Cardiovascular-kidney-metabolic (CKM) syndrome is highly prevalent among the elderly. Serum uric acid (SUA) may serve as a potential marker for CKM, but evidence on the association between SUA levels and the progression of CKM syndrome remains scarce and controversial. This study aims to investigate the relationship between SUA levels and CKM syndrome in elderly populations by utilizing cohort data from China and the United States. We analyzed 3,299 participants from the Shanghai Friendship Community Elderly Cohort (SFCEC) and 2,372 from the US National Health and Nutrition Examination Survey (NHANES) 2011-2018.SUA was measured using standardized assays. Ordinal logistic regression models were performed. Restricted cubic spline regression (RCS) was performed to visualize the dose-response relationship. The prevalence of CKM syndrome (stages 1-4) was strikingly high in both elderly cohorts (98.33% in the SFCEC cohort and 98.76% in the NHANES cohort). After comprehensive adjustment, multivariable analysis revealed that each 1 mg/dl increase in SUA was associated with 24.9% (OR = 1.249, 95% CI 1.186-1.315) and 27.8% (OR = 1.278, 95% CI 1.174-1.392) elevated risks of CKM stages in the SFCEC and NHANES cohorts, respectively. Compared with the lowest tertile, participants in the highest tertile demonstrated significantly increased CKM risks (SFCEC: OR = 1.966, 95% CI 1.653-2.339; NHANES: OR = 1.975, 95% CI 1.472-2.650). RCS analysis indicated a positive linear dose-response relationship between SUA levels and CKM staging. A significant interaction by sex was observed (P < 0.001), suggesting potential sex differences that warrant further investigation. This study reveals that elevated SUA levels are associated with higher CKM stages in the elderly population.Further research is needed to evaluate the potential role of SUA measurement in CKM risk assessment.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. Although generally indolent, a subset shows aggressive behaviour. Furthermore, the genetic heterogeneity of PTC is not fully explained by known driver mutations, underscoring the need to identify additional susceptibility genes and regulatory mechanisms. To identify additional susceptibility genes and regulatory mechanisms, we integrated transcriptome-wide association studies (TWAS) with summary-data-based Mendelian randomisation (SMR), joint/conditional testing (JCT), and colocalisation analyses across multiple independent cohorts, followed by heterogeneity in dependent instruments (HEIDI) test. Gene prioritisation analyses consistently highlighted TGFB2 and SMAD3 as candidate susceptibility genes for PTC, with SMR supporting putative protective effects. Besides, GEPIA confirmed the positive correlation between TGFB2 and SMAD3 expression in TCGA-THCA. Functional experiments in TPC-1 cells showed that TGFβ2 treatment inhibited cell proliferation and migration, induced apoptosis, and resulted in G0/G1 cell-cycle arrest, accompanied by increased SMAD3 phosphorylation, suggesting activation of canonical TGFβ signalling. Collectively, these findings bridge population-based genetic inference with mechanistic validation and suggest convergent evidence supporting a tumour-suppressive role of the TGFβ2/SMAD3 axis in PTC.

Background:Cardiovascular-kidney-metabolic (CKM) syndrome is an emerging multisystem disorder that predominantly affects older adults. The role of thyroid hormones in its pathogenesis remains underexplored. This study aimed to investigate the associations between thyroid hormone levels and CKM stages in elderly populations. Methods:A total of 3300 participants from the Shanghai Friendship Community Elderly Cohort (SFCEC, enrolled in 2020) and 1153 participants from the US National Health and Nutrition Examination Survey (NHANES 2007-2012) were included. All participants were elderly, defined as aged 60 to 80 years. Thyroid function markers (TSH, FT4, TT4, FT3, TT3) were measured using standardized assays. CKM syndrome was classified into five stages (0-4) according to American Heart Association (AHA) criteria. Multivariable ordinal logistic regression and restricted cubic splines (RCS) were employed to evaluate the associations. Results:The prevalence of CKM (stages 1-4) was strikingly high in both elderly cohorts (98.33% in SFCEC and 98.76% in NHANES). After full adjustment, consistent associations were observed across both cohorts: each 1 ug/dL increase in TT4 was associated with elevated CKM risk (SFCEC: OR=1.064, 95% CI: 1.030-1.100; NHANES: OR=1.145, 95% CI:1.070-1.225). Similarly, each 1 ng/dL increment in FT4 was associated with increased risk (OR=1.538, 95% CI:1.097-2.157 and OR=3.500, 95% CI:1.745-7.020, respectively). Participants in the highest tertile of TT4 exhibited significantly elevated CKM risk compared to the lowest tertile group (SFCEC: OR = 1.304, 95% CI: 1.114-1.528; NHANES: OR = 1.667, 95% CI: 1.219-2.277). A consistent pattern was observed for FT4, with the highest tertile showing increased odds of CKM compared to the lowest (SFCEC: OR = 1.250, 95% CI: 1.066-1.466; NHANES: OR = 1.534, 95% CI: 1.046-2.248). Notably,RCS analyses indicated that both TT4 and FT4 hormone levels were linearly associated with CKM Syndrome. (p- overall <0.05 and p-nonlinear >0.05). However, no significant associations were observed for TSH, FT3, or TT3 in the adjusted models. Conclusion:Elevated levels of TT4 and FT4 are associated with higher CKM stages in elderly populations. These findings suggest that T4 levels may serve as biomarkers for CKM risk stratification. Longitudinal studies are warranted to confirm these associations and to establish causality.

Hyponatremia is strongly associated with syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present an 82-year-old male with refractory hyponatremia unresponsive to the discontinuation of hydrochlorothiazide and comprehensive treatment (fluid restriction, sodium supplementation, and tolvaptan). Two consecutive urine cultures identified extensively drug-resistant Klebsiella pneumoniae (XDRKP). After tigecycline treatment, serum sodium returned to normal and remained stable during one-year follow-up. This case suggests a close relationship between XDRKP infection and SIADH, highlighting the need to evaluate drug-resistant pathogens in patients with refractory hyponatremia and the importance of antimicrobial therapy in the management of electrolyte disorders secondary to drug-resistant urinary tract infections.

The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of the FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.

Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for multiple sclerosis [1] and psoriasis, can inhibit the proliferation of ccRCC cells. Mechanistically, hepatocyte nuclear factor 1β (HNF1B), a transcription factor highly expressed in ccRCC, is succinated by DMF at cysteine residues, leading to its proteasomal degradation. Furthermore, HNF1B interacts with and stabilizes Yes-associated protein (YAP), thus DMF-mediated HNF1B degradation decreases YAP protein level and the expression of its target genes, resulting in the suppression of ccRCC cell proliferation. Importantly, oral administration of DMF sensitizes ccRCC to sunitinib treatment and enhances its efficacy in mice. In summary, we provide evidences supporting DMF as a potential drug for clinical treatment of ccRCC by targeting HNF1B and reveal a previously unrecognized role of HNF1B in regulating YAP in ccRCC.

Background: Previous clinical researches had uncovered lipid-lowering drug could be effective in the therapy of autoimmune thyroid disease (AITD), such as statins could treat Graves' ophthalmopathy (GO). However, whether the association between serum lipids or lipid-lowering targets and AITD is causal remains confusing.Methods: We conducted Mendelian randomization (MR) analysis using genetic variants as instrumental variables (IVs) to investigate the causal association between lipid traits, as well as 10 lipid-lowering drug targets (HMGCR, NPC1L1, PCSK9, ABCG58, LDLR, APOB, APOC3, ANGPTL3, LPL and CETP) and AITD. Summary statistics for AITD, including 3,176 patients with Graves' disease(GD), 691 patients with Graves' ophthalmology (GO) and 539 patients with autoimmune thyroiditis were obtained from latest FinnGen R10 datasets. Inverse-variance-weighted MR (IVW-MR) analysis was used to calculate the causal effects primarily and Summary-data-based MR (SMR) analysis was conducted as validation analysis. Furthermore, sensitivity test, heterogeneity test and positive control were performed to validate the robustness of the results.Findings: Our findings did not support dyslipidaemia as a causal factor for AITD risk (P＞0.05). However, it's worth noting that our analysis observed risk relevance between APOB mediating the level of LDL changes and autoimmune thyroiditis (OR=2.18, 95%CI=1.30-3.64; P =0.003). Similarly, SMR analysis also found APOB based on subcutaneous adipose expression was associated with higher risk of autoimmune thyroiditis (OR=1.16, 95%CI=1.01-1.32; P =0.034). In addition, we also found other therapeutic targets related to autoimmune thyroiditis, such as ANGPTL3 (OR=5.26,95%CI=1.54-17.94; P =0.008), LPL (OR=2.15,95%CI=1.31-3.53; P =0.003) and CETP (OR=0.10,95%CI=0.02-0.48; P =0.005). However, these positive effects were not replicated in SMR analysis. Oppositely, none of the analyses indicated any causal effects for GD or GO (P＞0.05).Interpretation: These findings found that APOB inhibitors might be the most promising therapeutic strategy for autoimmune thyroiditis. However, further clinical trials are needed to confirm this association and explain the underlying mechanisms.Funding: This work was supported by the Natural Science Foundation of Shanghai (Grant Number:22ZR1448700) and Foundation of Shanghai Fifth People's Hospital (Grant Number:2022WYZD01).Declaration of Interest: The authors had nothing to disclose. The funders had no influence on the data collection, analyses or conclusions of the study.

Objective Some observational studies have suggested the association between thyroid function and polycystic ovary syndrome (PCOS). However, it remains to be determined whether these associations are causal or not. The aim of this study was to investigate the underlying causal association between different thyroid function status and PCOS. Methods Bidirectional Mendelian randomization (MR) analysis was conducted to explore the impact of different thyroid function statuses on PCOS. The study included 10,074 individuals with PCOS and 103,164 controls for the primary analysis, with validation analysis repeated in the FinnGen R9 and EstBB PCOS cohorts. Female-specific thyroid function GWAS data were obtained from European population, including Hyperthyroidism (22,383 cases and 54,288 controls) and Hypothyroidism (27,383 cases and 54,288 controls) from the UK Biobank, and TSH (54,288 cases and 72,167 controls) and FT4 (49,269 cases and 72,167 controls) within the reference range from the ThyroidOmics Consortium. Inverse variance weighting (IVW) was chosen as the principal method, and sensitivity analysis was conducted to test for the presence of horizontal pleiotropy or heterogeneity. Results The IVW analysis indicated nominal significance between normal TSH levels and PCOS after adjusted for age and BMI [OR (95% CI) = 0.78(0.62,0.97), P = 0.029], suggesting that maintaining normal TSH levels might act as a protective factor against the pathogenesis of PCOS. Besides, in order to increase the statistical power, we pooled PCOS GWAS above together by meta-analysis and found PCOS contributed to the occurrence of hyperthyroidism [OR(95%CI) = 1.37(0.73,2.57), P = 0.012]. However, no causal relationship was found after Bonferroni correction ( P -value < 0.0031). Conclusion Although the MR analysis didn’t indicate genetic causal association between thyroid function and PCOS after Bonferroni correction. Further efforts are needed to interpret the potential causal relationship between thyroid function and PCOS in different age and BMI subgroup.

Background:Signal transducer and activator of transcription 6 (STAT6) is an important nuclear transcription factor. Previous studies demonstrated that blocking STAT6 can ameliorate thyroid function by reducing serum T3 and T4. Sodium/iodide symporter (NIS) is a key protein that mediates active iodine uptake and plays an important role in regulating thyroid function. This study explored the interaction between STAT6 and NIS. Methods:Immunohistochemical staining was performed for detecting the expression of NIS in different tissues. RT-PCR was performed for evaluating the mRNA level of NIS when Nthy-ori 3-1 cells were incubated with IL4, thyroid stimulating hormone (TSH), or monoclonal thyroid-specific stimulatory autoantibody (TSAb) for 24 h. Quantitative RT-PCR, western blot, and immunofluorescence analysis were performed for detecting NIS expression after inhibiting STAT6 phosphorylation by AS1517499. Finally, we used luciferase reporter assays to explore the ability of STAT6 to regulate the promoter activity of the NIS-coding gene. Results:NIS was highly expressed in thyroid epithelial cells of EAGD mice or Graves' disease (GD) patients, and TSAb increased the expression of NIS. We show that a STAT6 phosphorylation inhibitor can attenuate the effect of TSAb on increasing NIS protein and mRNA levels. Finally, we confirm that transcription factor STAT6 can mediate NIS transcription and co-activator P100 protein can enhance STAT6-dependent transcriptional activation. Conclusion:In GD, TSAb induces STAT6 signaling to upregulate NIS expression, and STAT6 blockade ameliorates thyroid function via downregulation of the NIS. Our study furthers understanding of the effects of STAT6 on thyroid function and reveals new avenues for GD treatment.

Previous observational studies found associations between Helicobacter pylori infection and autoimmune thyroid diseases (AITDs), but the causal nature of this association is still uncertain. We investigated the causal effect of six crucial antibodies against H. pylori on AITDs using a bidirectional Mendelian randomization (MR). We found that anti– H. pylori outer membrane protein (OMP) significantly increased the risk of hyperthyroidism and Graves’ disease (GD). In addition, our reverse MR analysis indicated that hyperthyroidism could increase the levels of cytotoxin-associated gene A and OMP antibodies. We also observed causal roles of GD on anti– H. pylori OMP. Our analyses indicate the mutual effects of H. pylori infection and AITDs, suggesting the existence of a gut-thyroid axis. These results also provide evidence of the bidirectional causal association between anti– H. pylori OMP with hyperthyroidism and GD, resulting in a vicious circle.

BACKGROUND:Vitamin D was shown to directly exert a protective effect on diabetic kidney disease (DKD) in our previous study. However, whether it has an effect on perirenal adipose tissue (PRAT) or the intestinal flora and its metabolites (trimethylamine N-oxide, TMAO) is unclear. METHODS:DKD mice were received different concentrations of 1,25-(OH)2D3 for 2 weeks. Serum TNF-α levels and TMAO levels were detected. 16S rRNA sequencing was used to analyze gut microbiota. qPCR was used to detect the expression of TLR4, NF-Κb, PGC1α, and UCP-1 in kidney and adipose tissue. Histological changes in kidney and perirenal adipose tissue were observed using HE, PAS, Masson and oil red staining. Immunofluorescence and immunohistochemistry were used to detect the expression of VDR, PGC1α, podocin, and UCP-1 in kidney and adipose tissue. Electron microscopy was used to observe the pathological changes in the kidney. VDR knockout mice were constructed to observe the changes in the gut and adipose tissue, and immunofluorescence and immunohistochemistry were used to detect the expression of UCP-1 and collagen IV in the kidney. RESULTS:1,25-(OH)2D3 could improve the dysbiosis of the intestinal flora of mice with DKD, increase the abundance of beneficial bacteria, decrease the abundance of harmful bacteria, reduce the pathological changes in the kidney, reduce fat infiltration, and downregulate the expression of TLR4 and NF-κB in kidneys. The serum TMAO concentration in mice with DKD was significantly higher than that of the control group, and was significantly positively correlated with the urine ACR. In addition, vitamin D stimulated the expression of the surface markers PGC1α, UCP-1 and VDR in the PRAT in DKD mice, and TMAO downregulated the expression of PRAT and renal VDR. CONCLUSIONS:The protective effect of 1,25-(OH)2D3 in DKD mice may affect the intestinal flora and its related metabolite TMAO on perirenal fat and kidneys.

BACKGROUND The incidence of differentiated thyroid cancer (DTC) has been increasing in recent years with high risk of recurrence and metastasis. Inducing programmed cell death (PCD) is one of the most promising therapy in the development of anti-DTC agents. However, which genes play the key roles in DTC remain unclear. METHODS Based on 14 kinds of PCD patterns, we leveraged Summary-data-based Mendelian randomization (SMR) analysis, integrating DTC GWAS (Cases comprised of 649 patients had histological proven) with expression quantitative trait loci (eQTL) from blood in eQTLGen and verifed in thyroid tissues of GTExV8 to explore the causality between different PCD genes and DTC in genomic and transcriptomic backgrounds. scRNA-seq analysis was linked to individual genetic variation to reveal cell specificity in peripheral blood mononuclear cells (PBMCs) and tumor microenvironment, respectively. Furthermore, we also analyzed the relationship of susceptibility genes and immune infiltration and clinicl correlation with the pathological stages. RESULTS The results suggested that 55 PCD genes in blood exhibited association with DTC, 48 of which were enriched in PBMCs. 13 genes were found in thyroid tissue cis-eQTL, 12 of which could be verified in tumor microenvironment. Among these, 6 genes consistently replicated in both blood and thyroid tissues were proposed preferentially. These genes were associated with 3 distinct PCD patterns: Apoptosis (NFATC4, RPS3 and TM2D1), Lysosome-dependent cell death (CTNS and GCC2), Autophagy (TPCN2). Besides, the expression levels of RRPS3 and TM2D1 genes in elderly (> 65 years old) patients with thyroid cancer were significantly lower than those in young. And it was worth noting that the expression levels of CTNS, GCC2, TM2D1 and TPCN2 genes gradually decreased with the increase of T stage. CONCLUSIONS This study uncovered several PCD related genes protecting against the development of DTC. These results provide a basis for further exploring the regulatory mechanisms of PCD on DTC, which might open up new therapy target for DTC based on inducing in programmed cell death.

BACKGROUND:Diabetic kidney disease (DKD) is the most frequent complication in patients with type 2 diabetes mellitus (T2DM). It causes a chronic and progressive decline in kidney function, and ultimately patients require renal replacement therapy. To date, an increasing number of clinical studies have been conducted to explore the potential and novel biomarkers, which can advance the diagnosis, estimate the prognosis, and optimize the therapeutic strategies at the early stage of DKD. In the current study, we sought to investigate the association of plasma myoglobin with DKD.METHODS:A total of 355 T2DM patients with DKD and 710 T2DM patients without DKD were enrolled in this study. Laboratory parameters including blood cell count, hemoglobin A1c, biochemical parameters, and plasma myoglobin were recorded. Patients were classified on admission according to the tertile of myoglobin and clinical parameters were compared between the groups. Pearson correlation analysis, linear regression, logistic regression, receiver operating characteristics (ROC) analysis, and spline regression were performed.RESULTS:Plasma myoglobin significantly increased in patients with DKD and was associated with renal function and inflammatory parameters. Plasma myoglobin was an independent risk factor for the development of DKD. The area under ROC curve of myoglobin was 0.831. Spline regression showed that there was a significant linear association between DKD incidence and a high level of plasma myoglobin when it exceeded 36.4 mg/mL.CONCLUSIONS:This study shows that elevated plasma myoglobin level is closely associated with the development of kidney injury in patients with T2DM.

Background Advanced glycation end products (AGEs) deposited in the lens are correlated with those in the kidneys, indicating a possible value in evaluating diabetic kidney disease (DKD). This study explored the value of noninvasively measuring lens AGEs to diagnose and evaluate the severity of diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM). Methodology A total of 134 T2DM patients admitted to the Fifth People's Hospital of Shanghai from March 2020 to May 2021 were selected randomly. Patients were divided into low-, medium-and high-risk groups according to the risk assessment criteria for DKD progression and into DKD and non-DKD (non-DKD) groups according to the Guidelines for the Prevention and Treatment of Diabetic Nephropathy in China. The concentrations of noninvasive AGEs in the lens in all the groups were retrospectively analyzed. Results The concentration of noninvasive lens AGEs in the high-risk patients, according to the 2012 guidelines of the Global Organization for Improving the Prognosis of Kidney Diseases, was significantly higher than that in the remaining groups. Regression analysis suggested the value of lens AGEs in diagnosing DKD and evaluating DKD severity. Cox regression analysis indicated that the noninvasive lens AGE concentration was positive correlated with the course of disease. Conclusion The receiver operating characteristic (ROC) curve suggested that using noninvasive lens AGE measurements has clinical value in the diagnosis of DKD (area under the curve 62.4%,95% confidence interval (CI) 52.4%–73.9%, p = 0.014) and in assessing the severity of DKD (area under the curve 83.2%, 95% CI 74.1%–92.3%, P < 0.001). Noninvasive lens AGE testing helps screen T2DM patients for DKD and evaluate the severity of DKD.

Objective Neutropenia is a complication of Graves' disease (GD), but there is currently no means by which to predict its occurrence. This study aimed to investigate the risk factors for the development of neutropenia in untreated GD. Methods This was a retrospective cohort study. Between January 1, 2010, and July 31, 2020, 1000 patients with new-onset or relapsing GD without treatment were enrolled in the study and divided into two groups: neutropenia group (neutrophil count < 2 × 109/L) and non-neutropenia group (neutrophil count ≥ 2 × 109/L). Clinical characteristics of subjects were compared between the two groups, and logistic regression analysis was applied to determine risk factors for neutropenia. To further explore the correlation of radioactive iodine uptake (RAIU) with neutropenia, subjects were first classified according to quartile of 3 h RAIU and 24 h RAIU prior to logistic regression analysis. Results Of all patients recruited, 293 (29.6%) were diagnosed with neutropenia. Compared with non-neutropenic patients, those with neutropenia had a higher level of free thyroxine (FT4) (56.64 ± 31.80 vs 47.64 ± 39.64, P = 0.001), 3 h RAIU (55.64 ± 17.04 vs 49.80 ± 17.21, P < 0.001) and 24 h RAIU (67.38 ± 12.54 vs 64.38 ± 13.58, P < 0.001). Univariate logistic regression analysis revealed that FT4, 3 h RAIU, 24 h RAIU, creatinine, and low-density lipoprotein were risk factors for development of neutropenia in GD. After adjusting for confounding factors of age, BMI, and sex, we determined that 3 h RAIU and 24 h RAIU (Model 1: OR = 1.021, 95% CI: 1.008–1.033, P = 0.001; Model 2: OR = 1.023, 95% CI: 1.007–1.039, P = 0.004), but not FT4, were associated with the development of neutropenia. Conclusions RAIU is associated with neutropenia in patients with untreated GD.

Objective To explore the relationship between estradiol (E2) and thyroid function during the second trimester of pregnancy and the effect of E2 on sodium iodide transporter (NIS) expression in cultured thyroid cells. Materials and methods We analyzed relationships between E2 and thyroid function in 196 pregnant women during the second trimester. Multiple linear regression analysis was performed between E2 and thyroid function. The human thyroid Nthy-ori3-1 cells were cultured in different E2 concentrations, and the mRNA levels of NIS, estrogen receptor (ER)-α, and ER-β were measured by quantitative real-time PCR. Their protein levels were assessed by western blot. Results E2 was positively correlated with thyroid-stimulating hormone (TSH) and negatively correlated with free thyroxine (FT4) (P < 0.05). When we corrected for age, BMI, alanine aminotransferase, and serum creatinine, E2 was still negatively correlated with FT4 (P < 0.5) during the second trimester. In Nthy-ori3-1 cells treated with 10 nM E2, NIS and ER-β mRNA levels were significantly reduced, while ER-α mRNA level was not altered (P > 0.5). Moreover, 10 nM E2 significantly decreased protein levels of ER-β, phosphorylated versions of protein kinase A (p-PKA), phosphorylated versions of cAMP response element-binding protein (p-CREB), and NIS, while treatment with the ER-β inhibitor restored the expression of p-PKA, p-CREB, and NIS (P < 0.05). Conclusion High concentration of E2 has a negative correlation with FT4. High concentration of E2 can inhibit the NIS expression through the ER-β-mediated pathway, which may cause thyroid hormone fluctuations during pregnancy.

桥本甲状腺炎( HT)又名慢性淋巴细胞细胞性甲状腺炎,发病核心是炎性细胞及炎症因子浸润甲状腺[1].最新研究发现,HT患者可伴有胰岛素抵抗( IR) [2-3] ,甲状腺功能亢进或减退均伴有不同程度的IR,但具体机制尚不清楚.此外,有学者发现HT患者肾脏组织甲状腺过氧化物酶抗体( TPO )染色阳性,也反映出HT患者中多器官的自身免疫损害[4].IR是一种慢性系统性低度炎症,巨噬细胞( M?)浸润内脏脂肪是IR发生的关键步骤[5].脂肪组织的M?存在不同的表型:M1 型M?,主要参与促进细胞免疫和炎症;M2 型M?,主要参与减轻炎症的发生[6] ,促进组织的修复.本课题组前期研究发现甲状腺功能正常的HT患者及诱导HT模型小鼠均伴有IR,本研究通过检测HT患者大网膜内M?的水平,明确内脏脂肪M?水平与IR的相关性及M?在其中所扮演的角色,为探讨IR治疗新靶点提供依据.

BACKGROUND:This study aims to investigate the potential association of peripheral inflammatory blood cell parameters with the incidence and progression of chronic kidney disease (CKD) in patients with diabetes. METHODS:The cross-sectional study included 1192 subjects with diabetes derived from one center. The cohort study included 2060 subjects with diabetes derived from another two centers followed up for 4 years. Logistic regression and Cox proportional hazards models were used to evaluate the association of peripheral inflammatory blood cell with CKD. RESULTS:In the cross-sectional study, neutrophil count performed best as an independent risk factor for CKD (odds ratio 2.556 [95% confidence interval 1.111, 5.879]) even after 1:1 case-control matching for age, gender, history of high blood pressure and duration of diabetes. Spline regression revealed a significant linear association of CKD incidence with continuous neutrophil count in excess of 3.6 × 109 /L. In the cohort study, subjects were grouped based on tertile of neutrophil count and neutrophil-to-lymphocyte ratio. Cox regression analysis results showed that only neutrophil count was independently associated with CKD progression (the highest group vs. the lowest group, hazard ratio 2.293 [95% confidence interval 1.260, 4.171]) after fully adjusting for potential confounders. The cumulative incidence of CKD progression in patients with diabetes gradually increased with increasing neutrophil count (53 (7.7%) subjects in the lowest group vs. 60 (8.2%) in the middle group vs. 78 (12.2%) in the highest group). CONCLUSIONS:This study suggested that neutrophil count is an independent risk factor for progression of CKD in patients with diabetes.

Abstract Background This study aims to investigate the potential association of peripheral inflammatory blood cell parameters with the incidence and progression of chronic kidney disease (CKD) in patients with diabetes. Methods The cross‐sectional study included 1192 subjects with diabetes derived from one center. The cohort study included 2060 subjects with diabetes derived from another two centers followed up for 4 years. Logistic regression and Cox proportional hazards models were used to evaluate the association of peripheral inflammatory blood cell with CKD. Results In the cross‐sectional study, neutrophil count performed best as an independent risk factor for CKD (odds ratio 2.556 [95% confidence interval 1.111, 5.879]) even after 1:1 case–control matching for age, gender, history of high blood pressure and duration of diabetes. Spline regression revealed a significant linear association of CKD incidence with continuous neutrophil count in excess of 3.6 × 109/L. In the cohort study, subjects were grouped based on tertile of neutrophil count and neutrophil‐to‐lymphocyte ratio. Cox regression analysis results showed that only neutrophil count was independently associated with CKD progression (the highest group vs. the lowest group, hazard ratio 2.293 [95% confidence interval 1.260, 4.171]) after fully adjusting for potential confounders. The cumulative incidence of CKD progression in patients with diabetes gradually increased with increasing neutrophil count (53 (7.7%) subjects in the lowest group vs. 60 (8.2%) in the middle group vs. 78 (12.2%) in the highest group). Conclusions This study suggested that neutrophil count is an independent risk factor for progression of CKD in patients with diabetes.

CONTEXT:The immune system plays a central role in the pathophysiology of gestational diabetes mellitus (GDM). Monocytes, the main innate immune cells, are especially important in the maintenance of a normal pregnancy. OBJECTIVE:Here, we investigated the potential effect of monocytes in GDM. METHODS:Monocyte count was monitored throughout pregnancy in 214 women with GDM and 926 women without in a case-control and cohort study. Circulating levels of inflammatory cytokines, placenta-derived macrophages, and their products were measured. RESULTS:Throughout pregnancy, monocyte count was significantly decreased in women with GDM, and was closely associated with glucose level, insulin resistance, and newborn weight. First-trimester monocyte count outperformed that of the second and third trimester as a risk factor and diagnostic predictor of GDM and macrosomia both in the case-control and cohort study. In addition, our cohort study showed that as first-trimester monocyte count decreased, GDM and macrosomia incidence, glucose level, and newborn weight increased in a stepwise manner. Risk of GDM started to decrease rapidly when first-trimester monocyte count exceeded 0.48 × 109/L. Notably, CD206 and interleukin 10 (IL-10) were significantly lower, whereas CD80, CD86, tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6) were higher both in GDM placental tissue and peripheral blood. First-trimester monocyte count was positively related to IL-10 and CD206, but negatively related to CD80, CD86, TNF-α, and IL-6. CONCLUSION:Decreased monocyte count throughout pregnancy was closely associated with the development of GDM, macrosomia, and the chronic inflammatory state of GDM. First-trimester monocyte count has great potential as an early diagnostic marker of GDM.