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1.
Nat Commun ; 11(1): 4912, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32999275

RESUMO

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Ilhotas Pancreáticas/metabolismo , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Glicemia/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Elementos Facilitadores Genéticos , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA-Seq , Análise de Sequência de DNA , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Adulto Jovem
2.
Wiad Lek ; 73(8): 1671-1676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33055332

RESUMO

OBJECTIVE: The aim: To determine changes of FSG of neutrophilic granulocytes of peripheral blood (NGPB) of patients with CHC with concomitant DM-2. PATIENTS AND METHODS: Materials and methods: We've examined 180 patients with CHC: 160 with concomitant diabetes mellitus and 20 ones without it. The NGPB genome was studied using cytogenetic method. There were analyzed 100 interphase NGPB nuclei in the preparation, structural characteristics were evaluated according to indices: chromatization (IC), nucleolar (IN), pathologically altered nuclei (PAN), micronuclei (MNI). RESULTS: Results: Violations of FSG OF NGPBwere found according to all indices in patients with CHC, they were more pronounced in patients with concomitant DM-2. CONCLUSION: Conclusions: FSG NGPB is more disordered in CHC with concomitant DM-2. The reduction of IC in CHC with concomitant DM-2 is more pronounced in men. Reduction of IN in patients with CHC with and without DM-2 is a marker of violations of the second stage of realization of hereditary information. The tendency to change the components of the cytogenetic status of all examined patients due to the frequency of MNI was determined.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatite C Crônica , Biomarcadores , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Granulócitos , Humanos , Masculino
3.
Medicine (Baltimore) ; 99(35): e21558, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871871

RESUMO

BACKGROUND: As indicated by numerous studies, there exists a relationship between the polymorphism of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to diabetic nephropathy (DN) in various populations; nonetheless, the findings remain inconsistent. Therefore, we carried out a meta-analysis to determine the relationship between the MTHFR gene polymorphism and DN susceptibility. MATERIALS AND METHOD: Related studies were identified from PubMed, Cochrane Library, EMBASE, and the China National Knowledge Infrastructure database (time period: from building the library to October 2019). The strength of the association was examined using odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: The findings illustrated that the C677T gene polymorphism was significantly associated with an enhanced susceptibility to DN compared to that with diabetes mellitus in allelic (OR = 1.64, 95% CI = 1.34-2.00, P < .001), dominant (OR = 1.85, 95% CI = 1.40-2.46, P < .001), codominant (heterozygote: OR = 1.67, 95% CI = 1.27-2.21, P < .001; homozygote: OR = 2.55, 95% CI = 1.82-3.57, P < .001), and recessive (OR = 1.89, 95% CI = 1.50-2.38, P < .001) models of the overall population. Moreover, as compared with the healthy controls, a significantly augmented susceptibility to DN was found in all 5 genetic comparison models (allelic: OR = 2.06, 95% CI = 1.58-2.67, P < .001; dominant: OR = 2.52, 95% CI = 1.73-3.69, P < .001; codominant: OR = 3.78, 95% CI = 2.50-5.70, P < .001; recessive: OR = 2.41, 95% CI = 1.96-2.97, P < .001). Furthermore, stratifying data by ethnicity revealed substantially augmented vulnerability to DN in not only Caucasian but also Asian populations. CONCLUSION: The present study suggests that the C677T polymorphism was associated with an augmented susceptibility to DN.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Humanos , Fatores de Risco
4.
Ther Umsch ; 77(7): 297-301, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32996427

RESUMO

Laboratory investigations in clinical diabetic practice Abstract. Laboratory analysis are useful to diagnose the proper form of diabetes mellitus, for follow-up of the metabolic control, and to identify secondary complications or associated diseases. The proof of auto-antibodies confirms Type 1 diabetes and a broad range of endocrine entities of the polyglandular autoimmune syndrome, and genetic testing classifies monogenetic diabetes like MODY or MIDDM. In secondary diabetes forms underlying disease can be detected by clinical and laboratory investigation, and thus, causal treatment of the diabetes may be possible.


Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Testes Genéticos , Humanos
5.
Adv Clin Exp Med ; 29(9): 1057-1063, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32926601

RESUMO

BACKGROUND: Diabetes mellitus (DM) has become more and more common and has a high morbidity and mortality rate worldwide. It is a multifactorial chronic disease affected by both genetic and environmental factors. OBJECTIVES: To evaluate the association between antioxidant enzyme activities and their genetic variations and the level of malondialdehyde (MDA) in type II diabetes patients living in the Adiyaman province in the southeast part of Turkey. MATERIAL AND METHODS: One hundred patients diagnosed with type II DM (T2DM) and 100 healthy controls were included in the study. Malondialdehyde levels and antioxidant enzyme activities were measured spectrophometrically. DNA isolation was performed and genotyping was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Our results revealed no significant differences in genotype distributions and allele frequencies of all polymorphisms between groups (p > 0.05). Significantly elevated MDA levels and a significant reduction in catalase (CAT) and paraoxonase (PON) enzyme activities were observed in patients compared to the control group in terms of study groups and genetic variations (p < 0.05). Moreover, CAT activity was reduced in TT genotype in terms of CAT -262 C/T polymorphism in patients (p < 0.05). Paraoxonase activity was observed to be lower in MM genotype in both groups (p < 0.05). CONCLUSIONS: CAT -262 C/T polymorphism may be one of the factors that lead to severe clinical situation in DM. Our results suggest that TT genotype may be more prone to lipid peroxidation.


Assuntos
Diabetes Mellitus Tipo 2 , Polimorfismo Genético , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/genética , Frequência do Gene , Genótipo , Humanos , Turquia
6.
Yonsei Med J ; 61(9): 780-788, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882762

RESUMO

PURPOSE: This research was designed to investigate how miR-542-5p regulates the progression of hyperglycemia and hyperlipoidemia. MATERIALS AND METHODS: An in vivo model with diabetic db/db mice and an in vitro model with forskolin/dexamethasone (FSK/DEX)-induced primary hepatocytes and HepG2 cells were employed in the study. Bioinformatics analysis was conducted to identify the expression of candidate miRNAs in the liver tissues of diabetic and control mice. H&E staining revealed liver morphology in diabetic and control mice. Pyruvate tolerance tests, insulin tolerance tests, and intraperitoneal glucose tolerance test were utilized to assess insulin resistance. ELISA was conducted to evaluate blood glucose and insulin levels. Red oil O staining showed lipid deposition in liver tissues. Luciferase reporter assay was used to depict binding between miR-542-5p and forkhead box O1 (FOXO1). RESULTS: MiR-542-5p expression was under-expressed in the livers of db/db mice. Further in vitro experiments revealed that FSK/DEX, which mimics the effects of glucagon and glucocorticoids, induced cellular glucose production in HepG2 cells and in primary hepatocytes cells. Notably, these changes were reversed by miR-542-5p. We found that transcription factor FOXO1 is a target of miR-542-5p. Further in vivo study indicated that miR-542-5p overexpression decreases FOXO1 expression, thereby reversing increases in blood glucose, blood lipids, and glucose-related enzymes in diabetic db/db mice. In contrast, anti-miR-542-5p exerted an adverse influence on blood glucose and blood lipid metabolism, and its stimulatory effects were significantly inhibited by sh-FOXO1 in normal control mice. CONCLUSION: Collectively, our results indicated that miR-542-5p inhibits hyperglycemia and hyperlipoidemia by targeting FOXO1.


Assuntos
Diabetes Mellitus Tipo 2/genética , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , MicroRNAs/genética , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Teste de Tolerância a Glucose , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hiperglicemia/metabolismo , Hiperlipidemias/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , MicroRNAs/metabolismo , MicroRNAs/farmacologia
7.
Medicine (Baltimore) ; 99(34): e21882, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846846

RESUMO

Thyroid cancer (TC) is the most well-known endocrine neoplasia as well as a common malignant tumor in the head and neck. Our study was designed to assess the prognostic meaningful of TNFRSF12A expression in TC dependent on data acquired from TCGA and so as to increase further knowledge into the biological pathways involved in TC pathogenesis related TNFRSF12A.Information on gene expression and comparing clinical data were identified and downloaded from TCGA. Gene set enrichment analysis (GSEA) created an arranged list of all genes indicated by their connection with TNFRSF12A expression.Our study cohort included 370 (73.1%) female and 136 (26.9%) male patients. The scatter plot and paired plot showed the difference of TNFRSF12A expression between normal and tumor samples (P < .01). The univariate analysis suggested that TNFRSF12A-low associated essentially with age (HR: 1.15; 95%CI: 1.08-1.22; P < .01), stage (HR: 2.79; 95%CI: 1.43-5.46; I vs IV; P = .003) and tumor stage (HR: 2.39; 95%CI: 1.08-5.30; P = .031). The GSEA results show that type II diabetes mellitus, pantothenate and CoA biosynthesis, adipocytokine signaling pathway, PPAR signaling pathway, mTOR signaling pathway, insulin signaling pathway, are enriched in TNFRSF12A low expression phenotype.TNFRSF12A expression may be a potential useful prognostic molecular biomarker of bad survival in thyroid cancer, in addition, PPAR signaling pathway, insulin signaling pathway, mTOR signaling pathway may be the key pathway controlled by TNFRSF12A in thyroid cancer. Further experimental ought to be performed to demonstrate the biologic effect of TNFRSF12A.


Assuntos
Transdução de Sinais , Receptor de TWEAK/genética , Neoplasias da Glândula Tireoide/genética , Adipocinas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Receptores Ativados por Proliferador de Peroxissomo/genética , Valor Preditivo dos Testes , Prognóstico , Serina-Treonina Quinases TOR/genética , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia
8.
Nat Commun ; 11(1): 3865, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737319

RESUMO

Polygenic scores (PGS) have been widely used to predict disease risk using variants identified from genome-wide association studies (GWAS). To date, most GWAS have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European ancestry populations. Here, we derive a theoretical model of the relative accuracy (RA) of PGS across ancestries. We show through extensive simulations that the RA of PGS based on genome-wide significant SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of causal SNP effects and heritability. We find that LD and MAF differences between ancestries can explain between 70 and 80% of the loss of RA of European-based PGS in African ancestry for traits like body mass index and type 2 diabetes. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWAS are mostly shared across continents.


Assuntos
Asma/genética , Diabetes Mellitus Tipo 2/genética , Hipertensão/genética , Modelos Genéticos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , África/epidemiologia , Idoso , Alelos , Ásia/epidemiologia , Asma/diagnóstico , Asma/epidemiologia , Asma/etnologia , Índice de Massa Corporal , Colesterol/sangue , Simulação por Computador , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etnologia , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/etnologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Prognóstico , Característica Quantitativa Herdável , Risco
9.
PLoS Med ; 17(8): e1003305, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841251

RESUMO

BACKGROUND: Many maternal traits are associated with a neonate's gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved. METHODS AND FINDINGS: Based on 10,734 mother-infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10-4). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10-17). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10-4). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10-3), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10-2 and p = 4.5 × 10-3, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10-6); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10-3). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10-3) and a stronger fetal effect (p = 1.3 × 10-5). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10-4) and increased maternal systolic BP during pregnancy (p = 2.2 × 10-2). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits. CONCLUSIONS: We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk-increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.


Assuntos
Peso ao Nascer/fisiologia , Estatura/fisiologia , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Testes Genéticos/métodos , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos Prospectivos
10.
BMC Bioinformatics ; 21(1): 372, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854616

RESUMO

BACKGROUND: About 90% of patients who have diabetes suffer from Type 2 DM (T2DM). Many studies suggest using the significant role of lncRNAs to improve the diagnosis of T2DM. Machine learning and Data Mining techniques are tools that can improve the analysis and interpretation or extraction of knowledge from the data. These techniques may enhance the prognosis and diagnosis associated with reducing diseases such as T2DM. We applied four classification models, including K-nearest neighbor (KNN), support vector machine (SVM), logistic regression, and artificial neural networks (ANN) for diagnosing T2DM, and we compared the diagnostic power of these algorithms with each other. We performed the algorithms on six LncRNA variables (LINC00523, LINC00995, HCG27_201, TPT1-AS1, LY86-AS1, DKFZP) and demographic data. RESULTS: To select the best performance, we considered the AUC, sensitivity, specificity, plotted the ROC curve, and showed the average curve and range. The mean AUC for the KNN algorithm was 91% with 0.09 standard deviation (SD); the mean sensitivity and specificity were 96 and 85%, respectively. After applying the SVM algorithm, the mean AUC obtained 95% after stratified 10-fold cross-validation, and the SD obtained 0.05. The mean sensitivity and specificity were 95 and 86%, respectively. The mean AUC for ANN and the SD were 93% and 0.03, also the mean sensitivity and specificity were 78 and 85%. At last, for the logistic regression algorithm, our results showed 95% of mean AUC, and the SD of 0.05, the mean sensitivity and specificity were 92 and 85%, respectively. According to the ROCs, the Logistic Regression and SVM had a better area under the curve compared to the others. CONCLUSION: We aimed to find the best data mining approach for the prediction of T2DM using six lncRNA expression. According to the finding, the maximum AUC dedicated to SVM and logistic regression, among others, KNN and ANN also had the high mean AUC and small standard deviations of AUC scores among the approaches, KNN had the highest mean sensitivity and the highest specificity belonged to SVM. This study's result could improve our knowledge about the early detection and diagnosis of T2DM using the lncRNAs as biomarkers.


Assuntos
Algoritmos , Diabetes Mellitus Tipo 2/diagnóstico , RNA Longo não Codificante/metabolismo , Área Sob a Curva , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/genética , Diagnóstico Precoce , Humanos , Modelos Logísticos , Curva ROC , Sensibilidade e Especificidade , Máquina de Vetores de Suporte
11.
Life Sci ; 258: 118155, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735887

RESUMO

AIMS: Aim of the present study was to investigate the effect of co-administration coenzyme Q10 and pioglitazone on the mRNA expression of adipocytokines in white adipose tissues of chemically induced type 2 diabetes mellitus in rats. MAIN METHODS: Diabetes was induced by administration of streptozotocin (65 mg/kg, i.p.), followed by nicotinamide (110 mg/kg, i.p.) 15 min later. The diabetic rats were treated coenzyme Q10 (Q10, 10 mg/kg, p.o.) or pioglitazone (PIO, 20 mg/kg, p.o.) alone and their combination for four weeks. Biochemical parameters like FBS level, insulin and HbA1c along with tissue levels of MDA, SOD, CAT and GSH were estimated. The mRNA levels of ADIPOQ, RBP4, RETN, IL-6 and TNF-α in White Adipose Tissue (WAT) were measured. KEY FINDINGS: Treatment with Q10 + PIO showed a significant reduction in the levels of FBS, HbA1c and a significant increase in insulin levels as compared to normal control group. Additionally, there was a significant change in the levels of biomarkers of oxidative stress after treatment with Q10 + PIO as compared to streptozotocin-nicotinamide group. Treatment with Q10 + PIO also significantly altered the mRNA expression of ADIPOQ, RETN, IL-6 and TNF-α when compared to monotherapy. However, mRNA expression of RBP4 did not alter in Q10 + PIO treated animal as compared to Q10 or PIO alone. SIGNIFICANCE: It is concluded that co-administration of Q10 and PIO has been shown the better therapeutic effect on the mRNA expression of adipocytokines and oxidative stress parameters as compared to either Q10 or PIO.


Assuntos
Adipocinas/genética , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Pioglitazona/uso terapêutico , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Masculino , Pioglitazona/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Ubiquinona/farmacologia , Ubiquinona/uso terapêutico , Vitaminas/farmacologia
12.
Gene ; 763: 145058, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32798635

RESUMO

BACKGROUND: The nuclear receptors Rev-erb alpha and Rev-erb beta are transcription factors that regulate the function of genes in glucose and lipid metabolism, and they also form a link between circadian rhythm and metabolism. We evaluated the variations in Rev-erb alpha and Rev-erb beta genes together with biochemical parameters as risk factors in type 2 diabetic (T2DM) patients. METHODS: Molecular analyses of Rev-erb alpha and Rev-erb beta genes were performed on genomic DNA by using next-generation sequencing in 42 T2DM patients (21 obese and 21 non-obese) and 66 healthy controls. RESULTS: We found 26 rare mutations in the study groups, including 13 missense mutations, 9 silent mutations, 3 5'UTR variations, and a 3'UTR variation, of which 9 were novel variations (5 missense and 3 silent and 1 5'UTR). Six common variations were also found in the Rev-erb genes; Rev-erb beta Chr3:24003765 A > G, Rev-erb beta rs924403442 (Chr3:24006717) G > T, Rev-erb alpha Chr17:38253751 T > C, Rev-erb alpha rs72836608 C > A, Rev-erb alpha rs2314339 C > T and Rev-erb alpha rs2102928 C > T. Of these, Rev-erb beta Chr3:24003765 A > G was a novel missense mutation (p.Q197R), while others were identified as intronic variants. T2DM patients with Rev-erb beta rs924403442 T allele had lower body surface area (BSA) than noncarriers (GG genotype) (p = 0.039). Rev-erb alpha rs72836608 A allele and Rev-erb alpha rs2314339 CC genotype were associated with decreased serum HDL-cholesterol levels in T2DM patients (p = 0.025 and p = 0.027, respectively). In our study, different effects of Rev-erbs polymorphisms were found according to gender and presence of obesity. Rev-erb alpha rs72836608 (C > A) and rs2314339 (C > T) and Rev-erb alpha rs2102928 (C > T) were associated with low HDL-C levels in male T2DM patients. In female patients, Rev-erb alpha rs2102928 (C > T) was associated with high microalbuminuria and Rev-erb beta rs9244403442 G > T was associated with low HDL and high BSA values. In addition, Rev-erb alpha Chr17: 38,253,751 (T > C), rs72836608 (C > A), and rs2314339 (C > T) and Rev-erb beta Chr3:24003765 (A > G) were associated with increased serum GGT levels in obese T2DM patients. In non-obese patients, Rev-erbs SNPs had no effect on serum GGT levels. CONCLUSION: Our findings indicate that variations in the Rev-erb alpha and Rev-erb beta genes can affect metabolic changes in T2DM and these effects may vary depending on gender and obesity.


Assuntos
Diabetes Mellitus Tipo 2/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Life Sci ; 258: 118243, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791154

RESUMO

AIMS: Although autophagy impairment is a well-established cause of muscle atrophy and P300 has recently been identified as an important regulator of autophagy, the effects of P300 on autophagy and muscle atrophy in type 2 diabetes (T2D) remain unexplored. We aimed at characterizing the role of P300 in diabetic muscle and its underlying mechanism. MAIN METHODS: Protein levels of phosphorylated P300, total P300, acetylated histone H3, LC3, p62 and myosin heavy chain, and mRNA levels of Atrogin-1 and MuRF1 were analyzed in palmitic acid (PA)-treated myotubes and db/db mice. Autophagic flux was assessed using transmission electron microscopy, immunofluorescence and mRFP-GFP-LC3 lentivirus transfection in cells. Muscle weight, blood glucose and grip strength were measured in mice. Hematoxylin and eosin (H&E) staining was performed to determine changes in muscle fiber size. To investigate the effects of P300 on autophagy and myofiber remodeling, a P300 specific inhibitor, c646, was utilized. 3-Methyladenine (3-MA) was utilized to inhibit autophagosomes formation, and chloroquine (CQ) was used to block autophagic flux. KEY FINDINGS: Phosphorylation of P300 in response to PA enhanced its activity and subsequently suppressed autophagic flux, leading to atrophy-related morphological and molecular changes in myotubes. Inhibition of P300 reestablished autophagic flux and ameliorated PA-induced myotubes atrophy. However, this effect was largely abolished by co-treatment with the autophagy inhibitor CQ. In vivo results demonstrated that inhibition of P300 partially rescued muscle wasting in db/db mice, accompanied with autophagy reactivation. SIGNIFICANCE: The findings revealed that T2D-induced overactivation of P300 contributes to muscle atrophy by blocking autophagic flux.


Assuntos
Autofagia/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Proteína p300 Associada a E1A/metabolismo , Atrofia Muscular/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Proteína p300 Associada a E1A/genética , Força da Mão/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular/genética , Atrofia Muscular/patologia , Mioblastos/metabolismo , Mioblastos/patologia
14.
Medicine (Baltimore) ; 99(30): e21383, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791750

RESUMO

Previous studies had reported that the CDKAL1 (cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1) rs10946398 C/A polymorphism associated with type 2 diabetes mellitus (T2DM) in various ethnic groups, however, inconsistent results have been obtained in studies of different populations.We performed a meta-analysis of 13 studies for rs10946398 of CDKAL1 on genetic susceptibility for T2DM.The results showed that CDKAL1 rs10946398 C/A polymorphism associated with T2DM under allelic (odds risk (OR): 1.17, 95% CI: 1.07-1.28, P = .0007), homozygous (OR: 1.39, 95% CI: 1.15-1.69, P = .0008), and dominant models (OR: 1.26, 95% CI: 1.09-1.46, P = .001).We found that rs10946398 C/A polymorphism was associated with T2DM, and this association was significantly in population of western country (Europe and United States) and Asian populations.


Assuntos
Diabetes Mellitus Tipo 2/genética , tRNA Metiltransferases/genética , Humanos , Polimorfismo de Nucleotídeo Único
15.
Medicine (Baltimore) ; 99(31): e21438, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756155

RESUMO

RATIONALE: Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene result in a very variable presentation, including maturity onset diabetes of the young (MODY), renal cysts, renal dysplasia, and autosomal dominant tubulointerstitial kidney disease (ADTKD), which is characterized by tubular damage, renal fibrosis, and progressive renal dysfunction. PATIENT CONCERNS: A 22-year-old man came to the hospital presenting with hyperglycemia, hyperuricemia and elevated serum creatinine. His urine protein was within the normal range. The ultrasound examination revealed shrunken kidneys with renal cysts. The patient's mother was diagnosed with diabetes mellitus when she was 25 years old. Her laboratory results showed elevated serum creatinine. Her ultrasonography revealed shrunken kidneys with renal cysts and hydronephrosis without kidney stones. The next-generation sequencing revealed that the proband and his mother held the same heterozygous missense mutation (c.530G>A, NM_000458, p.R177Q) in the HNF1B gene. Bioinformatic analyses predicted that the mutation was likely pathogenic. DIAGNOSIS: The patient and his mother were diagnosed as ADTKD and MODY5 due to HNF1B mutation. INTERVENTION: The proband was administered metformin at a dose of 500 mg/day. OUTCOMES: The patient had well-controlled blood glucose levels and a stable renal function at his 12-month follow-up. LESSONS: We should take into account the diagnoses of ADTKD and MODY5 if patients present with early onset diabetes and multiple renal cysts or evidence of renal tubulointerstitial dysplasia, especially those with negative proteinuria results. Genetic testing helps detect the HNF1B gene mutations.


Assuntos
Doenças do Sistema Nervoso Central/genética , Esmalte Dentário/anormalidades , Diabetes Mellitus Tipo 2/genética , Fator 1-beta Nuclear de Hepatócito/genética , Doenças Renais Císticas/genética , Nefrite Intersticial/genética , Assistência ao Convalescente , Doenças do Sistema Nervoso Central/complicações , Doenças do Sistema Nervoso Central/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Hiperglicemia/etiologia , Hiperuricemia/etiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Rim/diagnóstico por imagem , Rim/patologia , Rim/fisiopatologia , Doenças Renais Císticas/complicações , Doenças Renais Císticas/tratamento farmacológico , Doenças Renais Císticas/patologia , Masculino , Metformina/administração & dosagem , Metformina/uso terapêutico , Mutação de Sentido Incorreto , Nefrite Intersticial/complicações , Nefrite Intersticial/patologia , Linhagem , Ultrassonografia/métodos , Adulto Jovem
16.
PLoS Genet ; 16(7): e1008903, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678846

RESUMO

Genome wide association studies (GWAS) of human diseases have generally identified many loci associated with risk with relatively small effect sizes. The omnigenic model attempts to explain this observation by suggesting that diseases can be thought of as networks, where genes with direct involvement in disease-relevant biological pathways are named 'core genes', while peripheral genes influence disease risk via their interactions or regulatory effects on core genes. Here, we demonstrate a method for identifying candidate core genes solely from genes in or near disease-associated SNPs (GWAS hits) in conjunction with protein-protein interaction network data. Applied to 1,381 GWAS studies from 5 ancestries, we identify a total of 1,865 candidate core genes in 343 GWAS studies. Our analysis identifies several well-known disease-related genes that are not identified by GWAS, including BRCA1 in Breast Cancer, Amyloid Precursor Protein (APP) in Alzheimer's Disease, INS in A1C measurement and Type 2 Diabetes, and PCSK9 in LDL cholesterol, amongst others. Notably candidate core genes are preferentially enriched for disease relevance over GWAS hits and are enriched for both Clinvar pathogenic variants and known drug targets-consistent with the predictions of the omnigenic model. We subsequently use parent term annotations provided by the GWAS catalog, to merge related GWAS studies and identify candidate core genes in over-arching disease processes such as cancer-where we identify 109 candidate core genes.


Assuntos
Doença de Alzheimer/genética , Neoplasias da Mama/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Mapas de Interação de Proteínas/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Insulina/genética , Polimorfismo de Nucleotídeo Único/genética , Pró-Proteína Convertase 9/genética , Fatores de Risco
17.
Vasc Health Risk Manag ; 16: 241-248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606720

RESUMO

Aim: Type 2 diabetes (T2D), as a major cause of morbidity and mortality, is predicted to have a prevalence of 629 million by 2045. As diabetic patients show considerable inter-individual variation in response to antidiabetic treatment, this study aimed to investigate the gene polymorphism of cytochrome P450 as well as the effectiveness and safety of glibenclamide and gliclazide for different genotypes of CYP2C9. Besides, the chronic side effects of T2D including retinal microvasculature complications or retinopathy and renal dysfunction due to nephropathy in different genotypes were considered. Patients and Methods: The participants including 80 T2D patients treated with glibenclamide or gliclazide were recruited from university hospitals of Ahvaz Jundishpur University of Medical Sciences, Ahvaz, in the southwest of Iran. Blood samples were collected from the patients at 2.5h after the morning dose of glibenclamide and 12h after the last dose of gliclazide. Genotyping from the extracted DNA was, then, performed using PCR-RFLP. The plasma level of glibenclamide and gliclazide was, in turn, measured by the reverse-phase high-pressure liquid chromatography. Results: The results showed that the wild-type allele, i.e., CYP2C9*1, occurred in the highest frequency (0.8), while the frequency rates of the mutant allele, i.e., CYP2C9*2 and CYP2C9*3, were 0.15 and 0.05, respectively. Moreover, no significant association was found between any of the genotypes as well as the clinical and biochemical characteristics of the patients. The findings also showed that the plasma level of sulfonylureas (i.e., glibenclamide and gliclazide) was the highest in the patients with the CYP2C9*3 allele. It was also found that 75.9% of the patients with variant genotypes had experienced hypoglycemia events. Furthermore, in the absence of wild type allele, a significant increase was observed in retinopathy (p=0.039) and nephropathy (p=0.05). Conclusion: The findings can provide guidelines for the optimal management of the treatment protocols with sulfonylurea intended to control the T2D complications.


Assuntos
Glicemia/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/genética , Retinopatia Diabética/genética , Gliclazida/uso terapêutico , Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Variantes Farmacogenômicos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/diagnóstico , Retinopatia Diabética/diagnóstico , Feminino , Frequência do Gene , Gliclazida/efeitos adversos , Gliclazida/sangue , Glibureto/efeitos adversos , Glibureto/sangue , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
18.
PLoS Med ; 17(7): e1003209, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32722720

RESUMO

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. METHODS AND FINDINGS: In 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1-9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03-1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06-1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10-8) but not glycemic progression (HR: 1.01 [95% CI 0.96-1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. CONCLUSIONS: Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/genética , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Bancos de Espécimes Biológicos , Glicemia/análise , Índice de Massa Corporal , HDL-Colesterol/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/genética , Hong Kong/epidemiologia , Humanos , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Obesidade/epidemiologia , Resultado do Tratamento
19.
Gene ; 761: 144971, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32707301

RESUMO

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes across the world. Recently, many circular RNAs (circRNAs) can exert a crucial role in DN progression. Our investigation was designed to study whether circ_0123996 was associated with DN and aimed to find out the underlying mechanisms. We observed that circ_0123996 expression was significantly increased in Type 2 diabetes (T2D) with DN in comparison to those patients without DN. Consistently, circ_0123996 was also obviously elevated in DN mice models and high glucose (HG)-incubated MMCs. Then, it was proved transfection of circ_0123996 siRNA in mice mesangial cells (MMCs) restrained MMCs proliferation greatly. In addition, it was demonstrated that decrease of circ_0123996 alleviated fibrosis-related protein expression including FN and Col-4 in MMCs. Next, it was confirmed by our study that circ_0123996 can serve as a sponge for miR-149-5p. miR-149-5p has been identified in several diseases including diabetes. At present, we observed that miR-149-5p was decreased in DN. Overexpression of miR-149-5p greatly repressed the effect of circ_0123996 on MMCs. BTB and CNC homology 1 (Bach1) is reported in various disease including some vascular diseases.Here, Bach1 was confirmed as a target of miR-149-5p. Circ_0123996 upregulated Bach1 expression and restrained MMCs proliferation and fibrosis through sponging miR-149-5p. Thus, it was revealed that circ_0123996 was involved in DN via sponging miR-149-5p and modulating Bach1 expression.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Nefropatias Diabéticas/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Adulto , Animais , Apoptose/fisiologia , Fatores de Transcrição de Zíper de Leucina Básica/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Circular/genética
20.
PLoS One ; 15(7): e0236453, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726329

RESUMO

OBJECTIVES: To assess the potential value of some miRNAs as diagnostic biomarkers for mild cognitive impairment (MCI) among patients with type2 diabetes mellitus (T2DM) and to identify other risk factors for MCI among them. METHODS: This study enrolled 163 adults with T2DM using face to face interview. Cognitive function with its domains was assessed using Adenbrooke's Cognitive Examination III (ACE III). Lipid profile, glycated hemoglobin, and miR-128, miR-132, miR- 874, miR-134, miR-323, and miR-382 expressions, using quantitative real-time PCR, were assessed. RESULTS: MCI was detected among 59/163 (36.2%) patients with T2DM. Plasma expression of miR-132 was significantly higher in T2DM patients with MCI compared to those without MCI and to normal cognitive healthy individuals (median = 2, 1.1 and 1.2 respectively, P < 0.05. Logistic regression analysis showed that higher miR-132 expression with adjusted odds ratio (AOR): 1.2 (95% CI 1.0-1.3), female gender (AOR:2.1; 95%CI 1.0-4.3), education below postgraduate (secondary and university education with AOR: 9.5 & 19.4 respectively) were the significant predicting factors for MCI among T2DM patients. Using ROC curve, miR-132 was the only assayed miRNA that significantly differentiates T2DM patients with MCI from those with normal cognition with 72.3% sensitivity, 56.2% specificity, and 63.8% accuracy (P < 0.05). Other studied miRNAs showed lower sensitivity and specificity for detecting MCI among studied T2DM participants. CONCLUSION: MCI affects nearly one-third of adult patients with T2DM. A significantly over expression of miR-132 was detected among T2DM with MCI compared to those with normal cognition.


Assuntos
Biomarcadores/sangue , Disfunção Cognitiva/sangue , Diabetes Mellitus Tipo 2/sangue , MicroRNAs/sangue , Adulto , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Hemoglobina A Glicada/genética , Humanos , Lipídeos/sangue , Masculino , MicroRNAs/classificação , MicroRNAs/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco
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