A comprehensive epigenetic network can influence the occurrence of thyroid-associated ophthalmopathy by affecting immune and inflammatory response.

The primary objective of this study is to understand the regulatory role of epigenetics in thyroid-associated ophthalmopathy (TAO) using multi-omics sequencing data. We utilized tRFs sequencing data, DNA methylation sequencing data, and lncRNA/circRNA/mRNA sequencing data, as well as several RNA methylation target prediction websites, to analyze the regulatory effect of DNA methylation, non-coding RNA, and RNA methylation on TAO-associated genes. Through differential expression analysis, we identified 1019 differentially expressed genes, 985 differentially methylated genes, and 2601 non-coding RNA. Functional analysis showed that differentially expressed genes were mostly associated with the PI3K signaling pathway and the IL17 signaling pathway. Genes regulated by DNA epigenetic regulatory networks were mainly related to the Cytokine-cytokine receptor interaction pathway, whereas genes regulated by RNA epigenetic regulatory networks were primarily related to the T cell receptor signaling pathway. Finally, our integrated regulatory network analysis revealed that epigenetics mainly impacts the occurrence of TAO through its effects on key pathways such as cell killing, cytokine production, and immune response. In summary, this study is the first to reveal a new mechanism underlying the development of TAO and provides new directions for future TAO research.

Obesity is associated with subclinical hypothyroidism in the presence of thyroid autoantibodies: a cross-sectional study.

BACKGROUND: Both obesity and subclinical hypothyroidism (SCH) have adverse effects on human body, but the relationship between these two conditions remains inconsistent. The presence of thyroid autoantibodies influences thyroid hormone levels, and may further mediate the interaction between obesity and SCH. This study aimed to explore the association among obesity, SCH and thyroid autoantibodies. METHODS: This study was a cross-sectional survey of 2505 subjects. Obesity was defined as a body mass index ≥28 kg/m2. Serum concentrations of thyroid hormones, thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) were examined. Logistic analysis was used to explore the relation among obesity, SCH and thyroid autoantibodies. RESULTS: A proportion of 11.54% (289/2505) subjects were obese, and 165 subjects had SCH. The positive rates of thyroid autoantibodies, TPO-Ab and Tg-Ab were 17.64% (442/2505), 11.02% (276/2505) and 14.13% (354/2505), respectively. The proportion of SCH was significantly higher in obese than nonobese subjects among those with positive thyroid autoantibodies [22.41% (13/58) vs. 11.72% (45/384), p = 0.025, χ2 test]. Moreover, obesity was significantly associated with SCH in the presence of thyroid autoantibodies after adjusting for confounding factors (OR 2.212, 95% CI 1.103 to 4.433, p = 0.025). A higher proportion of subjects with obesity had Tg-Ab positivity [17.99% (52/289) vs. 13.63% (302/2216), p = 0.045, χ2 test], and obesity remained significantly associated with Tg-Ab positivity by multiple logistic analysis (OR 1.504, 95% CI 1.077 to 2.101, p = 0.017). CONCLUSIONS: Obesity was associated with SCH in the presence of thyroid autoantibodies. Examination of SCH is recommended in obese subjects with thyroid autoantibody positivity.

Iodine nutritional status, the prevalence of thyroid goiter and nodules in rural and urban residents: a cross-sectional study from Guangzhou, China.

OBJECTIVES: A variety of factors differed between rural and urban areas may further influence iodine status and thyroid structure. Hence, this study compared iodine nutrition, the prevalence of thyroid goiter, and nodules between rural and urban residents in Guangzhou, a southern coastal city of China. METHODS: A total of 1211 rural residents and 1305 urban residents were enrolled in this cross-sectional study. A questionnaire regarding personal characteristics was administered. Urinary iodine concentration (UIC) was examined. Ultrasonography of the thyroid was performed to evaluate thyroid goiter and nodules. Multiple logistic analysis was used to identify the potential associated factors. RESULTS: The median UIC was significantly lower in rural residents than in urban residents (120.80 µg/L vs 136.00 µg/L, P < 0.001). Although the coverage rate of iodized salt was much higher in rural residents than in urban residents (99.59% vs 97.29%, P < 0.001), the percentages of seafood intake (8.60% vs 29.29%, P < 0.001), iodine-containing drug consumption (0.33% vs 1.24%, P = 0.011), and iodine contrast medium injection (0.58% vs 1.87%, P = 0.004) were lower in rural residents than in urban residents. Both the prevalence of thyroid goiters and nodules was significantly higher in rural residents than in urban residents (goiter: 8.06% vs 1.20%, P < 0.001; nodules: 61.89% vs 55.04%, P = 0.023). Living in rural areas was associated with thyroid goiter (OR 5.114, 95% CI 2.893-9.040, P < 0.001). CONCLUSIONS: There were differences in iodine nutrition and the prevalence of thyroid goiter and nodules in rural and urban residents in Guangzhou. Differentiated and specialized monitoring is recommended in our area.

Interactions among endotoxin, uric acid, and lactate in relation to the risk of type 2 diabetes: A population-based study.

BACKGROUND: Blood levels of endotoxin, uric acid (UA), or lactate (LAC) are associated with type 2 diabetes mellitus (T2DM). Thus, we explored the interactions among blood endotoxin, UA, and LAC levels and the risk of T2DM. METHODS: This population-based cross-sectional study included 2520 Chinese adults. Fasting blood endotoxin, UA, and LAC levels were determined and the cut-off values were obtained from the receiver operating characteristic curve analysis. The study population was classified into two or four subgroups based on low or high, or both low and high levels of endotoxin, UA, and LAC, respectively. RESULTS: The odds ratios (ORs) for T2DM (all P < .05) were higher in the high groups than the low groups of endotoxin, UA, or LAC, respectively. Participants in the groups with high levels of both endotoxin and UA, endotoxin and LAC, or UA and LAC, had 4.71 (95% CI 3.01-7.37), 5.13 (95% CI 3.29-7.99), or 3.73 (95% CI 2.34-5.94) times higher risk for T2DM compared to those in groups with low levels of both endotoxin and UA, endotoxin and LAC, or UA and LAC (all P < 0.05), respectively. In the interaction analysis, an interactive effect between endotoxin and UA (P < .05), or endotoxin and LAC (P < .05), but not UA and LAC, was observed that contributed to an increased risk of T2DM. CONCLUSIONS: The interaction between levels of endotoxin and UA or levels of endotoxin and LAC was related to an increased risk of T2DM in the Chinese population.

Interactive association of lipopolysaccharide and free fatty acid with the prevalence of type 2 diabetes: A community-based cross-sectional study.

AIMS/INTRODUCTION: Increased blood lipopolysaccharide (LPS) or free fatty acid (FFA) levels correlate with an increased risk of type 2 diabetes. The purpose of the present study was to evaluate the interactive effect of serum LPS and FFA levels on the prevalence of type 2 diabetes. MATERIALS AND METHODS: This cross-sectional study included 2,553 community-dwelling Chinese adults. Fasting serum LPS levels were determined using the Limulus Amebocyte Lysate Chromogenic Endpoint assay, and FFA levels were determined using an enzymatic method. The participants were divided into three groups according to the tertiles of LPS or FFA levels or nine groups according to the tertiles of LPS and FFA levels. The odd ratios (ORs) for type 2 diabetes were estimated using logistic regression analysis. RESULTS: We found that higher serum LPS or FFA levels were associated with higher high-sensitivity C-reactive protein levels (P < 0.001), homeostatic model assessment of insulin resistance levels (P < 0.001) and ORs for type 2 diabetes (P < 0.01). Meanwhile, there were significant interactions between LPS and FFA in terms of the high-sensitivity C-reactive protein level (P < 0.001), homeostatic model assessment of insulin resistance level (P < 0.001) and ORs for type 2 diabetes (P < 0.001). In the fully adjusted logistic regression model, the OR for participants with type 2 diabetes in the higher LPS and FFA level group were 6.58 (95% confidence interval 3.05-14.18, P < 0.001) compared with that in participants in the lower LPS and FFA level group. CONCLUSIONS: The interaction between LPS and FFA was associated with an increased risk of type 2 diabetes in community-dwelling Chinese adults.

Association among plasma lactate, systemic inflammation, and mild cognitive impairment: a community-based study.

The level of lactate in the blood is associated with obesity, blood pressure, and type 2 diabetes. In addition, lactate is a pro-inflammatory cytokine, which plays an important role in the pathogenesis of cognitive impairment. However, the association between blood lactate, systemic inflammation, and mild cognitive impairment (MCI) has not been investigated. The aim of the study is to explore this association in a Chinese population. This community-based cross-sectional study included 2523 Chinese participants aged 18-88 years. Cognitive function was assessed using the Chinese version of the Mini-Mental State Examination. MCI was defined using education-based cutoffs. The concentration of plasma lactate and serum high-sensitivity C-reactive protein (hs-CRP) was measured using the lactate oxidase method and latex enhanced immunoturbidimetric assay, respectively. Compared with participants without a cognitive impairment, participants with a MCI had an increased concentration of plasma lactate and serum hs-CRP (P < 0.001). As blood lactate increased, the concentration of serum hs-CRP and prevalence of MCI also increased (P < 0.001). Logistic regression analysis showed that plasma lactate (odds ratio (OR) 2.76, 95% confidence interval (CI) 2.21-3.45, P < 0.001) and serum hs-CRP (OR 1.15, 95% CI 1.08-1.24, P < 0.001) were significant risk factors for MCI. The adjusted OR for MCI in participants in the fourth lactate quartile was 3.44 (95% CI 2.02-5.88, P < 0.001) compared with the first quartile. Our results showed that plasma lactate is associated with systemic inflammation and MCI.

Interaction Between Lactate and Uric Acid is Associated With a Higher Prevalence of Metabolic Syndrome: A Community-Based Study.

BACKGROUND: Increased blood lactate or uric acid (UA) levels are associated with an increased risk of metabolic syndrome (MS). The aim of this study was to investigate the effect of an interactive association between blood lactate and UA levels on MS. METHODS: This community-based cross-sectional study included 2584 Chinese subjects aged ≥ 18 years. Participants were classified into 3 groups based on lactate or UA level tertiles or into 9 groups based on a combination of lactate and UA level tertiles. RESULTS: The serum high-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels and odds ratios (ORs) for MS increased across the blood lactate or UA level tertiles (all P for trend<0.05). Interactions between lactate and UA with hs-CRP level, HOMA-IR level, and ORs for MS (P<0.05 for all interactions) were also observed. The adjusted ORs for MS in participants in the third tertile of lactate and UA levels, in the third tertile of lactate levels and first tertile of UA levels, and in the first tertile of lactate levels and third tertile of UA levels were 6.02 (95% CI 2.87-12.64, P<0.001), 2.92 (95% CI 1.39-6.10, P=0.005), and 2.70 (95% CI 1.23-5.96, P=0.014), respectively, compared with those in the first tertiles of both lactate and UA levels. CONCLUSION: The interaction between lactate and UA is associated with a higher prevalence of MS in the Chinese population.

Associations of lipid parameters with insulin resistance and diabetes: A population-based study.

OBJECTIVE: A dramatic gap exists between the clinical practice and guidelines for the dyslipidemia control in patients with diabetes. It is still uncertain which routinely available lipid measure is more applicable in estimation of insulin sensitivity and blood glucose control. The present study aims to investigate associations of routine lipid profiles with insulin resistance and diabetes, respectively. METHODS: We conducted a population-based study in 9764 Chinese participants. The homeostasis model assessment of insulin resistance was calculated to estimate insulin sensitivity. Diabetes was diagnosed according to the 1999 World Health Organization diagnostic criteria. RESULTS: Participants with insulin resistance or diabetes presented with significantly higher triglycerides (TG), Non-high-density lipoprotein cholesterol (Non-HDL-C), Non-HDL-C/HDL-C, TG/HDL-C and lower HDL-C when compared with control subjects (all P < 0.0001). Such lipid measures were significantly correlated with fasting insulin, fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) 2 h glucose and Hemoglobin A1c (HbA1c) in Pearson's correlation analysis and multivariate linear regression analysis (all P < 0.0001). In logistic regression analysis, subjects were more likely to have prevalent insulin resistance and diabetes with the elevated quartiles of TG, Non-HDL-C, Non-HDL-C/HDL-C and TG/HDL-C (all P < 0.05). TG/HDL-C ratio, compare with other lipid parameters, have shown the strongest correlation with increased odds of insulin resistance and diabetes. CONCLUSION: Our study suggests a discordant association of lipid parameters with blood glucose level and TG/HDL-C is a better marker for evaluating insulin resistance and diabetes in Chinese population when compared with other routine lipid measures.

Oxamate Enhances the Anti-Inflammatory and Insulin-Sensitizing Effects of Metformin in Diabetic Mice.

Metformin (MET) is the first-line drug for treating type 2 diabetes mellitus (T2DM). However, MET increases blood lactate levels in patients with T2DM. Lactate possesses proinflammatory properties and causes insulin resistance (IR). Oxamate (OXA), a lactate dehydrogenase inhibitor, can decrease tissue lactate production and blood lactate levels. This study was conducted to examine the effects of the combination of OXA and MET on inflammation, and IR in diabetic db/db mice. Supplementation of OXA to MET led to lowered tissue lactate production and serum lactate levels compared to MET alone, accompanied with further decreased tissue and blood levels of pro-inflammatory cytokines, along with better insulin sensitivity, beta-cell mass, and glycemic control in diabetic db/db mice. These results show that OXA enhances the anti-inflammatory and insulin-sensitizing effects of MET through the inhibition of tissue lactate production in db/db mice.

Oxamate Improves Glycemic Control and Insulin Sensitivity via Inhibition of Tissue Lactate Production in db/db Mice.

Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin-resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350-750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice. Meanwhile, OXA reduced the lactate production of adipose tissue and skeletal muscle and serum lactate levels and decreased serum levels of TG, FFA, CRP, IL-6, and TNF-α in db/db mice. The PCR array showed that OXA downregulated the expression of Tnf, Il6, leptin, Cxcr3, Map2k1, and Ikbkb, and upregulated the expression of Irs2, Nfkbia, and Pde3b in the skeletal muscle of db/db mice. Interestingly, LDH-A expression increased in the islet cells of db/db mice, and both treatment of OXA and pioglitazone decreased LDH-A expression, which might be related to the improvement of insulin secretion. Taken together, increased lactate production of adipose tissue and skeletal muscle may be at least partially responsible for insulin resistance and diabetes in db/db mice. OXA improved glycemic control and insulin sensitivity in db/db mice primarily via inhibition of tissue lactate production. Oxamic acid derivatives may be a potential drug for the treatment of type 2 diabetes.

Effect of age on aldosterone/renin ratio (ARR) and comparison of screening accuracy of ARR plus elevated serum aldosterone concentration for primary aldosteronism screening in different age groups.

The serum aldosterone concentration (SAC)/plasma renin activity (PRA) ratio (ARR) is considered a useful screening test in the differential diagnosis of essential hypertension (EH) and primary aldosteronism (PA). The purpose of this study is to investigate the effect of age on ARR and compare the screening accuracy of ARR plus elevated SAC for PA screening in different age groups. Thirty-nine patients with PA, 274 patients with EH, and 153 healthy volunteers were recruited. Blood was sampled for SAC and PRA measuring under keeping upright posture for 1 h. Levels of SAC, PRA, and ARR were compared at different ages range for the respective three groups of subjects. The screening accuracy of ARR plus elevated SAC was compared in different age groups and PA patients served as the same positive subjects. In the EH group, logarithmically transformed ARR (Log-ARR) increased with advancing age and reached its peak in the ≥ 60 years group; in the normotensives group, Log-ARR reached its peak in the 40-49 years group and slightly declined with advancing age. In the PA group, Log-ARR was not age dependent. Screening accuracy increased when combined index of ARR and SAC was used in the ≥ 40 years group but not in the <40 years group. Although the number of EH patients with elevated ARR increased with advancing age, but the screening accuracy and cutoff values of ARR were not affected by age. Using the combined index of ARR and SAC increased the screening accuracy for the patients older than 40 years, but not necessary for the patients younger than 40 years.

[Association between side effects of oral anti-diabetic drugs and self-reported mental health and quality of life among patients with type 2 diabetes].

OBJECTIVE: To examine the association between the side effects of oral anti-diabetic drugs (OAD) and self-reported mental health and quality of life among patients with type 2 diabetes mellitus (T2DM). METHODS: An observational, cross-sectional multicenter study with a retrospective medical chart review was conducted at 16 medical centers from around China. The T2DM patients were followed-up and treated with OAD alone prior to the index visit from January to September 2007. All subjects were ≥30 years old at the time of T2DM diagnosis and had received monotherapy or combination therapy of OAD for at least 6 months. Health-related quality of life was measured by the EuroQol-5D (EQ-5D) and Hypoglycemia Fear Survey (HFS)-II. RESULTS: The symptoms of hypoglycemia were reported by 41.8% (n=203) of participants, and 19.2% (n=93) experienced weight gain. For those reporting hypoglycemia, the scores were higher for HFS-II [7.00 (2.00-19.00) vs 0.00 (0.00-7.00), P<0.01] and lower for EQ-5D (0.90±0.12 vs 0.93±0.13, P=0.003) than those without hypoglycemic symptoms. According to the multivariate linear regression analysis, the symptoms of hypoglycemia were positively correlated with HFS-II (ß=5.78, P<0.01) and negatively with EQ-5D (ß=-0.04, P<0.05) after adjusting for patient and disease characteristics. CONCLUSION: There is a high possibility of hypoglycemic risks among T2DM patients on OAD therapy. The self-reported hypoglycemia is associated with health-related quality of life and hypoglycemic fear. They may have an impact on the long-term prognosis.

Association between peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C.

BACKGROUND: Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1alpha and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1alpha gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C. METHODS: The SNPs in all exons of the PGC-1alpha gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1alpha gene alter the interaction with MEF2C. RESULTS: Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1alpha gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P < 0.01). Even in controls, the 482Ser (A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly (G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between 482Ser variant and MEF2C. CONCLUSIONS: The results suggested that the 482Ser variant of PGC-1alpha conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants (Gly482Ser, Thr394Thr) in the PGC-1alpha gene and MEF2C.