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1.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34479991

RESUMO

COVID-19 induces a robust, extended inflammatory "cytokine storm" that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNß directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNß reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNß/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.


Assuntos
Coronavirus/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/virologia , Macrófagos/metabolismo , Animais , COVID-19/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/genética , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , SARS-CoV-2/metabolismo , Transdução de Sinais
2.
Adv Exp Med Biol ; 1325: 285-305, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495541

RESUMO

Diabetes mellitus is a group of metabolic disorders characterized by the presence of hyperglycaemia. Due to its high prevalence and substantial heterogeneity, many studies have been investigating markers that could identify predisposition for the disease development, differentiate between the various subtypes, establish early diagnosis, predict complications or represent novel therapeutic targets. N-glycans, complex oligosaccharide molecules covalently linked to proteins, emerged as potential markers and functional effectors of various diabetes subtypes, appearing to have the capacity to meet these requirements. For instance, it has been shown that N-glycome changes in patients with type 2 diabetes and that N-glycans can even identify individuals with an increased risk for its development. Moreover, genome-wide association studies identified glycosyltransferase genes as candidate causal genes for both type 1 and type 2 diabetes. N-glycans have also been suggested to have a major role in preventing the impairment of glucose-stimulated insulin secretion by modulating cell surface expression of glucose transporters. In this chapter we aimed to describe four major diabetes subtypes: type 1, type 2, gestational and monogenic diabetes, giving an overview of suggested role for N-glycosylation in their development, diagnosis and management.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Glicosilação , Humanos , Polissacarídeos
3.
Nat Commun ; 12(1): 5276, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489429

RESUMO

A promise of genomics in precision medicine is to provide individualized genetic risk predictions. Polygenic risk scores (PRS), computed by aggregating effects from many genomic variants, have been developed as a useful tool in complex disease research. However, the application of PRS as a tool for predicting an individual's disease susceptibility in a clinical setting is challenging because PRS typically provide a relative measure of risk evaluated at the level of a group of people but not at individual level. Here, we introduce a machine-learning technique, Mondrian Cross-Conformal Prediction (MCCP), to estimate the confidence bounds of PRS-to-disease-risk prediction. MCCP can report disease status conditional probability value for each individual and give a prediction at a desired error level. Moreover, with a user-defined prediction error rate, MCCP can estimate the proportion of sample (coverage) with a correct prediction.


Assuntos
Predisposição Genética para Doença/genética , Aprendizado de Máquina , Herança Multifatorial/genética , Fatores Etários , Bancos de Espécimes Biológicos , Neoplasias da Mama/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Masculino , Reprodutibilidade dos Testes , Esquizofrenia/genética , Suécia , Reino Unido
4.
J Hazard Mater ; 416: 125956, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492873

RESUMO

Exposure to a single organochlorine pesticide (OCP) at high concentration and over a short period of exposure constrain our understanding of the contribution of chemical exposure to type 2 diabetes (T2D). A total of 450 male and female zebrafish was exposed to mixtures of five OCPs at 0, 0.05, 0.25, 2.5, and 25 µg/L for 12 weeks. T2D-related hematological parameters (i.e., glucose, insulin, free fatty acid, and triglycerides) and mitochondrial complex I to IV activities were assessed. Metabolomics, proteomics, and transcriptomics were analyzed in female livers, and their data-driven integration was performed. High fasting glucose and low insulin levels were observed only at 0.05 µg/L of the OCP mixture in females, indicating a nonlinear and sexually dependent response. We found that exposure to the OCP mixture inhibited the activities of mitochondrial complexes, especially III and IV. Combining individual and integrated omics analysis, T2D-linked metabolic pathways that regulate mitochondrial function, insulin signaling, and energy homeostasis were altered by the OCP mixture, which explains the observed phenotypic hematological effects. We demonstrated the cause-and-effect relationship between exposures to OCP mixture and T2D using zebrafish model. This study gives an insight into mechanistic research of metabolic diseases caused by chemical exposure using zebrafish.


Assuntos
Diabetes Mellitus Tipo 2 , Hidrocarbonetos Clorados , Praguicidas , Animais , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/genética , Feminino , Insulina , Masculino , Praguicidas/análise , Praguicidas/toxicidade , Peixe-Zebra
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 891-894, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487539

RESUMO

OBJECTIVE: To explore the genetic basis for a juvenile with maturity-onset diabetes of the young type 12(MODY12). METHODS: High-throughput sequencing was carried out to screen for the variants. Candidate variant was verified by Sanger sequencing. Pathogenity of the variant was predicted by searching the genetic databases and analysis by using bioinformatic software. RESULTS: Genetic testing indicated that the patient and his mother have both carried a heterozygous c.3976G>A variant (p.Glu1326Lys) in exon 32 of the ABCC8 gene. Prediction of the protein structure suggested the variant to be deleterious. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be uncertain significance. CONCLUSION: Whether the c.3976G>A variant of the ABCC8 gene is the cause of the disease in this patient or not depends on the functional studies and more case data. Above finding has enriched the spectrum of ABCC8 gene variants.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/genética , Testes Genéticos , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação
6.
Nat Commun ; 12(1): 5242, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475398

RESUMO

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 ß cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions. We identify 1,982/6,621 (29.9%) SNP-containing elements that activate transcription in MIN6 and 879 SNP alleles that modulate MPRA activity. Multiple T2D-associated SNPs alter the activity of short interspersed nuclear element (SINE)-containing elements that are strongly induced by ER stress. We identify 220 functional variants at 104 T2D association signals, narrowing 54 signals to a single candidate SNP. Together, this study identifies elements driving ß cell steady state and ER stress-responsive transcriptional activation, nominates causal T2D SNPs, and uncovers potential roles for repetitive elements in ß cell transcriptional stress response and T2D genetics.


Assuntos
Diabetes Mellitus Tipo 2/genética , Estresse do Retículo Endoplasmático/genética , Células Secretoras de Insulina/patologia , Polimorfismo de Nucleotídeo Único , Ativação Transcricional/genética , Alelos , Animais , Linhagem Celular , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Locos de Características Quantitativas , Elementos Nucleotídeos Curtos e Dispersos/genética
7.
Endocrinol Metab Clin North Am ; 50(3): 337-355, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34399949

RESUMO

Type 2 diabetes (T2D) is a public health burden associated with immense health care and societal costs, early death, and morbidity. Largely because of epidemiologic changes, including nutrition transitions, urbanization, and sedentary lifestyles, T2D is increasing in every region of the world, particularly in low-income and middle-income countries. This article highlights global trends in T2D and discusses the role of genes, early-life exposures, and lifestyle risk factors in the cause of T2D, with an emphasis on populations in current hotspots of the epidemic. It also considers potential impacts of the coronavirus disease 2019 pandemic and T2D prevention policies and action.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/prevenção & controle , Humanos
8.
Stem Cell Res Ther ; 12(1): 449, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380570

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional ß-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. METHODS: Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on ß-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. RESULTS: Our results showed that bmMDEs reversed diabetic ß-cell dedifferentiation and improved ß-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved ß-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of ß-catenin signaling in ß-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve ß-cell function. CONCLUSIONS: These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic ß-cell dysfunction by acting on the NUMB/ß-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Exossomos , Células-Tronco Mesenquimais , MicroRNAs , Animais , Desdiferenciação Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/terapia , Exossomos/genética , MicroRNAs/genética , Ratos
9.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360895

RESUMO

BACKGROUND: Type 2 diabetes mellitus is one of the leading causes of morbidity and mortality worldwide and is derived from an accumulation of genetic and epigenetic changes. In this study, we aimed to construct Insilco, a competing endogenous RNA (ceRNA) network linked to the pathogenesis of insulin resistance followed by its experimental validation in patients', matched control and cell line samples, as well as to evaluate the efficacy of CRISPR/Cas9 as a potential therapeutic strategy to modulate the expression of this deregulated network. By applying bioinformatics tools through a two-step process, we identified and verified a ceRNA network panel of mRNAs, miRNAs and lncRNA related to insulin resistance, Then validated the expression in clinical samples (123 patients and 106 controls) and some of matched cell line samples using real time PCR. Next, two guide RNAs were designed to target the sequence flanking LncRNA/miRNAs interaction by CRISPER/Cas9 in cell culture. Gene editing tool efficacy was assessed by measuring the network downstream proteins GLUT4 and mTOR via immunofluorescence. RESULTS: LncRNA-RP11-773H22.4, together with RET, IGF1R and mTOR mRNAs, showed significant upregulation in T2DM compared with matched controls, while miRNA (i.e., miR-3163 and miR-1) and mRNA (i.e., GLUT4 and AKT2) expression displayed marked downregulation in diabetic samples. CRISPR/Cas9 successfully knocked out LncRNA-RP11-773H22.4, as evidenced by the reversal of the gene expression of the identified network at RNA and protein levels to the normal expression pattern after gene editing. CONCLUSIONS: The present study provides the significance of this ceRNA based network and its related target genes panel both in the pathogenesis of insulin resistance and as a therapeutic target for gene editing in T2DM.


Assuntos
Sistemas CRISPR-Cas , Biologia Computacional/métodos , Diabetes Mellitus Tipo 2/genética , Edição de Genes/métodos , Expressão Gênica , Resistência à Insulina/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Linhagem Celular , Diabetes Mellitus Tipo 2/sangue , Feminino , Redes Reguladoras de Genes , Hospitais Universitários , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade
10.
Comput Biol Med ; 136: 104668, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34340124

RESUMO

The ongoing COVID-19 outbreak, caused by SARS-CoV-2, has posed a massive threat to global public health, especially to people with underlying health conditions. Type 2 diabetes (T2D) is lethal comorbidity of COVID-19. However, its pathogenetic link remains unclear. This research aims to determine the genetic factors and processes contributing to the synergistic severity of SARS-CoV-2 infection among T2D patients through bioinformatics approaches. We analyzed two sets of transcriptomic data of SARS-CoV-2 infection obtained from lung epithelium cells and PBMCs, and two sets of T2D data from pancreatic islet cells and PBMCs to identify the associated differentially expressed genes (DEGs) followed by their functional enrichment analyses in terms of protein-protein interaction (PPI) to detect hub-proteins and associated comorbidities, transcription factors (TFs), microRNAs (miRNAs) as well as the potential drug candidates. In PPI analysis, four potential hub-proteins (i.e., BIRC3, C3, MME, and IL1B) were identified among 25 DEGs shared between the disease pair. Enrichment analyses using the mutually overlapped DEGs revealed the most prevalent GO and cell signalling pathways, including TNF signalling, cytokine-cytokine receptor interaction, and IL-17 signalling, which are related to cytokine activities. Furthermore, as significant TFs, we identified IRF1, KLF11, FOSL1, and CREB3L1 while miRNAs including miR-1-3p, 34a-5p, 16-5p, 155-5p, 20a-5p, and let-7b-5p were found to be noteworthy. The findings illustrated the significant association between COVID-19 and T2D at the molecular level. These genetic determinants can further be explored for their specific roles in disease progression and therapeutic intervention, while significant pathways can also be studied as molecular checkpoints. Finally, the identified drug candidates may be evaluated for their potency to minimize the severity of COVID-19 patients with pre-existing T2D.


Assuntos
COVID-19 , Diabetes Mellitus Tipo 2 , MicroRNAs , Biologia Computacional , Diabetes Mellitus Tipo 2/genética , Humanos , MicroRNAs/genética , SARS-CoV-2
11.
Int J Mol Sci ; 22(16)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34445261

RESUMO

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)ß/δ show promise. Remarkably, most of the antidiabetic effects of PPARß/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARß/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARß/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Resistência à Insulina , PPAR delta/metabolismo , PPAR beta/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Diabetes Mellitus Tipo 2/genética , Humanos , PPAR delta/genética , PPAR beta/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
12.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445304

RESUMO

Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.


Assuntos
Processamento Alternativo/fisiologia , Diabetes Mellitus Tipo 2/genética , Ilhotas Pancreáticas/metabolismo , Processamento Alternativo/genética , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Suscetibilidade a Doenças , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regulação para Cima/genética
13.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3643-3649, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402288

RESUMO

Type 2 diabetes mellitus( T2 DM) is a common chronic metabolic disease characterized by persistent hyperglycemia and insulin resistance. In pancreatic ß-cells,glucose-stimulated insulin secretion( GSIS) plays a pivotal role in maintaining the balance of blood glucose level. Previous studies have shown that geniposide,one of the active components of Gardenia jasminoides,could quickly regulate the absorption and metabolism of glucose,and affect glucose-stimulated insulin secretion in pancreatic ß cells,but the specific mechanism needs to be further explored. Emerging evidence indicated that glycosylation of glucose transporter( GLUT) has played a key role in sensing cell microenvironmental changes and regulating glucose homeostasis in eucaryotic cells. In this study,we studied the effects of geniposide on the key molecules of GLUT2 glycosylation in pancreatic ß cells. The results showed that geniposide could significantly up-regulate the mRNA and protein levels of Glc NAc T-Ⅳa glycosyltransferase( Gn T-Ⅳa) and galectin-9 but had no signi-ficant effect on the expression of clathrin,and geniposide could distinctively regulate the protein level of Gn T-Ⅳa in a short time( 1 h) under the conditions of low and medium glucose concentrations,but had no significant effect on the protein level of galectin-9. In addition,geniposide could also remarkably affect the protein level of glycosylated GLUT2 in a short-time treatment. The above results suggested that geniposide could quickly regulate the protein level of Gn T-Ⅳa,a key molecule of protein glycosylation in INS-1 rat pancreatic ßcells and affect the glycosylation of GLUT2. These findings suggested that the regulation of geniposide on glucose absorption,metabolism and glucose-stimulated insulin secretion might be associated with its efficacy in regulating GLUT2 glycosylation and affecting its distribution on the cell membrane and cytoplasm in pancreatic ß cells.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glicosilação , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Iridoides , Ratos
14.
BMC Res Notes ; 14(1): 309, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380558

RESUMO

OBJECTIVE: Many different genetic variants of proprotein convertase subtilisin kexin 9 (PCSK9) are related to the serum levels of cholesterol and LDL cholesterol (LDL-C). The rs615563 variant of PCSK9 (a gain-of-function mutation) is associated with increased triglycerides and cholesterol levels, but its association with the incidence of diabetes is not well defined. This study aimed to investigate the relationship between the PCSK9 rs615563 variant with the incidence of type 2 diabetes. The data reported in this study are based on subsamples from a 5-year (2009-2014) cohort study of the adult population (590 subjects) aged 20 years and older. The rs615563 polymorphism was genotyped using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. RESULTS: The distribution of PCSK9 rs615563 genotypes was not significantly different between the diabetic and non-diabetic individuals. The incidence of diabetes after five-years of follow-up was not different between the genotypes. Our findings also showed no significant relationship between this polymorphism and serum lipid parameters. The data extracted from our cohort study do not support the findings that the gain-of-function mutations of PCSK9 predispose to the incidence of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Pró-Proteína Convertase 9 , Adulto , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Humanos , Lipídeos , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertases , Serina Endopeptidases/genética
15.
Nat Commun ; 12(1): 4178, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234147

RESUMO

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10-10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10-12), 4 kg higher fat mass (p = 1.3 × 10-4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10-4) and 4.5 kg lower handgrip strength (p = 4.7 × 10-7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Y/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Mosaicismo , Adulto , Idoso , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Insulina/metabolismo , Leucócitos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/genética , Sequenciamento Completo do Exoma
16.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299336

RESUMO

The rising prevalence of metabolic diseases related to insulin resistance (IR) have stressed the urgent need of accurate and applicable tools for early diagnosis and treatment. In the last decade, non-coding RNAs (ncRNAs) have gained growing interest because of their potential role in IR modulation. NcRNAs are variable-length transcripts which are not translated into proteins but are involved in gene expression regulation. Thanks to their stability and easy detection in biological fluids, ncRNAs have been investigated as promising diagnostic and therapeutic markers in metabolic diseases, such as type 2 diabetes mellitus (T2D), obesity and non-alcoholic fatty liver disease (NAFLD). Here we review the emerging role of ncRNAs in the development of IR and related diseases such as obesity, T2D and NAFLD, and summarize current evidence concerning their potential clinical application.


Assuntos
Resistência à Insulina/genética , RNA não Traduzido/genética , Animais , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Insulina/metabolismo , Fígado/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/genética , Obesidade/metabolismo , RNA não Traduzido/metabolismo
17.
Comput Biol Med ; 135: 104640, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34261004

RESUMO

Cisplatin is a DNA-damaging chemotherapeutic agent used for treating cancer. Based on cDNA dataset analysis, we investigated how cisplatin modified gene expression and observed cisplatin-induced dysregulation and system-level variations relating to insulin resistance and type 2 diabetes mellitus (T2DM). T2DM is a multifactorial disease affecting 462 million people in the world, and drug-induced T2DM is a serious issue. To understand this etiology, we designed an integrative, system-level study to identify associations between cisplatin-induced differentially expressed genes (DEGs) and T2DM. From a list of differential expressed genes, cisplatin downregulated the cyclin-dependent kinase inhibitor 1 (CDKN1A), tumor necrosis factor (FAS), and sestrin-1 (SESN1) genes responsible for modifying signaling pathways, including the p53, JAK-STAT, FOXO, MAPK, mTOR, P13-AKT, Toll-like receptor (TLR), adipocytokine, and insulin signaling pathways. These enriched pathways were expressively associated with the disease. We observed significant gene signatures, including SMAD3, IRS, PDK1, PRKAA1, AKT, SOS, RAS, GRB2, MEK1/2, and ERK, interacting with source genes. This study revealed the value of system genetics for identifying the cisplatin-induced genetic variants responsible for the progression of T2DM. Also, by cross-validating gene expression data for T2DM islets, we found that downregulating IRS and PRK families is critical in insulin and T2DM signaling pathways. Cisplatin, by inhibiting CDKN1A, FAS, and SESN1, promotes IRS and PRK activity in a similar way to rosiglitazone (a popular drug used for T2DM treatment). Our integrative, network-based approach can help in understanding the drug-induced pathophysiological mechanisms of diabetes.


Assuntos
Antineoplásicos , Diabetes Mellitus Tipo 2 , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Proteínas de Choque Térmico/farmacologia , Proteínas de Choque Térmico/uso terapêutico , Humanos , Insulina/farmacologia , Transdução de Sinais
18.
BMC Res Notes ; 14(1): 294, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34321097

RESUMO

OBJECTIVE: MicroRNAs are known to regulate 60% of genes at post translational level. MicroRNAs including Micro RNA-29 family play a vital role in cellular activities and have validate role in numerous metabolic disorders inclusive of diabetes mellitus and its complications. While micro RNA profile changes years before the occurrence of disease. This cross-sectional study was conducted in non-diabetic adults of diabetic and non-diabetic parents to explore the early changes in expression of micro RNA-29 family as it can be served as early biomarker of type 2 diabetes in non-diabetic adults. This study was conducted from January 2019 to January 2021. Micro RNA was extracted from plasma of 50 participants and expression was compared through qPCR. While data was analyzed through SPSS version 21.0. RESULTS: 29a and 29b had lower expression in participants with family history of DM compared to those having no family history of DM (P < 0.0001). While micro RNA 29c was found to be significantly higher in participants with positive family history of type 2 diabetes as compared to those without family history of diabetes (P = 0.001).


Assuntos
Diabetes Mellitus Tipo 2 , MicroRNAs , Adulto , Biomarcadores , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Humanos
19.
Am J Hum Genet ; 108(9): 1578-1589, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34265237

RESUMO

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.


Assuntos
Aneurisma da Aorta Torácica/genética , Diabetes Mellitus Tipo 2/genética , Células Endoteliais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Locos de Características Quantitativas , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/patologia , Estudos de Casos e Controles , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/patologia , Regulação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Michigan , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Mutação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
20.
Cell Mol Life Sci ; 78(16): 6017-6031, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34245311

RESUMO

A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) "interchain" disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)-Cys(A11), is not required for anterograde trafficking, i.e., a "lose-A6/A11" mutant [Cys(A6), Cys(A11) both converted to Ser] is well secreted. Nevertheless, an unpaired Cys(A11) can participate in disulfide mispairings, causing ER retention of proinsulin. Among the many missense mutations causing the syndrome of Mutant INS gene-induced Diabetes of Youth (MIDY), all seem to exhibit perturbed proinsulin disulfide bond formation. Here, we have examined a series of seven MIDY mutants [including G(B8)V, Y(B26)C, L(A16)P, H(B5)D, V(B18)A, R(Cpep + 2)C, E(A4)K], six of which are essentially completely blocked in export from the ER in pancreatic ß-cells. Three of these mutants, however, must disrupt the Cys(A6)-Cys(A11) pairing to expose a critical unpaired cysteine thiol perturbation of proinsulin folding and ER export, because when introduced into the proinsulin lose-A6/A11 background, these mutants exhibit native-like disulfide bonding and improved trafficking. This maneuver also ameliorates dominant-negative blockade of export of co-expressed wild-type proinsulin. A growing molecular understanding of proinsulin misfolding may permit allele-specific pharmacological targeting for some MIDY mutants.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proinsulina/metabolismo , Adolescente , Células Cultivadas , Cisteína/genética , Cisteína/metabolismo , Diabetes Mellitus Tipo 2/genética , Dissulfetos/metabolismo , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Humanos , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Mutação de Sentido Incorreto/genética , Proinsulina/genética , Dobramento de Proteína
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