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1.
Acta Diabetol ; 2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35460376

RESUMO

AIMS: Endoplasmic reticulum (ER) stress is associated with obesity and type 2 diabetes mellitus (T2DM) and increasing evidence demonstrates that some ER stress markers can represent the severity of metabolic dysfunction in either cellular or animal models. However, no appropriate molecule has been identified to demonstrate these relationships in clinical practice. METHODS: To determine whether the serum level of the ER chaperone, protein disulfide isomerase family A, member 4 (PDIA4), is associated with type 2 diabetes mellitus, obesity, and insulin sensitivity, we conducted a cross-sectional study for which a total of 553 adults, including 159 with normal glucose tolerance (NGT), 169 with prediabetes (Pre-DM), and 225 with newly diagnosed T2DM, were recruited. RESULTS: Serum PDIA4 levels were significantly higher in patients with T2DM than in those with NGT (P < 0.001), even after adjustment for potential confounders. These levels correlated positively with fasting plasma glucose, BMI, waist circumference as well as high-sensitivity C-reactive protein levels, and negatively and strongly correlated with insulin sensitivity. In a multivariate logistic regression analysis, higher serum PDIA4 concentration was observed to be significantly associated with an increased risk of T2DM. CONCLUSIONS: Our findings provide new mechanistic insights linking ER stress, T2DM, insulin sensitivity, and obesity, which may, in part, account for the ER chaperone properties associated with PDIA4. The results suggest that PDIA4 may serve as a potential instigator of and a putative therapeutic target for T2DM.

2.
Sci Rep ; 12(1): 5519, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365700

RESUMO

The glucokinase regulator gene (GCKR) is located on chromosome 2p23. It plays a crucial role in maintaining plasma glucose homeostasis and metabolic traits. Recently, genome-wide association studies have revealed a positive association between hyperuricemia and GCKR variants in adults. This study investigated this genetic association in Taiwanese adolescents. Data were collected from our previous cross-sectional study (Taipei Children Heart Study). The frequencies of various genotypes (CC, CT, and TT) or alleles (C and T) of the GCKR intronic single-nucleotide polymorphism (SNP) rs780094 and the coding SNP rs1260326 (Pro446Leu, a common 1403C-T transition) were compared between a total of 968 Taiwanese adolescents (473 boys, 495 girls) with hyperuricemia or normal uric acid levels on the basis of gender differences. Logistic and linear regression analyses explored the role of GCKR in abnormal uric acid (UA) levels. Boys had higher UA levels than girls (6.68 ± 1.29 and 5.23 ± 0.95 mg/dl, respectively, p < 0.001). The analysis of both SNPs in girls revealed that the T allele was more likely to appear in patients with hyperuricemia than the C allele. After adjusting for confounders, the odds ratio (OR) for hyperuricemia incidence in the TT genotype was 1.75 (95% confidence interval [CI] 1.02-3.00), which was higher than that in the C allele carriers in rs1260326 in the girl population. Similarly, the TT genotypes had a higher risk of hyperuricemia, with an OR of 2.29 (95% CI 1.11-4.73) for rs1260326 and 2.28 (95% CI 1.09-4.75) for rs780094, than the CC genotype in girl adolescents. The T (Leu446) allele of GCKR rs1260326 polymorphism is associated with higher UA levels in Taiwanese adolescent girls.


Assuntos
Glucoquinase , Ácido Úrico , Adolescente , Criança , Feminino , Estudo de Associação Genômica Ampla , Glucoquinase/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Triglicerídeos
3.
Am J Med Sci ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35483434

RESUMO

BACKGROUND: Evidence of metformin-associated lactic acidosis (MALA) in advanced chronic kidney disease (CKD) has been limited due to high mortality rate but rare incidence rate. The mechanism of increased MALA in advanced CKD is mainly based on the hypothesis of decreased drug elimination, which might also be confounded by increased comorbidities as CKD progresses. The goal of the study is to analyze the incidence and associated factors of lactic acidosis between metformin user and non-user with advanced CKD. METHODS: This study used a three million population-based, propensity score-matched cohort from 2008 to 2016. The primary outcome was laboratory-defined lactic acidosis. Relationships between the probability of lactic acidosis and various estimated glomerular filtration rate (eGFR) values in advanced CKD patients were also presented in regression analysis. RESULTS: Adults with type 2 diabetes whose eGFR was <30 mL/min/1.73 m2 were enrolled in this study. After the process of propensity score matching, 7707 patients were divided into metformin and non-metformin groups. In linear regression model, metformin significantly increased the risk of lactic acidosis (p=0.0204) as the eGFR declined in advanced CKD over a mean follow up of over 600 days even after confounder adjustment with age, sex and comorbidities. CONCLUSIONS: Metformin was associated with a significant increased risk of laboratory-defined lactic acidosis (p=0.0204) even after adjusting confounder such as age, sex and underlying comorbidities. This "REMIND" study reminds us that metformin-associated lactic acidosis is mainly caused by decreased drug renal elimination other than underlying comorbidities in advanced CKD patients.

4.
Front Immunol ; 13: 852452, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35309328

RESUMO

Dengue is among the most rapidly spreading arboviral disease in the world. A low-cost, easy to use point-of-care diagnostic tool for the detection and differentiation of dengue virus serotypes could improve clinical management, disease prevention, epidemiological surveillance, and outbreak monitoring, particularly in regions where multiple serotypes co-circulate. Despite widespread deployment, no commercial dengue antigen diagnostic test has proven effective in differentiating among dengue virus serotypes. In the current study, we first established mAb pairs and developed a multiplex lateral flow immunoassay for the simultaneous detection of the dengue viral NS1 antigen and identification of serotype. The proposed system, called Dengue serotype NS1 Multiplex LFIA, provides high sensitivity and specificity. In testing for JEV, ZIKV, YFV, WNV, and CHIKV, the multiplex LFIA gave no indication of cross- reactivity with cell culture supernatants of other flaviviruses or chikungunya virus. In analyzing 187 samples from patients suspected of dengue infection, the detection sensitivity for serotype D1 to D4 was 90.0%, 88.24%, 82.61%, and 83.33% and serotype specificity was 98.74%, 96.13%, 99.39%, and 97.04%, respectively. Our multiplex LFIA can also identify mono- and co-infection of different serotype of dengue viruses in mosquitoes. The proposed Multiplex LFIA provides a simple tool for the rapid detection of dengue serotypes and in the differential diagnosis of fever patients in regions where medical resources are limited and/or multiple DENVs co-circulate.


Assuntos
Culicidae , Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Animais , Anticorpos Monoclonais , Anticorpos Antivirais , Humanos , Imunoensaio , Sorogrupo , Proteínas não Estruturais Virais
5.
BMC Genomics ; 23(1): 148, 2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35183128

RESUMO

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10- 7). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.


Assuntos
Estudo de Associação Genômica Ampla , Medicina de Precisão , Pressão Sanguínea/genética , Ligação Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
6.
Integr Med Res ; 11(2): 100831, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35059290

RESUMO

BACKGROUND: Diabetic patients are at high risk of developing cancer. Traditional Chinese medicine (TCM) has become increasingly popular as an adjuvant treatment for patients with chronic diseases, and some studies have identified its beneficial effect in diabetic patients with cancer. The purpoes of this study was to outline the potential of TCM to attenuate hospitalization and mortality rates in diabetic patients with carcinoma in situ (CIS). METHODS: A total of 6,987 diabetic subjects with CIS under TCM therapy were selected from the National Health Insurance Research Database of Taiwan, along with 38,800 of 1:1 sex-, age-, and index year-matched controls without TCM therapy. Cox proportional hazard analysis was conducted to compare hospitalization and mortality rates during an average of 15 years of follow-up. RESULTS: A total of 3,999/1,393 enrolled-subjects (28.62%/9.97%) had hospitalization/mortality, including 1,777/661 in the TCM group (25.43%/9.46%) and 2,222/732 in the control group (31.80%/10.48%). Cox proportional hazard regression analysis showed a lower rate of hospitalization and mortality for subjects in the TCM group (adjusted HR=0.536; 95% CI=0.367-0.780, P<0.001; adjusted HR=0.783; 95% CI=0.574-0.974, P = 0.022). Kaplan-Meier analysis showed that the cumulative risk of hospitalization and mortality in the case and control groups was significantly different (log rank, P<0.001 and P = 0.011, respectively). CONCLUSIONS: Diabetic patients with CIS under TCM therapy were associated with lower hospitalization and mortality rates compared to those without TCM therapy. Thus, TCM application may reduce the burden of national medical resources.

7.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576032

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.


Assuntos
COVID-19/complicações , Doenças Cardiovasculares/imunologia , Síndrome da Liberação de Citocina/imunologia , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Doenças Cardiovasculares/virologia , Diferenciação Celular , Linhagem Celular , Biologia Computacional , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Humanos , Células-Tronco Pluripotentes Induzidas , Miocárdio/citologia , Miocárdio/imunologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/virologia , Fosfoproteínas/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Regulação para Cima/imunologia , Internalização do Vírus/efeitos dos fármacos
8.
Nutrition ; 91-92: 111269, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34343727

RESUMO

OBJECTIVES: Muscle is crucial for blood glucose regulation. There is a need to prevent and treat sarcopenia in diabetes mellitus (DM). This study aimed to estimate the prevalence of sarcopenia and evaluate the association of nutritional counseling with the development of sarcopenia for people with DM. METHODS: In a cross-sectional and retrospective cohort study, people with type 2 DM were recruited from the Diabetes Shared Care Program of a teaching hospital. Muscle mass, muscle strength, and physical functional performance were evaluated using the Asian Working Group for Sarcopenia criteria. The skeletal muscle mass index was determined by dividing muscle mass by the square of the height. Clinical information, including the nutrition counseling record, was retrospectively obtained from medical records for a 2-y period. RESULTS: The prevalence of low skeletal muscle mass index (presarcopenia) and sarcopenia were, respectively, 20.4% and 9.6% (including 3.1% severe) among 1292 participants. Specifically, 15.3% of participants age ≥ 65 y were categorized as having sarcopenia. With more frequent nutritional counseling, there was a lesser risk of sarcopenia; the adjusted odds ratio (95% confidence interval) was 0.51 (0.27-0.94) for ≥ 3 times/2 y compared to no counseling. DM duration and age, glycemic status and medication, and body mass index and counseling frequency had no joint effects; however, these variables (except HbA1 c) were independent risk factors for low skeletal muscle mass index and sarcopenia. CONCLUSIONS: People with type 2 DM have a high risk of sarcopenia. Increased nutrition counseling in outpatients was associated with less sarcopenia. Education about sarcopenia-associated risk factors should be encouraged early in the onset of DM.


Assuntos
Diabetes Mellitus Tipo 2 , Sarcopenia , Índice de Massa Corporal , Aconselhamento , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Força da Mão , Humanos , Músculo Esquelético , Estudos Retrospectivos , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Sarcopenia/prevenção & controle
9.
Biomed J ; 44(3): 293-303, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34119448

RESUMO

BACKGROUND: While severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presents with mild or no symptoms in most cases, a significant number of patients become critically ill. Remdesivir has been approved for the treatment of coronavirus disease 2019 (COVID-19) in several countries, but its use as monotherapy has not substantially lowered mortality rates. Because agents from traditional Chinese medicine (TCM) have been successfully utilized to treat pandemic and endemic diseases, we designed the current study to identify novel anti-SARS-CoV-2 agents from TCM. METHODS: We initially used an antivirus-induced cell death assay to screen a panel of herbal extracts. The inhibition of the viral infection step was investigated through a time-of-drug-addition assay, whereas a plaque reduction assay was carried out to validate the antiviral activity. Direct interaction of the candidate TCM compound with viral particles was assessed using a viral inactivation assay. Finally, the potential synergistic efficacy of remdesivir and the TCM compound was examined with a combination assay. RESULTS: The herbal medicine Perilla leaf extract (PLE, approval number 022427 issued by the Ministry of Health and Welfare, Taiwan) had EC50 of 0.12 ± 0.06 mg/mL against SARS-CoV-2 in Vero E6 cells - with a selectivity index of 40.65. Non-cytotoxic PLE concentrations were capable of blocking viral RNA and protein synthesis. In addition, they significantly decreased virus-induced cytokine release and viral protein/RNA levels in the human lung epithelial cell line Calu-3. PLE inhibited viral replication by inactivating the virion and showed additive-to-synergistic efficacy against SARS-CoV-2 when used in combination with remdesivir. CONCLUSION: Our results demonstrate for the first time that PLE is capable of inhibiting SARS-CoV-2 replication by inactivating the virion. Our data may prompt additional investigation on the clinical usefulness of PLE for preventing or treating COVID-19.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Perilla frutescens , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Inativação de Vírus , Animais , COVID-19 , Chlorocebus aethiops , Humanos , Perilla frutescens/química
10.
Nat Commun ; 12(1): 2182, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846329

RESUMO

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.


Assuntos
Fatores de Risco Cardiometabólico , Cromossomos Humanos X/genética , Lipídeos/sangue , Proteínas do Olho/metabolismo , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Fenômica , Polimorfismo de Nucleotídeo Único/genética , Tela Subcutânea/metabolismo , Sequenciamento Completo do Genoma
11.
JAMA Netw Open ; 4(4): e217557, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33929522

RESUMO

Importance: Many health care systems lack the efficiency, preparedness, or resources needed to address the increasing number of patients with type 2 diabetes, especially in low- and middle-income countries. Objective: To examine the effects of a quality improvement intervention comprising information and communications technology and contact with nonphysician personnel on the care and cardiometabolic risk factors of patients with type 2 diabetes in 8 Asia-Pacific countries. Design, Setting, and Participants: This 12-month multinational open-label randomized clinical trial was conducted from June 28, 2012, to April 28, 2016, at 50 primary care or hospital-based diabetes centers in 8 Asia-Pacific countries (India, Indonesia, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam). Six countries were low and middle income, and 2 countries were high income. The study was conducted in 2 phases; phase 1 enrolled 7537 participants, and phase 2 enrolled 13 297 participants. Participants in both phases were randomized on a 1:1 ratio to intervention or control groups. Data were analyzed by intention to treat and per protocol from July 3, 2019, to July 21, 2020. Interventions: In both phases, the intervention group received 3 care components: a nurse-led Joint Asia Diabetes Evaluation (JADE) technology-guided structured evaluation, automated personalized reports to encourage patient empowerment, and 2 or more telephone or face-to-face contacts by nurses to increase patient engagement. In phase 1, the control group received the JADE technology-guided structured evaluation and automated personalized reports. In phase 2, the control group received the JADE technology-guided structured evaluation only. Main Outcomes and Measures: The primary outcome was the incidence of a composite of diabetes-associated end points, including cardiovascular disease, chronic kidney disease, visual impairment or eye surgery, lower extremity amputation or foot ulcers requiring hospitalization, all-site cancers, and death. The secondary outcomes were the attainment of 2 or more primary diabetes-associated targets (glycated hemoglobin A1c <7.0%, blood pressure <130/80 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL) and/or 2 or more key performance indices (reduction in glycated hemoglobin A1c≥0.5%, reduction in systolic blood pressure ≥5 mm Hg, reduction in low-density lipoprotein cholesterol ≥19 mg/dL, and reduction in body weight ≥3.0%). Results: A total of 20 834 patients with type 2 diabetes were randomized in phases 1 and 2. In phase 1, 7537 participants (mean [SD] age, 60.0 [11.3] years; 3914 men [51.9%]; 4855 patients [64.4%] from low- and middle-income countries) were randomized, with 3732 patients allocated to the intervention group and 3805 patients allocated to the control group. In phase 2, 13 297 participants (mean [SD] age, 54.0 [11.1] years; 7754 men [58.3%]; 13 297 patients [100%] from low- and middle-income countries) were randomized, with 6645 patients allocated to the intervention group and 6652 patients allocated to the control group. In phase 1, compared with the control group, the intervention group had a similar risk of experiencing any of the primary outcomes (odds ratio [OR], 0.94; 95% CI, 0.74-1.21) but had an increased likelihood of attaining 2 or more primary targets (OR, 1.34; 95% CI, 1.21-1.49) and 2 or more key performance indices (OR, 1.18; 95% CI, 1.04-1.34). In phase 2, the intervention group also had a similar risk of experiencing any of the primary outcomes (OR, 1.02; 95% CI, 0.83-1.25) and had a greater likelihood of attaining 2 or more primary targets (OR, 1.25; 95% CI, 1.14-1.37) and 2 or more key performance indices (OR, 1.50; 95% CI, 1.33-1.68) compared with the control group. For attainment of 2 or more primary targets, larger effects were observed among patients in low- and middle-income countries (OR, 1.50; 95% CI, 1.29-1.74) compared with high-income countries (OR, 1.20; 95% CI, 1.03-1.39) (P = .04). Conclusions and Relevance: In this 12-month clinical trial, the use of information and communications technology and nurses to empower and engage patients did not change the number of clinical events but did reduce cardiometabolic risk factors among patients with type 2 diabetes, especially those in low- and middle-income countries in the Asia-Pacific region. Trial Registration: ClinicalTrials.gov Identifier: NCT01631084.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Diabetes Mellitus Tipo 2/terapia , Autogestão , Tecnologia , Idoso , Amputação/estatística & dados numéricos , Ásia Sudeste , Pressão Sanguínea , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/metabolismo , Países em Desenvolvimento , Diabetes Mellitus Tipo 2/metabolismo , Pé Diabético/epidemiologia , Nefropatias Diabéticas/epidemiologia , Retinopatia Diabética/epidemiologia , Gerenciamento Clínico , Medicina Baseada em Evidências , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Mortalidade , Neoplasias/epidemiologia , Participação do Paciente , Melhoria de Qualidade , Insuficiência Renal Crônica/epidemiologia , Medição de Risco , Taiwan , Cooperação e Adesão ao Tratamento
12.
Diabetologia ; 64(7): 1613-1625, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33842983

RESUMO

AIMS/HYPOTHESIS: An elevated fasting glucose level in non-diabetic individuals is a key predictor of type 2 diabetes. Genome-wide association studies (GWAS) have identified hundreds of SNPs for fasting glucose but most of their functional roles in influencing the trait are unclear. This study aimed to identify the mediation effects of DNA methylation between SNPs identified as significant from GWAS and fasting glucose using Mendelian randomisation (MR) analyses. METHODS: We first performed GWAS analyses for three cohorts (Taiwan Biobank with 18,122 individuals, the Healthy Aging Longitudinal Study in Taiwan with 1989 individuals and the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance with 416 individuals) with individuals of Han Chinese ancestry in Taiwan, followed by a meta-analysis for combining the three GWAS analysis results to identify significant and independent SNPs for fasting glucose. We determined whether these SNPs were methylation quantitative trait loci (meQTLs) by testing their associations with DNA methylation levels at nearby CpG sites using a subsample of 1775 individuals from the Taiwan Biobank. The MR analysis was performed to identify DNA methylation with causal effects on fasting glucose using meQTLs as instrumental variables based on the 1775 individuals. We also used a two-sample MR strategy to perform replication analysis for CpG sites with significant MR effects based on literature data. RESULTS: Our meta-analysis identified 18 significant (p < 5 × 10-8) and independent SNPs for fasting glucose. Interestingly, all 18 SNPs were meQTLs. The MR analysis identified seven CpGs near the G6PC2 gene that mediated the effects of a significant SNP (rs2232326) in the gene on fasting glucose. The MR effects for two CpGs were replicated using summary data based on the European population, using an exonic SNP rs2232328 in G6PC2 as the instrument. CONCLUSIONS/INTERPRETATION: Our analysis results suggest that rs2232326 and rs2232328 in G6PC2 may affect DNA methylation at CpGs near the gene and that the methylation may have downstream effects on fasting glucose. Therefore, SNPs in G6PC2 and CpGs near G6PC2 may reside along the pathway that influences fasting glucose levels. This is the first study to report CpGs near G6PC2, an important gene for regulating insulin secretion, mediating the effects of GWAS-significant SNPs on fasting glucose.


Assuntos
Glicemia/genética , Ilhas de CpG/genética , Glucose-6-Fosfatase/genética , Estudos de Coortes , Metilação de DNA , Jejum/sangue , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Estudos Longitudinais , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Taiwan/epidemiologia
13.
EBioMedicine ; 63: 103157, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33418499

RESUMO

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants. METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity. FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants. INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.


Assuntos
Genômica , Taxa de Filtração Glomerular , Medicina de Precisão , Sequenciamento Completo do Genoma , Alelos , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Humanos , Masculino , National Heart, Lung, and Blood Institute (U.S.) , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Vigilância em Saúde Pública , Característica Quantitativa Herdável , Estados Unidos/epidemiologia
14.
J Diabetes Investig ; 12(4): 485-492, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32969596

RESUMO

AIMS/INTRODUCTION: Obesity is characterized by disturbed adipocytokine expression and insulin resistance in adipocytes. Growth arrest-specific 6 (GAS6) is a gene encoding the Gas6 protein, which is expressed in fibroblasts, and its related signaling might be associated with adipose tissue inflammation, glucose intolerance and insulin resistance. The aim of this study was to investigate the associations among Gas6, adipocytokines and insulin resistance in adipocytes. MATERIALS AND METHODS: Mature Simpson Golabi Behmel Syndrome adipocytes were treated with high levels of insulin to mimic insulin resistance, and were examined for the expressions of Gas6, cytokines and adipocytokines from preadipocytes in differentiation. In an animal study, high-fat diet-induced obese mice were used to verify the Gas6 expression in vitro. RESULTS: During the differentiation of adipocytes, the expression of Gas6 gradually decreased, and was obviously downregulated with adipocyte inflammation and insulin resistance. Gas6 levels were found to be in proportion to the expression of adiponectin, which has been regarded as closely relevant to improved insulin sensitivity after metformin treatment. Similar results were also confirmed in the animal study. CONCLUSIONS: Our results suggest that Gas6 might modulate the expression of adiponectin, and might therefore be associated with insulin resistance in adipose tissues.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Adipócitos/metabolismo , Adipogenia , Tecido Adiposo/efeitos dos fármacos , Animais , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
15.
PeerJ ; 8: e9998, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240585

RESUMO

AIMS/INTRODUCTION: To investigate the clinical outcomes of patients with type 2 diabetes mellitus (T2DM) who initiated dapagliflozin in real-world practice in Taiwan. MATERIALS AND METHODS: In this multicenter retrospective study, adult patients with T2DM who initiated dapagliflozin after May 1st 2016 either as add-on or switch therapy were included. Changes in clinical and laboratory parameters were evaluated at 3 and 6 months. Baseline factors associated with dapagliflozin response in glycated hemoglobin (HbA1c) were analyzed by univariate and multivariate logistic regression. RESULTS: A total of 1,960 patients were eligible. At 6 months, significant changes were observed: HbA1c by -0.73% (95% confidence interval [CI] -0.80, -0.67), body weight was -1.61 kg (95% CI -1.79, -1.42), and systolic/diastolic blood pressure by -3.6/-1.4 mmHg. Add-on dapagliflozin showed significantly greater HbA1c reduction (-0.82%) than switched therapy (-0.66%) (p = 0.002). The proportion of patients achieving HbA1c <7% target increased from 6% at baseline to 19% at Month 6. Almost 80% of patients experienced at least 1% reduction in HbA1c, and 65% of patients showed both weight loss and reduction in HbA1c. Around 37% of patients had at least 3% weight loss. Multivariate logistic regression analysis indicated patients with higher baseline HbA1c and those who initiated dapagliflozin as add-on therapy were associated with a greater reduction in HbA1c. CONCLUSIONS: In this real-world study with the highest patient number of Chinese population to date, the use of dapagliflozin was associated with significant improvement in glycemic control, body weight, and blood pressure in patients with T2DM. Initiating dapagliflozin as add-on therapy showed better glycemic control than as switch therapy.

16.
J Clin Med ; 9(9)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887312

RESUMO

Patients with diabetes are at increased risk of cancer development and osteoporosis. Metformin is an effective agent for diabetes management. Epidemiological studies have identified an association between metformin use and cancer prevention. This article outlines the potential for metformin to attenuate the rate of osteoporosis in diabetic patients with carcinoma in situ (CIS). From the National Health Insurance Research Database of Taiwan, 7827 patients with diabetes with CIS who were receiving metformin therapy were selected, along with 23,481 patients as 1:3 sex-, age- and index year-matched controls, who were not receiving metformin therapy. A Cox proportional hazard analysis was used to compare the rate of osteoporosis during an average of 15-year follow-up. Of the subjects who were enrolled, 801 (2.56%) had osteoporosis, including 168 from the metformin group (2.15%) and 633 from the without metformin group (2.70%). The metformin group presented a lower rate of osteoporosis at the end of follow-up (p = 0.009). The Cox proportional hazard regression analysis revealed a lower rate of osteoporosis for the metformin group (adjusted hazard ratio of 0.820; 95% confidence interval = 0.691-0.972, p = 0.022). Diabetic patients with CIS under metformin therapy presented lower osteoporosis rate than those who were not receiving metformin therapy.

17.
Medicine (Baltimore) ; 98(41): e17371, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593087

RESUMO

Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease associated with increased prevalence of type 2 diabetes mellitus (T2DM). Here, we investigated the effect of the combination of cyclooxygenase (COX)-2 inhibitors and metformin on the rate of admission in patients with RA and T2DM and compared it with that of only COX-2 inhibitors.In total, 1268 subjects with RA and T2DM under COX-2 inhibitor and metformin therapy were selected from the National Health Insurance Research Database of Taiwan, along with 2536 patients as 1:2 sex-, age-, and index year-matched controls without metformin therapy. Cox proportional hazard analysis was used to compare the rate of admission during the 10 years of follow-up.At the end of the follow-up, 72 enrolled subjects (1.89%) had admission, including 9 from the combination group (0.71%) and 63 from the COX-2 inhibitor group (2.48%). The combination group was associated with a lower rate of admission at the end of follow-up (P < .001). Cox proportional hazard regression analysis revealed the lower rate of admission for subjects under combination therapy (adjusted hazard ratio of 0.275; 95% confidence interval = 0.136-0.557, P < .001).Patients with RA and T2DM receiving the combination of COX-2 inhibitors and metformin were associated with lower admission rate than those on COX-2 inhibitors alone, and this effect may be attributed to the decrease in the levels of proinflammatory factors.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Idoso , Artrite Reumatoide/complicações , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/complicações , Quimioterapia Combinada , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia
18.
J Biomed Sci ; 26(1): 68, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492153

RESUMO

BACKGROUND: Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. OBJECTIVES: In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. METHOD: We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. RESULTS: Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. CONCLUSIONS: Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.


Assuntos
Cilostazol/farmacologia , Angiopatias Diabéticas/tratamento farmacológico , Glucose/efeitos adversos , Músculo Liso Vascular/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/farmacologia , Transdução de Sinais , Animais , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso Vascular/fisiopatologia , NF-kappa B/metabolismo , Ratos , Receptor para Produtos Finais de Glicação Avançada/metabolismo
19.
Medicine (Baltimore) ; 98(36): e16860, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490370

RESUMO

BACKGROUND: The blood glucose response to moderate-intensity exercise remains unclear for patients with type 2 diabetes (T2DM). In addition, little is known about determinants of blood glucose response to a 12-week moderate-intensity exercise training. Therefore, this study aimed to explore trends in blood glucose in response to a 12-week moderate-intensity exercise training in patients with T2DM and to explore the predictors of post-exercise blood glucose (PEBG) and exercise-induced glucose response (EIGR). METHODS: A prospective longitudinal study was conducted. Of the 66 participants with T2DM recruited from outpatient clinics of a medical center, 20 were eligible to enroll in a 12-week moderate-intensity exercise training. Participants were randomly assigned to 1 of 3 exercise times (morning, afternoon, or evening). Blood glucose were measured pre- and post-exercise. The EIGR was calculated by subtracting the PEBG from the before-exercise blood glucose (BEBG). Generalized estimating equations were used to examine the trends and predictors of PEBG and EIGR. RESULTS: The BEBG declined progressively (ß = -1.69, P < .001); while the PEBG (ß = -0.18, P = .08) remained stable over time during the 12-week exercise training. Higher BEBG predicted higher (ß = 0.53, P < .001) PEBG. Higher baseline maximum oxygen uptake (VO2max) contributed to a larger magnitude of EIGR; higher HgbA1c and BEBG predicted higher EIGR (ß = 0.27, P = .02; ß = 0.45, P < .001); afternoon or evening exercise predicted lower (ß = -13.2, P = .04; ß = -5.96, P = .005) EIGR than did morning exercise. CONCLUSIONS: A 12-week moderate-intensity exercise training appears safe for patients with T2DM. Time of day for exercise, baseline VO2max, and baseline metabolic control may influence the impact of exercise for individuals with T2DM. These findings provide considerations for design of optimal exercise training for T2DM patients.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/terapia , Exercício Físico/fisiologia , Adulto , Índice de Massa Corporal , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Estudos Prospectivos
20.
PLoS One ; 14(9): e0222815, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31550292

RESUMO

OBJECTIVES: Traits of metabolic syndrome (MetS) and biomarkers of inflammation and endothelial dysfunction were examined. We investigated the differences of various biomarkers among individuals with or without Mets in a gender-specific manner. The gender-specific associations between E-selectin and MetS were further evaluated. METHODS: A total of 205 patients were recruited from the outpatient clinics of Tri-Service General Hospital, Taipei, Taiwan. Inclusion criteria were age between 20-75 years and BMI < 35 kg/m2. Demographic, anthropometric and MetS index data were compared between genders. Markers of inflammation and endothelial dysfunction were compared between individuals with or without MetS by gender. RESULTS: Age-adjusted E-selectin values showed significant positive correlations with BMI, waist-hip ratio, fasting plasma glucose, systolic and diastolic blood pressure, triglycerides, TNF-α, hsCRP and ICAM-1, and inverse correlation with HDL cholesterol. E-selectin levels were positively correlated with numbers of MetS components in females (P < 0.001) but not in males (P = 0.125). CONCLUSIONS: Increased E-selectin levels are significantly associated with increased MetS risk in females, but not in males.


Assuntos
Selectina E/sangue , Síndrome Metabólica/epidemiologia , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fatores Sexuais , Adulto Jovem
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