Pub Date : 2024-08-09DOI: 10.3389/fendo.2024.1380047
John B. Psaltis, Qiaochu Wang, Gai Yan, Reem Gahtani, Nanxi Huang, Bassem R. Haddad, Mary Beth Martin
The estrogen receptor alpha (ERα) plays a central role in the etiology, progression, and treatment of breast cancers. Constitutively activating somatic mutations Y537S and D538G, in the ligand binding domain (LBD) of ESR1, are associated with acquired resistance to endocrine therapies. We have previously shown that the metalloestrogen calcium activates ERα through an interaction with the LBD of the receptor. This study shows that cadmium activates ERα through a mechanism similar to calcium and contributes to, and further increases, the constitutive activity of the ERα mutants Y537S and D538G. Mutational analysis identified C381, N532A, H516A/N519A/E523A, and E542/D545A on the solvent accessible surface of the LBD as possible calcium/metal interaction sites. In contrast to estradiol, which did not increase the activity of the Y537S and D538G mutants, cadmium increased the activity of the constitutive mutants. Mutation of the calcium/metal interaction sites in Y537S and D538G mutants resulted in a significant decrease in constitutive activity and cadmium induced activity. Mutation of calcium/metal interaction sites in wtERα diminished binding of the receptor to the enhancer of estrogen responsive genes and the binding of nuclear receptor coactivator 1 and RNA polymerase II. In contrast to wtERα, mutation of the calcium/metal interaction sites in the Y537S and D538G mutants did not diminish binding to DNA but prevented a stable interaction with the coactivator and polymerase. Growth assays further revealed that calcium channel blockers and chelators significantly decreased the growth of MCF7 cells expressing these constitutively active mutants. Taken together, the results suggest that exposure to cadmium plays a role in the etiology, progression, and response to treatment of breast cancer due, in part, to its ability to activate ERα.
{"title":"Cadmium activation of wild-type and constitutively active estrogen receptor alpha","authors":"John B. Psaltis, Qiaochu Wang, Gai Yan, Reem Gahtani, Nanxi Huang, Bassem R. Haddad, Mary Beth Martin","doi":"10.3389/fendo.2024.1380047","DOIUrl":"https://doi.org/10.3389/fendo.2024.1380047","url":null,"abstract":"The estrogen receptor alpha (ERα) plays a central role in the etiology, progression, and treatment of breast cancers. Constitutively activating somatic mutations Y537S and D538G, in the ligand binding domain (LBD) of ESR1, are associated with acquired resistance to endocrine therapies. We have previously shown that the metalloestrogen calcium activates ERα through an interaction with the LBD of the receptor. This study shows that cadmium activates ERα through a mechanism similar to calcium and contributes to, and further increases, the constitutive activity of the ERα mutants Y537S and D538G. Mutational analysis identified C381, N532A, H516A/N519A/E523A, and E542/D545A on the solvent accessible surface of the LBD as possible calcium/metal interaction sites. In contrast to estradiol, which did not increase the activity of the Y537S and D538G mutants, cadmium increased the activity of the constitutive mutants. Mutation of the calcium/metal interaction sites in Y537S and D538G mutants resulted in a significant decrease in constitutive activity and cadmium induced activity. Mutation of calcium/metal interaction sites in wtERα diminished binding of the receptor to the enhancer of estrogen responsive genes and the binding of nuclear receptor coactivator 1 and RNA polymerase II. In contrast to wtERα, mutation of the calcium/metal interaction sites in the Y537S and D538G mutants did not diminish binding to DNA but prevented a stable interaction with the coactivator and polymerase. Growth assays further revealed that calcium channel blockers and chelators significantly decreased the growth of MCF7 cells expressing these constitutively active mutants. Taken together, the results suggest that exposure to cadmium plays a role in the etiology, progression, and response to treatment of breast cancer due, in part, to its ability to activate ERα.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"49 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.3389/fendo.2024.1430675
XuWen Zheng, MaoBing Chen, Zhuang Yi, Liang Zhao, YongJun Qian, Jin Xu, JinNuo Fan
Numerous research studies have indicated a possible association between type 2 diabetes (T2DM) and gut microbiota. To explore specific metabolic pathways connecting gut microbiota and T2DM, we employed Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC) techniques.This research utilized data from genome-wide association studies (GWAS) that are publicly accessible. We evaluated the genetic correlation between gut microbiota and T2DM using LDSC. Causality was primarily determined through the inverse variance weighted (IVW) method. To verify the robustness of our results, we conducted sensitivity analyses using several approaches, including the weighted median, MR-Egger, and MR-PRESSO. We integrated summary effect estimates from LDSC, along with forward and reverse MR, into a meta-analysis for T2DM using various data sources. Additionally, mediation analysis was performed to explore the impact of plasma metabolites on the relationship between gut microbiota and T2DM.Our study indicated a significant genetic correlation between genus RuminococcaceaeUCG005 (Rg = −0.26, Rg_P = 2.07×10−4) and T2DM. Moreover, the forward MR analysis identified genus RuminococcaceaeUCG010 (OR = 0.857, 95% CI 0.795, 0.924; P = 6.33×10−5) and order Clostridiales (OR = 0.936, 95% CI 0.878, 0.997; P = 0.039) as being significantly associated with a decreased risk of T2DM. The analysis also highlighted several plasma metabolites as significant mediators in these relationships, with metabolites like octadecadienedioate (C18:2-DC) and branched chain 14:0 dicarboxylic acid being notably involved.The findings demonstrate a significant impact of gut microbiota on T2DM via plasma metabolites, suggesting potential metabolic pathways for therapeutic targeting. This study enhances our understanding of the microbiota’s role in T2DM pathogenesis and supports the development of microbiota-based interventions.
{"title":"Genetic associations between gut microbiota and type 2 diabetes mediated by plasma metabolites: a Mendelian randomization study","authors":"XuWen Zheng, MaoBing Chen, Zhuang Yi, Liang Zhao, YongJun Qian, Jin Xu, JinNuo Fan","doi":"10.3389/fendo.2024.1430675","DOIUrl":"https://doi.org/10.3389/fendo.2024.1430675","url":null,"abstract":"Numerous research studies have indicated a possible association between type 2 diabetes (T2DM) and gut microbiota. To explore specific metabolic pathways connecting gut microbiota and T2DM, we employed Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC) techniques.This research utilized data from genome-wide association studies (GWAS) that are publicly accessible. We evaluated the genetic correlation between gut microbiota and T2DM using LDSC. Causality was primarily determined through the inverse variance weighted (IVW) method. To verify the robustness of our results, we conducted sensitivity analyses using several approaches, including the weighted median, MR-Egger, and MR-PRESSO. We integrated summary effect estimates from LDSC, along with forward and reverse MR, into a meta-analysis for T2DM using various data sources. Additionally, mediation analysis was performed to explore the impact of plasma metabolites on the relationship between gut microbiota and T2DM.Our study indicated a significant genetic correlation between genus RuminococcaceaeUCG005 (Rg = −0.26, Rg_P = 2.07×10−4) and T2DM. Moreover, the forward MR analysis identified genus RuminococcaceaeUCG010 (OR = 0.857, 95% CI 0.795, 0.924; P = 6.33×10−5) and order Clostridiales (OR = 0.936, 95% CI 0.878, 0.997; P = 0.039) as being significantly associated with a decreased risk of T2DM. The analysis also highlighted several plasma metabolites as significant mediators in these relationships, with metabolites like octadecadienedioate (C18:2-DC) and branched chain 14:0 dicarboxylic acid being notably involved.The findings demonstrate a significant impact of gut microbiota on T2DM via plasma metabolites, suggesting potential metabolic pathways for therapeutic targeting. This study enhances our understanding of the microbiota’s role in T2DM pathogenesis and supports the development of microbiota-based interventions.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"34 35","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Depression ranks as a leading contributor to the global disease burden. The potential causal relationship between the use of antihypertensive medications and depression has garnered significant interest. Despite extensive investigation, the nature of this relationship remains a subject of ongoing debate. Therefore, this study aims to evaluate the influence of antihypertensive medications on depression by conducting a Mendelian randomization study focused on drug targets.We focused on the targets of five antihypertensive drug categories: ACE Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), Calcium Channel Blockers (CCBs), Beta-Blockers (BBs), and Thiazide Diuretics (TDs). We collected single-nucleotide polymorphisms (SNPs) associated with these drug targets from genome-wide association study (GWAS) statistics, using them as proxies for the drugs. Subsequently, we conducted a Mendelian randomization (MR) analysis targeting these drugs to explore their potential impact on depression.Our findings revealed that genetic proxies for Beta-Blockers (BBs) were associated with an elevated risk of depression (OR [95%CI] = 1.027 [1.013, 1.040], p < 0.001). Similarly, genetic proxies for Calcium Channel Blockers (CCBs) were linked to an increased risk of depression (OR [95%CI] = 1.030 [1.009, 1.051], p = 0.006). No significant associations were identified between the genetic markers of other antihypertensive medications and depression risk.The study suggests that genetic proxies associated with Beta-Blockers (BBs) and Calcium Channel Blockers (CCBs) could potentially elevate the risk of depression among patients. These findings underscore the importance of considering genetic predispositions when prescribing these medications, offering a strategic approach to preventing depression in susceptible individuals.
{"title":"The causal relationship between antihypertensive drugs and depression: a Mendelian randomization study of drug targets","authors":"Zixian Yang, Jinshuai Li, Peichu Huang, Zhichang Li, Jianfeng He, Dongchun Cai, Yuzheng Lai","doi":"10.3389/fendo.2024.1411343","DOIUrl":"https://doi.org/10.3389/fendo.2024.1411343","url":null,"abstract":"Depression ranks as a leading contributor to the global disease burden. The potential causal relationship between the use of antihypertensive medications and depression has garnered significant interest. Despite extensive investigation, the nature of this relationship remains a subject of ongoing debate. Therefore, this study aims to evaluate the influence of antihypertensive medications on depression by conducting a Mendelian randomization study focused on drug targets.We focused on the targets of five antihypertensive drug categories: ACE Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), Calcium Channel Blockers (CCBs), Beta-Blockers (BBs), and Thiazide Diuretics (TDs). We collected single-nucleotide polymorphisms (SNPs) associated with these drug targets from genome-wide association study (GWAS) statistics, using them as proxies for the drugs. Subsequently, we conducted a Mendelian randomization (MR) analysis targeting these drugs to explore their potential impact on depression.Our findings revealed that genetic proxies for Beta-Blockers (BBs) were associated with an elevated risk of depression (OR [95%CI] = 1.027 [1.013, 1.040], p < 0.001). Similarly, genetic proxies for Calcium Channel Blockers (CCBs) were linked to an increased risk of depression (OR [95%CI] = 1.030 [1.009, 1.051], p = 0.006). No significant associations were identified between the genetic markers of other antihypertensive medications and depression risk.The study suggests that genetic proxies associated with Beta-Blockers (BBs) and Calcium Channel Blockers (CCBs) could potentially elevate the risk of depression among patients. These findings underscore the importance of considering genetic predispositions when prescribing these medications, offering a strategic approach to preventing depression in susceptible individuals.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"41 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.3389/fendo.2024.1473603
M. D. Baldassarre, Teresa Paolucci, Kyoungmin Park, Caterina Pipino
{"title":"Editorial: Preventing cardiovascular complications of type 2 diabetes","authors":"M. D. Baldassarre, Teresa Paolucci, Kyoungmin Park, Caterina Pipino","doi":"10.3389/fendo.2024.1473603","DOIUrl":"https://doi.org/10.3389/fendo.2024.1473603","url":null,"abstract":"","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"27 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We investigated the capability and imaging criteria of T1 mapping and arterial spin labeling (ASL) MRI to identify renal injury in patients with liver cirrhosis.We recruited 27 patients with cirrhosis and normal renal function (cirrhosis-NR), 10 with cirrhosis and renal dysfunction (cirrhosis-RD) and 23 normal controls (NCs). All participants were examined via renal T1 mapping and ASL imaging. Renal blood flow (RBF) derived from ASL was measured from the renal cortex, and T1 values were measured from the renal parenchyma (cortex and medulla). MRI parameters were compared between groups. Diagnostic performances for detecting renal impairment were statistically analyzed.Cortical T1 (cT1) and medullary T1 (mT1) were significantly lower in the NCs than in the cirrhosis-NR group. The cortical RBF showed no significant changes between the NCs and cirrhosis-NR group but was markedly decreased in the cirrhosis-RD group. The areas under the curve (AUCs) for discriminating cirrhosis-NR from NCs were 0.883 and 0.826 by cT1 and mT1, respectively. Cortical RBF identified cirrhosis-RD with AUC of 0.978, and correlated with serum creatinine (r = −0.334) and the estimated glomerular filtration rate (r = 0.483). A classification and regression tree based on cortical RBF and cT1 achieved 85% accuracy in detecting renal impairment in the cirrhosis.Renal T1 values might be sensitive predictors of early renal impairment in patients with cirrhosis-NR. RBF enabled quantifying renal perfusion impairment in patients with cirrhosis-RD. The diagnostic algorithm based on cortical RBF and T1 values allowed detecting renal injury during cirrhosis.
{"title":"T1 mapping combined with arterial spin labeling MRI to identify renal injury in patients with liver cirrhosis","authors":"Shuangshuang Xie, Mengyao Chen, Chiyi Chen, Yumeng Zhao, Jiaming Qin, Caixin Qiu, Jinxia Zhu, M. Nickel, Bernd Kuehn, Wen Shen","doi":"10.3389/fendo.2024.1363797","DOIUrl":"https://doi.org/10.3389/fendo.2024.1363797","url":null,"abstract":"We investigated the capability and imaging criteria of T1 mapping and arterial spin labeling (ASL) MRI to identify renal injury in patients with liver cirrhosis.We recruited 27 patients with cirrhosis and normal renal function (cirrhosis-NR), 10 with cirrhosis and renal dysfunction (cirrhosis-RD) and 23 normal controls (NCs). All participants were examined via renal T1 mapping and ASL imaging. Renal blood flow (RBF) derived from ASL was measured from the renal cortex, and T1 values were measured from the renal parenchyma (cortex and medulla). MRI parameters were compared between groups. Diagnostic performances for detecting renal impairment were statistically analyzed.Cortical T1 (cT1) and medullary T1 (mT1) were significantly lower in the NCs than in the cirrhosis-NR group. The cortical RBF showed no significant changes between the NCs and cirrhosis-NR group but was markedly decreased in the cirrhosis-RD group. The areas under the curve (AUCs) for discriminating cirrhosis-NR from NCs were 0.883 and 0.826 by cT1 and mT1, respectively. Cortical RBF identified cirrhosis-RD with AUC of 0.978, and correlated with serum creatinine (r = −0.334) and the estimated glomerular filtration rate (r = 0.483). A classification and regression tree based on cortical RBF and cT1 achieved 85% accuracy in detecting renal impairment in the cirrhosis.Renal T1 values might be sensitive predictors of early renal impairment in patients with cirrhosis-NR. RBF enabled quantifying renal perfusion impairment in patients with cirrhosis-RD. The diagnostic algorithm based on cortical RBF and T1 values allowed detecting renal injury during cirrhosis.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"6 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.3389/fendo.2024.1424771
An Yu, Xiang Li, Wei Zhang, Yazhou Zhang, Xi Chen, Liuyan Wang, Mei Xie, Lei Yang
Obesity is widely recognized for its role in predisposing individuals to a spectrum of chronic health conditions. Emerging preliminary evidence points to the potential benefits of low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) in enhancing various health outcomes among those with obesity and associated disorders.This systematic review was designed to assess the effectiveness of Lo-TENS for managing obesity and its related chronic diseases.For this systematic review, we included randomized controlled trials that evaluated the impact of Lo-TENS on individuals with obesity and its associated chronic diseases.Eight trials encompassing 671 participants and spanning three unique populations: essential hypertension (EH), type 2 diabetes mellitus (T2DM), and obesity were deemed eligible for inclusion in this review. Compared to baseline measurements, Lo-TENS demonstrated a tendency to positively affect blood pressure in individuals with EH and metabolic parameters in those with T2DM. Nonetheless, the efficacy of Lo-TENS in treating obesity is not yet clear when contrasted with a no-intervention control group. When compared with other intervention modalities, three of the trials reported less favorable results.Although Lo-TENS did not consistently surpass other treatments or yield substantial improvements, it generally provided greater benefits than the majority of placebo controls. This suggests that Lo-TENS could potentially serve as a beneficial adjunctive therapy in the management of obesity and its associated conditions. However, given the limited number of trials assessed, the elevated risk of bias within these studies, and the scarce evidence currently available, it is too early to reach definitive conclusions. Caution should be exercised when interpreting the current findings. There is an imperative for further high-quality research to thoroughly investigate and substantiate the efficacy of Lo-TENS in relation to obesity and its related disorders.
{"title":"Adjunctive benefits of low-frequency transcutaneous electrical nerve stimulation for obesity frequent chronic conditions: a systematic review","authors":"An Yu, Xiang Li, Wei Zhang, Yazhou Zhang, Xi Chen, Liuyan Wang, Mei Xie, Lei Yang","doi":"10.3389/fendo.2024.1424771","DOIUrl":"https://doi.org/10.3389/fendo.2024.1424771","url":null,"abstract":"Obesity is widely recognized for its role in predisposing individuals to a spectrum of chronic health conditions. Emerging preliminary evidence points to the potential benefits of low-frequency transcutaneous electrical nerve stimulation (Lo-TENS) in enhancing various health outcomes among those with obesity and associated disorders.This systematic review was designed to assess the effectiveness of Lo-TENS for managing obesity and its related chronic diseases.For this systematic review, we included randomized controlled trials that evaluated the impact of Lo-TENS on individuals with obesity and its associated chronic diseases.Eight trials encompassing 671 participants and spanning three unique populations: essential hypertension (EH), type 2 diabetes mellitus (T2DM), and obesity were deemed eligible for inclusion in this review. Compared to baseline measurements, Lo-TENS demonstrated a tendency to positively affect blood pressure in individuals with EH and metabolic parameters in those with T2DM. Nonetheless, the efficacy of Lo-TENS in treating obesity is not yet clear when contrasted with a no-intervention control group. When compared with other intervention modalities, three of the trials reported less favorable results.Although Lo-TENS did not consistently surpass other treatments or yield substantial improvements, it generally provided greater benefits than the majority of placebo controls. This suggests that Lo-TENS could potentially serve as a beneficial adjunctive therapy in the management of obesity and its associated conditions. However, given the limited number of trials assessed, the elevated risk of bias within these studies, and the scarce evidence currently available, it is too early to reach definitive conclusions. Caution should be exercised when interpreting the current findings. There is an imperative for further high-quality research to thoroughly investigate and substantiate the efficacy of Lo-TENS in relation to obesity and its related disorders.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"64 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.3389/fendo.2024.1417009
Shaoshuai Yan, Jiawei He, Xudong Yu, Jianwei Shang, Yaosheng Zhang, Han Bai, Xingyu Zhu, Xiaoming Xie, Leanne Lee
Emerging evidence suggests alterations in gut microbiota (GM) composition following thyroid nodules (TNs) development, yet the causal relationship remains unclear. Utilizing Mendelian Randomization (MR), this study aims to elucidate the causal dynamics between GM and TNs.Employing summary statistics from the MiBioGen consortium (n=18,340) and FinnGen consortium (1,634 TNs cases, 263,704 controls), we conducted univariable and multivariable MR analyses to explore the GM-TNs association. Techniques including inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO were utilized for causal inference. Instrumental variable heterogeneity was assessed through Cochran’s Q statistic and leave-one-out analysis. Reverse MR was applied for taxa showing significant forward MR associations, with multivariate adjustments for confounders.Our findings suggest that certain microbiota, identified as Ruminococcaceae_NK4A214_group (OR, 1.89; 95%CI, 0.47-7.64; p = 0.040), Senegalimassilia (OR, 1.72; 95%CI, 1.03-2.87; p =0.037), Lachnospiraceae (OR,0.64; 95%CI,0.41-0.99; p =0.045), exhibit a protective influence against TNs’ development, indicated by negative causal associations. In contrast, microbiota categorized as Desulfovibrionales (OR, 0.63; 95%CI, 0.41-0.95; p =0.028), Prevotella_7 (OR, 0.79; 95%CI, 0.63-1.00; p =0.049), Faecalibacterium (OR, 0.66; 95%CI, 0.44-1.00; p =0.050), Desulfovibrionaceae (OR, 0.55; 95%CI, 0.35-0.86; p =0.008), Deltaproteobacteria (OR, 0.65; 95%CI, 0.43-0.97; p =0.036) are have a positive correlation with with TNs, suggesting they may serve as risk factors. Reverse MR analyses did not establish significant causal links. After comprehensive adjustment for confounders, taxa Desulfovibrionales (Order), Desulfovibrionaceae (Family), Deltaproteobacteria (Class) remain implicated as potential contributors to TNs’ risk.This study substantiates a significant causal link between GM composition and TNs development, underscoring the thyroid-gut axis’s relevance. The findings advocate for the integration of GM profiles in TNs’ prevention and management, offering a foundation for future research in this domain.
{"title":"Causal relationship between gut microbiota and thyroid nodules: a bidirectional two-sample Mendelian randomization study","authors":"Shaoshuai Yan, Jiawei He, Xudong Yu, Jianwei Shang, Yaosheng Zhang, Han Bai, Xingyu Zhu, Xiaoming Xie, Leanne Lee","doi":"10.3389/fendo.2024.1417009","DOIUrl":"https://doi.org/10.3389/fendo.2024.1417009","url":null,"abstract":"Emerging evidence suggests alterations in gut microbiota (GM) composition following thyroid nodules (TNs) development, yet the causal relationship remains unclear. Utilizing Mendelian Randomization (MR), this study aims to elucidate the causal dynamics between GM and TNs.Employing summary statistics from the MiBioGen consortium (n=18,340) and FinnGen consortium (1,634 TNs cases, 263,704 controls), we conducted univariable and multivariable MR analyses to explore the GM-TNs association. Techniques including inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO were utilized for causal inference. Instrumental variable heterogeneity was assessed through Cochran’s Q statistic and leave-one-out analysis. Reverse MR was applied for taxa showing significant forward MR associations, with multivariate adjustments for confounders.Our findings suggest that certain microbiota, identified as Ruminococcaceae_NK4A214_group (OR, 1.89; 95%CI, 0.47-7.64; p = 0.040), Senegalimassilia (OR, 1.72; 95%CI, 1.03-2.87; p =0.037), Lachnospiraceae (OR,0.64; 95%CI,0.41-0.99; p =0.045), exhibit a protective influence against TNs’ development, indicated by negative causal associations. In contrast, microbiota categorized as Desulfovibrionales (OR, 0.63; 95%CI, 0.41-0.95; p =0.028), Prevotella_7 (OR, 0.79; 95%CI, 0.63-1.00; p =0.049), Faecalibacterium (OR, 0.66; 95%CI, 0.44-1.00; p =0.050), Desulfovibrionaceae (OR, 0.55; 95%CI, 0.35-0.86; p =0.008), Deltaproteobacteria (OR, 0.65; 95%CI, 0.43-0.97; p =0.036) are have a positive correlation with with TNs, suggesting they may serve as risk factors. Reverse MR analyses did not establish significant causal links. After comprehensive adjustment for confounders, taxa Desulfovibrionales (Order), Desulfovibrionaceae (Family), Deltaproteobacteria (Class) remain implicated as potential contributors to TNs’ risk.This study substantiates a significant causal link between GM composition and TNs development, underscoring the thyroid-gut axis’s relevance. The findings advocate for the integration of GM profiles in TNs’ prevention and management, offering a foundation for future research in this domain.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141928139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gestational diabetes mellitus (GDM) can result in adverse maternal and neonatal outcomes. Predicting those at high risk of GDM and early interventions can reduce the development of GDM. The aim of this study was to examine the associations between first-trimester prenatal screening biomarkers and maternal characteristics in relation to GDM in Chinese women.We conducted a retrospective cohort study of singleton pregnant women who received first-trimester aneuploidy and preeclampsia screening between January 2019 and May 2021. First-trimester prenatal screening biomarkers, including pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotropin, and placental growth factor (PLGF), along with maternal characteristics, were collected for analysis in relation to GDM. Receiver operating characteristic (ROC) curve and logistic regression analyses were used to evaluate variables associated with GDM.Of the 1452 pregnant women enrolled, 96 developed GDM. PAPP-A (5.01 vs. 5.73 IU/L, P < 0.001) and PLGF (39.88 vs. 41.81 pg/mL, P = 0.044) were significantly lower in the GDM group than in the non-GDM group. The area under the ROC curve of combined maternal characteristics and biomarkers was 0.73 (95% confidence interval [CI] 0.68–0.79, P < 0.001). The formula for predicting GDM was as follows: P = 1/[1 + exp (-8.148 + 0.057 x age + 0.011 x pregestational body mass index + 1.752 x previous GDM history + 0.95 x previous preeclampsia history + 0.756 x family history of diabetes + 0.025 x chronic hypertension + 0.036 x mean arterial pressure - 0.09 x PAPP-A - 0.001 x PLGF)]. Logistic regression analysis revealed that higher pregestational body mass index (adjusted odds ratio [aOR] 1.03, 95% CI 1.01 - 1.06, P = 0.012), previous GDM history (aOR 9.97, 95% CI 3.92 - 25.37, P < 0.001), family history of diabetes (aOR 2.36, 95% CI 1.39 - 4.02, P = 0.001), higher mean arterial pressure (aOR 1.17, 95% CI 1.07 - 1.27, P < 0.001), and lower PAPP-A level (aOR 0.91, 95% CI 0.83 - 1.00, P = 0.040) were independently associated with the development of GDM. The Hosmer-Lemeshow test demonstrated that the model exhibited an excellent discrimination ability (chi-square = 3.089, df = 8, P = 0.929).Downregulation of first-trimester PAPP-A and PLGF was associated with the development of GDM. Combining first-trimester biomarkers with maternal characteristics could be valuable for predicting the risk of GDM.
妊娠期糖尿病（GDM）会对产妇和新生儿造成不良后果。预测妊娠糖尿病的高危人群并进行早期干预可以减少妊娠糖尿病的发生。我们对在2019年1月至2021年5月期间接受第一胎非整倍体和子痫前期筛查的单胎孕妇进行了一项回顾性队列研究。研究收集了第一胎产前筛查生物标志物，包括妊娠相关血浆蛋白A（PAPP-A）、游离β-人绒毛膜促性腺激素和胎盘生长因子（PLGF），并结合孕产妇特征，分析其与GDM的关系。采用接收器操作特征（ROC）曲线和逻辑回归分析来评估与 GDM 相关的变量。GDM组的PAPP-A（5.01 vs. 5.73 IU/L，P < 0.001）和PLGF（39.88 vs. 41.81 pg/mL，P = 0.044）明显低于非GDM组。综合母体特征和生物标志物的 ROC 曲线下面积为 0.73（95% 置信区间 [CI] 0.68-0.79，P < 0.001）。预测 GDM 的公式如下P = 1/[1+exp（-8.148 + 0.057 x 年龄 + 0.011 x 孕前体重指数 + 1.752 x 既往 GDM 史 + 0.95 x 既往子痫前期史 + 0.756 x 糖尿病家族史 + 0.025 x 慢性高血压 + 0.036 x 平均动脉压 - 0.09 x PAPP-A - 0.001 x PLGF）]。逻辑回归分析显示，较高的孕前体重指数（调整后的几率比 [aOR] 1.03，95% CI 1.01 - 1.06，P = 0.012）、既往 GDM 史（aOR 9.97，95% CI 3.92 - 25.37，P <0.001）、糖尿病家族史（aOR 2.36，95% CI 1.39 - 4.02，P = 0.001）、较高的平均动脉压（aOR 1.17，95% CI 1.07 - 1.27，P <0.001）和较低的 PAPP-A 水平（aOR 0.91，95% CI 0.83 - 1.00，P = 0.040）与 GDM 的发生独立相关。Hosmer-Lemeshow检验表明，该模型具有极佳的区分能力（chi-square = 3.089，df = 8，P = 0.929）。将第一胎生物标志物与母体特征相结合，对预测 GDM 的风险很有价值。
{"title":"Associations between first-trimester screening biomarkers and maternal characteristics with gestational diabetes mellitus in Chinese women","authors":"Yu-Ting Lu, Chie-Pein Chen, Fang-Ju Sun, Yi-Yung Chen, Liang-Kai Wang, Chen-Yu Chen","doi":"10.3389/fendo.2024.1383706","DOIUrl":"https://doi.org/10.3389/fendo.2024.1383706","url":null,"abstract":"Gestational diabetes mellitus (GDM) can result in adverse maternal and neonatal outcomes. Predicting those at high risk of GDM and early interventions can reduce the development of GDM. The aim of this study was to examine the associations between first-trimester prenatal screening biomarkers and maternal characteristics in relation to GDM in Chinese women.We conducted a retrospective cohort study of singleton pregnant women who received first-trimester aneuploidy and preeclampsia screening between January 2019 and May 2021. First-trimester prenatal screening biomarkers, including pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotropin, and placental growth factor (PLGF), along with maternal characteristics, were collected for analysis in relation to GDM. Receiver operating characteristic (ROC) curve and logistic regression analyses were used to evaluate variables associated with GDM.Of the 1452 pregnant women enrolled, 96 developed GDM. PAPP-A (5.01 vs. 5.73 IU/L, P < 0.001) and PLGF (39.88 vs. 41.81 pg/mL, P = 0.044) were significantly lower in the GDM group than in the non-GDM group. The area under the ROC curve of combined maternal characteristics and biomarkers was 0.73 (95% confidence interval [CI] 0.68–0.79, P < 0.001). The formula for predicting GDM was as follows: P = 1/[1 + exp (-8.148 + 0.057 x age + 0.011 x pregestational body mass index + 1.752 x previous GDM history + 0.95 x previous preeclampsia history + 0.756 x family history of diabetes + 0.025 x chronic hypertension + 0.036 x mean arterial pressure - 0.09 x PAPP-A - 0.001 x PLGF)]. Logistic regression analysis revealed that higher pregestational body mass index (adjusted odds ratio [aOR] 1.03, 95% CI 1.01 - 1.06, P = 0.012), previous GDM history (aOR 9.97, 95% CI 3.92 - 25.37, P < 0.001), family history of diabetes (aOR 2.36, 95% CI 1.39 - 4.02, P = 0.001), higher mean arterial pressure (aOR 1.17, 95% CI 1.07 - 1.27, P < 0.001), and lower PAPP-A level (aOR 0.91, 95% CI 0.83 - 1.00, P = 0.040) were independently associated with the development of GDM. The Hosmer-Lemeshow test demonstrated that the model exhibited an excellent discrimination ability (chi-square = 3.089, df = 8, P = 0.929).Downregulation of first-trimester PAPP-A and PLGF was associated with the development of GDM. Combining first-trimester biomarkers with maternal characteristics could be valuable for predicting the risk of GDM.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"114 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Previous studies have confirmed a positive correlation between the Triglyceride-Glucose (TyG) index and future risk of diabetes. However, evidence of this association in non-obese young populations remains limited. This study aims to investigate the relationship between the TyG index and the future risk of diabetes among non-obese young adults.This retrospective cohort study included 113,509 non-obese young adults from China and 9,549 from Japan. The mean age was 35.73 ± 6.38 years, and 56,469 participants (45.89%) were male. The median follow-up duration was 3.38 years. The association between baseline TyG index and risk of diabetes was examined using Cox proportional hazards regression models. Non-linear relationships between the TyG index and risk of diabetes were identified using cubic splines and smoothed curve fitting in the Cox models. Sensitivity and subgroup analyses were also conducted.After adjusting for covariates, the results indicated a positive correlation between the TyG index and risk of diabetes in non-obese young adults (HR=3.57, 95% CI: 2.92-4.36, P<0.0001). A non-linear relationship was observed with an inflection point at 7.3. The HR to the right of this inflection point was 3.70 (95% CI: 3.02-4.52, P<0.0001), while to the left, it was 0.34 (95% CI: 0.06-1.88, P=0.2161). The robustness of our findings was confirmed through a series of sensitivity analyses and subgroup analyses.This study reveals a positive and non-linear association between the TyG index and risk of diabetes among non-obese young adults. Interventions aimed at reducing the TyG index by lowering triglycerides or fasting glucose levels could substantially decrease the future likelihood of developing diabetes in this population.
{"title":"Elevated triglyceride-glucose index associated with increased risk of diabetes in non-obese young adults: a longitudinal retrospective cohort study from multiple Asian countries","authors":"Jian Han, Weifeng Dai, Lixia Chen, Zhenhua Huang, Chengzhi Li, Keke Wang","doi":"10.3389/fendo.2024.1427207","DOIUrl":"https://doi.org/10.3389/fendo.2024.1427207","url":null,"abstract":"Previous studies have confirmed a positive correlation between the Triglyceride-Glucose (TyG) index and future risk of diabetes. However, evidence of this association in non-obese young populations remains limited. This study aims to investigate the relationship between the TyG index and the future risk of diabetes among non-obese young adults.This retrospective cohort study included 113,509 non-obese young adults from China and 9,549 from Japan. The mean age was 35.73 ± 6.38 years, and 56,469 participants (45.89%) were male. The median follow-up duration was 3.38 years. The association between baseline TyG index and risk of diabetes was examined using Cox proportional hazards regression models. Non-linear relationships between the TyG index and risk of diabetes were identified using cubic splines and smoothed curve fitting in the Cox models. Sensitivity and subgroup analyses were also conducted.After adjusting for covariates, the results indicated a positive correlation between the TyG index and risk of diabetes in non-obese young adults (HR=3.57, 95% CI: 2.92-4.36, P<0.0001). A non-linear relationship was observed with an inflection point at 7.3. The HR to the right of this inflection point was 3.70 (95% CI: 3.02-4.52, P<0.0001), while to the left, it was 0.34 (95% CI: 0.06-1.88, P=0.2161). The robustness of our findings was confirmed through a series of sensitivity analyses and subgroup analyses.This study reveals a positive and non-linear association between the TyG index and risk of diabetes among non-obese young adults. Interventions aimed at reducing the TyG index by lowering triglycerides or fasting glucose levels could substantially decrease the future likelihood of developing diabetes in this population.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"29 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141926966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.3389/fendo.2024.1433378
Jennifer Apsan, O. Lekarev, Charlene Thomas, Yuan-Shan Zhu, Kaela Cohan, K. Lin-Su
Children and young adults with congenital adrenal hyperplasia (CAH) are at increased risk of obesity and insulin resistance. There is evidence that children with CAH have increased visceral adiposity, which has been linked to metabolic syndrome and cardiovascular disease (CVD). The adipokine adiponectin has been shown to correlate with reduced metabolic risk, whereas the adipokines visfatin and leptin have been linked to visceral fat and adipocyte inflammation and can serve as biomarkers of increased metabolic risk. Few studies to date have characterized adipokine levels in children and young adults with congenital adrenal hyperplasia. We sought to investigate the relationship between adiponectin, leptin and visfatin levels to metabolic risk factors and androgen levels in children and young adults with CAH.Fasting blood was obtained for visfatin, leptin, adiponectin, glucose, insulin, CRP, lipid panel, total cholesterol (TC), triglycerides (TG) and HbA1c, as well as standard laboratory tests to assess adrenal control, from children with CAH due to 21-hydroxylase deficiency. HOMA-IR was calculated based on fasting glucose and insulin. Anthropomorphic measurements of BMI and waist-to-hip ratio were also obtained.Adiponectin and androstenedione were inversely correlated (R = -0.57, p =0.016). There was a positive correlation between leptin and BMI percentile (R = 0.63, p <0.001) as well as leptin and HOMA-IR (R = 0.63, p <0.01). Glucocorticoid dose had a positive correlation with HOMA-IR (R=0.56, p = 0.021). Visfatin was inversely correlated with HDL cholesterol (R = -0.54, p = 0.026) and total cholesterol (R = -0.49, p <0.05). Overweight children and young adults had a significantly higher leptin (p = 0.02) and HOMA-IR (p=0.001) than non-overweight children and young adults.The inverse relationship between adiponectin and androstenedione suggests that better CAH control can reduce the risk of insulin resistance and metabolic syndrome. However, a high glucocorticoid dose appears to increase the risk of insulin resistance, underscoring the delicate balance required when treating CAH.
{"title":"Relationship between adipokines and androgens in children and young adults with congenital adrenal hyperplasia","authors":"Jennifer Apsan, O. Lekarev, Charlene Thomas, Yuan-Shan Zhu, Kaela Cohan, K. Lin-Su","doi":"10.3389/fendo.2024.1433378","DOIUrl":"https://doi.org/10.3389/fendo.2024.1433378","url":null,"abstract":"Children and young adults with congenital adrenal hyperplasia (CAH) are at increased risk of obesity and insulin resistance. There is evidence that children with CAH have increased visceral adiposity, which has been linked to metabolic syndrome and cardiovascular disease (CVD). The adipokine adiponectin has been shown to correlate with reduced metabolic risk, whereas the adipokines visfatin and leptin have been linked to visceral fat and adipocyte inflammation and can serve as biomarkers of increased metabolic risk. Few studies to date have characterized adipokine levels in children and young adults with congenital adrenal hyperplasia. We sought to investigate the relationship between adiponectin, leptin and visfatin levels to metabolic risk factors and androgen levels in children and young adults with CAH.Fasting blood was obtained for visfatin, leptin, adiponectin, glucose, insulin, CRP, lipid panel, total cholesterol (TC), triglycerides (TG) and HbA1c, as well as standard laboratory tests to assess adrenal control, from children with CAH due to 21-hydroxylase deficiency. HOMA-IR was calculated based on fasting glucose and insulin. Anthropomorphic measurements of BMI and waist-to-hip ratio were also obtained.Adiponectin and androstenedione were inversely correlated (R = -0.57, p =0.016). There was a positive correlation between leptin and BMI percentile (R = 0.63, p <0.001) as well as leptin and HOMA-IR (R = 0.63, p <0.01). Glucocorticoid dose had a positive correlation with HOMA-IR (R=0.56, p = 0.021). Visfatin was inversely correlated with HDL cholesterol (R = -0.54, p = 0.026) and total cholesterol (R = -0.49, p <0.05). Overweight children and young adults had a significantly higher leptin (p = 0.02) and HOMA-IR (p=0.001) than non-overweight children and young adults.The inverse relationship between adiponectin and androstenedione suggests that better CAH control can reduce the risk of insulin resistance and metabolic syndrome. However, a high glucocorticoid dose appears to increase the risk of insulin resistance, underscoring the delicate balance required when treating CAH.","PeriodicalId":505784,"journal":{"name":"Frontiers in Endocrinology","volume":"53 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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