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.

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.

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.

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.

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.

[Correlation between cognitive impairment and diabetic nephropathy in patients with Type 2 diabetes mellitus].

OBJECTIVE: To explore the correlation between diabetic nephropathy (DN) and cognitive impairment through examining the cognitive function and the metabolism of the cerebrum in Type 2 diabetes mellitus patients at different stages of renal function.
 METHODS: Eighty six patients with Type 2 diabetes mellitus (T2DM) were enrolled for this study. According to the urinary albumin excretion rate (UAER), the patients were divided into a T2DM without DN group (DM group, n=33), an early DN group (DN-III group, n=26) and a clinical stage group (DN-IV group, n=27). Thirty healthy adults were selected as a control group (NC group). Biochemical indexes and UAER were measured, and glomerular filtration rate (GFR) was detected by single-photon emission computed tomography (SPECT). The cognitive function was measured by Montreal Cognitive Assessment (MoCA, Beijing version) and mini-mental state examination (MMSE). The peak areas of N-acetylasparte (NAA), creatine (Cr), choline-containing compounds (Cho) were detected by proton magnetic resonance spectroscopy (1H-MRS).
 RESULTS: 1) There was no statistical difference in MMSE scores between the DM group and the control group. The scores of MoCA in the DN-III group or in the DN-IV group were significant less than that in the NC group (F=3.66, P<0.05); 2) There was significant difference in left N-acetylaspartate (LNAA), left choline (LCho) among the diabetes groups. Compared with the DM group, the level of LNAA was decreased significantly (t=3.826, P<0.05) while the LCho was increased significantly (t=4.373, P<0.05) in the DN groups, with statistic difference between the 2 groups (t=3.693, P<0.05); 3) The MoCA scores of T2DM patients were negatively correlated with UAER (r=-0.285, P<0.05), while positively correlated with GFR (r=0.379, P<0.05); 4) Logistic regression analysis indicated that UAER and GFR were the major risky factors for diabetic cognitive impairment.
 CONCLUSION: Diabetic cognitive impairment is closely correlated with the nephropathy in patients with Type 2 diabetes. With the decline in glomerular filtration function, the cognitive disorder tends to be aggravated. The hippocampal brain metabolism may have some changes in left side of Cho/Cr in patients with diabetic nephropathy.

mTOR-mediated hyperphosphorylation of tau in the hippocampus is involved in cognitive deficits in streptozotocin-induced diabetic mice.

Abnormal levels of mammalian target of rapamycin (mTOR) signaling have been recently implicated in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease (AD). However, the implication of mTOR in diabetes mellitus (DM)-related cognitive dysfunction still remains unknown. In the present study, we found that phosphorylated mTOR at Ser2448, phosphorylated p70S6K at Thr421/Ser424 and phosphorylated tau at Ser396 were significantly increased in the hippocampus of streptozotocin (STZ)-induced diabetic mice when compared with control mice. A low dose of rapamycin was used to elucidate the role of mTOR signaling in DM-related cognitive deficit. Rapamycin restored abnormal mTOR/p70S6K signaling and attenuated the phosphorylation of tau protein in the hippocampus of diabetic mice. Furthermore, the spatial learning and memory function of diabetic mice significantly impaired compared with control mice, was also reversed by rapamycin. These findings indicate that mTOR/p70S6K signaling pathway is hyperactive in the hippocampus of STZ-induced diabetic mice and inhibiting mTOR signaling with rapamycin prevents the DM-related cognitive deficits partly through attenuating the hyperphosphorylation of tau protein.

Diabetes knowledge, attitudes and practices among Chinese primary care physicians: a cross-sectional study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a public health crisis that requires adequate knowledge, attitudes, and practices (KAP) by health care providers to prevent or delay the progression of the disease. This study aimed to assess the KAP regarding T2DM among primary care providers (PCPs) in Central China. METHODS: This multicenter cross-sectional study was conducted among 971 PCPs using self-employed KAP questionnaires. Questionnaires were designed to evaluate KAP regarding T2DM among PCPs, and was measured with SPSS software. Descriptive statistics, the Pearson correlation coefficients and multiple regression models used to analyze the data.70%, 80% and 70% of total values were considered as the cut-off point for defining good knowledge, positive attitude and correct practice. RESULTS: A total of 971 PCPs with a mean age of 44.0 ± 10.2 years were evaluated. 620 (63.9%) PCPs worked at village clinic and 605 (62.3%) PCPs have been working more than 20 years. Only 26.3% of the respondents participated in Continued Medical Education (CME) programs regarding diabetes in the past year due to Covid-19 pandemic. Overall, despite positive attitudes toward diabetes, there were substantial gaps in knowledge and practices. The PCPs scored 7.25 out of 14 points on the knowledge subscales, 7.13 out of 8 on the attitude subscales, and 4.85 out of 11 on the practice subscales. Gender, age, practice setting, professional titles, duration of practice and CME attendance were significant predictors of knowledge; Age, practice setting and duration of practice were significant predictors of attitudes; and family history of diabetes affected PCP practices. CONCLUSIONS: Despite positive attitudes toward diabetes, there were substantial gaps in knowledge and practices. These findings call for action from relevant health authorities and policy makers to improve PCPs' KAP regarding diabetes in Central China.

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.

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.