Identification of potential immunotherapeutic targets and prognostic biomarkers in Graves' disease using weighted gene co-expression network analysis.

Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism resulting from autoantibody-induced stimulation of the thyroid gland. Despite recent advancements in understanding GD's pathogenesis, the molecular processes driving disease progression and treatment response remain poorly understood. In this study, we aimed to identify crucial immunogenic factors associated with GD prognosis and immunotherapeutic response. To achieve this, we implemented a comprehensive screening strategy that combined computational immunogenicity-potential scoring with multi-parametric cluster analysis to assess the immunomodulatory genes in GD-related subtypes involving stromal and immune cells. Utilizing weighted gene co-expression network analysis (WGCNA), we identified co-expressed gene modules linked to cellular senescence and immune infiltration in CD4+ and CD8+ GD samples. Additionally, gene set enrichment analysis enabled the identification of hallmark pathways distinguishing high- and low-immune subtypes. Our WGCNA analysis revealed 21 gene co-expression modules comprising 1,541 genes associated with immune infiltration components in various stages of GD, including T cells, M1 and M2 macrophages, NK cells, and Tregs. These genes primarily participated in T cell proliferation through purinergic signaling pathways, particularly neuroactive ligand-receptor interactions, and DNA binding transcription factor activity. Three genes, namely PRSS1, HCRTR1, and P2RY4, exhibited robustness in GD patients across multiple stages and were involved in immune cell infiltration during the late stage of GD (p < 0.05). Importantly, HCRTR1 and P2RY4 emerged as potential prognostic signatures for predicting overall survival in high-immunocore GD patients (p < 0.05). Overall, our study provides novel insights into the molecular mechanisms driving GD progression and highlights potential key immunogens for further investigation. These findings underscore the significance of immune infiltration-related cellular senescence in GD therapy and present promising targets for the development of new immunotherapeutic strategies.

Evaluation of the effects of vitamin D deficiency and cigarette smoking on insulin resistance in type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.

There are contradictory findings regarding the effects of vitamin D supplementation and cigarette smoking on glucose metabolism in individuals with type 2 diabetes mellitus (T2DM). Consequently, this meta-analysis focused on the association between vitamin D interventions and smoking cessation on glycemic control in T2DM patients. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Cochrane Library, EMBASE and PubMed databases were used for a language-inclusive literature search until November 2022. The primary outcomes of this meta-analysis were changes in glycated hemoglobin (HbA1c) level, vitamin D concentration and body mass index (BMI) values. This meta-analysis included 14 randomized controlled trials (RCTs) with a total of 23,289 individuals with T2DM. Nine RCTs were related to vitamin D supplementation interventions, and 5 RCTs were related to smoking cessation interventions. The studies on vitamin D supplementation showed a substantial change in the intervention group, with a risk ratio (RR) of 0.72 (95% confidence interval (95% CI): 0.58, 0.88; p = 0.001) and an odds ratio (OR) of 0.52 (95% CI: 0.34, 0.78; p = 0.002); high heterogeneity was observed (I2 ≥ 95%). Similarly, the smoking cessation studies showed a substantial change in the intervention group, with a RR of 0.92 (95% CI: 0.86, 0.99; p = 0.04) and an OR of 0.86 (95% CI: 0.74, 0.99; p = 0.04); high heterogeneity was observed (I2 = 87%). In conclusion, both vitamin D supplementation and smoking cessation are associated with moderate BMI decline and an improvement of insulin sensitivity in people with T2DM.

Diabetes remission in drug-naïve patients with type 2 diabetes after dorzagliatin treatment: A prospective cohort study.

AIM: To investigate the post-treatment effect of dorzagliatin in drug-naïve patients with type 2 diabetes (T2D) regarding the achievement of stable glycaemic control and drug-free diabetes remission. MATERIALS AND METHODS: Patients who completed dorzagliatin treatment in the SEED trial and achieved stable glycaemic control were enrolled in this 52-week study without any antidiabetic medication. The primary endpoint was the diabetes remission probability at week 52 using the Kaplan-Meier method. The potential factors that contribute to stable glycaemic control and diabetes remission based on the characteristics of patients before and after treatment with dorzagliatin were analysed. A post hoc sensitivity analysis of diabetes remission probability using the American Diabetes Association (ADA) definition was conducted. RESULTS: The Kaplan-Meier remission probability was 65.2% (95% CI: 52.0%, 75.6%) at week 52. Based on the ADA definition, the remission probability was 52.0% (95% CI: 31.2%, 69.2%) at week 12. The significant improvements in the insulin secretion index ΔC30/ΔG30 (41.46 ± 77.68, P = .0238), disposition index (1.22 ± 1.65, P = .0030), and steady-state variables of HOMA2-ß (11.49 ± 14.58, P < .0001) and HOMA2-IR (-0.16 ± 0.36, P = .0130) during the SEED trial were important factors in achieving drug-free remission. A significant improvement in time in range (TIR), a measure of glucose homeostasis, in the SEED trial from 60% to more than 80% (estimated treatment difference, 23.8%; 95% CI: 7.3%, 40.2%; P = .0084) was observed. CONCLUSIONS: In drug-naïve patients with T2D, dorzagliatin treatment leads to stable glycaemic control and drug-free diabetes remission. Improvements in ß-cell function and TIR in these patients are important contributors to diabetes remission.

Pharmacokinetics, Pharmacodynamics and Safety of Janagliflozin in Chinese Type 2 Diabetes Mellitus Patients with Renal Impairment.

BACKGROUND: Janagliflozin is a novel sodium-glucose cotransport-2 inhibitor. Despite its remarkable effect in glycemic control, no systematic research has evaluated the effect of renal impairment (RI) on its pharmacokinetics and pharmacodynamics. METHODS: Here, patients with T2DM (n = 30) were divided into normal renal function (eGFR ≥ 90 mL/min/1.73 m2), mild RI (eGFR between 60 and 89 mL/min/1.73 m2), moderate RI-I (eGFR between 45 and 59 mL/min/1.73 m2), and moderate RI-II (eGFR between 30 and 44 mL/min/1.73 m2) groups. They were administered 50 mg janagliflozin orally, and plasma and urine samples were collected for the determination of janagliflozin concentration. RESULTS: Following oral administration, janagliflozin was rapidly absorbed, with the time to Cmax of 2-6 h for janagliflozin and 3-6 h for its metabolite XZP-5185. Plasma exposure levels were similar for janagliflozin in T2DM patients with or without RI but decreased for the metabolite XZP-5185 in T2DM patients with eGFR between 45 and 89 mL/min/1.73 m2. Janagliflozin significantly promoted the excretion of urinary glucose, even in patients with reduced eGFR. Janagliflozin was well tolerated in patients with T2DM with or without RI, and no serious adverse events (SAEs) occurred during this trial. CONCLUSIONS: The exposure levels of janagliflozin in T2DM patients were slightly increased with worsening of RI (i.e., 11% increase in the AUC in patients with moderate RI compared with the normal renal function group). Despite worsening of renal function, janagliflozin exerted a significant pharmacologic effect and was well tolerated, even in patients with moderate RI, implying a promising role in the treatment of patients with in T2DM. REGISTRATION: China Drug Trial register ( http://www.chinadrugtrials.org.cn/I ) identifier no.: CTR20192721.

Bioinformatic analysis of specific genes in diabetic nephropathy.

OBJECTIVE: We attempt to explore the pathogenesis and specific genes with aberrant expression in diabetic nephropathy (DN). METHODS: The gene expression profile of GSE1009 was downloaded from Gene Expression Omnibus database, including 3 normal function glomeruli and DN glomeruli from cadaveric donor kidneys. The differentially expressed genes (DEGs) were analyzed and the aberrant gene-related functions were predicted by informatics methods. The protein-protein interaction (PPI) networks for DEGs were constructed and the functional sub-network was screened. RESULTS: A total of 416 DEGs were found to be differentially expressed in DN samples comparing with normal controls, including 404 up-regulated genes and 12 down-regulated genes. DEGs were involved in the process of combination to saccharides and the decline of tissue repairing ability of the organisms. The genes of VEGFA, ACTG1, HSP90AA1 had high degree in the PPI network. The main biological process of genes in the sub-network was related with cell proliferation and signal transmitting of cell membrane receptor. CONCLUSION: Significant nodes in PPI network provide new insights to understand the mechanism of DN. VEGFA, ACTG1 and HSP90AA1 may be the potential targets in the DN treatment.