , Mitocondrias/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Podocitos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Secuencia de Aminoácidos , Animales , Catalasa/genética , Catalasa/metabolismo , Caveolina 1/genética , Caveolina 1/farmacología , Línea Celular , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Regulación de la Expresión Génica , Glutamato-Cisteína Ligasa/genética , Glutamato-Cisteína Ligasa/metabolismo , Peróxido de Hidrógeno/antagonistas & inhibidores , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Péptidos/farmacología , Podocitos/citología , Podocitos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Transducción de Señal , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Andrographolide, the main bioactive component of the medicinal plant Andrographis paniculata, has been shown to possess potent anti-inflammatory activity. Endothelin 1 (ET-1), a potent vasoconstrictor peptide produced by vascular endothelial cells, displays proinflammatory property. Hypoxia-inducible factor 1α (HIF-1α), the regulatory member of the transcription factor heterodimer HIF-1α/ß, is one of the most important molecules that responds to hypoxia. Changes in cellular HIF-1α protein level are the result of altered gene transcription and protein stability, with the latter being dependent on prolyl hydroxylases (PHDs). In this study, inhibition of pro-inflammatory ET-1 expression and changes of HIF-1α gene transcription and protein stability under hypoxia by andrographolide in EA.hy926 endothelial-like cells were investigated. Hypoxic conditions were created using the hypoxia-mimetic agent CoCl2. We found that hypoxia stimulated the production of reactive oxygen species (ROS), the expression of HIF-1α mRNA and protein, and the expression and secretion of ET-1. These effects, however, were attenuated by co-exposure to andrographolide, bilirubin, and RuCO. Silencing Nrf2 and heme oxygenase 1 (HO-1) reversed the inhibitory effects of andrographolide on hypxoia-induced HIF-1α mRNA and protein expression. Moreover, andrographolide increased the expression of prolyl hydroxylases (PHD) 2/3, which hydroxylate HIF-1α and promotes HIF-1α proteasome degradation, with an increase in HIF-1α hydroxylation was noted under hypoxia. Inhibition of p38 MAPK abrogated the hypoxia-induced increases in HIF-1α mRNA and protein expression as well as ET-1 mRNA expression and secretion. Taken together, these results suggest that andrographolide suppresses hypoxia-induced pro-inflammatory ET-1 expression by activating Nrf2/HO-1, inhibiting p38 MAPK signaling, and promoting PHD2/3 expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 918-930, 2017.
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Diterpenos/farmacología , Endotelina-1/metabolismo , Hemo-Oxigenasa 1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Prolil Hidroxilasas/metabolismo , Hipoxia de la Célula , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cobalto/toxicidad , Células Endoteliales/citología , Células Endoteliales/metabolismo , Endotelina-1/genética , Hemo-Oxigenasa 1/antagonistas & inhibidores , Hemo-Oxigenasa 1/genética , Humanos , Hidroxilación , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/genética , Prolil Hidroxilasas/genética , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: The aim of the present study was to examine the association between glycemic excursions before treatment and HbA1c reduction after treatment intensification with acarbose or glibenclamide in patients with type 2 diabetes (T2D). METHODS: Patients receiving single or dual oral antidiabetic drug treatment with an HbA1c of 7.0-11.0 % (53-97 mmol/mol) were switched to metformin monotherapy (500 mg, t.i.d.) for 8 weeks, followed by randomization to either acarbose (100 mg, t.i.d.) or glibenclamide (5 mg, t.i.d.) as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring. Treatment efficacy was evaluated as relative HbA1c reduction (%), calculated as (baseline HbA1c - post-treatment HbA1c)/baseline HbA1c × 100. RESULTS: Fifty patients (mean [±SD] age 53.5 ± 8.2 years, 48 % men, mean baseline HbA1c 8.4 ± 1.2 %) were analyzed. Baseline MAGE was positively correlated with relative HbA1c reduction from baseline in patients treated with acarbose (r = 0.421, P = 0.029) but not glibenclamide (r = 0.052, P = 0.813). Linear regression analysis revealed that the association between baseline MAGE and relative HbA1c reduction from baseline (ß = 0.125, P = 0.029) in patients treated with acarbose remained significant after adjustment for several confounders (P < 0.05 for all models). CONCLUSIONS: In patients with T2D on metformin monotherapy, baseline MAGE was positively correlated with relative HbA1c reduction from baseline after treatment with acarbose, but not glibenclamide. These findings highlight the importance of glycemic excursions in individualized treatment for patients with T2D.
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Acarbosa/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gliburida/uso terapéutico , Hemoglobina Glucada/metabolismo , Metformina/uso terapéutico , Adulto , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada , Femenino , Inhibidores de Glicósido Hidrolasas/uso terapéutico , Humanos , Hipoglucemiantes/uso terapéutico , Modelos Lineales , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Far infrared radiation (FIR) is currently investigated as a potential therapeutic strategy in various diseases though the mechanism is unknown. Presently, we tested if FIR mediates beneficial effects in a cell model of the neurodegenerative disease spinocerebellar ataxia type 3 (SCA3). SCA3 is caused by a mutation leading to an abnormal polyglutamine expansion (PolyQ) in ataxin-3 protein. The consequent aggregation of mutant ataxin-3 results in disruption of vital cell functions. In this study, neuroblastoma cells (SK-N-SH) was transduced to express either non-pathogenic ataxin-3-26Q or pathogenic ataxin-3-78Q proteins. The cells expressing ataxin-3-78Q demonstrated decreased viability, and increased sensitivity to metabolic stress in the presence rotenone, an inhibitor of mitochondrial respiration. FIR exposure was found to protect against these effects. Moreover, FIR improved mitochondrial respiratory function, which was significantly compromised in ataxin-3-78Q and ataxin-3-26Q expressing cells. This was accompanied by decreased levels of mitochondrial fragmentation in FIR treated cells, as observed by fluorescence microscopy and protein expression analysis. Finally, the expression profile LC3-II, Beclin-1 and p62 suggested that FIR prevent the autophagy inhibiting effects observed in ataxin-3-78Q expressing cells. In summary, our results suggest that FIR have rescuing effects in cells expressing mutated pathogenic ataxin-3, through recovery of mitochondrial function and autophagy.
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Rayos Infrarrojos , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Modelos Biológicos , Péptidos/metabolismo , Ataxias Espinocerebelosas/patología , Ataxina-3 , Autofagia/efectos de la radiación , Línea Celular Tumoral , Respiración de la Célula/efectos de la radiación , Supervivencia Celular/efectos de la radiación , Humanos , Dinámicas Mitocondriales/efectos de la radiación , Estrés Oxidativo/efectos de la radiación , Consumo de Oxígeno/efectos de la radiaciónRESUMEN
Caveolin-1 (CAV-1) participates in regulating vesicular transport, signal transduction, tumor progression, and cholesterol homeostasis. In the present study, we tested the hypothesis that CAV-1 improves dyslipidemia, inhibits cyclophilin A (CypA)- mediated ROS production, prevents mitochondrial compensatory action and attenuates oxidative stress responses in cholesterol-induced hypercholesterolemia. To determine the role of CAV-1 in mediating oxidative and antioxidative as well as cholesterol homeostasis, hypercholesterolemic rabbits were intravenously administered antenapedia-CAV-1 (AP-CAV-1) peptide for 2 wk. AP-CAV-1 enhanced CAV-1 expression by Ë15%, inhibited CypA expression by Ë50% (P < 0.05) and significantly improved dyslipidemia, thus reducing neutral lipid peroxidation. Moreover, CAV-1 attenuated hypercholesterolemia-induced changes in mitochondrial morphology and biogenesis and preserved mitochondrial respiratory function. In addition, CAV-1 protected against hypercholesterol-induced oxidative stress responses by reducing the degree of oxidative damage and enhancing the expression of antioxidant enzymes. CAV-1 treatment significantly suppressed apoptotic cell death, as evidenced by the reduction in the number of terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells. We concluded that CAV-1 plays a critical role in inhibiting CypA-mediated ROS production, improving dyslipidemia, maintaining mitochondrial function, and suppressing oxidative stress responses that are vital for cell survival in hypercholesterol-affected renal organs.
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Caveolina 1/genética , Colesterol/efectos adversos , Hipercolesterolemia/tratamiento farmacológico , Riñón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Péptidos/farmacología , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Caveolina 1/metabolismo , Caveolina 1/farmacología , Ciclofilina A/antagonistas & inhibidores , Ciclofilina A/genética , Ciclofilina A/metabolismo , Modelos Animales de Enfermedad , Transporte de Electrón/efectos de los fármacos , Regulación de la Expresión Génica , Humanos , Hipercolesterolemia/inducido químicamente , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Mitocondrias/metabolismo , Estrés Oxidativo , Péptidos/síntesis química , Conejos , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
No study has evaluated whether subnormal estimated glomerular filtration rate (eGFR) (between 61 and 90âmL/min) and high normal albumin-creatinine ratio (ACR) (<30âmg/g) are associated with cardiovascular (CV) events and mortality in type 2 diabetic (T2DM) patients with normoalbuminuria.We observed a longitudinal cohort study of 1291 T2DM patients with normoalbuminuria who were receiving intensified multifactorial treatment from 2004 to 2008. Cox regression models were used to evaluate eGFR and ACR as the risk factors of major CV events (nonfatal myocardial infarction and stroke) and mortality.During the 4-year period, 56 patients died and 159 patients developed major CV events. We found eGFR, but not ACR, to be associated with major CV events. Compared to those with eGFR higher than 90âmL/min, patients with subnormal eGFR (HR: 3.133, 1.402-7.002, Pâ=â0.005) were at greater risk of incident major CV events. Extremely low eGFR (<30âmL/min) was associated with mortality only in patients under 65 years old.Subnormal eGFR was a strong predictor of major CV events in diabetic patients with normoalbuminuria. Normoalbuminuric diabetic patients with subnormal eGFR may need intensive CV risk factor intervention to prevent and treat CV events.
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Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/complicaciones , Tasa de Filtración Glomerular , Albuminuria/orina , Enfermedades Cardiovasculares/mortalidad , Creatinina/orina , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Taiwán/epidemiologíaRESUMEN
AIM: The aim of this study was to examine the association between glycemic excursions and duration of hypoglycemia after treatment intensification in patients with type 2 diabetes (T2D). METHODS: Patients with T2D on oral anti-diabetes drug (OAD) with glycated hemoglobin (HbA1c) of 7.0-11.0% were switched to metformin monotherapy (500 mg thrice daily) for 8 weeks, followed by randomization to either glibenclamide or acarbose as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring (CGM) before randomization and at the end of study. Hypoglycemia was defined as sensor glucose level of less than 60 mg/dl in two or more consecutive readings from CGM. RESULTS: A total of 50 patients (mean age 53.5 ± 8.2 years, male 48%, mean baseline HbA1c 8.4 ± 1.2%) were analyzed. Duration of hypoglycemia significantly increased after treatment with glibenclamide (from 5.5 ± 13.8 to 18.8 ± 35.8 min/day, p=0.041), but not with acarbose (from 2.9 ± 10.9 to 14.7 ± 41.9 min/day, p=0.114). Post treatment MAGE was positively associated with change from baseline in duration of hypoglycemia after treatment with either glibenclamide (ß coefficient 0.345, p=0.036) or acarbose (ß coefficient 0.674, p=0.046). The association remained significant after multivariate adjustment (p<0.05 for all models). CONCLUSIONS: Post treatment glycemic excursions are associated with changes in duration of hypoglycemia after treatment intensification with OAD in patients with T2D. Glycemic excursions should be an important treatment target for T2D to reduce the risk of hypoglycemia.
Asunto(s)
Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemiantes/uso terapéutico , Acarbosa/uso terapéutico , Adulto , Anciano , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada , Femenino , Gliburida/uso terapéutico , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/sangre , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Monitoreo AmbulatorioRESUMEN
AIMS: Our aims were to investigate the prevalence of diabetes mellitus (DM) among patients with newly-diagnosed tuberculosis (TB) and to determine its associated factors in an Asian population. METHODS: The data were obtained from the National Health Insurance Research Database and included 9831 newly-diagnosed TB individuals in the period of 2000-2010. The data were divided into a DM group and a non-DM group. We measured the prevalence and the associated comorbidities of DM. RESULTS: During 2000-2010, the prevalence of DM progressively increased, with an average prevalence rate of 27.9%. The patients with ages of 55-64 years had the highest association of DM (OR=3.53) compared with those under 45 years. TB patients with heart failure, ischemic heart disease, cerebral vascular disease, hypertension, dyslipidemia, chronic kidney disease, and liver disease were more likely to associate with DM (ORs=1.27, 1.23, 1.30, 2.32, 3.26, 1.6, and 1.68, respectively) compared to those without the variables. CONCLUSIONS: The prevalence of DM among TB patients in Taiwan was high and tended to increase in the past decade. Clinically, inquiring about DM history and screening routinely for those without DM history among TB patients should be carried out in Taiwan.
Asunto(s)
Diabetes Mellitus/epidemiología , Tuberculosis/epidemiología , Adulto , Distribución por Edad , Anciano , Distribución de Chi-Cuadrado , Comorbilidad , Estudios Transversales , Bases de Datos Factuales , Diabetes Mellitus/diagnóstico , Femenino , Encuestas Epidemiológicas , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Prevalencia , Factores de Riesgo , Taiwán/epidemiología , Factores de Tiempo , Tuberculosis/diagnósticoRESUMEN
BACKGROUND: This study aimed to explore parameters which will predict good control of HbA1c after adding a second anti-diabetic drug in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy. METHODS: Fifty-one patients (M/F: 25/26, mean age: 53.7 ± 8.2 years, mean glycated hemoglobin [HbA1c] 8.4 ± 1.2%) with T2DM inadequately controlled with metformin were randomized to add-on glibenclamide or acarbose for 16 weeks. Before and after combination therapy, the subjects underwent a 2-hour liquid mixed meal tolerance test to determine insulin secretion (HOMA-ß, insulinogenic index, and disposition index [DI]) and insulin sensitivity (HOMA-IR and Matsuda insulin sensitivity index). RESULTS: At baseline, there was a significant inverse relationship between DI120 and HbA1c (p = 0.001) in all subjects. The addition of glibenclamide and acarbose improved HbA1c significantly from 8.6 ± 1.6% to 7.4 ± 1.2% (p < 0.001), and from 8.2 ± 0.8% to 7.5 ± 0.8% (p < 0.001), respectively. In the glibenclamide group, DI120 significantly increased from 51.2 ± 24.2 to 74.9 ± 41.9 (p < 0.05), and in the acarbose group, from 62.5 ± 31.4 to 91.7 ± 36.2 (p < 0.05), respectively. Multiple regression analyses showed that both baseline HbA1c and DI120 independently predicted reduction of HbA1c as well as final HbA1c after combination therapy. CONCLUSIONS: In patients with T2DM inadequately controlled with metformin, add-on oral anti-diabetic agent with glibenclamide or acarbose resulted in the significant HbA1c reduction and improvement of ß-cell function. Subjects with greater baseline ß-cell function reserve displayed better glycemic response in the combination therapy of metformin with glibenclamide or acarbose. TRIAL REGISTRATION: This study was registered in the ClinicalTrials.gov with registration number of NCT00417729.
RESUMEN
Caveolins are an essential component of cholesterol-rich invaginations of the plasma membrane known as caveolae. These flask-shaped, invaginated structures participate in a number of important cellular processes, including vesicular transport, cholesterol homeostasis, and signal transduction. We investigated the effects of CAV-1 on mitochondrial biogenesis and antioxidant enzymes in hypercholesterolemia-affected target organs. A total of eighteen male New Zealand white rabbits were divided into three groups: a normal-diet group, an untreated hypercholesterolemia-induced group, and a hypercholesterolemia-induced group that received intravenous administration of antennapedia-CAV-1 (AP-CAV-1) peptide every 2 days for 2 weeks. Serum biochemistry, CAV-1 distribution, neutral lipid distribution, mitochondrial morphology, biogenesis-mediated protein content, oxidative stress balance, antioxidant enzyme levels, and apoptotic cell death of liver tissue were analysed. Hepatic and circulating cholesterol and low-density lipoprotein cholesterol (LDL-C) levels differed significantly between the three groups (P<0.05). Immunohistochemical staining intensity of CAV-1 was greater in AP-CAV-1-treated rabbits than in untreated rabbits, especially in the vicinity of the liver vasculature. The high levels of neutral lipids, malondialdehyde, peroxisome proliferator-activated receptor-γ coactive 1α (PGC-1α), and nuclear respiratory factor-1 (NRF-1) seen in untreated hypercholesteremic animals were attenuated by administration of AP-CAV-1 (P<0.05). In addition, mitochondria in animals that received treatment exhibited darker electron-dense matrix and integrated cristae. Furthermore, the levels of ROS modulator 1 (Romo1) and superoxide dismutase (SOD)-2, as well as catalase activity were significantly lower in CAV-1-treated hypercholesterolemic rabbits (P<0.05). AP-CAV-1 treatment also restored mitochondrial respiratory chain subunit protein content (OXPHOS complexes I-V), thereby preserving mitochondrial function (P<0.05). Furthermore, AP-CAV-1 treatment significantly suppressed apoptotic cell death, as evidenced by a reduction in the number of TUNEL-positive cells. Our results indirectly indicate that CAV-1 mediates the negative effects of PGC-1α on hepatic mitochondrial respiratory chain function, promotes the antioxidant enzyme defence system, and maintains mitochondrial biogenesis.
Asunto(s)
Caveolina 1/metabolismo , Hipercolesterolemia/metabolismo , Hígado/metabolismo , Animales , Apoptosis/fisiología , Dieta , Dieta Aterogénica , Transporte de Electrón , Hepatocitos/metabolismo , Hipercolesterolemia/sangre , Metabolismo de los Lípidos , Hígado/patología , Masculino , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Conejos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Vascular cytokines, total nitrite, and cyclophilin-A (CyP-A) may be related to the pathogenesis of untreated hypertension. Forty males with normotensive and untreated essential hypertension were recruited in this cytokines survey. Body mass index (BMI), hyperlipidemia, and plasma CyP-A were increased in the hypertensive group (p < 0.05). However, only BMI (p = 0.022) and plasma CyP-A (p = 0.020) were found to be significant contributors to hypertension by multiple regression analysis. CyP-A was also positively correlated with systolic blood pressure (p = 0.029) and diastolic blood pressure (p = 0.047). These findings indicated that plasma CyP-A is a critical molecular biomarker in the early pathogenesis of essential hypertension.