Pathogenesis Of Type 2 Diabetes Mellitus Research Articles

Oxidative stress and type 2 diabetes: the development and the pathogenesis, Jordanian cross-sectional study

Accumulation of reactive oxygen species (ROS) can disrupt the antioxidant defense system, leading to oxidative stress that leads to pathological damage to vital human organs, including hormone-producing glands. Normal physiological function is subsequently disrupted and disorders such as Type 2 Diabetes Mellitus (T2DM) may develop. The critical role of the antioxidant defense system in counteracting ROS and mitigating oxidative stress is fundamental to understanding the pathogenesis of T2DM. In our study, we monitored the oxidant/antioxidant status in a selected Jordanian population to further elucidate this relationship. Our results show higher serum levels of Malondialdehyde (MDA); 0.230 ± 0.05 and 0.207 ± 0.06 μmol/l for the diabetic and the obese groups, respectively, relative to 0.135 ± 0.04 μmol/l for the non-obese healthy group. Lower activity of Catalase (CAT) was recorded among the diabetic (9.2 ± 3.2) and obese groups (11.0 ± 2.8), compared to the non-obese healthy group (12.1 ± 3.5). Significant elevations (P < 0.05) were observed in uric acid concentrations in diabetic and obese subjects: 451 ± 57 mg/dl and 430 ± 51, respectively, versus 342 ± 57 mg/dl in the non-obese healthy group. Moreover, no significant differences were obtained between all the studied groups for the serum albumin and total protein concentrations. Our findings demonstrate the potential role of oxidative stress in the development and occurrence of T2DM.

High-Density Lipoprotein Modifications: Causes and Functional Consequences in Type 2 Diabetes Mellitus.

High-density lipoprotein (HDL) is a group of small, dense, and protein-rich lipoproteins that play a role in cholesterol metabolism and various cellular processes. Decreased levels of HDL and HDL dysfunction are commonly observed in individuals with type 2 diabetes mellitus (T2DM), which is also associated with an increased risk for cardiovascular disease (CVD). Due to hyperglycemia, oxidative stress, and inflammation that develop in T2DM, HDL undergoes several post-translational modifications such as glycation, oxidation, and carbamylation, as well as other alterations in its lipid and protein composition. It is increasingly recognized that the generation of HDL modifications in T2DM seems to be the main cause of HDL dysfunction and may in turn influence the development and progression of T2DM and its related cardiovascular complications. This review provides a general introduction to HDL structure and function and summarizes the main modifications of HDL that occur in T2DM. Furthermore, the potential impact of HDL modifications on the pathogenesis of T2DM and CVD, based on the altered interactions between modified HDL and various cell types that are involved in glucose homeostasis and atherosclerotic plaque generation, will be discussed. In addition, some perspectives for future research regarding the T2DM-related HDL modifications are addressed.

Association of polymorphisms within P2RX4 with type 2 diabetes mellitus: a preliminary case-control study

Objective Type 2 diabetes mellitus (T2DM) is a complex heterogenic metabolic with a wide range of etiology. Purinergic receptors have pivotal roles in different processes and are hypothesized to have roles in the pathogenesis of T2DM. Materials and Methods Three hundred subjects affected by T2DM and 300 healthy subjects were genotyped by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). SPSS V16.0 was recruited for statistical analysis. Results The findings showed that the G allele of rs25644A > G increases the risk of T2DM in our population statistically (OR = 1.51, 95% CI = 1.14–1.99, p = 0.003). This allele in some genotype models, including the dominant model, caused an increase in the risk of T2DM. The interaction of genotypes between studied variants in the P2XR4 gene increased the risk of T2DM. Haplotype analysis showed that Ars1169727/Grs25644 haplotype caused an increase in the risk of T2DM. Conclusions The findings suggest that rs25644A > G plays a role in our population’s increased risk of T2DM.

Investigating the causal association between gut microbiota and type 2 diabetes: a meta-analysis and Mendelian randomization.

Studies have shown that gut dysbiosis contributes to the pathophysiology of type 2 diabetes mellitus (T2DM). Identifying specific gut microbiota dysbiosis may provide insight into the pathogenesis of T2DM. This study investigated the causal relationship between gut microbiota and T2DM using meta-analysis and Mendelian randomization (MR). In the first part, we searched for literature on gut microbiota and T2DM, and conducted a meta-analysis. We observed differences in glycosylated hemoglobin and fasting blood glucose levels in both groups. Second, we obtained GWAS data from genome-wide association study database 19 (GWAS). We used two-sample MR analysis to verify the forward and reverse causal associations between gut microbiota and T2DM. Additionally, we selected the European GWAS data from the European Bioinformatics Institute (EBI) as a validation set for external validation of the MR analysis. In the third part, we aimed to clarify which gut microbiota contribute to the degree of causal association between group disorders and T2DM through multivariate MR analysis and Bayesian model averaging (MR-BMA). 1. According to the meta-analysis results, the glycated hemoglobin concentration in the gut probiotic intervention group was significantly lower than in the control group. Following treatment, fasting blood glucose levels in the intervention group were significantly lower than those in the control group. 2. The results of two samples MR analysis revealed that there were causal relationships between six gut microbiota and T2DM. Genus Haemophilus and order Pasteurellaceae were negatively correlated with T2DM. Genus Actinomycetes, class Melanobacteria and genus Lactobacillus were positively correlated. Reverse MR analysis demonstrated that T2DM and gut microbiota did not have any reverse causal relationship. The external validation data set showed a causal relationship between gut microbiota and T2DM. 3. Multivariate MR analysis and MR-BMA results showed that the independent genus Haemophilus collection had the largest PP. Our research results suggest that gut microbiota is closely related to T2DM pathogenesis. The results of further MR research and an analysis of the prediction model indicate that a variety of gut microbiota disorders, including genus Haemophilus, are causally related to the development of T2DM. The findings of this study may provide some insight into the diagnosis and treatment of T2DM. https://www.crd.york.ac.uk/PROSPERO.

Dysregulated bile acid homeostasis: unveiling its role in metabolic diseases

Abstract Maintaining bile acid homeostasis is essential for metabolic health. Bile acid homeostasis encompasses a complex interplay between biosynthesis, conjugation, secretion, and reabsorption. Beyond their vital role in digestion and absorption of lipid-soluble nutrients, bile acids are pivotal in systemic metabolic regulation. Recent studies have linked bile acid dysregulation to the pathogenesis of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). Bile acids are essential signaling molecules that regulate many critical biological processes, including lipid metabolism, energy expenditure, insulin sensitivity, and glucose metabolism. Disruption in bile acid homeostasis contributes to metabolic disease via altered bile acid feedback mechanisms, hormonal dysregulation, interactions with the gut microbiota, and changes in the expression and function of bile acid transporters and receptors. This review summarized the essential molecular pathways and regulatory mechanisms through which bile acid dysregulation contributes to the pathogenesis and progression of obesity, T2DM, and MASLD. We aim to underscore the significance of bile acids as potential diagnostic markers and therapeutic agents in the context of metabolic diseases, providing insights into their application in translational medicine.

WITHDRAWN: Research on Traditional Chinese Medicine Syndrome Animal Models and Multi-omics Biomarkers in Type II Diabetes: A Review

IntroductionDiabetes, a chronic metabolic disease marked by hyperglycemia, predominantly manifests as Type 2 Diabetes Mellitus (T2DM), representing over 90% of diabetes cases with intricate pathogenesis and varied pathological attributes. Drawing upon Traditional Chinese Medicine (TCM) principles, this article outlines the methodology and evaluation criteria for integrating TCM syndromes into animal models for T2DM while comprehensively examining T2DM pathogenic mechanisms and physiological characteristics from various omics perspectives to pinpoint essential biomarkers. MethodsResearchers conducted comprehensive searches using databases such as Web of Science, Google Scholar, Baidu Scholar and CNKI. Selection criteria were based on content relevance and publication date, resulting in the inclusion of 223 articles, including Chinese and English journal papers, master's and doctoral theses. This comprehensive review aims to highlight the importance of TCM in research related to T2DM, as well as its compatibility with modern technology, providing guidance for future development of targeted drugs and clinical treatment for T2DM. ResultsThis article, based on the fundamental theories of Traditional Chinese Medicine, summarized the methodology and evaluation criteria for constructing 6 types of T2DM animal models: Blood Stasis Syndrome, Kidney Yin Deficiency Syndrome, Spleen Deficiency Syndrome, Yang Deficiency Syndrome, Qi and Yin Deficiency Syndrome, and Yin and Yang Deficiency Syndrome. It comprehensively analyzed the latest research progress on the pathogenic mechanisms and physiological characteristics of T2DM from the perspectives of genomics, proteomics, transcriptomics, metabolomics, and gut microbiomics, providing crucial insights for the discovery of potential biomarkers for T2DM. DiscussionsThe broad use of multi-omics tech aids in T2DM pathogenesis understanding. For comprehensive insight, analyzing genes, proteins, metabolites and microbiota is vital. As a metabolic disorder, T2DM has a prolonged development process, necessitating the selection of different biomarkers for various stages of the disease progression and long-term monitoring of the overall changes in key biomarkers. The development of a “disease-syndrome” animal model is pivotal for the advancement of targeted drug therapies. The crux lies in the accuracy, repeatability, and stability of the model and its assessment criteria. Future investigations should focus on multi-omics analyses across diverse T2DM syndromes to facilitate personalized treatment strategies.

Comprehensive machine learning models for predicting therapeutic targets in type 2 diabetes utilizing molecular and biochemical features in rats

IntroductionWith the increasing prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need to discover effective therapeutic targets for this complex condition. Coding and non-coding RNAs, with traditional biochemical parameters, have shown promise as viable targets for therapy. Machine learning (ML) techniques have emerged as powerful tools for predicting drug responses.MethodIn this study, we developed an ML-based model to identify the most influential features for drug response in the treatment of type 2 diabetes using three medicinal plant-based drugs (Rosavin, Caffeic acid, and Isorhamnetin), and a probiotics drug (Z-biotic), at different doses. A hundred rats were randomly assigned to ten groups, including a normal group, a streptozotocin-induced diabetic group, and eight treated groups. Serum samples were collected for biochemical analysis, while liver tissues (L) and adipose tissues (A) underwent histopathological examination and molecular biomarker extraction using quantitative PCR. Utilizing five machine learning algorithms, we integrated 32 molecular features and 12 biochemical features to select the most predictive targets for each model and the combined model.Results and discussionOur results indicated that high doses of the selected drugs effectively mitigated liver inflammation, reduced insulin resistance, and improved lipid profiles and renal function biomarkers. The machine learning model identified 13 molecular features, 10 biochemical features, and 20 combined features with an accuracy of 80% and AUC (0.894, 0.93, and 0.896), respectively. This study presents an ML model that accurately identifies effective therapeutic targets implicated in the molecular pathways associated with T2DM pathogenesis.

Role of serum endotoxin, FGF19, TLR2, TNF-α, IL-12 and IL-10 in NAFLD-associated T2DM pathogenesis: Insights into Th1 bias and protective mechanisms.

Non-alcoholic fatty liver disease (NAFLD) in non-obese patients is pathophysiologically distinct, exhibiting common immunological link with type-2 diabetes mellitus (T2DM). This study aims to delineate the role of Toll-like receptor 2 (TLR2)-mediated immuno-modulation along with its association with fibroblast growth factor receptor 4 (FGFR4) and its ligand fibroblast growth factor 19 (FGF19) in the pathogenesis of NAFLD without or with T2DM. Blood samples were collected from patients with NAFLD (n = 90), NAFLD with T2DM (n = 90) and healthy cohorts (n = 90) with consent and clinical records. Real-time polymerase chain reaction (PCR), enzyme-linked immunoassay (ELIZA) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to analyze messenger ribonucleic acid (mRNA), protein expression and gene polymorphism. The molecular genetic analysis revealed the prevalence of variant allele(A) in FGFR4 gene in both cases compared to controls. The mRNA expression of FGF19 and TLR2 exhibited significant upregulation in NAFLD without T2DM compared to NAFLD with T2DM. Tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12) showed upregulation in both disease cohorts compared to control while IL-10 showed significant downregulation in NAFLD with T2DM compared to the other two cohorts. Correlation analysis between FGF19 and TLR2 revealed significant positive association in both NAFLD with and without T2DM. The Th1:Th2 ratio showed significant upregulation in NAFLD with T2DM compared to NAFLD without T2DM. In conclusion, elevated serum endotoxin levels appear to contribute to NAFLD and T2DM development. Upregulated FGF19 seems to be protective against developing T2DM in NAFLD patients. Higher TLR2, TNF-α and IL-12 expression in NAFLD without T2DM suggests a Th1 bias in its pathogenesis, while reduced IL-10 in NAFLD with T2DM implies a more skewed Th1 state in this condition.

Diabetic ketoacidosis in type 1 diabetes mellitus in children and adolescents

Background: Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes mellitus (T1DM). Although T1DM can occur in children and adults, DKA caused by T1DM is more severe in children and adolescents and metabolic changes occur more rapidly. This review discusses clinical factors associated with DKA assessed during diagnosis in children and adolescents with T1DM.Current Concepts: DKA is a severe complication that can occur in children with T1DM because of insulin deficiency, leading to high levels of catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, muscle proteolysis, hyperglycemia, and osmotic diuresis. High levels of counterregulatory hormones that enhance ketogenesis have also been noted. High blood sugar levels, dehydration, and the release of ketone bodies into the circulation cause high occurrence of acidosis. DKA can lead to life-threatening complications, such as cerebral edema, which is more common in children than in adults. Other potential complications include kidney failure, respiratory distress, and cardiovascular collapse. Children with T1DM are at a higher risk of developing DKA, particularly during times of illness or stress, or when insulin doses are missed or insufficient. In addition, undiagnosed T1DM in children can lead to DKA when the body enters a state of severe insulin deficiency.Discussion and Conclusion: The risks should be detected earlier and the pathogenesis of T1DM should be understood and assessed by physicians in children and adolescents during check-ups. Furthermore, efforts to increase public awareness are required to reduce the cognitive delays associated with DKA.

Plasma 16:0 ceramide as a marker of cardiovascular risk estimated by carotid intima-media thickness in people with type 2 diabetes

AimNew tools are required to better assess cardiovascular risk in individuals with type 2 diabetes mellitus (T2DM). Plasma ceramides emerge as promising candidates, given their substantial influence on the pathogenesis of both T2DM and atherosclerosis. The current study aimed to investigate whether plasma ceramides in patients with T2DM are a predictive factor for carotid intima-media thickness (CIMT), a well-established noninvasive marker for atherosclerosis that predicts adverse cardiovascular outcomes. MethodsA lipidomic analysis was carried out on the circulating ceramides of a large cohort consisting of 246 patients with T2DM who underwent a high-resolution real-time B ultrasonography to measure CIMT. ResultsBoth plasma 16:0 ceramide and the 16:0/24:0 ceramide ratio were positively associated with CIMT, even after adjustment for traditional cardiovascular risk factors [standardized β ± standard error: 0.168 ± 0.072 (P = 0.020) and 0.180 ± 0.068 (P = 0.009), respectively]. Similar independent associations were found with respect to the prediction of CIMT ≥ 0.80 mm [β = 8.07 ± 3.90 (P = 0.038) and 16.5 ± 7.0 (P = 0.019), respectively]. The goodness-of-fit for multivariate models in predicting CIMT was 5.7 and 7.6 times higher when plasma 16:0 ceramide or the 16:0/24:0 ceramide ratio were included in combination with traditional cardiovascular risk factors (P = 0.020 and 0.015, respectively). This reached a 3.1 and 10.0-fold increase regarding the ability to predict CIMT ≥ 0.80 mm (P = 0.039 and 0.008, respectively). ConclusionsOur findings suggest that 16:0 ceramide and the 16:0/24:0 ceramide ratio may serve as plasma biomarkers to improve cardiovascular risk assessment in individuals with T2DM.

Induction of diabetes by Tacrolimus in a phenotypic model of obesity and metabolic syndrome.

The pathogenesis of Post-Transplant Diabetes Mellitus (PTDM) is complex and multifactorial and it resembles that of Type-2 Diabetes Mellitus (T2DM). One risk factor specific to PTDM differentiates both entities: the use of immunosuppressive therapy. Specifically, Tacrolimus interacts with obesity and insulin resistance (IR) in accelerating the onset of PTDM. In a genotypic model of IR, the obese Zucker rats, Tacrolimus is highly diabetogenic by promoting the same changes in beta-cell already modified by IR. Nevertheless, genotypic animal models have their limitations and may not resemble the real pathophysiology of diabetes. In this study, we have evaluated the interaction between beta-cell damage and Tacrolimus in a non-genotypic animal model of obesity and metabolic syndrome. Sprague Dawley rats were fed a high-fat enriched diet during 45 days to induce obesity and metabolic dysregulation. On top of this established obesity, the administration of Tacrolimus (1mg/kg/day) during 15 days induced severe hyperglycaemia and changes in morphological and structural characteristics of the pancreas. Obese animals administered with Tacrolimus showed increased size of islets of Langerhans and reduced beta-cell proliferation without changes in apoptosis. There were also changes in beta-cell nuclear factors such as a decrease in nuclear expression of MafA and a nuclear overexpression of FoxO1A, PDX-1 and NeuroD1. These animals also showed increased levels of pancreatic insulin and glucagon. This model could be evidence of the relationship between the T2DM and PTDM physiopathology and, eventually, the model may be instrumental to study the pathogenesis of T2DM.

Regulation of the Function of T Follicular Helper Cells and B Cells in Type 1 Diabetes Mellitus by the OX40/OX40L Axis.

To study the expression of OX40 on T follicular helper (Tfh) cells and the ligand OX40L on antigen-presenting cells (APCs) in peripheral blood of patients with Type 1 diabetes mellitus (T1DM) and the role of OX40 signaling in promoting Tfh cells to assist B-cell differentiation. Cross-sectional study. Endocrinology department of a university hospital. Twenty-five patients with T1DM and 35 with newly diagnosed T2DM from January 2021-December 2021 (39 males, 21 females; mean age: 31.0 ± 4.5, range: 19-46 years). None. The peripheral blood proportion of CD4+CD25-CD127+CXCR5+PD1+ Tfh cells in patients with T1DM or T2DM and the OX40L expression in CD14+ monocytes and CD19+ B cells were analyzed by flow cytometry. The OX40 signal effect on Tfh-cell function was analyzed by co-incubating B cells with Tfh cells under different conditions. Flow cytometry detected the ratio of CD19-CD138+ plasmacytes. The Tfh cells ratio and intracellular IL-21 expression in peripheral blood was significantly higher in patients with T1DM than with T2DM, and the OX40 expression in peripheral Tfh cells and OX40L expression in APC were significantly higher in T1DM. After adding OX40L protein, the CD19-CD138+-plasmacytes percentage was significantly increased and higher in T1DM. Blocking of anti-OX40L monoclonal antibodies significantly reduced the plasmacytes ratio. The peripheral Tfh cells proportion increased and the OX40 expression in peripheral Tfh cells was upregulated in patients with T1DM versus patients with T2DM. OX40/OX40L signaling enhanced the Tfh-cell function to assist B-cell differentiation, which may contribute to the pathogenesis of T1DM.

Oxidized guanosines induce mitochondrial dysfunction and loss of viability in β-cells

The production of reactive oxygen species and oxidative stress promote β-cell dysfunction and impair insulin secretion, thereby contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). The nucleobase guanine is highly sensitive to oxidation, which results in the formation of 8-oxoguanosine (8oxoG) and 8-oxodeoxyguanosine (8oxodG). The urinary excretion of 8oxoG is associated with the risk of mortality in people with T2DM, including from diabetic complications such as cardiovascular disease. However, the cellular mechanisms responsible for this association are poorly defined. Therefore, in this study, we examined the effect of 8oxoG, 8oxodG and other oxidized guanosine derivatives, on the INS-1E β-cell line. Exposure of INS-1E cells to 8oxoG and 8oxodG decreased metabolic activity and promoted cell death by apoptosis. The change in cell viability was similar to that induced by treatment of INS-1E cells with the inflammatory cytokines interleukin 1β (Il-1β) and tumour necrosis factor α (TNFα). Changes in mitochondrial membrane permeability and superoxide radical formation were also observed with 8oxoG, but there was no significant change in the oxidation state of mitochondrial cytochromes or hydrogen peroxide levels in the INS-1E cells. Interestingly, exposure to 8oxoG and 8-oxodG also increased the mRNA expression of stress response genes, including NADPH dehydrogenase quinone 1 (NQO1), and thioredoxin-interacting protein (TXNIP). Together, these results support a potential role of oxidized guanosine derivatives in the induction of β-cell dysfunction, which could be relevant to the pathogenesis of T2DM.

Glucometabolic-Related Genes as Diagnostic Biomarkers and Therapeutic Targets for Alzheimer's Disease and Type 2 Diabetes Mellitus: A Bioinformatics Analysis.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two widespread chronic disorders characterized by shared risk factors and molecular pathways. Glucose metabolism, pivotal for cellular homeostasis and energy supply, plays a critical role in these diseases. Its disturbance has been linked to the pathogenesis of both AD and T2DM. However, a comprehensive investigation into the specific roles of glucometabolic genes in the onset and progression of AD and T2DM has yet to be conducted. By analyzing microarray datasets from the Gene Expression Omnibus (GEO) repository, we identified differentially expressed glucometabolic genes (DEGs) in AD and T2DM cohorts. A range of bioinformatics tools were employed for functional annotation, pathway enrichment, protein interaction network construction, module analysis, ROC curve assessment, correlation matrix construction, gene set enrichment analysis, and gene-drug interaction mapping of these DEGs. Key genes were further validated using quantitative real-time polymerase chain reaction (qRT-PCR) in AD and T2DM murine models. Our investigation identified 41 glucometabolic-related DEGs, with six prominent genes (G6PD, PKM, ENO3, PFKL, PGD, and TALDO1) being common in both AD and T2DM cohorts. These genes play crucial roles in metabolic pathways including glycolysis, pentose phosphate pathway, and amino sugar metabolism. Their diagnostic potential was highlighted by area under curve (AUC) values exceeding 0.6 for AD and 0.8 for T2DM. Further analysis explored the interactions, pathway enrichments, regulatory mechanisms, and potential drug interactions of these key genes. In the AD murine model, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed significant upregulation of G6pd, Eno3, and Taldo1. Similarly, in the T2DM murine model, elevated expression levels of G6pd, Pfkl, Eno3, and Pgd were observed. Our rigorous research sheds light on the molecular interconnections between AD and T2DM from a glucometabolic perspective, revealing new opportunities for pharmacological innovation and therapeutic approaches. This study appears to be the first to extensively investigate glucometabolic-associated DEGs and key genes in both AD and T2DM, utilizing multiple datasets. These insights are set to enhance our understanding of the complex pathophysiology underlying these widespread chronic diseases.

Prolactin effects on the pathogenesis of diabetes mellitus.

Prolactin (PRL) is a pituitary hormone promoting lactation in response to the suckling reflex. Beyond its well-known effects, novel tissue-specific and metabolic functions of PRL are emerging. To dissect PRL as a critical mediator of whole-body gluco-insulinemic sensitivity. PubMed-based search with the following terms 'prolactin', 'glucose metabolism', 'type 2 diabetes mellitus', 'type 1 diabetes mellitus', 'gestational diabetes mellitus' was performed. The identification of the PRL-glucose metabolism network poses the basis for unprecedented avenues of research in the pathogenesis of diabetes mellitus type 1 or 2, as well as of gestational diabetes. In this regard, it is of timely relevance to define properly the homeostatic PRL serum levels since glucose metabolism could be influenced by the circulating amount of the hormone. This review underscores the basic mechanisms of regulation of pancreatic β-cell functions by PRL and provides a revision of articles which have investigated the connection between PRL unbalancing and diabetes mellitus. Future studies are needed to elucidate the burden and the role of PRL in the regulation of glucose metabolism and determine the specific PRL threshold that may impact the management of diabetes. A careful evaluation and context-driven interpretation of PRL levels (e.g., pregnancy, PRL-secreting pituitary adenomas, drug-related hyper- and hypoprolactinemia) could be critical for the correct screening and management of glucometabolic disorders, such as type 1 or 2 as well as gestational diabetes mellitus.

CD8+ T and NK cells characterized by upregulation of NPEPPS and ABHD17A are associated with the co-occurrence of type 2 diabetes and coronary artery disease.

Coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) are closely related. The function of immunocytes in the pathogenesis of CAD and T2DM has not been extensively studied. The quantitative bioinformatics analysis of the public RNA sequencing database was applied to study the key genes that mediate both CAD and T2DM. The biological characteristics of associated key genes and mechanism of CD8+ T and NK cells in CAD and T2DM are our research focus. With expression profiles of GSE66360 and GSE78721 from the Gene Expression Omnibus (GEO) database, we identified core modules associated with gene co-expression relationships and up-regulated genes in CAD and T2DM using Weighted Gene Co-expression Network Analysis (WGCNA) and the 'limma' software package. The enriched pathways of the candidate hub genes were then explored using GO, KEGG and GSEA in conjunction with the immune gene set (from the MSigDB database). A diagnostic model was constructed using logistic regression analysis composed of candidate hub genes in CAD and T2DM. Univariate Cox regression analysis revealed hazard ratios (HRs), 95% confidence intervals (CIs), and p-values for candidate hub genes in diagnostic model, while CIBERSORT and immune infiltration were used to assess the immune microenvironment. Finally, monocytes from peripheral blood samples and their immune cell ratios were analyzed by flow cytometry to validate our findings. Sixteen candidate hub genes were identified as being correlated with immune infiltration. Univariate Cox regression analysis revealed that NPEPPS and ABHD17A were highly correlated with the diagnosis of CAD and T2DM. The results indicate that CD8+ T cells (p = 0.04) and NKbright cells (p = 3.7e-3) are significantly higher in healthy controls than in individuals with CAD or CAD combined with T2DM. The bioinformatics results on immune infiltration were well validated by flow cytometry. A series of bioinformatics studies have shown ABHD17A and NPEPPS as key genes for the co-occurrence of CAD and T2DM. Our study highlights the important effect of CD8+ T and NK cells in the pathogenesis of both diseases, indicating that they may serve as viable targets for diagnosis and therapeutic intervention.

Increased monocytic myeloid-derived suppressor cells in type 2 diabetes correlate with hyperglycemic and was a risk factor of infection and tumor occurrence

To investigate the frequency of monocytic myeloid-derived suppressor cells (M-MDSCs) in type 2 diabetes mellitus (T2DM) patients and explore the potential associations between M-MDSCs, glycemic control, and the occurrence of infections and tumor. 102 healthy and 77 T2DM individuals were enrolled. We assessed the M-MDSCs frequency, levels of fasting plasma glucose (FPG), haemoglobin A1c (HbA1c), and other relevant indicators. Each patient underwent a follow-up of at least 6 months after M-MDSCs detection. The M-MDSCs frequency was significantly higher in patients with poor glycemic control (PGC) compared to the healthy population (P < 0.001), whereas there was no significant difference between patients with good glycemic control and the healthy (P > 0.05). There was a positive correlation between the M-MDSCs frequency and FPG, HbA1c (R = 0.517 and 0.315, P < 0.001, respectively). T2DM patients with abnormally increased M-MDSCs have a higher incidence of infection and tumor (48.57% and 11.43% respectively). Our results shed new light on the pathogenesis of T2DM, help to understand why T2DM patients are susceptible to infection and tumor and providing novel insights for future prevention and treatment of T2DM.

Unraveling the epigenetic fabric of type 2 diabetes mellitus: pathogenic mechanisms and therapeutic implications.

Type 2 diabetes mellitus (T2DM) is a rapidly escalating global health concern, with its prevalence projected to increase significantly in the near future. This review delves into the intricate role of epigenetic modifications - including DNA methylation, histone acetylation, and micro-ribonucleic acid (miRNA) expression - in the pathogenesis and progression of T2DM. We critically examine how these epigenetic changes contribute to the onset and exacerbation of T2DM by influencing key pathogenic processes such as obesity, insulin resistance, β-cell dysfunction, cellular senescence, and mitochondrial dysfunction. Furthermore, we explore the involvement of epigenetic dysregulation in T2DM-associated complications, including diabetic retinopathy, atherosclerosis, neuropathy, and cardiomyopathy. This review highlights recent studies that underscore the diagnostic and therapeutic potential of targeting epigenetic modifications in T2DM. We also provide an overview of the impact of lifestyle factors such as exercise and diet on the epigenetic landscape of T2DM, underscoring their relevance in disease management. Our synthesis of the current literature aims to illuminate the complex epigenetic underpinnings of T2DM, offering insights into novel preventative and therapeutic strategies that could revolutionize its management.

Gut microbiota and type 2 diabetes mellitus: a focus on the gut-brain axis.

Type 2 diabetes mellitus (T2DM) has become one of the most serious public healthcare challenges, contributing to increased mortality and disability. In the past decades, significant progress has been made in understanding the pathogenesis of T2DM. Mounting evidence suggested that gut microbiota (GM) plays a significant role in the development of T2DM. Communication between the GM and the brain is a complex bidirectional connection, known as the "gut-brain axis," via the nervous, neuroendocrine, and immune systems. Gut-brain axis has an essential impact on various physiological processes, including glucose metabolism, food intake, gut motility, etc. In this review, we provide an outline of the gut-brain axis. We also highlight how the dysbiosis of the gut-brain axis affects glucose homeostasis and even results in T2DM.

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer's disease, and their co-morbidities.

The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance in vivo, serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.