Predictors of and barriers to follow-up uptake: analysis of factors and perceived barriers among high-risk individuals with diabetes after screening in China.

OBJECTIVE: The objective of this study was to identify variables that predict adherence to follow-up visits among people who are positive for diabetes during screening and to investigate barriers to follow-up. STUDY DESIGN: A retrospective cohort study linking individual-level registry data was performed. METHODS: First, we compared the characteristics of attenders and non-attenders. Second, we investigated perceived barriers using a questionnaire in a random sample of people who failed to attend the follow-up visit. RESULTS: A total of 27,806 (16.4%) patients attended the follow-up visits. Multiple logistic regression analysis revealed that individuals aged ≥75 years were more likely to attend follow-up than were those aged 35-45 years (odds ratio [OR]: 1.97 [95% confidence interval {CI}: 1.82-2.15]), male (OR: 1.15 [95% CI: 1.12-1.18]), obese (OR: 1.36 [95% CI: 1.29-1.43]), had positive family history of diabetes (OR: 1.37 [95% CI: 1.30-1.45]), hypertension (OR: 1.05 [95% CI: 1.01-1.09]), high glucose levels (OR: 1.10 [95% CI: 1.09-1.11]), and high diabetes risk scores (OR: 1.02 [95% CI: 1.02-1.03]) facilitated follow-up. However, overweight (OR: 0.95 [95% CI: 0.92-0.99]) and central obesity (OR: 0.86 [95% CI: 0.83-0.90]) predicted no follow-up. Among nonattenders, diabetes beliefs, time restrictions and distance from home to hospitals were the top three barriers hindering follow-up visits. CONCLUSIONS: Specific individual-level characteristics predicted adherence to follow-up visits, and some personal and sociocultural barriers hindered follow-up visits.

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.

Hsa_circRNA_405498 and hsa_circRNA_100033 Serve as Potential Biomarkers for Differential Diagnosis of Type 1 Diabetes.

CONTEXT: The role of circular RNAs (circRNAs) in type 1 diabetes (T1D) is largely unknown. OBJECTIVE: We aimed to identify some circRNAs as differential diagnostic biomarkers for T1D to distinguish between patients with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). METHODS: The circRNA expression profiles were determined by Arraystar human circRNA microarray in T1D compared to controls (n = 6 each). The differentially expressed circRNAs were validated by real-time quantitative polymerase chain reaction using a validation cohort with 20 T1D and 20 controls. The diagnostic performances of the candidate circRNAs and the clinical parameters were assessed using the logistic least absolute shrinkage and selection operator (LASSO) regression model in a larger cohort with 457 individuals, including patients with T1D, T2D, and LADA, and controls. RESULTS: We identified 110 differentially expressed circular transcripts (53 upregulated and 57 downregulated) in T1D patients compared with controls. Further analysis showed that the levels of hsa_circRNA_405498 and hsa_circRNA_100033 were significantly downregulated in T1D compared to controls (both P < .05). Moreover, the expression levels of these 2 circRNAs showed sequential downregulation from controls, patients with T2D, LADA, to T1D (P < .05). The area under the curve (AUC) of receiver operating characteristic plots in logistic LASSO regression model showed high diagnostic accuracy for combination model with the 2 circRNAs and some clinical parameters in distinguishing T1D from LADA (AUC = 0.915), T2D (AUC = 0.993), and controls (AUC = 0.992). CONCLUSION: Our study demonstrated that hsa_circRNA_405498 and hsa_circRNA_100033 are promising novel differential diagnostic biomarkers for T1D.

Using point-of-care HbA1c to facilitate the identification of diabetes and abnormal glucose regulation in primary healthcare settings.

Background: Glycated hemoglobin A1c (HbA1c) is a critical index for the diagnosis and glycemic control evaluation of diabetes. However, a standardized method for HbA1c measurement is unaffordable and unavailable among the Chinese population in low-resource rural settings. Point-of-care (POC) HbA1c testing is convenient and inexpensive, but its performance remains to be elucidated. Objective: To investigate the value of POC HbA1c for identifying diabetes and abnormal glucose regulation (AGR) in the resource-limited Chinese population. Methods: Participants were recruited from 6 Township Health Centers in Hunan Province. Samples for POC HbA1c, venous HbA1c, fasting plasma glucose, and 2 h-plasma glucose were obtained after physical examination. The oral glucose tolerance test was performed as the gold standard for diagnosis. The diagnostic capacities of the POC HbA1c measurement in predicting undiagnosed diabetes and AGR were evaluated. Results: Among 388 participants, 274 (70.6%) normoglycemic controls, 63 (16.2%) prediabetes patients, and 51 (13.1%) diabetes patients were identified with oral glucose tolerance test (OGTT). Meanwhile, among 97 participants who underwent two HbA1c detection methods simultaneously, a positive correlation was found between POC HbA1c and standardized HbA1c (r = 0.75, P < 0.001). No notable systematic difference was observed from the Bland-Altman Plots. The POC HbA1c cutoff values were 5.95 and 5.25%, which efficiently identified diabetes (AUC 0.92) and AGR (AUC 0.89), respectively. Conclusions: The alternative POC HbA1c test efficiently discriminated AGR and diabetes from normoglycemia, especially among the Chinese population in primary healthcare settings.

Effect of smartphone apps on glycemic control in young patients with type 1 diabetes: A meta-analysis.

Objectives: Achieving glycemic control is a great challenge for young patients with type 1 diabetes (T1D), especially during the transition from childhood to adulthood. As various smartphone apps have been developed to improve glycemic control in T1D, we performed a meta-analysis of randomized controlled trials to assess the effect of smartphone apps on glycemic control in young patients with T1D. Methods: We systematically searched PubMed, Embase, and the Cochrane Library for randomized controlled trials comparing combined usual care and smartphone app treatment to usual care alone. This meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The primary outcomes were the weighted difference in means (WMD) of HbA1c change from baseline and the person-years incidence of mild hypoglycemia or severe hypoglycemia between intervention and control groups. We assessed pooled data by use of a random-effects model. Results: Of 1,190 identified studies, nine were eligible and included in our analysis (N = 748 participants). Relative to the control, using smartphone apps yielded a non-significant reduction in glycated hemoglobin (HbA1c) (WMD = -0.26, 95% CI: -0.56 to 0.05; p = 0.10) and no increased frequency of mild hypoglycemia (WMD = 1.87, 95% CI: -1.52 to 5.27; p = 0.49) or severe hypoglycemia (WMD = -0.04, 95% CI: -0.35 to 0.27; p = 0.80). In further subgroup analysis, compared with the recording-style app group, the auxiliary-style app group exhibited a significant reduction in HbA1c (WMD = -0.83, 95% CI: -1.10 to -0.56, p < 0.001). Conclusion: The current pooled data analysis did not reveal a significant reduction in HbA1c in young patients with T1D undergoing treatment with smartphone apps and usual care in combination. However, auxiliary-style apps with insulin or carbo calculators were beneficial in reducing HbA1c.

Primary care providers' knowledge, attitudes, and practices related to prediabetes in China: A cross-sectional study.

Background: The management of prediabetes has great clinical significance, and primary care providers (PCPs) play important roles in the management and prevention of diabetes in China. Nevertheless, little is known about PCPs' knowledge, attitudes, and practices (KAP) regarding prediabetes. This cross-sectional study aimed to assess the KAP regarding prediabetes among PCPs in the Central China region. Methods: This cross-sectional study was conducted using self-administered KAP questionnaires among PCPs from Central China region. Results: In total, 720 PCPs completed the survey. Most physicians (85.8%) claimed to be aware of the adverse effects of prediabetes and reported positive attitudes toward prediabetes prevention, but the PCPs' knowledge of prediabetes and management practices showed substantial gaps. The prediabetes knowledge level and practice subscale scores of the PCPs were only 54.7% and 32.6%, respectively, of the corresponding optimal scores. Female PCPs showed higher prediabetes knowledge level scores (p = 0.04) and better practice scores (p = 0.038). Knowledge and attitude scores were inversely correlated with participants' age and duration of practice (p < 0.001). The PCPs who served in township hospitals had significantly higher knowledge and attitude scores than those who served in village clinics (p < 0.001). Furthermore, knowledge and practice scores increased with increasing professional titles. Recent continuing medical education (CME) attendance had a significant positive influence on knowledge of prediabetes (p = 0.029), but more than four-fifths of the surveyed PCPs did not participate in diabetes-related CME in the past year. Conclusions: Substantial gaps were observed in PCPs' knowledge and practices regarding prediabetes in the Central China region. CME programmes were under-utilized by PCPs. Structured programmes are required to improve PCPs' prediabetes-related knowledge and practices in China.

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.

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 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.

Increasing Imbalance of Treg/Th17 Indicates More Severe Glucose Metabolism Dysfunction in Overweight/obese Patients.

BACKGROUND: Chronic low-grade inflammation and dysfunction of metabolism has been reported to be involved in obesity. Regulatory T cell (Treg) and helper T cell 17 (Th17) are involved in chronic inflammatory diseases. Impaired balance of Treg/Th17 is one of the major factors contributing to inflammatory status in obesity. METHODS: Overweight/obese patients (n = 80) were recruited and classified into three subgroups: normal glucose tolerance group (NGT, n = 32), impaired glucose regulation group (IGR, n = 19) and type two diabetes mellitus group (T2DM, n = 29). Healthy individuals were paired as normal control group (NC, n = 37). We used flow cytometry to test the frequencies of circulating Treg and Th17 cells of all subjects. Serum IL-6, IL-10, TNF-α, IL-17A levels were detected by cytometric bead array and clinical information was extracted from medical records. RESULTS: In group IGR and T2DM, we revealed a severe decrease in peripheral ratio of Treg/Th17 compared with NC, but no significant difference was seen in group NGT. The serum level of IL-6 in group NGT and T2DM was higher than healthy subjects. The FPG and HbA1c levels were negatively correlated with the ratio of Treg/Th17 in overweight/obese patients. ROC curve analysis revealed that peripheral Treg/Th17 ratio <1.255 was a risk factor for prediabetes and diabetes in overweight/obese patients. CONCLUSION: Peripheral Treg/Th17 imbalance exists in overweight/obese patients with IGR or T2DM and peripheral Treg/Th17 imbalance might be a risk factor for prediabetes and diabetes in overweight/obese patients.

Organ-specific autoantibodies in Chinese patients newly diagnosed with type 1 diabetes mellitus.

This study aims to investigate the prevalence of islet autoantibodies and other organ-specific autoantibodies in type 1 diabetes mellitus (T1DM) patients and characterize their clinical features. Glutamic acid decarboxylase antibody (GADA), insulinoma antigen 2 antibody (IA-2A), zinc transporter 8 antibody (ZnT8A) and tetraspanin7 antibody (TSPAN7A) were assayed by radioligand or luciferase immunoprecipitation system assays in 205 newly diagnosed acute-onset T1DM patients and 170 healthy controls. Other organ-specific autoantibodies, including thyroid peroxidase antibody (TPOA), thyroglobulin antibody (TGA), tissue transglutaminase antibody (tTGA) and 21-hydroxylase antibody (21-OHA), were also measured. The prevalence of GADA, IA-2A, ZnT8A, TSPAN7A, TPOA, TGA and 21-OHA was higher in T1DM patients than in healthy controls. The combinational assay of various islet autoantibodies could increase the frequency of autoantibody positivity in T1DM to 85.4%. GADA+ IA-2A+ T1DM patients preferentially had TPOA and TGA, while IA-2A+ patients often had tTGA. Patients positive for two or more islet autoantibodies often had TPOA and TGA. BMI of multiple islet autoantibody-positive patients was lower than that of patients with single or no islet autoantibodies, and there were no significant differences in C-peptide and glycated hemoglobin between patients positive for islet autoantibodies combined with other organ-specific antibodies and noncombined patients. Younger female patients who were islet autoantibody positive were more likely to have TPOA and TGA. The frequency of Graves' disease was much higher in T1DM patients than in healthy controls. T1DM usually occurs together with other organ-specific autoantibodies. Measuring of other organ-specific autoantibodies will be beneficial for T1DM patients.

Regulation of B cell homeostasis by Ptpn22 contributes to type 1 diabetes in NOD mice.

PURPOSE: A coding variant in PTPN22 (C1858T) is one of the most important genetic risk factors in type 1 diabetes (T1D). The role of the PTPN22 risk allele in B cells is still incompletely understood and has not been investigated directly in T1D. This study aimed to explore the role of PTPN22 in the homeostasis of B cells and its influence in T1D. METHODS: Wild-type (WT) and Ptpn22 inducible knockdown (KD) NOD mice were treated with 200 µg/ml doxycycline at the age of 10 weeks for 1-2 months. B cell compositions in the bone marrow, peritoneal cavity and spleen were examined. The pathogenicity of Ptpn22 KD B cells was explored by adoptive cell transfer. RESULTS: Ptpn22 silencing increased the frequency of recirculating mature B cells in the bone marrow, decreased the frequency of B-1a cells in the peritoneal cavity and suppressed the formation of marginal zone B cells and plasma cells in the spleen. Changes in the composition of the peripheral B cell compartment caused by altered cell proliferation while rates of apoptosis were not affected. Significantly, co-transfer of Ptpn22 KD B cells with NY8.3 diabetogenic T cells diminished the frequency of diabetes in recipient NOD.scid mice compared with co-transfer of WT B cells. CONCLUSIONS: Our study constitutes the first functional study of Ptpn22 in B cells in NOD mice. Our findings suggest that Ptpn22 variation contributes to T1D by modifying the B cell compartment and support a gain-of-function for the PTPN22 disease variant.

Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune-mediated destruction of insulin-producing ß cells. Recent studies showed that in addition to malaria, artemisinin and its derivative, artesunate (AS), could alleviate several autoimmune diseases. However, whether AS has a role in the prevention or treatment of T1D is still unknown. Therefore, in this study we administrated AS or DMSO in the drinking water of nonobese diabetic (NOD) mice, a mouse model of T1D. We found that AS administration significantly prevented the incidence of T1D. The frequency of IL-4-producing CD4+ single-positive T cells and CD8+ T cells was significantly elevated, and IFN-γ-producing T cells were reduced in the spleen and pancreatic lymph nodes. In the pancreas, the skewing to IL-4-producing T cells was also observed. In addition, more regulatory T cells were found in the pancreas. mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, were decreased. In addition, AS administration promoted the functional maturity of ß cells in vitro. Our findings demonstrate that AS administration can prevent T1D in NOD mice mainly by reducing autoimmune T cells and increasing protective T cells. Our data constitute the first functional study of AS in T1D, which may provide a new rationale for future translational studies.-Li, Z., Shi, X., Liu, J., Shao, F., Huang, G., Zhou, Z., Zheng, P. Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL-4-producing T cells and regulatory T cells.

Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether tetraspanin 7 autoantibodies (TSPAN7A) are valuable in predicting poor beta cell function in individuals with latent autoimmune diabetes in adults (LADA). METHODS: The cross-sectional study involved participants with LADA (n = 173), type 1 diabetes (n = 158), type 2 diabetes (n = 204) and healthy control participants (n = 170). The longitudinal study involved 53 participants with LADA, with a 3-year follow-up. In both cohorts, TSPAN7A in the sera were measured by a luciferase immunoprecipitation system assay, and physical and clinical characteristics were recorded. RESULTS: The prevalence of TSPAN7A in LADA, type 1 diabetes, type 2 diabetes and healthy control participants was 21.4% (37/173), 26% (41/158), 0.5% (1/204) and 1.2% (2/170), respectively. Importantly, measurement of TSPAN7A significantly increased the number of individuals with LADA found to be positive for multiple antibodies (32.4% vs 22%; p < 0.001). Further logistic regression analysis demonstrated that positivity for TSPAN7A (OR 2.87, p = 0.034), disease duration (OR 1.83, p = 0.019) and GAD antibody titre (OR 2.67, p = 0.009) were risk factors for beta cell function in LADA, while BMI (OR 0.34, p = 0.001) was a protective factor. In the prospective study in individuals with LADA, the median annual decrease in rates of fasting C-peptide and 2 h postprandial C-peptide in individuals who were positive for TSPAN7A was significantly higher when compared with the decrease in those who were negative for TSPAN7A (34.6% vs 7.9%, p = 0.043 and 33.2% vs 11%, p = 0.041, respectively). CONCLUSIONS/INTERPRETATION: TSPAN7A are valid islet autoantibodies for use in East Asian populations with autoimmune diabetes and can discriminate individuals with LADA who have lower beta cell function after disease progression.

The autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes.

The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.

Activation of Sirtuin 1 Attenuates High Glucose-Induced Neuronal Apoptosis by Deacetylating p53.

Diabetes mellitus (DM) has been proven to be a key risk factor for cognitive impairment. Previous studies have implicated hippocampal neuronal apoptosis in diabetes-related cognitive impairment. However, the underlying mechanism remains unknown. Sirtuin 1 (SIRT1) is a protein deacetylase depended on nicotinamide adenine dinucleotide. Furthermore, it is indispensable in normal learning and memory. Whether SIRT1 is taken part in diabetes-induced neuronal apoptosis and thus involve in the development of diabetic cognitive impairment is still not clear. To address this issue, we examined the possible role of SIRT1 in hippocampal neuronal apoptosis in streptozotocin-induced diabetic mice. Furthermore, the possible mechanism was investigated in high glucose-induced SH-SY5Y cells. We found that downregulation of the activity and expression of SIRT1 was associated with increased hippocampal neuronal apoptosis in mice. In vitro, cell apoptosis induced by high glucose which was accompanied by a downregulation of SIRT1 and an increased acetylation of p53. On the contrary, activation of SIRT1 using its agonist resveratrol ameliorated cell apoptosis via deacetylating p53. Our data suggest that high concentration of glucose can induce neuronal apoptosis through downregulation of SIRT1 and increased acetylation of p53, which likely contribute to the development of cognitive impairment in diabetes.

High glucose forces a positive feedback loop connecting ErbB4 expression and mTOR/S6K pathway to aggravate the formation of tau hyperphosphorylation in differentiated SH-SY5Y cells.

High glucose (HG)-induced mammalian target of rapamycin (mTOR) overactivation acts as a signaling hub for the formation of tau hyperphosphorylation, which contributes to the development of diabetes-associated cognitive deficit. How HG induces the sustained activation of mTOR in neurons is not clearly understood. ErbB4, a member of the receptor tyrosine kinase family, plays critical roles in development and function of neural circuitry, relevant to behavioral deficits. Here, we showed HG-induced ErbB4 overexpression in differentiated SH-SY5Y cells and primary hippocampal neurons and hippocampal pyramidal neurons of streptozotocin-induced diabetic rats. Inhibition of ErbB4 signaling prevented the HG-induced activation of mTOR/S6K signaling to suppress tau hyperphosphorylation. In contrast, ErbB4 overexpression increased the activation of mTOR/S6K signaling, resulting in tau hyperphosphorylation similar to HG treatment. We also demonstrated that HG upregulated the expression of ErbB4 at a mTOR-dependent posttranscriptional level. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of mTOR involving overexpressed ErbB4, leading to the formation of tau hyperphosphorylation under HG condition. Therefore, ErbB4 is a potential therapeutic target for diabetes-associated neurodegeneration.