Changes of B cell subsets in different types of diabetes and its effect on the progression of latent autoimmune diabetes in adults.

PURPOSE: Developmental abnormalities in B cells is one of the key players in autoimmune diabetes, but little is known about its role in latent autoimmune diabetes in adults (LADA). This study aimed to investigate the distribution of B cell subsets in different types of diabetes and to analyze their correlations with other biochemical parameters. METHODS: A total of 140 participants were prospectively enrolled from January 2021 to December 2022. Diabetes-related autoantibodies and laboratory indicators were tested. Flow cytometry was used to analyze the percentage of circulating B cell subsets and T follicular cells. The correlation of B cell subsets with different indicators was assessed by Spearman's correlation method. RESULTS: We observed that the Naïve phenotype cells tended to be less frequent in patients with diabetes than in healthy controls. The frequency of plasmablasts (PB) and Breg cell-related phenotype (B10) were significantly higher in LADA. Notably, the percentage of PB was positively associated with levels of islet cell antibody (ICA) and insulin autoantibody (IAA), but inversely associated with fasting C-peptide (FCP), further indicating that PB may promote the destruction of ß-cell in patients with diabetes. CONCLUSIONS: This study showed that patients with LADA had significantly altered frequencies of B cell subsets, particularly in the naïve to memory B cell ratio. Our study provided valuable information on the distribution characteristics of B cell subsets in LADA and suggested the feasibility of B-cell targeted therapy in LADA patients.

Development and validation of a multivariable risk prediction model for identifying ketosis-prone type 2 diabetes.

BACKGROUND: To develop and validate a multivariable risk prediction model for ketosis-prone type 2 diabetes mellitus (T2DM) based on clinical characteristics. METHODS: A total of 964 participants newly diagnosed with T2DM were enrolled in the modeling and validation cohort. Baseline clinical data were collected and analyzed. Multivariable logistic regression analysis was performed to select independent risk factors, develop the prediction model, and construct the nomogram. The model's reliability and validity were checked using the receiver operating characteristic curve and the calibration curve. RESULTS: A high morbidity of ketosis-prone T2DM was observed (20.2%), who presented as lower age and fasting C-peptide, and higher free fatty acids, glycated hemoglobin A1c and urinary protein. Based on these five independent influence factors, we developed a risk prediction model for ketosis-prone T2DM and constructed the nomogram. Areas under the curve of the modeling and validation cohorts were 0.806 (95% confidence interval [CI]: 0.760-0.851) and 0.856 (95% CI: 0.803-0.908). The calibration curves that were both internally and externally checked indicated that the projected results were reasonably close to the actual values. CONCLUSIONS: Our study provided an effective clinical risk prediction model for ketosis-prone T2DM, which could help for precise classification and management.

Urinary N-acetyl-ß-d-glucosaminidase-creatine ratio is a valuable predictor for advanced diabetic kidney disease.

BACKGROUND: Many biomarkers show high diagnostic values for diabetic kidney disease (DKD), but fewer studies focus on the predictive assessment of DKD progression by blood and urinary biomarkers. AIM: This study aims to find powerful risk predictors and identifying biomarkers in blood and urine for DKD progression. METHODS: A total of 117 patients with type 2 DKD including early and advanced stages and their laboratory parameters were statistically assessed. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the significance of discriminating between early and advanced DKD, and the predictive power for advanced DKD was analyzed by regression analysis and trisector grouping. RESULTS: N-acetyl-ß-d-glucosaminidase-creatine (NAG/CR) level in advanced DKD was statistically higher than that in early DKD (p < 0.05), and there was a higher incidence of advanced DKD (72% vs. 56%) and high odds ratio (OR: 3.917, 95% CI: 1.579-10.011) of NAG/CR with ≥2.79 U/mmol compared with <2.79 U/mmol (p < 0.05). NAG/CR ratio also showed a higher area under the ROC curve of 0.727 (95% CI: 0.616-0.828, p = 0.010) with a high sensitivity (0.75) and a moderate specificity (0.66) when 1.93 U/mmol was set as the optimal cutoff value. The adjusted-multivariable analysis revealed that NAG/CR had an OR of 1.021 (95% CI: 1.024-1.038) and 2.223 (95% CI: 1.231-4.463) based on a continuous and categorical variable, respectively, for risk of advanced DKD. Moreover, the prevalence of advanced DKD exhibited an increasing tendency by an increment of the trisector of NAG/CR. CONCLUSIONS: This study suggests that NAG/CR ratio is an independent predictor for advanced DKD, and it also can be used as a powerful identifying marker between early and advanced DKD.

Association Between Elevated Thyroid Peroxidase Antibody and Abdominal Fat Distribution in Patients with Type 2 Diabetes Mellitus.

Objective: Obesity and autoimmune thyroid disease (AITD) are both common disorders in the general population, which are major drivers for adverse medical conditions. While an interaction between thyroid function and visceral obesity is thought to exist, but very few studies have examined the relationship between AITD and visceral obesity, especially in the patients with type 2 diabetes mellitus (T2DM). In the present study, we investigated the association between elevated thyroid peroxidase antibody (TPOAb) titer and visceral fat area in T2DM patients. Methods: A total of 390 T2DM patients who met the criteria for admission and joined the National Metabolic Management Center (MMC) in the Zhejiang Provincial People's Hospital from April 2020 to December 2020 were enrolled in this study. The participants were divided into two groups based on visceral obesity. Thyroid function, thyroid associated antibody and other metabolic indicators were measured by blood tests. The visceral fat area (VFA) and the subcutaneous fat area (SFA) were measured by bioelectrical impedance analysis. Results: There were 185 participants (47.4%) had visceral obesity. The positive rate of TPOAb was significantly higher in T2DM patients with visceral obesity (12.97% vs 5.37%, p < 0.01). Free triiodothyronine (FT3) and thyroid-stimulating hormone (TSH) were both significantly higher in T2DM patients with visceral obesity (p < 0.05). The increased TPOAb titer was significantly positively correlated with visceral fat area (r = 0.175, p < 0.01). Binary logistic analysis showed that the positive rate of TPOAb was associated with an increased risk of visceral obesity [(OR) 4.258, 95% confidence interval (CI) 1.594, 11.375, p = 0.004]. Conclusion: TPOAb-positive is more common in T2DM patients with visceral obesity, which has some effects on visceral obesity independent of thyroid function. This suggests that elevated TPOAb titer is a predictor of visceral obesity in T2DM patients.

Clinical and predictive significance of Plasma Fibrinogen Concentrations combined Monocyte-lymphocyte ratio in patients with Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most common causes of blindness and visual impairment. Therefore, early prediction of its occurrence and progression is important. This study aimed to assess the clinical and predictive significance of plasma fibrinogen concentrations combined monocyte-lymphocyte ratio (FC-MLR) in patients with DR. A total of 307 patients with type 2 diabetes (T2D) were enrolled. Plasma fibrinogen concentrations and peripheral white blood cells were measured, and MLR was calculated, and the associations of FC-MLR with DR and severity of disease were assessed. Regression analysis and receiver operating characteristic (ROC) curves were performed to evaluate the risk factors and predictive power of FC-MLR for DR and severity of disease, respectively. DR patients showed higher fibrinogen concentrations and a higher MLR than did T2D patients without complications (P<0.01); Moreover, DR patients in proliferative stage also showed higher fibrinogen concentrations and a higher MLR than did those in non-proliferative stage (P<0.01). FC-MLR was closely associated with occurrence and severity of DR (P<0.01), and was an independent risk factor for them (OR=6.123, 95%CI: 3.122-17.102; and 7.932, 95%CI: 4.315-16.671, respectively; P<0.001). The predictive sensitivity and specificity for DR and severity of disease were 0.86 and 0.68, and 0.85 and 0.73, respectively. The study suggests that FC-MLR may be used as a predictor for the risk and progression of diabetic retinopathy.

Monocyte-lymphocyte ratio is a valuable predictor for diabetic nephropathy in patients with type 2 diabetes.

Diabetic nephropathy (DN) is serious threat to human health. Therefore, early prediction of its occurrence is important. This study aimed to assess the predictive significance of monocyte-lymphocyte ratio (MLR) for DN.A total of 301 patients with type 2 diabetes (T2D), including 212 T2D patients without diabetic-related complications and 99 DN patients, were enrolled. Peripheral white blood cells were measured before treatment to calculate MLR, and the risk factors and predictive significance for T2D and DN were assessed.T2D patients without diabetic-related complications had higher MLR than control patients (P < .01). However, MLR was significantly higher in DN patients than in T2D patients without diabetic-related complications (P < .001). According to MLR quartiles, higher MLR in DN patients was correlated with higher serum creatinine, estimated glomerular filtration rate, and urinary albumin excretion (UAE) levels (P < .01 or P < .001). Furthermore, MLR was positively correlated with UAE level (R = 0.5973; P < .01) and an independent predictor for DN (odds ratio: 7.667; 95% confidence interval [CI]: 3.689-21.312; P < .001). The area under the receiver-operating characteristic (ROC) curve for MLR was 0.874 (95%CI: 0.830-0.918, P < .001). When the optimal cutoff value was 0.23, the sensitivity and specificity of MLR for DN prediction were 0.85 and 0.74, respectively.The present findings suggest that MLR is a powerful independent predictor for DN.

Increased circulating follicular regulatory T cells in Hashimoto's thyroiditis.

OBJECTIVE: Follicular T helper (Tfh) cells are involved in the pathogenesis of Hashimoto's thyroiditis (HT), while follicular T regulatory (Tfr) cells inhibit Tfh cells, which mediate B cell responses. However, the role of Tfr cells in HT remains unclear. METHODS: Forty-six healthy controls (HCs) and 84 HT patients were enrolled in the study. The percentage of Treg cells, CXCR5- Treg cells, and Tfr cells; the Tfr/Tfh ratio; and the percentage of ICOS, PD-1, CTLA-4, CXCR3 and CCR6 in Tfr cells were investigated; furthermore, the associations between the percentage of Tfr cells or the Tfr/Tfh ratio and the autoantibody indices were investigated. RESULTS: Compared with that in the HCs, the percentage of Treg cells in the HT patients was not significantly changed, but the percentage of CXCR5- Tfr cells was decreased. In contrast, both the percentage of Tfr cells and the Tfr/Tfh ratio were significantly increased in the HT patients. Among the Tfr cells, the percentage of Th2-like Tfr cells was increased in the HT patients, while the percentage of Th17-like Tfr cells was decreased. Moreover, the percentages of ICOS and PD-1 on Tfr cells were significantly increased in the HT patients, while the percentage of CTLA-4 on Tfr cells was significantly decreased. However, the percentage of ICOS, PD-1 and CTLA-4 on Treg or CXCR5- Treg cells was not significantly changed. Last, no association was found between either the percentage of Tfr cells or the Tfr/Tfh ratio and the antithyroglobulin and antithyroid peroxidase antibody levels in the HT patients. CONCLUSIONS: In the HT patients, the circulating Tfr cell percentage and Tfr/Tfh ratio were significantly increased, but the humoral immune function of Tfr cells might be impaired.

Increased circulating Tfh17 and PD-1+Tfh cells are associated with autoantibodies in Hashimoto's thyroiditis.

OBJECTIVE: Hashimoto's thyroiditis (HT) is characterized by autoantibodies targeting the thyroid. Abnormal CD4+CXCR5+T cell levels were previously shown to be associated with HT. However, Tfh cells consist of heterogeneous subpopulations, and which T follicular helper (Tfh) cell subpopulation participates in the pathogenesis of HT remains poorly understood. METHODS: Thirty healthy controls (HCs) and 52 HT patients were enrolled in the study. The percentages of Tfh, ICOS+Tfh, PD1+Tfh, Tfh1, Tfh2, Tfh17, effector Tfh, resting Tfh, effector memory Tfh, central memory Tfh, and naïve Tfh cells in the peripheral blood were all determined via flow cytometry, and the associations between the percentages of these cells and thyroid function indices were also investigated. RESULTS: The percentage of Tfh cells was significantly higher in HT patients than in HCs. Examination of the Tfh cell subsets revealed that the percentages of Tfh1, Tfh2, and resting Tfh cells were significantly decreased, while those of the ICOS+Tfh, PD1+Tfh, Tfh17, and effector Tfh cells were significantly increased in HT patients. No significant differences in effector memory, central memory or naïve Tfh cell percentages were noted between the HC and HT groups. Furthermore, the percentage of PD1+Tfh cells was positively correlated with anti-thyroglobulin antibody levels. Most importantly, only Tfh17 cell percentages were positively correlated with anti-thyroglobulin and anti-thyroid peroxidase antibody levels and were negatively correlated serum free T3 and free T4 levels in HT patients. CONCLUSIONS: Increased circulating Tfh17 cell and PD1+Tfh percentages are associated with higher autoantibody levels in HT patients, which imply that Tfh17 or PD1+Tfh cells may play a pathogenic role in the development of HT.

Berberine alleviates adipose tissue fibrosis by inducing AMP-activated kinase signaling in high-fat diet-induced obese mice.

Adipose tissue fibrosis is a novel mechanism for the development of obesity related insulin resistance. Berberine (BBR) has been shown to relieve several metabolic disorders, including obesity and type 2 diabetes. However, the effects of BBR on obesity related adipose fibrosis remain poorly understood. The objective of this study was to assess the effects of BBR on adipose tissue fibrosis in high fat diet (HFD)-induced obese mice. The results showed that BBR reduced animal body weight and significantly improved glucose tolerance in HFD mice. In addition, BBR treatment markedly attenuated collagen deposition and reversed the up-regulation of fibrosis associated genes in the adipose tissue of HFD mice. Moreover, BBR treatment activated AMP-activated kinase signaling and reduced TGF-ß1 and Smad3 phosphorylation. Of note, the inhibitory effects of BBR on adipose tissue fibrosis were significantly blocked by AMPK inhibition with compound C, an AMPK inhibitor. Macrophage infiltration and polarization induced by HFD were also reversed after BBR administration. These findings suggest that BBR displays beneficial effects in the treatment of obesity, in part via improvement of adipose tissue fibrosis.

Interleukin-10 -592C/A, -819C/T and -1082A/G Polymorphisms with Risk of Type 2 Diabetes Mellitus: A HuGE Review and Meta-analysis.

BACKGROUND: Several studies have been conducted in recent years to evaluate the risk of type 2 diabetes mellitus (T2DM) and polymorphisms of interleukin (IL)-10. However, the results remain conflicting rather than conclusive. This meta-analysis aimed to summarize the current evidence from case-control studies that evaluated this association. METHODS: We carried out a search in Medline, EMBASE, and the Chinese National Knowledge Infrastructure (CNKI) database for relevant studies. Data were extracted using a standardized form and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association. RESULTS: 10 studies were included in our meta-analysis and systemic review. Our meta-analysis indicated that IL-10 -1082A/G polymorphism was associated with the risk of T2DM (GA vs. AA: OR = 1.21, 95% CI = 1.03-1.14; GA/GG vs. AA: OR = 1.22, 95% CI = 1.05-1.41), whereas there was no association between IL-10 -592C/A (CC/CA vs. AA: OR = 1.07, 95% CI = 0.59-1.93) or -819C/T (CC/CT vs. TT: OR = 0.93, 95% CI = 0.49-1.75) polymorphism and T2DM risk was found in our study. CONCLUSIONS: This meta-analysis provides strong evidence that IL-10 -1082A/G polymorphism associated with risk of T2DM. However, no association of the IL-10 -592C/A or -819C/T polymorphism with T2DM risk was found. Additional well-designed large studies were required for the validation of our results.

Disturbed subjective sleep in Chinese females with type 2 diabetes on insulin therapy.

OBJECTIVES: The aim of this study is to investigate the prevalence and determine the possible risk factors of poor sleep quality in Chinese type 2 diabetes patients with insulin treatment. METHODS: 140 type 2 diabetes patients with insulin treatments were enrolled in our study. General characteristics and laboratory testing such glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG) were measured. Every patient completed Chinese version of Pittsburgh Sleep Quality Index (PSQI) questionnaire. PSQI global score>5 was defined as poor sleep quality. RESULTS: Global PSQI score was significantly higher in female type 2 diabetes patients with insulin treatment than male (7.52 vs 6.08, P<0.05). After adjusting for age, BMI, FPG, PPG, HbA1c and duration of diabetes, female is still an independent risk factor for poor sleep quality [OR = 2.55, 95% confidence interval (CI) = 1.24-5.27, P = 0.01]. CONCLUSION: The results suggest that we found poor sleep quality in female Chinese type 2 diabetes patients with insulin treatment and these findings may contribute to sleep disorder control in female type 2 diabetes.