The role of regulated necrosis in diabetes and its complications.

Morphologically, cell death can be divided into apoptosis and necrosis. Apoptosis, which is a type of regulated cell death, is well tolerated by the immune system and is responsible for hemostasis and cellular turnover under physiological conditions. In contrast, necrosis is defined as a form of passive cell death that leads to a dramatic inflammatory response (also referred to as necroinflammation) and causes organ dysfunction under pathological conditions. Recently, a novel form of cell death named regulated necrosis (such as necroptosis, pyroptosis, and ferroptosis) was discovered. Distinct from apoptosis, regulated necrosis is modulated by multiple internal or external factors, but meanwhile, it results in inflammation and immune response. Accumulating evidence has indicated that regulated necrosis is associated with multiple diseases, including diabetes. Diabetes is characterized by hyperglycemia caused by insulin deficiency and/or insulin resistance, and long-term high glucose leads to various diabetes-related complications. Here, we summarize the mechanisms of necroptosis, pyroptosis, and ferroptosis, and introduce recent advances in characterizing the associations between these three types of regulated necrosis and diabetes and its complications.

Plasma-derived exosomal miRNA profiles associated with type 1 diabetes.

AIMS: Recently, exosomal miRNAs have been shown to play important roles in multiple diseases, including type 1 diabetes (T1D). To assess the biomarker potential of exosomal miRNAs for T1D, we measured the expression profiles of plasma-derived exosomal miRNAs in T1D and explored their potential functions by bioinformatic analysis. MATERIALS AND METHODS: In the discovery phase, exosome samples were isolated from plasma by size exclusion chromatography from 10 T1D patients and 10 sex- (p = 0.36), age- (p = 0.97), and body mass index-matched (p = 0.47) healthy control subjects. Exosomal miRNA expression profiles were measured using the Illumina NovaSeq 6000 platform. With verification by quantitative real-time PCR (qRT-PCR), we used multiple bioinformatics approaches to explore the potential biological functions of the identified differentially expressed miRNAs. The diagnostic signature of exosomal miRNAs was evaluated by least absolute shrinkage and selection operator (LASSO) regression and evaluated based on the area under the receiver operating characteristic curve (AUC). RESULTS: In total, 43 differentially expressed miRNAs, among which 34 were upregulated and 9 were downregulated, were identified in T1D. After correcting for multiple testing using false discovery rate, 11 identified exosomal miRNAs still showed statistical significance. Among the 5 selected miRNAs, 3 miRNAs (miR-103a-3p, miR-144-5p and miR-454-3p) were successfully validated by qRT-PCR. The biological analysis-enriched terms included protein autophosphorylation and the Hedgehog signalling pathway. The highest AUC of exosomal miRNA was 0.889 under the LASSO model. The expression levels of 5 selected exosomal miRNAs were correlated with multiple clinical characteristics such as fasting C-peptide and postprandial C-peptide. CONCLUSIONS: Our results indicated that plasma-derived exosomal miRNAs could serve as promising diagnostic biomarkers of T1D.

Association of RPS26 gene polymorphism with different types of diabetes in Chinese individuals.

AIMS/INTRODUCTION: Different types of diabetes show distinct genetic characteristics, but the specific genetic susceptibility factors remain unclear. Our study aimed to explore the associations between the ribosomal protein S26 (RPS26) gene rs1131017 polymorphisms and susceptibility to type 1 diabetes mellitus, latent autoimmune diabetes in adults (LADA) and type 2 diabetes mellitus in the Chinese Han population, and their correlations with clinical features. MATERIALS AND METHODS: Genotyping of the rs1131017 variant was carried out for 1,006 type 1 diabetes mellitus patients, 210 LADA patients, 642 type 2 diabetes mellitus patients and 2,099 control individuals. RESULTS: We found that the rs1131017 C allele was a risk locus for both type 1 diabetes mellitus and LADA (odds ratio [OR] 1.50, 95% confidence interval [CI] 1.33-1.69, P < 0.001; OR 1.31, 95% CI 1.04-1.64, P = 0.021, respectively). Nevertheless, this association was not found for type 2 diabetes mellitus. Carrying the C allele genotype was associated with a lower postprandial C-peptide for type 1 diabetes mellitus (OR 1.41, 95% CI 1.11-1.80, P = 0.006) and lower fasting C-peptide for LADA (OR 1.55, 95% CI 1.01-2.38, P = 0.047). Interestingly, a lower GC frequency was noted for LADA than for type 1 diabetes mellitus, regardless of classification based on age at diagnosis, C-peptide or glutamic acid decarboxylase antibody positivity. CONCLUSIONS: The RPS26 polymorphism was associated with susceptibility and clinical characteristics of type 1 diabetes mellitus and LADA in the Chinese population, but was not related to type 2 diabetes mellitus. Thus, it might serve as a novel biomarker for particular types of diabetes.

Association of the rs1990760, rs3747517, and rs10930046 polymorphisms in the IFIH1 gene with susceptibility to autoimmune diseases: a meta-analysis.

Objective: Interferon induced with helicase C domain 1 (IFIH1) single-nucleotide polymorphisms (SNP) rs1990760, rs3747517, and rs10930046 have been shown to be closely related to the risk of autoimmune diseases. The aim of this study was firstly to examine the association of the rs1990760 with type 1 diabetes (T1D) in a Chinese population. Secondly, to assess the association of SNP rs1990760, rs3747517, and rs10930046 with autoimmune diseases susceptibility. Methods: A total of 1,273 T1D patients and 1,010 healthy control subjects in a Chinese population were enrolled in this case-control study. Subsequently, we performed a meta-analysis on the association of the SNP rs1990760, rs3747517, and rs10930046 in the IFIH1 gene with susceptibility to autoimmune diseases. The random and fixed genetic effects models were used to evaluate the association and the effect sizes, including odds ratios (OR) and 95% confidence intervals (CI). Stratification analyses based on ethnicity and the type of autoimmune diseases were performed. Results: IFIH1 SNP rs1990760 was not associated with a significant risk of T1D in the Chinese population in the case-control study. A total of 35 studies including 70,966 patients and 124,509 controls were identified and included in the meta-analysis. The results displayed significant associations between IFIH1 rs1990760 A allele and rs3747517 C allele and autoimmune diseases risk (OR=1.09, 95% CI: 1.01~1.17; OR=1.24, 95% CI: 1.15~1.25, respectively). Stratified analysis indicated a significant association rs1990760 and rs3747517 with autoimmune diseases risk in the Caucasian population (OR=1.11, 95% CI: 1.02~1.20, OR=1.29, 95% CI: 1.18~1.41, respectively). Conclusions: This study revealed no association between IFIH1 SNP rs1990760 and T1D in Chinese. Furthermore, the meta-analysis indicated that rs1990760 and rs3747517 polymorphisms, confer susceptibility to autoimmune diseases, especially in the Caucasian population.

Plasma-derived exosomal miRNAs as potentially novel biomarkers for latent autoimmune diabetes in adults.

AIM: To characterize the exosomal miRNA profiles of latent autoimmune diabetes in adults (LADA) and evaluate the biomarker potential of selected miRNAs to distinguish LADA from type 2 diabetes (T2D). METHODS: Plasma-derived exosomal miRNA expression profiles were measured in patients with LADA (N = 5) and control subjects (N = 5). Five differentially expressed miRNAs were selected to validate their expression levels and assess their diagnostic potential by quantitative real-time PCR (qRT-PCR) in a larger cohort. RESULTS: Seventy-five differentially expressed plasma-derived exosomal miRNAs were identified in LADA patients compared to healthy subjects. The expression levels of three exosomal miRNAs (hsa-miR-146a-5p, hsa-miR-223-3p and hsa-miR-21-5p) were significantly different between the LADA group and the T2D group. The three miRNAs exhibited areas under the receiver operating characteristic curves of 0.978, 0.96 and 0.809, respectively. CONCLUSIONS: This study uncovers the miRNA profiles of plasma-derived exosomes from LADA patients and identifies exosomal miRNAs as potential biomarkers to discriminate LADA from T2D for the first time. Our data demonstrate the function of exosomal miRNAs in the development of LADA and contribute to an in-depth understanding of the precise mechanisms underlying the pathogenesis of LADA.

The m6A methylation profiles of immune cells in type 1 diabetes mellitus.

Background: Type 1 diabetes mellitus (T1DM) is caused by immune cell-mediated ß-cell dysfunction. In recent decades, N6-methyladenosine (m6A) has attracted widespread attention in the scientific research field because it plays vital roles in the pathogenesis of immunity-related diseases, including autoimmune diseases. However, neither the m6A modification profile nor the potential role it plays in T1DM pathogenesis has been investigated to date. Materials and Methods: An m6A mRNA epitranscriptomic microarray analysis was performed to analyze m6A regulator expression patterns and m6A methylation patterns in immune cells of T1DM patients (n=6) and healthy individuals (n=6). A bioinformatics analysis was subsequently performed to explore the potential biological functions and signaling pathways underlying T1DM pathogenesis. Furthermore, mRNA expression and m6A methylation levels were subsequently verified by qRT-PCR and methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), respectively, in the T1DM and healthy groups (n=6 per group). Results: Among the multiple m6A regulators, METTL3 and IGF2BP2 had significantly downregulated expression, and YTHDC1 and HNRNPA2B1 had significantly upregulated expression in the T1DM group relative to the healthy group. The microarray analysis revealed 4247 differentially methylated transcripts, including 932 hypermethylated and 3315 hypomethylated transcripts, and 4264 differentially expressed transcripts, including 1818 upregulated transcripts and 2446 downregulated transcripts in the T1DM group relative to the healthy group. An association analysis between methylation and gene expression demonstrated that the expression of 590 hypermethylated transcripts was upregulated, and that of 1890 hypomethylated transcripts was downregulated. Pearson correlation analysis showed significant correlations between the expression levels of differentially expressed m6A regulators and the methylation levels of differentially methylated transcripts and significant correlations between the expression levels of differentially expressed m6A regulators and that of differentially expressed transcripts. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that differentially methylated transcripts were involved in pathways related to immunity, including some closely associated with T1DM. Conclusions: Our study presents m6A regulator expression patterns and m6A methylation patterns of immune cells in T1DM, showing that the m6A mark and m6A regulators are promising targets for T1DM diagnosis and treatment.

Differential Expression and Bioinformatics Analysis of Plasma-Derived Exosomal circRNA in Type 1 Diabetes Mellitus.

Backgrounds: Both exosome and circular RNA (circRNA) have been reported to participate in the pathogenesis of type 1 diabetes mellitus (T1DM). However, the exact role of exosomal circRNA in T1DM is largely unknown. Here, we identified the exosomal circRNA expression profiles in the plasma of T1DM patients and explored their potential function using bioinformatics analysis. Material and Methods. Exosomes were extracted by the size exclusion chromatography method from plasma of 10 T1DM patients and 10 age- and sex- matched control subjects. Illumina Novaseq6000 platform was used to detect the exosomal circRNA expression profiles. Multiple bioinformatics analysis was applied to investigate the potential biological functions of exosomal circRNAs. Results: A total of 784 differentially expressed exosomal circRNAs have been identified in T1DM patients, of which 528 were upregulated and 256 were downregulated. Gene Ontology analysis enriched terms such as protein ubiquitination involved in ubiquitin-dependent protein catabolic protein (GO:0042787), membrane (GO:0016020), and GTPase activator activity (GO:0005096). The most enriched pathway in Kyoto Encyclopedia of Genes and Genomes was ubiquitin-mediated proteolysis (ko04120). The miRNA-targeting prediction method was used to identify the miRNAs that bind to circRNAs, and circRNA-miRNA-mRNA pathways were constructed, indicating that interactions between circRNA, miRNA, and gene might be involved in the disease progression. Conclusions: The present study identified the exosomal circRNA expression profiles in T1DM for the first time. Our results threw novel insights into the molecular mechanisms of T1DM.

Plasma-derived exosomal mRNA profiles associated with type 1 diabetes mellitus.

Background: Exosomes carry various types of transcripts, such as messenger RNAs (mRNAs), and play an important role in mediating cell-to-cell communication, thus influencing multiple physiological and pathological processes. However, the role of exosomal mRNAs in T1DM is largely unknown. Here, we aimed to identify the plasma-derived exosomal mRNA expression profiles in T1DM and to explore their potential biological functions in T1DM. Materials and Methods: Plasma-derived exosomes were isolated from 10 patients with T1DM and 10 age- and sex-matched control subjects by size exclusion chromatography methods. Transmission electron microscopy, nanoparticle tracking analysis, and western blot analysis confirmed the presence of exosomes. The exosomal mRNAs were analyzed using the Illumina HiSeq platform. Six differentially expressed mRNAs (DEMs) were randomly selected to determine the expression level by quantitative real-time PCR (qRT-PCR) in a larger cohort (T1DM subjects N=40; control subjects N=40). The biological functions of DEMs were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Protein-protein interaction networks were constructed to explore the potential associations among DEMs. Results: In total, 112 DEMs were identified in T1DM, among which 66 mRNAs were upregulated and 46 mRNAs were downregulated. Four of six candidate exosomal mRNAs were successfully validated by qRT-PCR. Bioinformatics analysis indicated that these mRNAs were most significantly involved in positive regulation by host viral transcription (GO enrichment analysis) and oxidative phosphorylation (KEGG pathway analysis). Conclusions: Our study reported the plasma-derived exosomal mRNA expression profiles of T1DM for the first time. The identified DEMs might be associated with the pathogenesis of T1DM, and some DEMs have the potential to serve as biomarkers and therapeutic targets for T1DM.

Circular RNAs in diabetes mellitus and its complications.

Diabetes mellitus (DM) is an endocrine disorder characterized by a relative or absolute lack of insulin due to the dysfunction or destruction of ß-cells. DM is one of the fastest growing challenges to global health in the 21st century and places a tremendous burden on affected individuals and their families and countries. Although insulin and antidiabetic drugs have been used to treat DM, a radical cure for the disease is unavailable. The pathogenesis of DM remains unclear. Emerging roles of circular RNAs (circRNAs) in DM have become a subject of global research. CircRNAs have been verified to participate in the onset and progression of DM, implying their potential roles as novel biomarkers and treatment tools. In the present review, we briefly introduce the characteristics of circRNAs. Next, we focus on specific roles of circRNAs in type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus and diabetes-associated complications.

The missing heritability in type 1 diabetes.

Type 1 diabetes (T1D) is a complex autoimmune disease characterized by an absolute deficiency of insulin. It affects more than 20 million people worldwide and imposes an enormous financial burden on patients. The underlying pathogenic mechanisms of T1D are still obscure, but it is widely accepted that both genetics and the environment play an important role in its onset and development. Previous studies have identified more than 60 susceptible loci associated with T1D, explaining approximately 80%-85% of the heritability. However, most identified variants confer only small increases in risk, which restricts their potential clinical application. In addition, there is still a so-called 'missing heritability' phenomenon. While the gap between known heritability and true heritability in T1D is small compared with that in other complex traits and disorders, further elucidation of T1D genetics has the potential to bring novel insights into its aetiology and provide new therapeutic targets. Many hypotheses have been proposed to explain the missing heritability, including variants remaining to be found (variants with small effect sizes, rare variants and structural variants) and interactions (gene-gene and gene-environment interactions; e.g. epigenetic effects). In the following review, we introduce the possible sources of missing heritability and discuss the existing related knowledge in the context of T1D.

Characterization of lncRNA Profiles of Plasma-Derived Exosomes From Type 1 Diabetes Mellitus.

Backgrounds: Exosomes contain several types of transcripts, including long non-coding RNAs (lncRNAs), and have been shown to exert important effects in human diseases. However, the roles of exosomal lncRNAs in type 1 diabetes mellitus (T1DM) have not been well investigated. In the present study, we characterized the plasma-derived exosomal lncRNAs expression profiles of T1DM and predict their potential function in the pathogenesis of T1DM. Material and Methods: Exosomal lncRNA expression profiles were detected by Illumina Hiseq platform (T1DM subjects N=10; age-, sex- matched Control subjects N=10). Six exosomal lncRNAs were selected to validate their expression level by using quantitative real-time PCR (qRT-PCR) (T1DM subjects N=30; age-, sex- matched Control subjects N=30). Bioinformatics analysis approaches were carried out to explore the potential biological function of differentially expressed lncRNAs. Results: A total of 162 differentially expressed exosomal lncRNAs were identified in T1DM patients compared with control subjects, among which 77 up-regulated and 85 down-regulated. The expression level of the selected six lncRNAs didn't show significant difference in the following qRT-PCR analysis. Gene Ontology analysis enriched terms such as activation of phospholipase D activity, neuronal cell body membrane, and calcium sensitive guanylate cyclase activator activity for cis-acting genes of lncRNAs, and metal ion binding for trans-acting genes. The most enriched Kyoto Encyclopedia of Genes and Genomes pathways for the lncRNAs were associated with oxidative phosphorylation and Parkinson's disease for cis-acting genes, and pathways in cancer as well as focal adhesion for trans-acting genes. Conclusions: This study characterized the lncRNA profiles of plasma-derived exosomes from T1DM for the first time and these results highlighted the potential role of exosomal lncRNAs in T1DM pathogenesis. A better understanding of exosomal lncRNA profiling will provide novel insights into its molecular mechanisms.

The Association of CTLA-4 rs231775 and rs3087243 Polymorphisms with Latent Autoimmune Diabetes in Adults: A Meta-Analysis.

Polymorphisms rs231775 and rs3087243 of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) gene have been associated with risk of latent autoimmune diabetes in adults (LADA). However, the results were inconsistent. The purpose of this study was to quantitatively assess the relationship between polymorphisms rs231775 and rs3087243 of CTLA-4 and LADA in a larger pooled population by performing a meta-analysis. Systematic search for eligible studies was conducted in PubMed, Web of Science, and Embase. Case-control studies containing genotype frequencies of polymorphisms rs231775 or rs3087243 were selected, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the associations between polymorphisms of CTLA-4 and LADA in allelic, dominant and recessive genetic model. A total of eleven studies, in which five studies reported rs231775, two studies reported rs3087342, and four studies reported both rs231775 and rs3087243, were identified. Among them, one study wasn't included in the following meta-analysis because the distribution of genotypes in the control group didn't comply with Hardy-Weinberg equilibrium. Significant associations with susceptibility to LADA were detected for rs231775 (785 cases and 3435 controls) and for rs3087243 (820 cases and 4824 controls) in overall population. Further subgroup analyses for ethnicity (Asian, Caucasian, and African) have also indicated the positive association between rs231775 and LADA. As for rs3087243, subgroup analyses detected the association between polymorphism and LADA in Caucasian population under recessive model. Polymorphisms rs231775 and rs3087243 of CTLA-4 gene are potential risk factors for LADA and may serve as novel genetic biomarkers of LADA.

Novel Roles of the Tim Family in Immune Regulation and Autoimmune Diseases.

T cell Ig and mucin domain (Tim) protein family members were identified to be important regulators of the immune response. As their name indicates, Tim proteins were originally considered a T cell-specific markers, and they mainly regulate the responses of T helper cells. However, accumulating evidence indicates that Tims are also expressed on antigen-presenting cells (APCs), such as monocytes, macrophages, dendritic cells (DCs) and B cells, and even plays various roles in natural killer cells (NKs) and mast cells. In recent years, the expression and function of Tims on different cells and the identification of new ligands for the Tim family have suggested that the Tim family plays a crucial role in immune regulation. In addition, the relationship between Tim family gene polymorphisms and susceptibility to several autoimmune diseases has expanded our knowledge of the role of Tim proteins in immune regulation. In this review, we discuss how the Tim family affects immunomodulatory function and the potential role of the Tim family in typical autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D). A deeper understanding of the immunoregulatory mechanism of the Tim family might provide new insights into the clinical diagnosis and treatment of autoimmune diseases.

The polymorphism of the CARD8 inflammasome-related gene is associated with glutamic-acid-decarboxylase-antibody positivity in patients with type 1 diabetes mellitus.

BACKGROUND: This study sought to examine the correlation between 2 single-nucleotide polymorphisms (SNPs; rs10403848 and rs2043211) in the caspase recruitment domain-containing protein 8 (CARD8) gene and the risks and clinical features of patients with type 1 diabetes mellitus (T1DM) in the Han Chinese population. METHODS: A case-control study involving the Han Chinese population was designed, and individuals diagnosed with classical T1DM and healthy controls were enrolled in this study. MassARRAY genotyped the SNPs of rs10403848 and rs2043211. Logistic regression and chi-square analyses were conducted to compare the allele distributions and genotypes of the T1DM and healthy control participants. A Kruskal-Wallis 1-way analysis of variance was used to perform the genotype-phenotype analysis for the T1DM patients. RESULTS: In total, 510 participants with classical T1DM and 531 sex-matched healthy control participants participated in this study. The CARD8 SNP of rs2043211 was significantly associated with the rate of glutamic-acid-decarboxylase-antibody (GADA) positivity among T1DM patients (P=0.021). However, no significant differences in the distributions of alleles or the genotypes of rs10403848 and rs2043211 were observed between the case and control groups, and these 2 SNPs were not associated with T1DM under various inheritance models. CONCLUSIONS: The rs10403848 and rs2043211 polymorphisms of CARD8 were not associated with susceptibility to T1DM. However, rs2043211 was found to be correlated with GADA positivity in participants with T1DM.

Emerging roles of rare and low-frequency genetic variants in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is defined as an autoimmune disorder and has enormous complexity and heterogeneity. Although its precise pathogenic mechanisms are obscure, this disease is widely acknowledged to be precipitated by environmental factors in individuals with genetic susceptibility. To date, the known susceptibility loci, which have mostly been identified by genome-wide association studies, can explain 80%-85% of the heritability of T1DM. Researchers believe that at least a part of its missing genetic component is caused by undetected rare and low-frequency variants. Most common variants have only small to modest effect sizes, which increases the difficulty of dissecting their functions and restricts their potential clinical application. Intriguingly, many studies have indicated that rare and low-frequency variants have larger effect sizes and play more significant roles in susceptibility to common diseases, including T1DM, than common variants do. Therefore, better recognition of rare and low-frequency variants is beneficial for revealing the genetic architecture of T1DM and for providing new and potent therapeutic targets for this disease. Here, we will discuss existing challenges as well as the great significance of this field and review current knowledge of the contributions of rare and low-frequency variants to T1DM.

Emerging Roles of Exosomes in T1DM.

Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.

The NLRP3 Inflammasome and Its Role in T1DM.

The NLRP3 (nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome is a protein complex expressed in cells. It detects danger signals and induces the production of active caspase-1 and the maturation and release of IL (interleukin)-33, IL-18, IL-1ß and other cytokines. T1DM (type 1 diabetes mellitus) is defined as a chronic autoimmune disorder characterized by the autoreactive T cell-mediated elimination of insulin-positive pancreatic beta-cells. Although the exact underlying mechanisms are obscure, researchers have proposed that both environmental and genetic factors are involved in the pathogenesis of T1DM. Furthermore, immune responses, including innate and adaptive immunity, play an important role in this process. Recently, the NLRP3 inflammasome, a critical component of innate immunity, was reported to be associated with T1DM. Here, we review the assembly and function of the NLRP3 inflammasome. In addition, the activation and regulatory mechanisms that enhance or attenuate NLRP3 inflammasome activation are discussed. Finally, we focus on the relationship between the NLRP3 inflammasome and T1DM, as well as its potential value for clinical use.

Advances in Knowledge of Candidate Genes Acting at the Beta-Cell Level in the Pathogenesis of T1DM.

T1DM (type 1 diabetes mellitus), which results from the irreversible elimination of beta-cells mediated by autoreactive T cells, is defined as an autoimmune disease. It is widely accepted that T1DM is caused by a combination of genetic and environmental factors, but the precise underlying molecular mechanisms are still unknown. To date, more than 50 genetic risk regions contributing to the pathogenesis of T1DM have been identified by GWAS (genome-wide association studies). Notably, more than 60% of the identified candidate genes are expressed in islets and beta-cells, which makes it plausible that these genes act at the beta-cell level and play a key role in the pathogenesis of T1DM. In this review, we focus on the current status of candidate genes that act at the beta-cell level by regulating the innate immune response and antiviral activity, affecting susceptibility to proapoptotic stimuli and influencing the pancreatic beta-cell phenotype.