RESUMO
Background: Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications. Methods: We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications. Results: The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed. Conclusions: Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.
Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Análise da Randomização Mendeliana , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/epidemiologia , Masculino , Ácidos Graxos Insaturados , Ácidos Graxos Ômega-3 , Ácidos Graxos Ômega-6 , Retinopatia Diabética/genética , Retinopatia Diabética/epidemiologia , Feminino , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/genética , Pessoa de Meia-IdadeRESUMO
Background: Central retinal artery occlusion (CRAO) is a medical condition characterized by sudden blockage of the central retinal artery, which leads to a significant and often irreversible loss of vision. Observational studies have indicated that diabetes mellitus is a risk factor for CRAO; however, there is no research on the causal relationship between diabetes mellitus, particularly type 2 diabetes, and CRAO. This study aimed to perform Mendelian randomization (MR) analysis to clarify the causal relationship between type 2 diabetes and CRAO. Methods: Genetic variants associated with type 2 diabetes were selected from two different datasets. A recent genome-wide association study of CRAO conducted using the FinnGen database was used as the outcome data. A two-sample MR was performed to evaluate the causal relationship between type 2 diabetes and CRAO. Inverse variance weighting was the primary method, and MR-Egger, maximum likelihood, and median weighting were used as complementary methods. A multivariate MR (MVMR) analysis was performed to further evaluate the robustness of the results. Cochran's Q test, MR-Egger intercept test, and MR-PRESSO global test were used for the sensitivity analyses. Results: Genetically predicted type 2 diabetes was causally associated with CRAO(odds ratio [OR] =2.108, 95% confidence interval [CI]: 1.221-3.638, P=7.423×10-3), which was consistent with the results from the validation dataset (OR=1.398, 95%CI: 1.015-1.925, P=0.040). The MVMR analysis suggested that type 2 diabetes may be an independent risk factor for CRAO (adjusted OR=1.696; 95%CI=1.150-2.500; P=7.655×10-3), which was assumed by the validation dataset (adjusted OR=1.356; 95%CI=1.015-1.812; P=0.039). Conclusion: Our results show that genetically predicted type 2 diabetes may be causally associated with CRAO in European populations. This suggests that preventing and controlling type 2 diabetes may reduce the risk of CRAO.
Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Oclusão da Artéria Retiniana , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Humanos , Oclusão da Artéria Retiniana/genética , Oclusão da Artéria Retiniana/epidemiologia , Oclusão da Artéria Retiniana/complicações , Fatores de Risco , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
Background: Type 2 Diabetes Mellitus (T2D) and Osteoarthritis (OA) are both prevalent diseases that significantly impact the health of patients. Increasing evidence suggests that there is a big correlation between T2D and OA, but the molecular mechanisms remain elusive. The aims of this study are to investigate the shared biomarkers and potential molecular mechanisms in T2D combined with OA. Methods: T2D and OA-related differentially expressed genes (DEGs) were identified via bioinformatic analysis on Gene Expression Omnibus (GEO) datasets GSE26168 and GSE114007 respectively. Subsequently, extensive target prediction and network analysis were finished with Gene Ontology (GO), protein-protein interaction (PPI), and pathway enrichment with DEGs. The transcription factors (TFs) and miRNAs coupled in co-expressed DEGs involved in T2D and OA were predicted as well. The key genes expressed both in the clinical tissues of T2D and OA were detected with western blot and qRT-PCR assay. Finally, the most promising candidate compounds were predicted with the Drug-Gene Interaction Database (DGIdb) and molecular docking. Results: In this study, 209 shared DEGs between T2D and OA were identified. Functional analysis disclosed that these DEGs are predominantly related to ossification, regulation of leukocyte migration, extracellular matrix (ECM) structural constituents, PI3K/AKT, and Wnt signaling pathways. Further analysis via Protein-Protein Interaction (PPI) analysis and validation with external datasets emphasized MMP9 and ANGPTL4 as crucial genes in both T2D and OA. Our findings were validated through qRT-PCR and Western blot analyses, which indicated high expression levels of these pivotal genes in T2D, OA, and T2D combined with OA cases. Additionally, the analysis of Transcription Factors (TFs)-miRNA interactions identified 7 TFs and one miRNA that jointly regulate these important genes. The Receiver Operating characteristic (ROC) analysis demonstrated the significant diagnostic potential of MMP9 and ANGPTL4.Moreover, we identified raloxifene, ezetimibe, and S-3304 as promising agents for patients with both T2D and OA. Conclusion: This study uncovers the shared signaling pathways, biomarkers, potential therapeutics, and diagnostic models for individuals suffering from both T2D and OA. These findings not only present novel perspectives on the complex interplay between T2D and OA but also hold significant promise for improving the clinical management and prognosis of patients with this concurrent condition.
Assuntos
Biologia Computacional , Diabetes Mellitus Tipo 2 , Redes Reguladoras de Genes , Osteoartrite , Mapas de Interação de Proteínas , Humanos , Diabetes Mellitus Tipo 2/genética , Osteoartrite/genética , Osteoartrite/metabolismo , Biologia Computacional/métodos , Perfilação da Expressão Gênica , MicroRNAs/genética , Regulação da Expressão Gênica , Bases de Dados Genéticas , Proteína 4 Semelhante a Angiopoietina/genética , Proteína 4 Semelhante a Angiopoietina/metabolismo , Simulação de Acoplamento Molecular , Biomarcadores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Weiwei Wei, Hao Tian, Xiandong Fu, Rongrong Yao, Dewang Su. Long Non-Coding RNA (lncRNA) SNHG5 Participates in Vertical Sleeve Gastrectomy for Type II Diabetes Mellitus by Regulating TGR5. Med Sci Monit, 2020; 26: e920628. DOI: 10.12659/MSM.920628.
Assuntos
Diabetes Mellitus Tipo 2 , Gastrectomia , RNA Longo não Codificante , Receptores Acoplados a Proteínas G , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/cirurgia , Gastrectomia/métodos , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Animais , MasculinoRESUMO
Objective: The relationship between diabetes mellitus (DM) and autism spectrum disorder (ASD) remains controversial. This study aimed to analyze the causal relationship between different types of DM and ASD by bidirectional Mendelian randomization (MR). Methods: Single nucleotide polymorphisms for type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and ASD were obtained from genome-wide association studies. Subsequently, inverse variance weighted, MR-Egger, and weighted median were used to test the exposure-outcome causality. Finally, MR-Egger's intercept, Cochran's Q, and leave-one-out method were used to assess horizontal pleiotropy, heterogeneity, and sensitivity of the results, respectively. Results: The positive analysis showed that T2DM was associated with an increased risk of ASD, whereas neither T1DM nor GDM was associated with the risk of ASD. The reverse analysis showed that ASD was associated with an increased risk of T2DM, while it was not associated with the risk of either T1DM or GDM. MR-Egger intercept showed no horizontal pleiotropy (p > 0.05) for these results. Cochran's Q showed no heterogeneity expect for the results of T1DM on the risk of ASD, and leave-one-out sensitivity analysis showed these results were robust. Conclusion: This MR analysis suggests that T2DM and ASD are reciprocal risk factors and that they may create an intergenerational risk cycling in female patients. Aggressive prevention and treatment of T2DM and ASD help to break the trap of this risk cycling. Additionally, this study does not support a causal relationship between T1DM and ASD, as well as GDM and ASD. And more studies are needed in the future to continue to explore the interactions and underlying mechanisms between different types of DM and ASD.
Assuntos
Transtorno do Espectro Autista , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/etiologia , Feminino , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Gravidez , Diabetes Gestacional/genética , Diabetes Gestacional/epidemiologia , Fatores de Risco , Predisposição Genética para Doença , MasculinoRESUMO
Because of the advent of genome-editing technology, gene knockout (KO) hamsters have become attractive research models for diverse diseases in humans. This study established a new KO model of diabetes by disrupting the insulin receptor substrate-2 (Irs2) gene in the golden (Syrian) hamster. Homozygous KO animals were born alive but with delayed postnatal growth until adulthood. They showed hyperglycemia, high HbA1c, and impaired glucose tolerance. However, they normally responded to insulin stimulation, unlike Irs2 KO mice, an obese type 2 diabetes (T2D) model. Consistent with this, Irs2 KO hamsters did not increase serum insulin levels upon glucose administration and showed ß-cell hypoplasia in their pancreas. Thus, our Irs2 KO hamster provide a unique T2D animal model that is distinct from the obese T2D models. This model may contribute to a better understanding of the pathophysiology of human non-obese T2D with ß-cell dysfunction, the most common type of T2D in East Asian countries, including Japan.
Assuntos
Diabetes Mellitus Tipo 2 , Modelos Animais de Doenças , Proteínas Substratos do Receptor de Insulina , Mesocricetus , Animais , Cricetinae , Humanos , Masculino , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Técnicas de Inativação de Genes , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologiaRESUMO
Type 2 diabetes (T2D) and Clear-cell renal cell carcinoma (ccRCC) are both complicated diseases which incidence rates gradually increasing. Population based studies show that severity of ccRCC might be associated with T2D. However, so far, no researcher yet investigated about the molecular mechanisms of their association. This study explored T2D and ccRCC causing shared key genes (sKGs) from multiple transcriptomics profiles to investigate their common pathogenetic processes and associated drug molecules. We identified 259 shared differentially expressed genes (sDEGs) that can separate both T2D and ccRCC patients from control samples. Local correlation analysis based on the expressions of sDEGs indicated significant association between T2D and ccRCC. Then ten sDEGs (CDC42, SCARB1, GOT2, CXCL8, FN1, IL1B, JUN, TLR2, TLR4, and VIM) were selected as the sKGs through the protein-protein interaction (PPI) network analysis. These sKGs were found significantly associated with different CpG sites of DNA methylation that might be the cause of ccRCC. The sKGs-set enrichment analysis with Gene Ontology (GO) terms and KEGG pathways revealed some crucial shared molecular functions, biological process, cellular components and KEGG pathways that might be associated with development of both T2D and ccRCC. The regulatory network analysis of sKGs identified six post-transcriptional regulators (hsa-mir-93-5p, hsa-mir-203a-3p, hsa-mir-204-5p, hsa-mir-335-5p, hsa-mir-26b-5p, and hsa-mir-1-3p) and five transcriptional regulators (YY1, FOXL1, FOXC1, NR2F1 and GATA2) of sKGs. Finally, sKGs-guided top-ranked three repurposable drug molecules (Digoxin, Imatinib, and Dovitinib) were recommended as the common treatment for both T2D and ccRCC by molecular docking and ADME/T analysis. Therefore, the results of this study may be useful for diagnosis and therapies of ccRCC patients who are also suffering from T2D.
Assuntos
Carcinoma de Células Renais , Biologia Computacional , Diabetes Mellitus Tipo 2 , Neoplasias Renais , Mapas de Interação de Proteínas , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Biologia Computacional/métodos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Regulação Neoplásica da Expressão Gênica , Metilação de DNA , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , TranscriptomaRESUMO
In-depth multiomic phenotyping provides molecular insights into complex physiological processes and their pathologies. Here, we report on integrating 18 diverse deep molecular phenotyping (omics-) technologies applied to urine, blood, and saliva samples from 391 participants of the multiethnic diabetes Qatar Metabolomics Study of Diabetes (QMDiab). Using 6,304 quantitative molecular traits with 1,221,345 genetic variants, methylation at 470,837 DNA CpG sites, and gene expression of 57,000 transcripts, we determine (1) within-platform partial correlations, (2) between-platform mutual best correlations, and (3) genome-, epigenome-, transcriptome-, and phenome-wide associations. Combined into a molecular network of > 34,000 statistically significant trait-trait links in biofluids, our study portrays "The Molecular Human". We describe the variances explained by each omics in the phenotypes (age, sex, BMI, and diabetes state), platform complementarity, and the inherent correlation structures of multiomics data. Further, we construct multi-molecular network of diabetes subtypes. Finally, we generated an open-access web interface to "The Molecular Human" ( http://comics.metabolomix.com ), providing interactive data exploration and hypotheses generation possibilities.
Assuntos
Fenótipo , Humanos , Masculino , Feminino , Metabolômica/métodos , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Metilação de DNA , Transcriptoma , Pessoa de Meia-Idade , Estudo de Associação Genômica Ampla , Catar/epidemiologia , Epigenoma , Adulto , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , MultiômicaRESUMO
Background: Coronary artery diseases may be affected by several genetic and nongenetic factors. Single-nucleotide polymorphism (SNP) rs599839 and type 2 diabetes mellitus (T2DM) can affect the occurrence and severity of coronary artery disease (CAD). Methods: Our aim was to investigate how T2DM and the rs599839 variant affected serum lipid levels and the degree of CAD patients' coronary artery stenosis. rs599839 polymorphism genotyping was done on Saudi patients with coronary angiography performed previously. Patients enrolled were divided into group A (360 DM patients), group B (225 DM patients with CAD), and group C (190 healthy volunteers as control). Results: Individuals with diabetes and CAD who possessed the GG genotype in rs599839 exhibited markedly reduced means of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG; 224.5, 116.2, and 221.4 versus 251.6, 131.3, and 261.7 mg/dl, p=0.003, 0.007, and 0.025, respectively) than AA genotype. The odds ratio and the confidence interval of 95% for G allele carriers of rs599839 were OR = 0.62, 95% CI: 0.41-0.82, and p=0.003, among diabetic patients with CAD. Conclusions: In patients with diabetic CAD, the locus 1p13.3 polymorphism rs599839 was found to be substantially correlated with serum lipid levels. Furthermore, among Saudi patients with diabetes, the G allele of rs599839 variant lowers the CAD risk.
Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Polimorfismo de Nucleotídeo Único , Humanos , Masculino , Feminino , Diabetes Mellitus Tipo 2/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/sangue , Pessoa de Meia-Idade , Arábia Saudita , Estudos de Casos e Controles , Idoso , Predisposição Genética para Doença , Fatores de Risco , Triglicerídeos/sangueRESUMO
Glucagon-like peptide 1 (GLP1), which is mainly processed and cleaved from proglucagon in enteroendocrine cells (EECs) of the intestinal tract, acts on the GLP1 receptor in pancreatic cells to stimulate insulin secretion and to inhibit glucagon secretion. However, GLP1 processing is not fully understood. Here, we show that reticulon 4B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, interacts with the major proglucagon fragment of proglucagon to retain proglucagon on the ER, thereby inhibiting PCSK1-mediated cleavage of proglucagon in the Golgi. Intestinal Nogo-B knockout in male type 2 diabetes mellitus (T2DM) mice increases GLP1 and insulin levels and decreases glucagon levels, thereby alleviating pancreatic injury and insulin resistance. Finally, we identify aberrantly elevated Nogo-B expression and inhibited proglucagon cleavage in EECs from diabetic patients. Our study reveals the subcellular regulatory processes involving Nogo-B during GLP1 production and suggests intestinal Nogo-B as a potential therapeutic target for T2DM.
Assuntos
Diabetes Mellitus Tipo 2 , Retículo Endoplasmático , Peptídeo 1 Semelhante ao Glucagon , Proteínas Nogo , Proglucagon , Pró-Proteína Convertase 1 , Animais , Humanos , Masculino , Camundongos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Retículo Endoplasmático/metabolismo , Células Enteroendócrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Complexo de Golgi/metabolismo , Células HEK293 , Insulina/metabolismo , Resistência à Insulina , Intestinos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nogo/metabolismo , Proteínas Nogo/genética , Proglucagon/metabolismo , Proglucagon/genética , Pró-Proteína Convertase 1/metabolismo , Pró-Proteína Convertase 1/genética , Ligação Proteica , ProteóliseRESUMO
The increased prevalence of metabolic diseases in the Arab countries is mainly associated with genetic susceptibility, lifestyle behaviours, such as physical inactivity, and an unhealthy diet. The objective of this review was to investigate and summarise the findings of the gene-lifestyle interaction studies on metabolic diseases such as obesity and type 2 diabetes in Arab populations. Relevant articles were retrieved from a literature search on PubMed, Web of Science, and Google Scholar starting at the earliest indexing date through to January 2024. Articles that reported an interaction between gene variants and diet or physical activity were included and excluded if no interaction was investigated or if they were conducted among a non-Arab population. In total, five articles were included in this review. To date, among three out of twenty-two Arab populations, fourteen interactions have been found between the FTO rs9939609, TCF7L2 rs7903146, MC4R rs17782313, and MTHFR rs1801133 polymorphisms and diet or physical activity on obesity and type 2 diabetes outcomes. The majority of the reported gene-diet/ gene-physical activity interactions (twelve) appeared only once in the review. Consequently, replication, comparisons, and generalisation of the findings are limited due to the sample size, study designs, dietary assessment tools, statistical analysis, and genetic heterogeneity of the studied sample.
Assuntos
Árabes , Exercício Físico , Predisposição Genética para Doença , Estilo de Vida , Doenças Metabólicas , Feminino , Humanos , Masculino , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Árabes/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Dieta , Interação Gene-Ambiente , Doenças Metabólicas/genética , Doenças Metabólicas/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Obesidade/genética , Obesidade/epidemiologia , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina , Proteína 2 Semelhante ao Fator 7 de Transcrição/genéticaRESUMO
Derived from enteroendocrine cells (EECs), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are pivotal incretin hormones crucial for blood glucose regulation. Medications of GLP-1 analogs and GLP-1 receptor activators are extensively used in the treatment of type 2 diabetes (T2D) and obesity. However, there are currently no agents to stimulate endogenous incretin secretion. Here, we find the pivotal role of KCNH2 potassium channels in the regulation of incretin secretion. Co-localization of KCNH2 with incretin-secreting EECs in the intestinal epithelium of rodents highlights its significance. Gut epithelial cell-specific KCNH2 knockout in mice improves glucose tolerance and increases oral glucose-triggered GLP-1 and GIP secretion, particularly GIP. Furthermore, KCNH2-deficient primary intestinal epithelial cells exhibit heightened incretin, especially GIP secretion upon nutrient stimulation. Mechanistically, KCNH2 knockdown in EECs leads to reduced K+ currents, prolonged action potential duration, and elevated intracellular calcium levels. Finally, we found that dofetilide, a KCNH2-specific inhibitor, could promote incretin secretion in enteroendocrine STC-1 cells in vitro and in hyperglycemic mice in vivo. These findings elucidate, for the first time, the mechanism and application of KCNH2 in regulating incretin secretion by EECs. Given the therapeutic promise of GLP-1 and GIP in diabetes and obesity management, this study advances our understanding of incretin regulation, paving the way for potential incretin secretagogue therapies in the treatment of diabetes and obesity.
Assuntos
Células Enteroendócrinas , Peptídeo 1 Semelhante ao Glucagon , Incretinas , Animais , Camundongos , Incretinas/farmacologia , Células Enteroendócrinas/metabolismo , Células Enteroendócrinas/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Polipeptídeo Inibidor Gástrico/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Secretagogos/farmacologia , Camundongos Knockout , Canal de Potássio ERG1RESUMO
BACKGROUND: Type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) are prevalent metabolic disorders with overlapping pathophysiological mechanisms. A comprehensive understanding of the shared molecular pathways involved in these conditions can advance the development of effective therapeutic interventions. METHODS: We used two datasets sourced from the Gene Expression Omnibus (GEO) database to identify common differentially expressed genes (DEGs) between T2D and NAFLD. Subsequently, we conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to identify the enriched biological processes and signaling pathways. In addition, we performed a protein-protein interaction (PPI) network analysis to identify hub genes with pivotal roles. To validate our findings, we established a type 2 diabetic mouse model with NAFLD. RESULTS: Our analysis identified 53 DEGs shared between T2D and NAFLD. Enrichment analysis revealed their involvement in signal transduction, transcriptional regulation, and cell proliferation as well as in the ferroptosis signaling pathways. PPI network analysis identified ten hub genes, namely CD44, CASP3, FYN, KLF4, HNRNPM, HNRNPU, FUBP1, RUNX1, NOTCH3, and ANXA2. We validated the differential expression of FYN, HNRNPU, and FUBP1 in liver tissues of a type 2 diabetic mouse model with NAFLD. CONCLUSIONS: Our study offers valuable insights into the shared molecular mechanisms underlying T2D and NAFLD. The identified hub genes and pathways present promising prospects as therapeutic targets to address these prevalent metabolic disorders.
Assuntos
Biologia Computacional , Diabetes Mellitus Tipo 2 , Modelos Animais de Doenças , Hepatopatia Gordurosa não Alcoólica , Mapas de Interação de Proteínas , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Camundongos , Biologia Computacional/métodos , Fator 4 Semelhante a Kruppel , Masculino , Camundongos Endogâmicos C57BL , Redes Reguladoras de Genes , Transdução de Sinais , Perfilação da Expressão Gênica , HumanosRESUMO
Introduction: Type 2 diabetes mellitus (T2DM) is a major cause of atherosclerosis (AS). However, definitive evidence regarding the common molecular mechanisms underlying these two diseases are lacking. This study aimed to investigate the mechanisms underlying the association between T2DM and AS. Methods: The gene expression profiles of T2DM (GSE159984) and AS (GSE100927) were obtained from the Gene Expression Omnibus, after which overlapping differentially expressed gene identification, bioinformatics enrichment analyses, protein-protein interaction network construction, and core genes identification were performed. We confirmed the discriminatory capacity of core genes using receiver operating curve analysis. We further identified transcription factors using TRRUST database to build a transcription factor-mRNA regulatory network. Finally, the immune infiltration and the correlation between core genes and differential infiltrating immune cells were analyzed. Results: A total of 27 overlapping differentially expressed genes were identified under the two-stress conditions. Functional analyses revealed that immune responses and transcriptional regulation may be involved in the potential pathogenesis. After protein-protein interaction network deconstruction, external datasets, and qRT-PCR experimental validation, four core genes (IL1B, C1QA, CCR5, and MSR1) were identified. ROC analysis further showed the reliable value of these core genes. Four common differential infiltrating immune cells (B cells, CD4+ T cells, regulatory T cells, and M2 macrophages) between T2DM and AS datasets were selected based on immune cell infiltration. A significant correlation between core genes and common differential immune cells. Additionally, five transcription factors (RELA, NFκB1, JUN, YY1, and SPI1) regulating the transcription of core genes were mined using upstream gene regulator analysis. Discussion: In this study, common target genes and co-immune infiltration landscapes were identified between T2DM and AS. The relationship among five transcription factors, four core genes, and four immune cells profiles may be crucial to understanding T2DM complicated with AS pathogenesis and therapeutic direction.
Assuntos
Aterosclerose , Biomarcadores , Biologia Computacional , Diabetes Mellitus Tipo 2 , Mapas de Interação de Proteínas , Humanos , Biologia Computacional/métodos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Aterosclerose/genética , Aterosclerose/imunologia , Biomarcadores/metabolismo , Mapas de Interação de Proteínas/genética , Redes Reguladoras de Genes , Perfilação da Expressão Gênica , TranscriptomaRESUMO
Analyzing changes in gene expression within specific brain regions of individuals with Type 2 Diabetes (T2DM) who do not exhibit significant cognitive deficits can yield valuable insights into the mechanisms underlying the progression towards a more severe phenotype. In this study, transcriptomic analysis of the cortex and hippocampus of mice with long-term T2DM revealed alterations in the expression of 28 genes in the cerebral cortex and 15 genes in the hippocampus. Among these genes, six displayed consistent changes in both the cortex and hippocampus: Interferon regulatory factor 7 (Irf7), Hypoxia-inducible factor 3 alpha (Hif-3α), period circadian clock 2 (Per2), xanthine dehydrogenase (Xdh), and Transforming growth factor ß-stimulated clone 22/TSC22 (Tsc22d3) were upregulated, while Claudin-5 (Cldn5) was downregulated. Confirmation of these changes was achieved through RT-qPCR. At the protein level, CLDN5 and IRF7 exhibited similar alterations, with CLDN5 being downregulated and IRF7 being upregulated. In addition, the hippocampus and cortex of the T2DM mice showed decreased levels of IκBα, implying the involvement of NF-κB pathways as well. Taken together, these results suggest that the weakening of the blood-brain barrier and an abnormal inflammatory response via the Interferon 1 and NF-κB pathways underlie cognitive impairment in individuals with long-standing T2DM.
Assuntos
Córtex Cerebral , Claudina-5 , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Hipocampo , Fator Regulador 7 de Interferon , Animais , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Claudina-5/metabolismo , Claudina-5/genética , Camundongos , Diabetes Mellitus Experimental/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Fator Regulador 7 de Interferon/genética , Masculino , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Camundongos Endogâmicos C57BLRESUMO
Previous observational studies have identified a link between obesity, adiposity distribution, type 1 Diabetes Mellitus (T1DM), type 2 Diabetes Mellitus (T2DM), and the risk of pressure ulcers (PUs). However, the definitive causality between obesity and PUs, and potential DM mediators remains unclear. Univariable, multivariable, and mediation Mendelian randomization (MR) analyses were conducted to explore the mediating role of T1DM or T2DM in the association between obesity, adiposity distribution, and PUs. Instrumental variables for obesity and adiposity distribution, including Body Mass Index (BMI), waist circumference, hip circumference, trunk fat mass, whole body fat mass, trunk fat percentage, and body fat percentage, were selected from two genome-wide association studies (GWAS). In univariable MR analysis, BMI, hip circumference, and obesity were associated with PUs using inverse variance weighted (IVW) regression. These findings were further corroborated by the replication cohorts and meta-analysis (BMI: OR = 1.537, 95% CI = 1.294-1.824, p < 0.001; Hip circumference: OR = 1.369, 95% CI = 1.147-1.635, p < 0.001; Obesity: OR = 1.235, 95% CI = 1.067-1.431, p = 0.005), respectively. Even after adjusting for confounding factors such as T1DM and T2DM, BMI and hip circumference remained statistically significant in multivariable MR analyses. T2DM may mediate the pathogenesis of BMI-related (OR = 1.106, 95% CI = 1.054-1.160, p = 0.037) and obesity-related PUs (OR = 1.053, 95% CI = 1.034-1.973, p = 0.004). These findings provide insights for the prevention and treatment of PUs, particularly in patients with obesity or DM.
Assuntos
Adiposidade , Índice de Massa Corporal , Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Análise de Mediação , Análise da Randomização Mendeliana , Obesidade , Úlcera por Pressão , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Obesidade/genética , Obesidade/epidemiologia , Úlcera por Pressão/epidemiologia , Úlcera por Pressão/etiologia , Fatores de Risco , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/epidemiologia , Circunferência da Cintura , MasculinoRESUMO
BACKGROUND: The Lin-Sca1+c-Kit+ (LSK) fraction of the bone marrow (BM) comprises multipotent hematopoietic stem cells (HSCs), which are vital to tissue homeostasis and vascular repair. While diabetes affects HSC homeostasis overall, the molecular signature of mRNA and miRNA transcriptomic under the conditions of long-standing type 2 diabetes (T2D;>6 months) remains unexplored. METHODS: In this study, we assessed the transcriptomic signature of HSCs in db/db mice, a well-known and widely used model for T2D. LSK cells of db/db mice enriched using a cell sorter were subjected to paired-end mRNA and single-end miRNA seq library and sequenced on Illumina NovaSeq 6000. The mRNA sequence reads were mapped using STAR (Spliced Transcripts Alignment to a Reference), and the miRNA sequence reads were mapped to the designated reference genome using the Qiagen GeneGlobe RNA-seq Analysis Portal with default parameters for miRNA. RESULTS: We uncovered 2076 out of 13,708 mRNAs and 35 out of 191 miRNAs that were expressed significantly in db/db animals; strikingly, previously unreported miRNAs (miR-3968 and miR-1971) were found to be downregulated in db/db mice. Furthermore, we observed a molecular shift in the transcriptome of HSCs of diabetes with an increase in pro-inflammatory cytokines (Il4, Tlr4, and Tnf11α) and a decrease in anti-inflammatory cytokine IL10. Pathway mapping demonstrated inflammation mediated by chemokine, cytokine, and angiogenesis as one of the top pathways with a significantly higher number of transcripts in db/db mice. These molecular changes were reflected in an overt defect in LSK mobility in the bone marrow. miRNA downstream target analysis unveils several mRNAs targeting leukocyte migration, microglia activation, phagosome formation, and macrophage activation signaling as their primary pathways, suggesting a shift to an inflammatory phenotype. CONCLUSION: Our findings highlight that chronic diabetes adversely alters HSCs' homeostasis at the transcriptional level, thus potentially contributing to the inflammatory phenotype of HSCs under long-term diabetes. We also believe that identifying HSCs-based biomarkers in miRNAs or mRNAs could serve as diagnostic markers and potential therapeutic targets for diabetes and associated vascular complications.
Assuntos
Diabetes Mellitus Tipo 2 , Células-Tronco Hematopoéticas , MicroRNAs , Transcriptoma , Animais , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Perfilação da Expressão Gênica , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Masculino , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismoRESUMO
Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004-/-). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004-/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004-/- mice. Additionally, stimulation with transforming growth factor-ß1 (TGF-ß1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004-/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004-/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.
Assuntos
Fibrose , Animais , Camundongos , Masculino , Humanos , Transição Epitelial-Mesenquimal , Camundongos Knockout , Obstrução Ureteral/patologia , Obstrução Ureteral/complicações , Rim/patologia , Rim/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Actinas/metabolismo , Camundongos Endogâmicos C57BL , Caderinas/metabolismo , Caderinas/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/genéticaRESUMO
Bullous pemphigoid (BP), although a rare disease, is the most frequent subepidermal autoimmune disorder. Treatment with gliptins, used for type 2 diabetes, was reported as associated with BP onset. To identify HLA alleles that may reflect a higher susceptibility to BP in the Italian population, we analysed 30 patients affected by idiopathic bullous pemphigoid (IBP) and 86 gliptin-associated BP (GABP) patients. A significant association between HLA-DQB1*03:01 allele and IBP and GABP patients was found. Of note, both IBP and GABP were significantly associated with one of the following haplotypes: DRB1*11:01, DRB3*02:02, DQA1*05:05, DQB1*03:01 or DRB1*11:04, DRB3*02:02, DQA1*05:05 and DQB1*03:01. These data identify, for the first time, potential markers of susceptibility to BP in the Italian population, especially when associated with gliptin intake.
Assuntos
Alelos , Predisposição Genética para Doença , Haplótipos , Penfigoide Bolhoso , Humanos , Penfigoide Bolhoso/genética , Penfigoide Bolhoso/induzido quimicamente , Itália , Feminino , Masculino , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cadeias beta de HLA-DQ/genética , Pessoa de Meia-Idade , Frequência do Gene , Idoso de 80 Anos ou maisRESUMO
This study aimed to perform exhaustive bioinformatic analysis by using GSE29221 micro-array maps obtained from healthy controls and Type 2 Diabetes (T2DM) patients. Raw data are downloaded from the Gene Expression Omnibus database and processed by the limma package in R software to identify Differentially Expressed Genes (DEGs). Gene ontology functional analysis and Kyoto Gene Encyclopedia and Genome Pathway analysis are performed to determine the biological functions and pathways of DEGs. A protein interaction network is constructed using the STRING database and Cytoscape software to identify key genes. Finally, immune infiltration analysis is performed using the Cibersort method. This study has implications for understanding the underlying molecular mechanism of T2DM and provides potential targets for further research.