Fulminant type 1 diabetes: Focusing on triggering factors.

Fulminant type 1 diabetes (FT1D) is a novel type of type 1 diabetes that is caused by extremely rapid destruction of the pancreatic ß cells. Early diagnosis or prediction of FT1D is critical for the prevention or timely treatment of diabetes ketoacidosis, which can be life-threatening. Understanding its triggers or promoting factors plays an important role in the prevention and treatment of FT1D. In this review, we summarised the various triggering factors of FT1D, including susceptibility genes, immunological factors (cellular and humoural immunity), immune checkpoint inhibitor therapies, drug reactions with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome, pregnancy, viral infections, and vaccine inoculation. This review provides the basis for future research into the pathogenetic mechanisms that regulate FT1D development and progression to further improve the prognosis and clinical management of patients with FT1D.

Peer victimization and non-suicidal self-injury among high school students: the mediating role of social anxiety, mobile phone addiction, and sex differences.

BACKGROUND: Peer victimization (PV) is one of the major causes of non-suicidal self-injury. Non-suicidal self-injury (NSSI), peer victimization, social anxiety, and mobile phone addiction are significantly related; however, the interaction mechanism and effect of sex differences remain to be determined. OBJECTIVE: Herein, we investigated the relationship between peer victimization and NSSI among Chinese high school students. We also explored the chain mediating roles of social anxiety and mobile phone addiction and the regulatory role of sex. The findings of this study provide insights for theoretical interventions based on internal mechanisms. METHOD: A self-reported survey of 14,666 high school students from Sichuan County was conducted using a peer victimization scale, NSSI scale, social anxiety scale, and mobile phone addiction scale. A self-administered questionnaire was used to capture sociodemographic information. RESULTS: Peer victimization, social anxiety, and mobile phone addiction were positively correlated with NSSI. Peer victimization had significant direct predictive effects on NSSI (95% CI: 0.341, 0.385) and significant indirect predictive effects on NSSI through social anxiety (95% CI: 0.008, 0.019) or mobile phone addiction (95% CI: 0.036, 0.053). Peer victimization had significant indirect predictive effects on NSSI through social anxiety as well as mobile phone addiction (95% CI: 0.009, 0.014). The first stage (predicting the effect of peer victimization on NSSI) and the third stage (predicting the effect of mobile phone addiction on NSSI) were both moderated by sex. CONCLUSIONS: Peer victimization could directly predict NSSI and indirectly predict NSSI through social anxiety and mobile phone addiction. Thus, social anxiety and mobile phone addiction exhibited chain mediating effects between peer victimization and NSSI in high school students; moreover, sex might be involved in the regulation of the mediation process.

Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation.

BACKGROUND: Stroke is a type of acute brain damage that can lead to a series of serious public health challenges. Demonstrating the molecular mechanism of stroke-related neural cell degeneration could help identify a more efficient treatment for stroke patients. Further elucidation of factors that regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may lead to a promising strategy for treating neuroinflammation after ischaemic stroke. In this study, we investigated the possible role of pterostilbene (PTS) in Nrf1 regulation in cell and animal models of ischaemia stroke. METHODS: We administered PTS, ITSA1 (an HDAC activator) and RGFP966 (a selective HDAC3 inhibitor) in a mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and a model of microglial oxygen‒glucose deprivation/reperfusion (OGD/R). The brain infarct size, neuroinflammation and microglial availability were also determined. Dual-luciferase reporter, Nrf1 protein stability and co-immunoprecipitation assays were conducted to analyse histone deacetylase 3 (HDAC3)/Nrf1-regulated Nrf1 in an OGD/R-induced microglial injury model. RESULTS: We found that PTS decreased HDAC3 expression and activity, increased Nrf1 acetylation in the cell nucleus and inhibited the interaction of Nrf1 with p65 and p65 accumulation, which reduced infarct volume and neuroinflammation (iNOS/Arg1, TNF-α and IL-1ß levels) after ischaemic stroke. Furthermore, the CSF1R inhibitor PLX5622 induced elimination of microglia and attenuated the therapeutic effect of PTS following MCAO/R. In the OGD/R model, PTS relieved OGD/R-induced microglial injury and TNF-α and IL-1ß release, which were dependent on Nrf1 acetylation through the upregulation of HDAC3/Nrf1 signalling in microglia. However, the K105R or/and K139R mutants of Nrf1 counteracted the impact of PTS in the OGD/R-induced microglial injury model, which indicates that PTS treatment might be a promising strategy for ischaemia stroke therapy. CONCLUSION: The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of natural products such as PTS.

Clinical and immunological characteristics of PD-1 associated fulminant type 1 diabetes mellitus. / PD-1ç›¸å ³æ€§æš´å‘æ€§1åž‹ç³–å°¿ç— çš„ä¸´åºŠä¸Žå ç–«ç‰¹å¾.

OBJECTIVES: Programmed death 1 (PD-1) associated fulminant type 1 diabetes (PFD) is a rare acute and critical in internal medicine, and its clinical characteristics are still unclear. This study aims to analyze the clinical characteristics of PFD patients to improve clinical diagnosis and treatment. METHODS: We retrospectively analyzed the clinical data of 10 patients with PFD admitted to the Second Xiangya Hospital of Central South University, combined with the data of 66 patients reported in the relevant literature, analyzed and summarized their clinical and immunological characteristics, and compared the patients with PFD with different islet autoantibody status. RESULTS: Combined with our hospital and literature data, a total of 76 patients with PFD were reported, with the age of (60.9±12.1) years old, 60.0% male and body mass index of (22.1±5.2) kg/m2. In 76 patients, the most common tumors were lung cancer (43.4%) and melanoma (22.4%). Among PD-1 inhibitors, the most common drugs are nivolumab (37.5%) and pembrolizumab (38.9%). 82.2% of PFD patients developed diabetes ketoacidosis. The median onset time from PD-1 related inhibitor treatment to hyperglycemia was 95 (36.0, 164.5) d, and the median treatment cycle before the onset of diabetes was 6 (2.3, 8.0) cycles. 26% (19/73) of PFD patients had positive islet autoantibodies, and the proportion of ketoacidosis in the positive group was significantly higher than that in the negative group (100.0% vs 75.0%, P<0.05). The onset time and infusion times of diabetes after PD-1 inhibitor treatment in the autoantibody positive group were significantly lower than those in the autoantibody negative group (28.5 d vs 120.0 d; 2 cycles vs 7 cycles, both P<0.001). CONCLUSIONS: After initiation of tumor immunotherapy, it is necessary to be alert to the occurrence of adverse reactions of PFD, and the onset of PFD with islet autoantibody positive is faster and more serious than that of patients with autoantibodies negative. Detection of islet autoantibodies and blood glucose before and after treatment with PD-1 inhibitors is of great value for early warning and prediction of PFD.

The fulminant index: A method of rapidly differentiating fulminant type 1 diabetes from diabetic ketoacidosis.

AIMS AND OBJECTIVES: Fulminant type 1 diabetes (FT1D) could present diabetes ketoacidosis (DKA) at early onset. It is crucial to identify FT1D from DKA manifestations in time at clinical practice. This study was aimed at investigating whether the fulminant index (FI), encompassing plasma glucose (PG) to glycated haemoglobin (HbA1c) ratio (PG/HbA1c), serum potassium ion (K+ ) to HbA1c ratio (K+ /HbA1c) and serum sodium ion (Na+ ) multiplied by HbA1c (Na+ *HbA1c), is a feasible indicator for early FT1D diagnosis. MATERIALS AND METHODS: A total of 78 subjects were enroled, including 40 FT1D patients and 38 non-FT1D patients with DKA. We utilised receiver operating characteristic (ROC) curve analysis to determine the FI cut-off values between FT1D and non-FT1D groups and examined efficacies of FI based on statistics. RESULTS: ROC curve analyses showed that the maximum Youden's index for PG/HbA1c bonding to a cut-off value of 4.389, with the sensitivity of 75.0% and specificity of 81.6% in identifying FT1D from DKA. And optimal K+ /HbA1c cut-off value was 0.728 with a sensitivity of 90.0% and specificity of 84.2%. For Na+ *HbA1c, the best cut-off value was 923.65, and its sensitivity and specificity were 85% and 73.7%, respectively. CONCLUSIONS: These results suggested FI could work as a valid and convenient indicator for differentiating FT1D from initial DKA patients. FI (K+ /HbA1c) presented the best efficacy as an independent index.

Grey Model Optimized by Particle Swarm Optimization for Data Analysis and Application of Multi-Sensors.

Data on the effective operation of new pumping station is scarce, and the unit structure is complex, as the temperature changes of different parts of the unit are coupled with multiple factors. The multivariable grey system prediction model can effectively predict the multiple parameter change of a nonlinear system model by using a small amount of data, but the value of its q parameters greatly influences the prediction accuracy of the model. Therefore, the particle swarm optimization algorithm is used to optimize the q parameters and the multi-sensor temperature data of a pumping station unit is processed. Then, the change trends of the temperature data are analyzed and predicted. Comparing the results with the unoptimized multi-variable grey model and the BP neural network prediction method trained under insufficient data conditions, it is proved that the relative error of the multi-variable grey model after optimizing the q parameters is smaller.

A meta-analysis of association of vitamin D receptor BsmI gene polymorphism with the risk of type 1 diabetes mellitus.

Association between vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism and the risk of type 1 diabetes mellitus (T1DM) from the published reports are still conflicting. This study was conducted to evaluate the relationship between VDR BsmI gene polymorphism and the risk of T1DM using meta-analysis method. The association studies were identified from PubMed, and Cochrane Library on 1 December 2013, and eligible investigations were included and synthesized using meta-analysis method. Twenty-three reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with T1DM susceptibility. In overall populations, bb genotype was associated with T1DM, but the B allele and BB genotype were not. In Asians and Latino population, B allele and bb genotype were associated with TIDM risk, but BB genotype was not. In Caucasians, VDR BsmI gene polymorphism was not associated with the T1DM risk. In Africans, B allele and BB genotype were associated with T1DM risk, but the bb genotype was not. However, the sample size for Latino population and Africans was small. In conclusion, VDR BsmI B allele, bb genotype was associated with T1DM risk in Asians, and bb genotype was associated with T1DM risk in overall populations. However, more studies should be conducted to confirm it.

Identification of hsa_circRNA_100632 as a novel molecular biomarker for fulminant type 1 diabetes.

Objective: Circular RNAs (circRNAs) are associated with diabetes, but their role in fulminant type 1 diabetes (FT1D) is unclear. Thus, we characterized the role of circRNAs in FT1D. Research design and methods: CircRNA expression profiles were detected in peripheral blood mononuclear cells (PBMCs) of five FT1D patients and five controls using a circRNA microarray. An independent cohort comprised of 40 FT1D cases, 75 type 1 diabetes (T1D) cases, and 115 controls was used to verify the circRNAs using quantitative real-time polymerase chain reaction (qRT-PCR). Spearman's correlation analysis and receiver operating characteristic (ROC) curve analysis were performed to determine the clinical diagnostic capability of circRNAs. Bioinformatics was used to identify potential biological functions and circRNA-miRNA-mRNA interactions. Results: There were 13 upregulated and 13 downregulated circRNAs in PBMCs of patients with FT1D. Five circRNAs were further verified in a second cohort. Hsa_circRNA_100632 was significantly upregulated in the FT1D and T1D groups. Hsa_circRNA_100632 was differentiated between patients with FT1D and controls [area under the curve (AUC) 0.846; 95% CI 0.776-0.916; P<0.0001] as well as between patients with FT1D and patients with T1D (AUC 0.726; 95% CI 0.633-0.820; P<0.0001). Bioinformatics analysis showed that hsa_circRNA_100632 may be involved in 47 circRNA-miRNA-mRNA signaling pathways associated with diabetes. Conclusions: CircRNAs were aberrantly expressed in PBMCs of patients with FT1D, and hsa_circRNA_100632 may be a diagnostic marker of FT1D.

An Integrative Model of Tourists' Pro-Environmental Behavior Based on the Dual Path of Rational Planning and Embodied Emotion.

Tourists' pro-environmental behavior is one of the key factors for the sustainable development of natural scenic spots. Although this behavior depends on the surroundings and context, the existing literature lacks the perspective of specific scenarios, especially that of embodied emotions. This research integrated the theory of planned behavior and embodied theory to construct an integrative model of pro-environmental behavior that combined tourists' "rational planning" and "embodied emotion" and conducted an empirical study. The results show that in natural scenic spots, "rational planning" and "embodied emotion" affect tourists' pro-environmental behavior simultaneously on dual paths, and factors such as behavioral attitude, perceived behavioral control, subjective norm, engagement with nature, and connectedness to nature have different effects on high- and low-effort pro-environmental behavioral intentions. The findings of the study provide a new explanatory perspective for individual pro-environmental behaviors and a basis for effectively predicting and guiding tourists' pro-environmental behaviors in natural scenic spots.

Latent autoimmune diabetes in adults in China.

Latent autoimmune diabetes in adults (LADA) is a type of diabetes caused by slow progression of autoimmune damage to pancreatic beta cells. According to the etiological classification, LADA should belong to the autoimmune subtype of type 1 diabetes (T1D). Previous studies have found general immune genetic effects associated with LADA, but there are also some racial differences. Multicenter studies have been conducted in different countries worldwide, but it is still unclear how the Chinese and Caucasian populations differ. The epidemiology and phenotypic characteristics of LADA may vary between Caucasian and Chinese diabetic patients as lifestyle, food habits, and body mass index differ between these two populations. The prevalence of LADA in China has reached a high level compared to other countries. The prevalence of LADA in China has reached a high level compared to other countries, and the number of patients with LADA ranks first in the world. Previous studies have found general immune genetic effects associated with LADA, but some racial differences also exist. The prevalence of LADA among newly diagnosed type 2 diabetes patients over the age of 30 years in China is 5.9%, and LADA patients account for 65% of the newly diagnosed T1D patients in the country. As a country with a large population, China has many people with LADA. A summary and analysis of these studies will enhance further understanding of LADA in China. In addition, comparing the similarities and differences between the Chinese and the Caucasian population from the perspectives of epidemiology, clinical, immunology and genetics will help to improve the understanding of LADA, and then promote LADA studies in individual populations.

Characterization of immune checkpoint inhibitor-associated fulminant type 1 diabetes associated with autoantibody status and ethnic origin.

Objective: Fulminant type 1 diabetes may uniquely occur as a fatal adverse event during immune checkpoint inhibitor (ICI) therapy. We investigated the clinical and immunological characteristics of ICI-associated fulminant type 1 diabetes (IFD). Research design and methods: We enrolled 80 patients with IFD (77 cases from the literature), 56 patients with ICI-associated type 1 diabetes (IT1D) (55 cases from the literature), 45 patients with traditional fulminant type 1 diabetes (TFD), and 43 patients with acute-onset type 1 diabetes for comprehensive analysis including islet autoantibodies and subgroup analysis based on ethnic origin. Results: Patients with IFD accounted for 58.8% (80/136) of patients with ICI-related diabetes. IFD had a more rapid onset than IT1D after ICI therapy (90.5 days vs. 120 days, p <0.05). The onset time and number of infusions after ICI therapy initiation were lower in the antibody-positive IFD group than that in the antibody-negative IFD group (both p <0.001). IFD had a more rapid onset and more serious among Caucasians than that among Asians (p <0.01, p <0.05, respectively), and the prevalence of islet autoantibody positivity in the Caucasian IFD were prominently higher than those in the Asian IFD (p <0.05). Onset age and plasma glucose levels were significantly higher in the IFD group than those in the TFD and acute-onset type 1 diabetes groups. HbA1c levels were slightly higher in patients with IFD than those with TFD. Conclusions: IFD is relatively common in Caucasian population where TFD is very rare or almost absent. IFD occurrence is significantly related to islet autoantibody status and ethnic origin.

Altered Tim-1 and IL-10 Expression in Regulatory B Cell Subsets in Type 1 Diabetes.

Background: Type 1 diabetes (T1D) is an autoimmune disease with a complex aetiology. B cells play an important role in the pathogenesis of T1D. Regulatory B cells (Bregs) are a subset of B cells that produce and secrete the inhibitory factor interleukin-10 (IL-10), thereby exerting an anti-inflammatory effect. It was recently discovered that T-cell immunoglobulin mucin domain 1 (Tim-1) is essential for maintaining Bregs function related to immune tolerance. However, the detailed understanding of Tim-1+ Bregs and IL-10+ Bregs in T1D patients is lacking. This study aimed to characterize the profile of B cell subsets in T1D patients compared with that in controls and determine whether Tim-1+ Bregs and IL-10+ Bregs play roles in T1D. Materials and Methods: A total of 47 patients with T1D, 30 patients with type 2 diabetes (T2D) and 24 healthy controls were recruited in this study. Flow cytometry was used to measure the levels of different B cell subsets (including B cells, plasmablasts, and Bregs) in the peripheral blood. Radiobinding assays were performed to detect the antibody titres of T1D patients. In addition, the correlations between different B cell subsets and patient parameters were investigated. Results: Compared with healthy controls, differences in frequency of Tim-1+ Bregs were significantly decreased in patients with T1D (36.53 ± 6.51 vs. 42.25 ± 6.83, P=0.02*), and frequency of IL-10+ Bregs were lower than healthy controls (17.64 ± 7.21vs. 24.52 ± 11.69, P=0.009**), the frequency of total Bregs in PBMC was also decreased in patients with T1D (1.42 ± 0.53vs. 1.99 ± 0.93, P=0.002.**). We analyzed whether these alterations in B cells subsets were associated with clinical features. The frequencies of Tim-1+ Bregs and IL-10+ Bregs were negatively related to fasting blood glucose (FBG) (r=-0.25 and -0.22; P=0.01* and 0.03*, respectively). The frequencies of Tim-1+ Bregs and IL-10+ Bregs are positively correlated with fast C-peptide (FCP) (r=0.23 and 0.37; P=0.02* and 0.0001***, respectively). In addition, the frequency of IL-10+ Breg was also negatively related to glycosylated haemoglobin (HbA1c) (r=-0.20, P=0.04*). The frequencies of Tim-1+ Bregs, IL-10+ Bregs and Bregs in T2D patients were reduced, but no statistically significant difference was found between other groups. Interestingly, there was positive correlation between the frequencies of Tim-1+ Bregs and IL-10+ Bregs in T1D (r=0.37, P=0.01*). Of note, it is worth noting that our study did not observe any correlations between B cell subsets and autoantibody titres. Conclusions: Our study showed altered Tim-1 and IL-10 expression in regulatory B cell in T1D patients. Tim-1, as suggested by the present study, is associated with islet function and blood glucose levels. These findings indicate that Tim-1+ Bregs and IL-10+ Bregs were involved in the pathogenesis of T1D.

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.