Enhanced predictive validity of integrative models for refractory hyperthyroidism considering baseline and early therapy characteristics: a prospective cohort study.

BACKGROUND: A subset of Graves' disease (GD) patients develops refractory hyperthyroidism, posing challenges in treatment decisions. The predictive value of baseline characteristics and early therapy indicators in identifying high risk individuals is an area worth exploration. METHODS: A prospective cohort study (2018-2022) involved 597 newly diagnosed adult GD patients undergoing methimazole (MMI) treatment. Baseline characteristics and 3-month therapy parameters were utilized to develop predictive models for refractory GD, considering antithyroid drug (ATD) dosage regimens. RESULTS: Among 346 patients analyzed, 49.7% developed ATD-refractory GD, marked by recurrence and sustained Thyrotropin Receptor Antibody (TRAb) positivity. Key baseline factors, including younger age, Graves' ophthalmopathy (GO), larger goiter size, and higher initial free triiodothyronine (fT3), free thyroxine (fT4), and TRAb levels, were all significantly associated with an increased risk of refractory GD, forming the baseline predictive model (Model A). Subsequent analysis based on MMI cumulative dosage at 3 months resulted in two subgroups: a high cumulative dosage group (average ≥ 20 mg/day) and a medium-low cumulative dosage group (average < 20 mg/day). Absolute values, percentage changes, and cumulative values of thyroid function and autoantibodies at 3 months were analyzed. Two combined predictive models, Model B (high cumulative dosage) and Model C (medium-low cumulative dosage), were developed based on stepwise regression and multivariate analysis, incorporating additional 3-month parameters beyond the baseline. In both groups, these combined models outperformed the baseline model in terms of discriminative ability (measured by AUC), concordance with actual outcomes (66.2% comprehensive improvement), and risk classification accuracy (especially for Class I and II patients with baseline predictive risk < 71%). The reliability of the above models was confirmed through additional analysis using random forests. This study also explored ATD dosage regimens, revealing differences in refractory outcomes between predicted risk groups. However, adjusting MMI dosage after early risk assessment did not conclusively improve the prognosis of refractory GD. CONCLUSION: Integrating baseline and early therapy characteristics enhances the predictive capability for refractory GD outcomes. The study provides valuable insights into refining risk assessment and guiding personalized treatment decisions for GD patients.

Real-world adherence to toxicity management guidelines for immune checkpoint inhibitor-induced diabetes mellitus.

Objective: Immune checkpoint inhibitors(ICIs) have improved survival and are increasingly used for cancer. However, ICIs use may be limited by immune-related adverse events (irAEs), such as ICI-induced diabetes mellitus(ICI-DM). The objective of the present study was to characterize ICI-DM patients and real-world adherence to guidelines. Research design and methods: The present study was a retrospective review of electronic records of ICI-DM patients at the First Affiliated Hospital of Nanjing Medical University between July 2018 and October 2022. Results: 34.8% (8/23)patients monitored blood glucose in every treatment cycle. The proportion of patients with severe diabetic ketoacidosis(DKA) was lower in the tight glycemic monitoring group than the non-tight glycemic monitoring group (16.7% vs. 55.6%, p = 0.049). 78.3%(18/23) patients with hyperglycemia visited a non-endocrinologist first, but 95.7% of patients were then referred to an endocrinologist. Twenty patients were tested for distinguishing the etiology of hyperglycemia and 20% patients with positive glutamic acid decarboxylase antibody(GADA), 55% with C-peptide <3.33pmol/L. High screening rates for other ICI-induced endocrinopathies were observed and half of the patients with ICI-DM developed other endocrine gland irAEs, with the most common being thyroiditis. Moreover, five patients developed non-endocrine serious adverse events(SAEs). Twelve (52.2%) patients were withdrawn from ICI due to ICI-DM. The time to progression of tumor in ICI-DM patients in the continue and interruption group was longer than in the withdrawal group (333.5 ± 82.5 days vs. 183.1 ± 62.4 days, p = 0.161). Only 17.4% of ICI-DM patients were completely managed according to guidelines. Thus, the present study proposed a screening, diagnosis, and management algorithm for ICI-DM in real-world practice. Conclusion: The present study reported the largest number of ICI-DM cases described in a single institute, providing insight into real-world ICI-DM management guideline adherence and highlighting the clinical challenges in ICI-DM management.

Association of subclass distribution of insulin antibody with glucose control in insulin-treated type 2 diabetes mellitus: a retrospective observational study.

Objective: To examine the distribution and effects of the subclass of insulin antibodies on glucose control and side events in patients with type 2 diabetes treated with premixed insulin analog. Methods: A total of 516 patients treated with premixed insulin analog were sequentially enrolled from the First Affiliated Hospital of Nanjing Medical University from June 2016 to August 2020. Subclass-specific insulin antibodies (IAs) (IgG1-4, IgA, IgD, IgE, and IgM) were detected in IA-positive patients by electrochemiluminescence. We analyzed glucose control, serum insulin, and insulin-related events between IA-positive and IA-negative groups, as well as among patients with different IA subclasses. Results: Overall, 98 of 516 subjects (19.0%) were positive for total IAs after premixed insulin analog therapy; of these participants, 92 had subclass IAs, and IgG-IA was the predominant subclass, followed by IgE-IA. IAs were associated with serum total insulin increase and local injection-site reactions but not glycemic control and hypoglycemia. In the subgroup analysis in patients with IA-positive, the IgE-IA and IA subclass numbers were more associated with increased serum total insulin levels. Additionally, IgE-IA might be correlated more strongly with local responses and weakly with hypoglycemia, while IgM-IA might be correlated more strongly with hypoglycemia. Conclusion: We concluded that IAs or IA subclasses might be associated with unfavorable events in patients receiving premixed insulin analog therapy, which can be used as an adjunctive monitoring indicator in clinical insulin trials.

Growth differentiation factor-15/adiponectin ratio as a potential biomarker for metabolic syndrome in Han Chinese.

Aims: Growth differentiation factor-15 (GDF-15) and adiponectin are adipokines that regulate metabolism. This study aimed to evaluate the roles of GDF-15, adiponectin, and GDF-15/adiponectin ratio (G/A ratio) as biomarkers for detecting metabolic syndrome (MS). Materials and methods: This cross-sectional study included 676 participants aged 20-70 years in Jurong, China. The participants were divided into four groups based on sex and age (<40 and ≥40 years). MS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Receiver operating characteristic curves were used to evaluate the performance of GDF-15, adiponectin, and the G/A ratio in predicting MS. Results: The prevalence of MS was 22.0% (149/676). Logistic regression analysis indicated that the G/A ratio and adiponectin levels, but not GDF-15 levels, were correlated with MS [odds ratio; 95% CI 1.010 (1.006-1.013) and 0.798 (0.735-0.865), respectively] after adjusting for confounding factors. The G/A ratio displayed a significant relationship with MS in each subgroup and with each MS component in both men and women; however, adiponectin concentrations were significantly associated with MS and all its components only in men (all P <0.05). The area under the curve (AUC) of the G/A ratio and the adiponectin level for MS was 0.758 and 0.748, respectively. The highest AUC was 0.757 for the adiponectin level in men and 0.724 for the G/A ratio in women. Conclusions: This study suggests that the G/A ratio and adiponectin are potential biomarkers for detecting MS in women and men, respectively.

Diagnosis, treatment and genetic analysis of a case of hypoglycemia caused by glucokinase gene mutation.

Congenital hyperinsulinemia (CHI) is a disease phenotype characterized by persistent or recurrent hypoglycemia due to abnormal secretion of insulin by ß cells of the pancreas. CHI induced by activation mutation of a single allele of glucokinase (GCK) is the rarest type. In this paper, the clinical data of a patient with hypoglycemia of unknown cause were collected without obvious clinical symptoms. And a heterozygous missense mutation (c.295T> C:p.W99R) was detected in exon 3 of the GCK gene. The mutation was found in both the son and daughter of the proband, and the blood glucose level was low, while the others were normal. By summarizing and analyzing the characteristics of this case and the genetic pedigree of the family, the possibility of congenital hyperinsulinemia caused by a single gene mutation should be considered for hypoglycemia whose etiology is difficult to be determined clinically. This case also provides new clinical data for subsequent genetic studies of the disease.

The Frequency of Intrathyroidal Follicular Helper T Cells Varies with the Progression of Graves' Disease and Hashimoto's Thyroiditis.

OBJECTIVE: Autoimmune thyroid diseases (AITD), mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common organ-specific autoimmune diseases characterized by circulating antibodies and lymphocyte infiltration. Follicular helper T (Tfh) cell dysregulation is involved in the development of autoimmune pathologies. We aimed to explore the role of intrathyroidal and circulating Tfh cells in patients with GD and HT. METHODS: Ultrasound-guided thyroid fine-needle aspiration (FNA) was conducted in 35 patients with GD, 40 patients with HT, and 22 patients with nonautoimmune thyroid disease (nAITD). Peripheral blood samples were also obtained from 40 patients with GD, 40 patients with HT, and 40 healthy controls. The frequencies of intrathyroidal and circulating Tfh cells from FNA and peripheral blood samples were assessed by flow cytometry. Additionally, the correlations between the frequencies of the Tfh cells and the levels of autoantibodies and hormones or disease duration were analyzed. RESULTS: The frequency of intrathyroidal CD4+CXCR5+ICOShigh Tfh cells was higher in HT patients than in GD patients. Significant correlations were identified between the percentages of circulating and intrathyroidal Tfh cells and the serum concentrations of thyroid autoantibodies, especially thyroglobulin antibodies (TgAb), in AITD. Intrathyroidal CD4+CXCR5+ICOShigh Tfh cells were positively correlated with free triiodothyronine (FT3) in HT patients but negatively correlated with FT3 in GD patients. In addition, HT patients with a longer disease duration had an increased frequency of intrathyroidal CD4+CXCR5+ICOShigh and CD4+CXCR5+PD-1+ Tfh cells. In contrast, in the GD patients, a longer disease duration did not affect the frequency of intrathyroidal CD4+CXCR5+ICOShigh but was associated with a lower frequency of CD4+CXCR5+PD-1+ Tfh cells. CONCLUSIONS: Our data suggest that intrathyroidal Tfh cells might play a role in the pathogenesis of AITD and they are potential immunobiomarkers for AITD.

Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles.

OBJECTIVE: To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). RESEARCH DESIGN AND METHODS: In cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance. RESULTS: All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; ß = -0.335, P = 0.004) and taurodeoxycholic acid (TDCA; ß = -0.333, P = 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (ß = 0.335, P = 0.002) was positively correlated with insulin clearance. CONCLUSIONS: Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.

Proteomics and Organoid Culture Reveal the Underlying Pathogenesis of Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT) is an autoimmune disease, and its incidence continues to rise. Although scientists have studied this disease for many years and discovered the potential effects of various proteins in it, the specific pathogenesis is still not fully comprehended. To understand HT and translate this knowledge to clinical applications, we took the mass spectrometric analysis on thyroid tissue fine-needle puncture from HT patients and healthy people in an attempt to make a further understanding of the pathogenesis of HT. A total of 44 proteins with differential expression were identified in HT patients, and these proteins play vital roles in cell adhesion, cell metabolism, and thyroxine synthesis. Combining patient clinical trial sample information, we further compared the transient changes of gene expression regulation in HT and papillary thyroid carcinoma (PTC) samples. More importantly, we developed patient-derived HT and PTC organoids as a promising new preclinical model to verify these potential markers. Our data revealed a marked characteristic of HT organoid in upregulating chemokines that include C-C motif chemokine ligand (CCL) 2 and CCL3, which play a key role in the pathogenesis of HT. Overall, our research has enriched everyone's understanding of the pathogenesis of HT and provides a certain reference for the treatment of the disease.

Autoimmune thyroid disease correlates to islet autoimmunity on zinc transporter 8 autoantibody.

OBJECTIVE: The most common coexisting organ-specific autoimmune disease in patients with type 1 diabetes mellitus (T1DM) is autoimmune thyroid disease (AITD). However, there have been few clinical reports based on a large population about the prevalence of zinc transporter 8 autoantibody (ZnT8A) and other islet autoantibodies in AITD patients. We aimed to explore the presence of islet autoantibodies, ZnT8A, glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen 2 autoantibodies (IA-2A) compared with thyroid autoantibodies, thyroid peroxidase autoantibodies (TPOAb) and thyroglobulin autoantibodies (TGAb) and thyrotropin receptor autoantibodies (TRAb) in patients with Graves' disease (GD), Hashimoto's thyroiditis (HT) and T1DM patients with AITD. METHODS: Totally, 389 patients with GD, 334 patients with HT, 108 T1DM patients with AITD and 115 healthy controls (HC) were recruited in the study. Islet autoantibodies (ZnT8A, GADA and IA-2A) were detected by radioligand binding assay. Thyroid autoantibodies, TPOAb and TGAb were detected by chemiluminescence assay, and TRAb was detected by RIA. RESULTS: The prevalence of ZnT8A, GADA and IA-2A was higher in GD and HT patients than that of HC (ZnT8A: GD 8.48%, HT 10.8% vs HC 1.74%; GADA: GD 7.46%, HT 7.74% vs HC 0.870%; IA-2A: GD 4.88%, HT 3.59% vs HC 0%; All P < 0.05) but lower than that of T1DM subjects with AITD (ZnT8A: 42.6%; IA-2A: 44.4%; GADA: 74.1%; all P < 0.0001). CONCLUSIONS: An increased prevalence of ZnT8A as well as GADA and IA-2A was found in both GD and HT patients, indicating that there is a potential link between thyroid autoimmunity and islet autoimmunity.

Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto's thyroiditis: A prospective randomized-controlled trial.

Selenium (Se) is an essential trace element in human. Recent studies of Se supplementation on the effect of Hashimoto's thyroiditis (HT) have been reported, but the exact benefit is unclear as well as the underlying immunologic mechanism. We aimed to evaluate the clinical effect of Se supplement in patients with HT, and explore the potential mechanism against thyroid autoimmunity. A prospective, randomized-controlled study was performed in patients with HT assigned to two groups. Se-treated group (n = 43) received selenious yeast tablet (SYT) for 6 months, whereas no treatment in control group (n = 47). The primary outcome is the change of thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TGAb). Second, thyroid function, urinary iodine, Se, Glutathione peroxidase3 (GPx3), and Selenoprotein P1 (SePP1) levels were measured during the SYT treatment. Meanwhile, regulatory T cells (Tregs) and their subsets activated Tregs (aTregs), resting Tregs, and secreting Tregs, as well as Helios and PD-1 expression on these cells were also detected. The results showed that SYT treatment significantly decreased TPOAb, TGAb, and thyroid stimulating hormone (TSH) levels, accompanied with the increased Se, GPx3, and SePP1, compared with the control group. Subgroup analysis revealed that subclinical HT may benefit more from this treatment in the decrease of TSH levels by interaction test. Moreover, the percentage of aTregs, Helios/Tregs, and Helios/aTregs were significantly higher in the Se-treated group than control. In conclusion, Se supplementation may have a beneficial effect on thyroid autoantibodies and thyroid function by increasing the antioxidant activity and upregulating the activated Treg cells.

Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 or programmed death 1 and its ligand (programmed death ligand 1) have been approved for the treatment of a variety of cancers. However, ICI therapy is associated with a risk of immune-related adverse events. In this study, we reviewed reported cases of adrenalitis and primary adrenal insufficiency (PAI)-rare but lethal endocrine immune-related adverse events-in patients who underwent ICI therapy. METHODS: We searched multiple databases (PubMed, Web of Science, Cochrane, and Scopus) up to February 2020 for case reports on adrenalitis and PAI caused by ICIs. RESULTS: We identified 15 case reports on ICI-induced adrenalitis and PAI and reviewed their clinical presentation, characteristics, immunologic and imaging features, and treatment. We also developed a screening strategy for PAI in patients treated with ICIs. CONCLUSION: Given the morbidity and mortality associated with acute adrenal crisis, physicians-especially endocrinologists and oncologists-should be aware of this particular risk. PAI caused by autoimmune adrenalitis predominantly occurs in patients treated with programmed death 1 inhibitor monotherapy. PAI often coexists with other endocrinopathies and requires mineralocorticoid as well as glucocorticoid replacement. Even after withdrawal of ICIs, PAI can persist and requires lifelong replacement therapy.

Safety, Pharmacokinetics, and Pharmacodynamics of Globalagliatin, a Glucokinase Activator, in Chinese Patients with Type 2 Diabetes Mellitus: A Randomized, Phase Ib, 28-day Ascending Dose Study.

BACKGROUND AND OBJECTIVES: Globalagliatin, a glucokinase activator, plays a vital role in glucose homeostasis. The aim of this study was to assess the safety, pharmacokinetics, and pharmacodynamics of globalagliatin in Chinese patients with type 2 diabetes. METHODS: In this dose-titration study, 24 patients were randomized (3:1 ratio) to receive globalagliatin or placebo. The 28-day titration was divided into two stages, each comprising 12 subjects. In stage I (low-dose), globalagliatin or placebo was administered at ascending doses of 20, 40, 80, and 120 mg once daily, increased at weekly intervals. As the treatment was well tolerated, stage II (high-dose) was initiated, with ascending doses of 80, 160, 240, and 320 mg. Safety, pharmacokinetic and pharmacodynamic analysis were conducted. RESULTS: Following once-daily titration with ascending doses of globalagliatin of 20-120 mg (stage I) and 80-320 mg (stage II) for 7 days, globalagliatin caused mildly high incidences of hypoglycemia and hypertriglyceridemia. The mean maximum plasma concentration (Cmax) of globalagliatin increased from 7.76 to 138.13 ng/mL (stage I), and 29.36 to 471.50 ng/mL (stage II), which occurred at 3-5 h post-dose. A steady state was achieved after 7 days of once-daily dosing in stage I and stage II, respectively. Mean area under the plasma-concentration curve for steady-state 24-h interval (AUC0-24) increased from 106.13 to 2461.95 ng·h/mL (stage I) and 369.71 to 9218.38 ng·h/mL (stage II). Fasting plasma glucose (FPG) decreased continuously during the titration period. Compared with the placebo, high-dose globalagliatin significantly increased the reductions in FPG, the area under the curve of 24-h glucose levels, and glycated albumin, with least-squares mean changes (relative to baseline) of - 4.08 mmol/L (95% CI - 5.05 to - 3.12) (P < 0.01), - 103.93 mmol/L (95% CI - 135.80 to - 72.06) (P < 0.01), and - 4.71% (95% CI - 6.91 to - 2.51) (P < 0.01)), respectively. High-dose globalagliatin significantly increased the Matsuda index, indicating improved insulin resistance. CONCLUSIONS: Globalagliatin was well tolerated and showed favorable pharmacokinetic profiles in Chinese patients with type 2 diabetes. High-dose globalagliatin reduced plasma glucose, and improved insulin resistance. TRIAL REGISTRATION: Clinicaltrials.gov indentifier, NCT03414892.

ICPis-Induced Autoimmune Polyendocrine Syndrome Type 2: A Review of the Literature and a Protocol for Optimal Management.

CONTEXT: Immune checkpoint inhibitors (ICPis) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand (PD-L1) are now approved to treat a variety of cancers. However, ICPis therapy is associated with a risk of immune-related adverse events (irAEs). Autoimmune polyendocrine syndrome type 2 (APS-2) is a rare endocrine irAE. EVIDENCE ACQUISITION: Several databases (PubMed, Web of Science, Cochrane Central Registry of Controlled Trials, ClinicalTrials.gov, and Scopus) were searched up to February 18, 2020, for case reports on endocrine irAEs and ICPis. The reported side effects and adverse events of the ICPis therapy in the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) adverse events pharmacovigilance registries are also included. EVIDENCE SYNTHESIS: Here, we provide an overview of all published and reported cases (n = 30) of ICPis-induced APS-2. We summarize the clinical characteristics, autoantibodies, human leukocyte antigen (HLA) genotypes, and therapies and propose an APS-2 screening strategy. CONCLUSIONS: Given the life-threatening risks of endocrine dysfunction if it is not promptly recognized (such as diabetic ketoacidosis and acute adrenal crisis), physicians (especially endocrinologists and oncologists) should be familiar with APS-2. After diagnosis of an autoimmune disease induced by ICPis (especially PD-1 inhibitors), patients with a high-risk HLA allele (HLA-DR4) require close monitoring for the development of APS-2.

Efficacy and safety of stem cells transplantation in patients with type 1 diabetes mellitus-a systematic review and meta-analysis.

Stem cells (SCs) therapy is a new promising therapeutic modality for type 1 diabetes (T1DM). We performed a systematic review and meta-analysis to evaluate the efficacy and safety of stem cells transplantation (SCT) in patients with T1DM. We searched five literature databases (MEDLINE, EMBASE, Web of Science, WanFang and CENTRAL) up to 31 October 2019. 29 studies (487 patients with T1DM) were included in our meta-analysis. There was no substantial publication bias. Meta-analysis showed the SCT had significant effect to decrease HbA1c (SMD, 1.40; 95% CI, 0.93 to 1.86; p < 0.00001; I2 = 89%) and to improve C-peptide levels (SMD, -0.62; 95% CI, -1.22 to -0.02; p = 0.04; I2 = 92%) at 1 year follow-up. Subgroup analyses showed the heterogeneity level of the results was high. Significant improvement of metabolic outcomes was observed in the subgroups of mesenchymal stem cells (MSCs) combined with hematopoietic stem cells (HSCs) and HSCs. The older age showed significant association with the efficacy in HSCs subgroup. The higher GADA positive rate before treatment also significantly associated with the decrease of daily insulin requirement. The transient insulin independence rate at last follow-up was 9.6 per 100 person-years (95% CI: 5.8-13.5%). The mean length of insulin independence was 15.6 months (95% CI: 12.3-18.9). The mortality of SCT was 3.4% (95% CI: 2.1-5.5%). Therefore, SCT is an efficacious and safe method for treating patients with T1DM especially in the subgroups of MSCs + HSCs and HSCs. Well designed, double blind and randomized controlled trails with large sample size and long-term follow-up are needed for further evaluation.

Analysis of Regulatory T Cell Subsets and Their Expression of Helios and PD-1 in Patients with Hashimoto Thyroiditis.

Hashimoto thyroiditis (HT) is an autoimmune disease that presumably arises consequent to loss of immune tolerance to autoantigen in thyroid. Regulatory T cells (Tregs) are considered to play a vital role in maintaining the immune balance, as they own intensive suppressive function. This study was undertaken to analyze numbers of Tregs and their expressions of Helios and PD-1 in HT patients. It also aimed to explore the relationship of these with thyroid function and specific autoantibodies. Peripheral blood mononuclear cells (PBMCs) were extracted from blood of 20 healthy controls (HC) and 42 HT patients with varying thyroid functions (10 overt hypothyroidism, 12 subclinical hypothyroidism, and 20 euthyroidism). We performed flow cytometry analysis in PBMCs to detect CD4+CD25+Foxp3+Tregs and their subsets, including CD45RO+Foxp3high activated Treg cells (aTregs), CD45RO-Foxp3low resting Tregs cells (rTregs), and CD45RO+Foxp3low secreting Treg cells (sTregs), as well as the expression of Helios and PD-1 on these cells. The results showed that the percentage of Tregs, aTregs was significantly lower in HT patients and it showed inverse correlation to thyroid function states, in comparison with these in healthy controls. In addition, patients with HT showed decreased expression of Helios in aTregs, while having increased expression of PD-1 in Tregs and sTregs. The levels of Tregs, aTregs, and Helios expressing aTregs were all negatively correlated with antithyroid antibodies. In conclusion, the deficiency of Tregs frequency and aberrant expressions of Helios and PD-1 may possibly contribute to thyroid immune damage in HT.

Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study.

OBJECTIVE: Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS: We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS: We observed a high genetic correlation between children/adolescents and adult T1D case subjects (r g = 0.87), as well as subgroups of autoantibody status (r g ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10-8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10-8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10-232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10-20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10-12), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10-11) and lower fasting C-peptide levels (P = 7.19 × 10-3) in individuals newly diagnosed with T1D. CONCLUSIONS: Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.

A systematic survey on the diagnosis strategy and patient management of type 1 diabetes by Chinese physicians.

The qualification of physicians is a key factor in controlling type 1 diabetes (T1D) since they provide crucial information to their patients about self-management. To investigate whether Chinese physicians' medical strategies influence the control of T1D in their patients, we designed a questionnaire to survey Chinese physicians, which covered their diagnosis and patient-management strategies for T1D. A total of 442 completed questionnaires were received from 35 public hospitals in 12 cities. The results showed Chinese physicians mainly diagnosed T1D based on the clinical features and islet dysfunction. One-third of physicians in this study still prescribed non-basal-bolus insulin regimens to their T1D patients. More than 80% of the doctors prescribed alpha-glucosidase inhibitors as adjunctive therapy, in addition to insulin therapy. Moreover, most of the physicians in China did not pay attention to identify coexistent autoimmune diseases. T1D patients in China were not armed with self-management knowledge and skills, which should be provided by their doctors. One of the circumstances leading to insufficient disease control in Chinese T1D patients is the ineffective therapeutic strategy prescribed by their physicians. We need to promote knowledge of efficient strategies among physicians in China to achieve better disease control in Chinese T1D patients in the future.

Type 2 Diabetes Risk Allele UBE2E2 Is Associated With Decreased Glucose-Stimulated Insulin Release in Elderly Chinese Han Individuals.

Recently, rs163182 in KCNQ1, rs7612463 in UBE2E2, rs7119 in HMG20A, and rs6815464 in MAEA were discovered as type 2 diabetes (T2D) loci unique to Asians, and rs13342692 in SLC16A11 were newly reported as T2D loci in multiethnicities by genome-wide association (GWA) studies. The aim of the present study is to ascertain the potential associations between these variants and T2D risk in the Chinese population, and characterize diabetic-related quantitative traits underlying these variants.A total of 4268 Chinese Han individuals (1754 patients with T2D and 2514 glucose-tolerant health subjects, age ≥40 years) were genotyped for these 5 variants. All the health individuals underwent an oral glucose tolerance test (OGTT), and measures of insulin release and sensitivity were estimated from insulinogenic, BIGTT, Matsuda, and disposition indices. The associations were determined by using logistic regression analysis.After adjustment for age, sex, and BMI, rs163182 in KCNQ1 (P = 0.002) and rs7612463 in UBE2E2 (P = 0.024) were found to be associated with T2D risk in Chinese Han population. The risk C allele of rs7612463 in UBE2E2 is associated with decreased IGI (P = 0.001), BIGTT-AIR (P = 0.002), CIR (P = 0.002), and DI (P = 0.006). The other 4 variants did not associate with insulin release or sensitivity.UBE2E2 rs7612463 may mediate its diabetogenic impact on insulin response, which highly depends on the impairment of ß-cell function.

Association between TSHR gene polymorphism and the risk of Graves' disease: a meta-analysis.

Thyroid stimulating hormone receptor (TSHR) is thought to be a significant candidate for genetic susceptibility to Graves' disease (GD). However, the association between TSHR gene polymorphism and the risk of GD remains controversial. In this study, we investigated the relationship between the two conditions by meta-analysis. We searched all relevant case-control studies in PubMed, Web of Science, CNKI and Wanfang for literature available until May 2015, and chose studies on two single nucleotide polymorphisms (SNPs): rs179247 and rs12101255, within TSHR intron-1. Bias of heterogeneity test among studies was determined by the fixed or random effect pooled measure, and publication bias was examined by modified Begg's and Egger's test. Eight eligible studies with 15 outcomes were involved in this meta-analysis, including 6,976 GD cases and 7,089 controls from China, Japan, Poland, UK and Brazil. Pooled odds ratios (ORs) for allelic comparisons showed that both TSHR rs179247A/G and rs12101255T/C polymorphism had significant association with GD (OR=1.422, 95%CI=1.353-1.495, P<0.001, Pheterogeneity=0.448; OR=1.502, 95%CI: 1.410-1.600, P<0.001, Pheterogeneity=0.642), and the associations were the same under dominant, recessive and co-dominant models. In subgroup analyses, the conclusions are also consistent with all those in Asian, European and South America subgroups (P<0.001). Our meta-analysis revealed a significant association between TSHR rs179247A/G and rs12101255T/C polymorphism with GD in five different populations from Asia, Europe and South America. Further studies are needed in other ethnic backgrounds to independently confirm our findings.