Journal of Diabetes最新文献_第6页

Does Metabolic Status Associate With IVF Outcomes in Women Within Similar Body Mass Index Category: Evidence From a Large Cohort Study 代谢状态是否与相似体重指数类别的女性体外受精结果相关：来自大型队列研究的证据

IF 3.7 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-08-01 DOI: 10.1111/1753-0407.70132

Lin Ding, Xiaojing Lin, Peipei Pan, Yan Li, Wei Chen, Liying He, Yunsheng Xu, Hsun-Ming Chang, Haiyan Yang, Guiquan Wang, Liangshan Mu

Objectives

Whether diverse metabolic statuses within a similar body mass index (BMI) category associate with different in vitro fertilization (IVF) outcomes.

Design

A retrospective cohort study.

Setting

Wenzhou, Zhengjiang Province, China.

Population

This retrospective cohort study prescreened 16 458 women who underwent their first IVF and fresh embryo transfer cycle between January 2010 and December 2021.

Methods

Metabolic status was assessed using the National Cholesterol Education Program–Adult Treatment Panel III criteria. Patients were then categorized into six groups: metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight, metabolically unhealthy overweight, metabolically healthy obese, and metabolically unhealthy obese.

Main Outcome Measures

The primary outcome was live birth rate.

Results

Regarding live birth, rates in normal weight women were initially lower for metabolically unhealthy normal weight versus metabolically healthy normal weight (44.6% vs. 48.6%), but this was not significant after multivariate adjustment. In obese women, live birth rates were similar between metabolically unhealthy obese and metabolically healthy obese (41.5% vs. 43.9%), with no adjusted difference. For secondary outcomes, metabolically unhealthy normal weight patients had lower biochemical pregnancy rates than metabolically healthy normal weight (OR: 0.86, 95% CI: 0.76–0.98); high blood pressure was a significant risk factor for this outcome in metabolically unhealthy normal weight (OR: 0.84, 95% CI: 0.72–0.98).

Conclusion

Our findings indicated that different cardio-metabolic risk factors but a similar BMI category may have limited adverse effects on live birth rate.

目的：在相似的体重指数（BMI）类别中，不同的代谢状态是否与不同的体外受精（IVF）结果相关。设计回顾性队列研究。地点：中国浙江省温州市。本回顾性队列研究对2010年1月至2021年12月期间接受第一次体外受精和新鲜胚胎移植周期的16458名妇女进行了预筛选。方法采用国家胆固醇教育计划-成人治疗小组III标准评估代谢状态。然后将患者分为六组：代谢健康正常体重组、代谢不健康正常体重组、代谢健康超重组、代谢不健康超重组、代谢健康肥胖组和代谢不健康肥胖组。主要结局指标主要结局指标为活产率。结果：在活产方面，正常体重妇女中代谢不健康的正常体重的比率最初低于代谢健康的正常体重的比率（44.6%比48.6%），但在多变量调整后，这一差异并不显著。在肥胖妇女中，代谢不健康肥胖和代谢健康肥胖的活产率相似（41.5%对43.9%），没有调整后的差异。对于次要结局，代谢不健康的正常体重患者的生化妊娠率低于代谢健康的正常体重患者（OR: 0.86, 95% CI: 0.76-0.98）；在代谢不健康的正常体重患者中，高血压是该结果的重要危险因素（OR: 0.84, 95% CI: 0.72-0.98）。结论不同的心脏代谢危险因素但相似的BMI类别可能对活产率的不良影响有限。

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引用次数: 0

The Potential of SARMs and Antimyostatin Agents in Addressing Lean Body Mass Loss From GLP-1 Agonists: A Literature Review SARMs和抗生长抑素药物在解决GLP-1激动剂引起的瘦体重损失方面的潜力：文献综述

IF 3.7 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-31 DOI: 10.1111/1753-0407.70119

Jimmy Wen, Ubaid Ansari, Mouhamad Shehabat, Zaid Ansari, Burhaan Syed, Adam Razick, Daniel Razick, Muzammil Akhtar, Eldo Frezza

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated substantial weight loss effects among patients with diabetes and obesity. However, given the rapid weight loss induced, there is concern about the total change in body composition, including lean body mass (LBM). Current literature on these effects contains significant heterogeneity, with some studies reporting a loss of 40%–60% of LBM and others reporting 15% or less. To combat this, selective androgen receptor modulators (SARMs) have become a popular candidate. Given their androgen receptor selectivity, SARMs have notable anabolic properties and proposed improved safety profiles over traditional anabolic compounds. Several of these agents, such as enobosarm, have been investigated in clinical trials involving older patient populations or patients with cachexia or sarcopenia secondary to chronic diseases. Furthermore, other agents to maintain or enhance LBM, such as antimyostatin agents, are also under investigation. Exploring this potential synergy could lead to better weight loss and body composition management in patients using GLP-1 RAs for diabetes or weight loss therapy. This review aims to evaluate the potential benefits and uses of SARMs in ameliorating the body composition changes induced by GLP-1 RAs. Other investigational agents to retain or increase muscle mass and the future possibilities of these drugs will be discussed.

胰高血糖素样肽-1受体激动剂（GLP-1 RAs）在糖尿病和肥胖患者中显示出显著的减肥效果。然而，考虑到体重的快速下降，人们担心身体成分的总体变化，包括瘦体重（LBM）。目前关于这些影响的文献存在显著的异质性，一些研究报告LBM的损失为40%-60%，而其他研究报告的损失为15%或更少。为了解决这个问题，选择性雄激素受体调节剂（SARMs）已成为一种流行的候选药物。鉴于其雄激素受体选择性，SARMs具有显著的合成代谢特性，并提出了比传统合成代谢化合物更高的安全性。其中一些药物，如enobosarm，已在老年患者群体或继发于慢性疾病的恶病质或肌肉减少症患者的临床试验中进行了研究。此外，其他维持或增强LBM的药物，如抗生长抑素药物，也在研究中。探索这种潜在的协同作用可以为使用GLP-1 RAs治疗糖尿病或减肥治疗的患者带来更好的体重减轻和身体成分管理。本文旨在评价SARMs在改善GLP-1 RAs诱导的体成分变化方面的潜在益处和用途。其他保留或增加肌肉质量的研究药物以及这些药物的未来可能性将被讨论。

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引用次数: 0

Non-Traditional Lipid Parameters and Risk of Adverse Pregnancy Outcomes in Gestational Diabetes Mellitus: Mediation by Maternal Metabolites 妊娠期糖尿病的非传统脂质参数和不良妊娠结局的风险：母体代谢物的中介作用

IF 3.7 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-31 DOI: 10.1111/1753-0407.70118

Jing-yi Guo, Dan-dan Yan, Wei Chen, Su-na Wang, Yan-wei Zheng, Wei-tuo Zhang, Cheng Hu, Ming-juan Luo, Xiang-tian Yu

Aims

To examine the association between non-traditional lipid parameters and adverse pregnancy outcomes (APOs) in women with gestational diabetes mellitus (GDM) and the mediating role of maternal serum metabolites during pregnancy.

Materials and Methods

This prospective observational study enrolled 399 women with GDM. Multivariate logistic regression was used to examine the association between non-traditional lipid parameters and APOs risk. Additionally, we assessed the mediating role of single and composite maternal serum metabolites during pregnancy using causal mediation analysis and high-dimensional mediation analysis, respectively.

Results

APOs were observed in 12.0% (N = 48) of participants. Seven non-traditional lipid parameters, except for the RC/HDL-C ratio, were associated with APOs risk, with the highest estimate for the atherogenic index of plasma (AIP) (OR = 3.873, 95% CI: 1.079–13.934, p = 0.037) after adjusting for confounders. Maternal metabolic markers mediated these associations, with mediation effect proportions of 21.9%–39.4%. Seven key metabolic markers were identified as potential mediators primarily involved in the biosynthesis of the unsaturated fatty acids pathway. Gene set variation analysis revealed significant differences in the positive regulation of this pathway between the APO and normal pregnancy outcome groups (p = 0.015).

Conclusions

Non-traditional lipid parameters were positively associated with APOs risk in women with GDM. Maternal serum metabolites, predominantly involved in the biosynthesis of unsaturated fatty acids, contribute to these associations.

目的探讨妊娠期糖尿病（GDM）妇女非传统脂质参数与不良妊娠结局（APOs）的关系及妊娠期间母体血清代谢物的调节作用。材料和方法这项前瞻性观察性研究纳入了399名患有GDM的女性。采用多因素logistic回归分析非传统脂质参数与APOs风险之间的关系。此外，我们分别使用因果中介分析和高维中介分析评估了妊娠期间母体血清单一代谢物和复合代谢物的中介作用。结果12.0% （N = 48）的患者出现apo。除RC/HDL-C比值外，7个非传统脂质参数与APOs风险相关，在调整混杂因素后，血浆动脉粥样硬化指数（AIP）的估计最高（OR = 3.873, 95% CI: 1.079-13.934, p = 0.037）。母体代谢标志物介导了这些关联，中介效应比例为21.9% ~ 39.4%。七个关键的代谢标记物被确定为主要参与不饱和脂肪酸途径生物合成的潜在介质。基因集变异分析显示，APO与正常妊娠结局组在该通路的正调控上存在显著差异（p = 0.015）。结论非传统脂质参数与GDM女性apo风险呈正相关。母体血清代谢物，主要参与不饱和脂肪酸的生物合成，有助于这些关联。

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引用次数: 0

The Association Between Subclinical Atherosclerosis Serum Markers and Oxidative DNA Damage in Normoglycemic Normotolerant Offspring of Diabetic Parents 糖尿病父母正常血糖耐受后代亚临床动脉粥样硬化血清标志物与氧化DNA损伤的关系

IF 3.7 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-30 DOI: 10.1111/1753-0407.70133

Masoumeh Rahimi, Farhad Ghadiri Soufi, Shabnaz Koochakkhani, Behnaz Rahnama Inchehsablagh, Abnoos Azarbad, Masoumeh Mahmoudi, Masoumeh Kheirandish, Farideh Jalali Mashayekhi, Ebrahim Eftekhar

Introduction

It has been shown that offspring of type 2 diabetic parents have a high risk for developing diabetes and atherosclerosis, but the exact mechanism is unclear. In the present study, the possible association between oxidative stress and subclinical atherosclerosis serum markers in this population was investigated.

Method

LDL/HDL ratio, triglyceride-glucose index (TyG), atherogenic index of plasma (AIP), single-point insulin sensitivity estimator (SPISE) index, oxidized LDL (Ox-LDL), intercellular adhesion molecules (ICAM-1 and E-selectin), as well as the marker of oxidative DNA damage were compared among 150 offspring of diabetic parents (90 normoglycemic and normotolerant offspring, 31 offspring with impaired fasting glucose (IFG), and 29 offspring with impaired glucose tolerance (IGT)), and 40 age-and sex-matched healthy control individuals. The control subjects were among individuals with no family history of diabetes.

Results

All three groups with diabetic parents, that is, norm-offspring, IFG, and IGT groups, had higher serum levels of Ox-LDL, ICAM-1, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) than the controls. In the whole population, ICAM-1 correlated with Ox-LDL, fasting plasma glucose (FPG) and 8-OHdG, and Ox-LDL correlated with LDL/HDL, fasting plasma glucose, TyG index, and 8-OHdG after adjustment for age, sex, and BMI.

Conclusion

This study shows that subclinical atherosclerosis and oxidative DNA damage are present in normotolerant normoglycemic offspring of type 2 diabetic parents, and they progress with impaired fasting glucose and/or impaired glucose tolerance. Also, our results indicate that a marker of subclinical atherosclerosis, ICAM-1, was directly correlated with the DNA damage marker, 8-OHdG.

已有研究表明，2型糖尿病父母的后代患糖尿病和动脉粥样硬化的风险较高，但确切的机制尚不清楚。在本研究中，研究了氧化应激与亚临床动脉粥样硬化血清标志物之间的可能联系。方法比较150例糖尿病亲本后代（90例血糖正常和耐受正常后代，31例空腹血糖受损后代，31例血糖正常和耐受正常后代）LDL/HDL比值、甘油三酯-葡萄糖指数（TyG）、血浆致动脉粥样硬化指数（AIP）、单点胰岛素敏感性估计因子（SPISE）指数、氧化LDL （Ox-LDL）、细胞间粘附分子（ICAM-1和e-选择素）以及氧化DNA损伤标志物的变化。29名糖耐量（IGT）受损的后代，以及40名年龄和性别匹配的健康对照个体。对照组为无糖尿病家族史的个体。结果3组糖尿病患儿血清Ox-LDL、ICAM-1和8-羟基-2′-脱氧鸟苷（8-OHdG）水平均高于对照组，即正常子代组、IFG组和IGT组。在整个人群中，ICAM-1与Ox-LDL、空腹血糖（FPG）和8-OHdG相关，Ox-LDL与LDL/HDL、空腹血糖、TyG指数和8-OHdG相关，在调整年龄、性别和BMI后。结论本研究表明，在2型糖尿病父母的正常耐受正常血糖的后代中存在亚临床动脉粥样硬化和氧化DNA损伤，并随着空腹血糖和/或糖耐量受损而进展。此外，我们的研究结果表明，亚临床动脉粥样硬化的标志物ICAM-1与DNA损伤标志物8-OHdG直接相关。

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引用次数: 0

Association of Abnormal Glucose Metabolism and Inflammation With Prognosis in Patients With Acute Coronary Syndrome 急性冠脉综合征患者糖代谢异常、炎症与预后的关系

IF 3.7 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-30 DOI: 10.1111/1753-0407.70134

Chong Zhang, Wenjin Peng, Tianqi Wang, Meng Ning, Yi Chen, Yingwu Liu

Background

In acute coronary syndrome (ACS) patients, the relationship between abnormal glucose metabolism markers, such as the triglyceride-glucose (TyG) index and stress hyperglycemia ratio (SHR), and inflammatory markers remains unclear. Furthermore, their interaction and impact on long-term prognosis have yet to be investigated in clinical cohorts.

Methods

In this study, K-means clustering was performed on the TyG index, SHR, and inflammatory markers, including high mobility group box-1 protein, platelet-derived growth factor, phenylacetylglutamine, lysophosphatidic acid, and citrullinated histone H3. A Cox proportional hazards model was used to assess the association between cluster phenotypes and 1-year major adverse cardiovascular events (MACE) risk in ACS patients.

Results

Among 363 ACS patients, 62 developed MACE during the 1-year follow-up. SHR correlated positively with the TyG index and inflammatory markers. K-means clustering identified two phenotypes: normal glucose metabolism/low inflammation and abnormal glucose metabolism/high inflammation. Multivariable Cox analysis showed the latter was strongly linked to MACE (adjusted hazard ratio: 3.84, 95% confidence interval: 1.93–7.64), and early guideline-directed medical therapy reduced MACE risk in this high-risk group.

Conclusions

ACS patients with abnormal glucose metabolism and high inflammation have a higher long-term MACE risk than those with normal glucose metabolism and low inflammation. Early guideline-directed medical therapy, alongside anti-inflammatory therapy and hypoglycemic agents, may improve long-term outcomes in this high-risk group.

背景在急性冠脉综合征（ACS）患者中，异常糖代谢标志物如甘油三酯-葡萄糖（TyG）指数和应激性高血糖比（SHR）与炎症标志物之间的关系尚不清楚。此外，它们的相互作用和对长期预后的影响尚未在临床队列中进行研究。方法在本研究中，对TyG指数、SHR和炎症标志物进行k均值聚类，包括高迁移率group box-1蛋白、血小板衍生生长因子、苯乙酰谷氨酰胺、溶血磷脂酸和葡氨酸组蛋白H3。采用Cox比例风险模型评估ACS患者聚类表型与1年主要不良心血管事件（MACE）风险之间的关系。结果363例ACS患者中，62例在1年随访期间发生MACE。SHR与TyG指数、炎症指标呈正相关。K-means聚类鉴定出两种表型：正常糖代谢/低炎症和异常糖代谢/高炎症。多变量Cox分析显示，后者与MACE密切相关（调整后的风险比：3.84,95%可信区间：1.93-7.64），早期指导的药物治疗降低了这一高危人群的MACE风险。结论糖代谢异常、高炎症的ACS患者长期发生MACE的风险高于糖代谢正常、低炎症的ACS患者。早期指导的药物治疗，以及抗炎治疗和降糖药，可能改善这一高危人群的长期预后。

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引用次数: 0

Gene-Smoking Interaction in Insulin Sensitivity and β-Cell Function Among Normal Glucose Tolerance Individuals 基因与吸烟在正常糖耐量个体胰岛素敏感性和β细胞功能中的相互作用

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-28 DOI: 10.1111/1753-0407.70131

Pan Gu, Shuai Zheng, Sijie Zhang, Jie Yuan, Hao Hong, Jinglan Dai, Jingyi Zhao, Kuanfeng Xu, Tao Yang, Qi Fu, Sipeng Shen, Hao Dai

Objective

To identify genetic loci that exhibit potential interactions with smoking status on insulin sensitivity and islet β-cell function within normal glucose tolerance (NGT) populations.

Methods

All participants underwent an OGTT to confirm NGT status, followed by assessments of insulin sensitivity and β-cell function. Analyses were performed in NGT participants from Nanjing (N = 4808) and Jurong (N = 508) for discovery and validation, respectively. Smoking status was categorized into nonsmokers and smokers. After excluding ineligible individuals, a two-stage genome-wide interaction association analysis (GWIS) was conducted in NGT individuals, with the discovery phase (N = 1377) identifying gene–environment interactions and the validation phase (N = 485) confirming significant loci. Subsequent analyses included stratified analysis and expression quantitative trait locus (eQTL) colocalization.

Results

GWIS identified ten SNPs in three loci, including rs4713207 (OR14J1, P_meta = 3.95 × 10⁻⁸) for insulin resistance, rs17708475 (NKAIN2, P_meta = 4.83 × 10⁻⁸) for insulin sensitivity, and rs201613 (MYH3, P_meta = 1.05 × 10⁻⁸) for disposition index. Stratified analyses revealed differential effects of smoking across genotypes at these loci. Specifically, smoking was associated with increased insulin resistance in rs4713207 homozygotes (p = 2.15 × 10⁻⁵), while an opposite effect was observed in wild-type individuals (p = 0.022). Colocalization analysis indicated that the smoking-related interaction near rs4713207 is driven by a shared causal variant influencing HCG4 (PP.H4 = 0.70) and ZNF311 (PP.H4 = 0.74) expression in the pancreas.

Conclusions

Our findings reveal gene-smoking interactions that affect insulin sensitivity and β-cell function, providing new insights into the heterogeneity of metabolic phenotypes and advancing personalized risk assessment.

目的在正常糖耐量（NGT）人群中，寻找与吸烟状况对胰岛素敏感性和胰岛β细胞功能可能相互作用的基因位点。方法所有参与者均接受OGTT以确认NGT状态，随后评估胰岛素敏感性和β细胞功能。对来自南京（N = 4808）和句容（N = 508）的NGT参与者进行分析，分别进行发现和验证。吸烟状况分为不吸烟者和吸烟者。在排除不符合条件的个体后，对NGT个体进行了两阶段的全基因组相互作用关联分析（GWIS），其中发现阶段（N = 1377）鉴定基因-环境相互作用，验证阶段（N = 485）确认显著位点。随后的分析包括分层分析和表达数量性状位点（eQTL）共定位。结果GWIS在3个基因座中鉴定出10个snp，其中胰岛素抵抗基因位点rs4713207 (OR14J1, Pmeta = 3.95 × 10−8)，胰岛素敏感性基因位点rs17708475 (NKAIN2, Pmeta = 4.83 × 10−8)，倾向指数基因位点rs201613 （MYH3, Pmeta = 1.05 × 10−8）。分层分析揭示了这些基因座上不同基因型吸烟的不同影响。具体而言，吸烟与rs4713207纯合子的胰岛素抵抗增加有关（p = 2.15 × 10−5），而在野生型个体中观察到相反的效果（p = 0.022）。共定位分析表明，rs4713207附近吸烟相关的相互作用是由影响胰腺中HCG4 （PP.H4 = 0.70）和ZNF311 （PP.H4 = 0.74）表达的共同因果变异驱动的。我们的研究结果揭示了基因-吸烟相互作用影响胰岛素敏感性和β细胞功能，为代谢表型的异质性提供了新的见解，并推进了个性化的风险评估。

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引用次数: 0

Fatty Acid Binding Protein 4 Regulates the Antigen-Presenting Function of Dendritic Cells Resulting in T Cell Priming in Streptozotocin-Induced Type 1 Diabetes Mice 脂肪酸结合蛋白4在链脲佐菌素诱导的1型糖尿病小鼠中调控树突状细胞抗原呈递功能导致T细胞启动

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-26 DOI: 10.1111/1753-0407.70123

Hailan Zou, Lingxiang Xie, Jingyi Hu, Rong Zhang, Yanfei Wang, Aimin Xu, Zhiguang Zhou, Xiaoyu Xiao, Yang Xiao

Background

Type 1 diabetes is an autoimmune disease with progressive destruction of insulin-producing β cells in islets of Langerhans of the pancreas. However, the early pathogenic factors triggering the recruitment and activation of innate immune cells remain unclear. A study reported that FABP4 accelerates the onset of type 1 diabetes in NOD mice by inducing the polarization of proinflammatory macrophages and their infiltration into pancreatic islets. Nonetheless, the role of FABP4 in mediating crosstalk between innate immunity and adaptive immunity in T1D is unclear.

Methods

Intraperitoneal injections of streptozotocin were used to establish a type 1 diabetes mouse model. Blood glucose was monitored, and intraperitoneal glucose tolerance test (IPGTT) was conducted to compare glucose homeostasis. The peripheral immune cells were detected using flow cytometry. Mixed lymphocyte reactions were applied to examine the function of FABP4 on antigen-presenting in dendritic cells.

Results

We found that genetic ablation of FABP4 in mice alleviated STZ-induced diabetic damage by reducing diabetogenic T lymphocytes and their production of inflammatory cytokines. In vitro studies, FABP4 deficiency dendritic cells expressed lower properties of CD86 and CD80, showing impaired antigen-presenting functions.

Conclusions

Genetic ablation of FABP4 in mice alleviated STZ-induced diabetic damage by impairing the antigen-presenting function of dendritic cells through downregulating the phosphorylation levels of the ERK and JNK pathways.

背景1型糖尿病是一种自身免疫性疾病，伴有胰腺朗格汉斯胰岛中产生胰岛素的β细胞的进行性破坏。然而，触发先天免疫细胞募集和激活的早期致病因素尚不清楚。有研究报道，FABP4通过诱导促炎巨噬细胞极化并向胰岛浸润，加速NOD小鼠1型糖尿病的发病。尽管如此，FABP4在T1D中介导先天免疫和适应性免疫之间的串扰中的作用尚不清楚。方法采用腹腔注射链脲佐菌素建立1型糖尿病小鼠模型。监测血糖，并进行腹腔葡萄糖耐量试验（IPGTT）比较葡萄糖稳态。采用流式细胞术检测外周血免疫细胞。采用混合淋巴细胞反应检测FABP4对树突状细胞抗原呈递的作用。结果我们发现，基因消融小鼠FABP4可通过减少致糖尿病T淋巴细胞及其炎症细胞因子的产生来减轻stz诱导的糖尿病损伤。在体外研究中，FABP4缺陷树突状细胞表达CD86和CD80的特性较低，表现出抗原提呈功能受损。结论基因消融小鼠FABP4可通过下调ERK和JNK通路磷酸化水平，损害树突状细胞抗原呈递功能，减轻stz诱导的糖尿病损伤。

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引用次数: 0

Analysis of HMGCS2 Expression and TG Lipidomics in the Perirenal Adipose Tissue of Obese Diabetic Nephropathy Mice 肥胖糖尿病肾病小鼠肾周脂肪组织HMGCS2表达及TG脂质组学分析

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-25 DOI: 10.1111/1753-0407.70125

Yuhong Huang, Miao Zeng, Mengxue Yang, Xiaodi Zheng, Lulu Jin, Rui Zhang, Yueyue Wu, Fei Li, Bo Yang, Jun Liu

Background and Aims

Renal HMGCS2 upregulation is associated with lipid deposition. However, the expression pattern and role of Hmgcs2 in the perirenal adipose tissue (PRAT) is not clear. This study was designed to elucidate the contribution of Hmgcs2 in the pathogenesis of obese diabetic kidney disease mice.

Methods

12-week-old db/db (diabetic) and db/m (control) mice were fed high-fat or normal diets, respectively. At 12, 16, and 20 weeks, mice (n = 4/group/timepoint) were euthanized for metabolic profiling (body weight, blood glucose, urinary ACR) and tissue collection (kidney, PRAT). Tissues were analyzed for TNF-α mRNA (qPCR), HMGCS2 expression (IHC/WB/IF), lipid deposition (Oil Red O), and histopathology (HE staining). PRAT triglycerides (colorimetric assay) and lipidomics (UPLC–MS/MS) were assessed. HMGCS2-knockout mice (CRISPR-generated) underwent metabolic tests (OGTT/ITT) before terminal tissue analysis.

Results

(1) Compared with db/mPRAT, db/db PRAT had significantly enlarged adipocytes and increased TG content. The expression of HMGCS2 in renal and PRAT was significantly greater in db/db mice. (2) Hmgcs2 was equally expressed in db/db renal and PRAT. PRAT expansion increases the inflammatory factor TNF-α, which occurs earlier in PRAT than in renal tissue.(3) Genetic ablation of HMGCS2 in mice significantly decreased renal and PRAT TG accumulation, concomitant with attenuated inflammation. (4) LC–MS/MS analysis revealed that TGs are the main PRAT lipid component. Db/db PRAT TG content was significantly greater than that in db/m. Db/db proximal PRAT TG content is greater than that of the distal region, with seven upregulated TG lipid molecules (TG (38:3)+NH4, TG (50:5)+NH4, TG (52:12e)+Na, TG (56:9e)+H, TG (57:6e)+H, FA (18:1)+H, and ST (m45:3)+NH4), among which TG (38:3) has the highest expression.

Conclusion

Our study strongly suggests that lipids, especially TGs, are deposited in the kidneys and PRAT of DKD mice, with proximal–distal PRAT differences. HMGCS2 may be involved in kidneys and PRAT TG deposition. PRAT-lipid-metabolism-induced inflammation may occur before blood-glucose-related kidney damage.

背景与目的肾HMGCS2上调与脂质沉积有关。然而，Hmgcs2在肾周脂肪组织（PRAT）中的表达模式和作用尚不清楚。本研究旨在阐明Hmgcs2在肥胖糖尿病肾病小鼠发病机制中的作用。方法12周龄db/db（糖尿病小鼠）和db/m（对照组小鼠）分别饲喂高脂饲料和正常饲料。在12、16和20周时，对小鼠（n = 4/组/时间点）实施安乐死，进行代谢分析（体重、血糖、尿ACR）和组织收集（肾脏、PRAT）。组织分析TNF-α mRNA （qPCR）、HMGCS2表达（IHC/WB/IF）、脂质沉积（Oil Red O）和组织病理学（HE染色）。评估PRAT甘油三酯（比色法）和脂质组学（UPLC-MS /MS）。hmgcs2敲除小鼠（crispr生成）在进行终末组织分析之前进行代谢测试（OGTT/ITT）。结果(1)与db/mPRAT相比，db/db PRAT显著增大脂肪细胞，增加TG含量。HMGCS2在肾和PRAT中的表达在db/db小鼠中显著增加。(2) Hmgcs2在db/db肾组织和PRAT组织中表达量相等。PRAT扩张增加炎症因子TNF-α，其在PRAT中比在肾组织中更早发生。(3)小鼠HMGCS2基因消融可显著降低肾脏和PRAT TG积累，并伴有炎症减轻。(4) LC-MS /MS分析显示tg是PRAT的主要脂质成分。Db/ Db PRAT TG含量显著高于Db/ m。近端PRAT区TG含量Db/ Db大于远端，7种TG脂质分子(TG (38:3)+NH4、TG (50:5)+NH4、TG (52:12e)+Na、TG (56:9e)+H、TG (57:6e)+H、FA （18:1)+H、ST (m45:3)+NH4）表达上调，其中TG（38:3）表达量最高。结论脂质，尤其是tg，在DKD小鼠的肾脏和PRAT中沉积，且PRAT近端和远端存在差异。HMGCS2可能参与肾脏和PRAT的TG沉积。prat -脂质代谢引起的炎症可能发生在血糖相关性肾损害之前。

{"title":"Analysis of HMGCS2 Expression and TG Lipidomics in the Perirenal Adipose Tissue of Obese Diabetic Nephropathy Mice","authors":"Yuhong Huang, Miao Zeng, Mengxue Yang, Xiaodi Zheng, Lulu Jin, Rui Zhang, Yueyue Wu, Fei Li, Bo Yang, Jun Liu","doi":"10.1111/1753-0407.70125","DOIUrl":"https://doi.org/10.1111/1753-0407.70125","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Renal HMGCS2 upregulation is associated with lipid deposition. However, the expression pattern and role of Hmgcs2 in the perirenal adipose tissue (PRAT) is not clear. This study was designed to elucidate the contribution of Hmgcs2 in the pathogenesis of obese diabetic kidney disease mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>12-week-old db/db (diabetic) and db/m (control) mice were fed high-fat or normal diets, respectively. At 12, 16, and 20 weeks, mice (<i>n</i> = 4/group/timepoint) were euthanized for metabolic profiling (body weight, blood glucose, urinary ACR) and tissue collection (kidney, PRAT). Tissues were analyzed for TNF-α mRNA (qPCR), HMGCS2 expression (IHC/WB/IF), lipid deposition (Oil Red O), and histopathology (HE staining). PRAT triglycerides (colorimetric assay) and lipidomics (UPLC–MS/MS) were assessed. HMGCS2-knockout mice (CRISPR-generated) underwent metabolic tests (OGTT/ITT) before terminal tissue analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>(1) Compared with db/mPRAT, db/db PRAT had significantly enlarged adipocytes and increased TG content. The expression of HMGCS2 in renal and PRAT was significantly greater in db/db mice. (2) Hmgcs2 was equally expressed in db/db renal and PRAT. PRAT expansion increases the inflammatory factor TNF-α, which occurs earlier in PRAT than in renal tissue.(3) Genetic ablation of HMGCS2 in mice significantly decreased renal and PRAT TG accumulation, concomitant with attenuated inflammation. (4) LC–MS/MS analysis revealed that TGs are the main PRAT lipid component. Db/db PRAT TG content was significantly greater than that in db/m. Db/db proximal PRAT TG content is greater than that of the distal region, with seven upregulated TG lipid molecules (TG (38:3)+NH4, TG (50:5)+NH4, TG (52:12e)+Na, TG (56:9e)+H, TG (57:6e)+H, FA (18:1)+H, and ST (m45:3)+NH4), among which TG (38:3) has the highest expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study strongly suggests that lipids, especially TGs, are deposited in the kidneys and PRAT of DKD mice, with proximal–distal PRAT differences. HMGCS2 may be involved in kidneys and PRAT TG deposition. PRAT-lipid-metabolism-induced inflammation may occur before blood-glucose-related kidney damage.</p>\u0000 </section>\u0000 </div>","PeriodicalId":189,"journal":{"name":"Journal of Diabetes","volume":"17 7","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1753-0407.70125","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144695763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comment on “Time Trends in Cardiovascular Event Incidence in New-Onset Type 2 Diabetes: A Population-Based Cohort Study From Germany” 《新发2型糖尿病心血管事件发生率的时间趋势：一项来自德国的基于人群的队列研究》

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-23 DOI: 10.1111/1753-0407.70130

Saraswati Sah, Rachana Mehta, Ranjana Sah

<p>We read with great interest the study by Sarabhai et al., which provides valuable insights into the temporal evolution of cardiovascular events in newly diagnosed type 2 diabetes (T2D) patients in Germany over a 17-year period [<span>1</span>]. Although the reduction in the 5-year incidence of coronary heart disease (CHD) and transient ischemic attack (TIA) is encouraging, we believe several methodological and conceptual limitations deserve further discussion to contextualize the findings.</p><p>First, the study's exclusion of laboratory parameters such as glycated hemoglobin (HbA1c), lipid panels, and renal function significantly constrains the capacity to adjust for the quality of glycemic and metabolic control—central determinants of cardiovascular outcomes in T2D [<span>2, 3</span>]. Reliance solely on ICD-10 codes, though validated for primary diagnoses, does not differentiate between stable and unstable angina, nor does it account for silent myocardial infarctions, which are prevalent in diabetic populations [<span>4</span>]. This coding limitation may partially explain the paradoxically unchanged incidence of myocardial infarction (MI) despite improvements in CHD.</p><p>Second, the use of chronic obstructive pulmonary disease (COPD) as a proxy for smoking status introduces exposure misclassification. Smoking is a potent modifiable risk factor for both MI and ischemic stroke (IS) [<span>5</span>], and its secular decline in Germany over this period likely contributed to cardiovascular risk reduction. Without direct smoking data, the differential attribution of risk to diabetes-specific interventions versus population-wide trends remains unresolved.</p><p>Third, the apparent stability in MI and IS incidence may also be an artifact of cohort composition rather than a true epidemiological plateau. Although the authors matched for age and sex, no stratification by socioeconomic status, regional healthcare access, or medication use—particularly statins and antihypertensives—was undertaken. These variables influence the uptake and effectiveness of cardioprotective interventions [<span>6</span>]. Furthermore, the analysis does not disaggregate event timing within the five-year follow-up, thereby overlooking early versus late event clustering, which may offer clues about legacy effects from undiagnosed prediabetes.</p><p>Fourth, the demographic distribution masks evolving baseline risk. Although mean age and sex proportions remained unchanged, the increased prevalence of hypertension and obesity in the later cohort signals rising baseline cardiovascular risk. Paradoxically, these upward shifts might dilute the observable impact of improved care. Consequently, the unchanged IS and MI rates may reflect counterbalancing effects between therapeutic progress and population-level risk escalation.</p><p>Finally, the study's conclusion that CHD and TIA reduction reflects successful diabetes management may overstate causality. CHD includes chronic, often

我们非常感兴趣地阅读了Sarabhai等人的研究，该研究为德国新诊断的2型糖尿病（T2D）患者心血管事件的时间演变提供了宝贵的见解，为期17年[10]。尽管5年冠心病（CHD）和短暂性脑缺血发作（TIA）发病率的降低令人鼓舞，但我们认为，一些方法学和概念上的局限性值得进一步讨论，以便将研究结果与背景联系起来。首先，该研究排除了实验室参数，如糖化血红蛋白（HbA1c）、脂质面板和肾功能，这明显限制了对血糖和代谢控制质量的调整能力，而血糖和代谢控制是糖尿病心血管结局的核心决定因素[2,3]。仅依赖ICD-10编码，虽然在初级诊断中得到了验证，但不能区分稳定型和不稳定型心绞痛，也不能解释在糖尿病人群中普遍存在的无症状心肌梗死[10]。这种编码限制可能部分解释了尽管冠心病有所改善，但心肌梗死（MI）发生率却矛盾地没有变化。其次，使用慢性阻塞性肺疾病（COPD）作为吸烟状况的代表会导致暴露错误分类。吸烟是心肌梗死和缺血性卒中（is）的一个有效的可改变的危险因素，在这一时期，吸烟在德国的长期下降可能有助于心血管风险的降低。在没有直接吸烟数据的情况下，糖尿病特定干预措施的风险归因与人群整体趋势的差异仍未得到解决。第三，心肌梗死和IS发病率的明显稳定性也可能是队列组成的人为因素，而不是真正的流行病学平台期。虽然作者的年龄和性别相匹配，但没有按社会经济地位、地区医疗保健获取或药物使用（特别是他汀类药物和抗高血压药物）进行分层。这些变量影响心脏保护干预措施的吸收和有效性。此外，该分析没有分解5年随访期间的事件时间，从而忽略了早期和晚期事件聚类，这可能为未确诊的前驱糖尿病的遗留影响提供线索。第四，人口分布掩盖了不断变化的基线风险。虽然平均年龄和性别比例保持不变，但后期队列中高血压和肥胖患病率的增加表明基线心血管风险上升。矛盾的是，这些向上的转变可能会淡化改善护理的可观察到的影响。因此，不变的IS和MI率可能反映了治疗进展和人群水平风险升级之间的平衡效应。最后，该研究的结论是冠心病和TIA的减少反映了成功的糖尿病管理，这可能夸大了因果关系。冠心病包括慢性的，通常是无症状的病理，需要长期的门诊治疗和诊断的进步。相比之下，心肌梗死和IS通常反映了急性的、不可逆的血管损伤终末累积，甚至可能在明显的T2D诊断之前。这提出了一种可能性，即本研究未解决的糖尿病前期血管损伤可能是结果停滞的主要驱动因素。总之，虽然该研究捕捉到了重要的时间变化，但对于从更广泛的流行病学转变中解开糖尿病特异性干预的贡献，更细粒度、生物标志物信息和纵向分层分析是必不可少的。Saraswati Sah：概念化，方法论，验证，写作-原稿，写作-审查和编辑。Rachana Mehta：写作-原稿，写作-审查和编辑。Ranjana Sah：监督，项目管理，写作-原稿，写作-审查和编辑。作者没有什么可报告的。作者没有什么可报告的。作者声明无利益冲突。

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引用次数: 0

Author Response to the Comment on “Time Trends in Cardiovascular Event Incidence in New-Onset Type 2 Diabetes: A Population-Based Cohort Study From Germany” 作者对“新发2型糖尿病心血管事件发生率的时间趋势：来自德国的一项基于人群的队列研究”评论的回应

IF 3 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Journal of Diabetes

Pub Date : 2025-07-23 DOI: 10.1111/1753-0407.70128

Theresia Sarabhai, Karel Kostev

<p>We sincerely thank the authors of the comment and appreciate the opportunity to respond to clarify specific aspects of our study.</p><p>First of all, we agree that laboratory parameters are key indicators of metabolic control and cardiovascular risk. Although the Disease Analyzer database includes laboratory data from a subset of practices, laboratory values were not consistently available over time and across patients in our cohort. Therefore, we opted not to include them in our analyses. To address this limitation, we adjusted for chronic comorbidities known to be associated with poor metabolic control, such as hypertension, dyslipidemia, and obesity (coded diagnoses). Previous studies demonstrated the validity of the Disease Analyzer database especially for case–control studies focusing on diabetes mellitus [<span>1</span>]. Furthermore, by focusing on first cardiovascular events in a well-defined incident T2D cohort without prior CVD, we aimed to reduce confounding and improve internal validity despite the absence of uniformly available laboratory markers.</p><p>We acknowledge the potential limitations of relying solely on ICD-10 codes, as we stated in the manuscript. However, the Disease Analyzer database has been extensively validated and has demonstrated a high positive predictive value for major cardiovascular diagnoses, including MI [<span>1-3</span>]. We appreciate the reference by Tsai et al. [<span>4</span>], which highlights the strong validity of ICD-10-CM codes for identifying AMI subtypes. Although their work confirms excellent performance metrics, our interest was not the subtype but rather the trend in overall MI incidence.</p><p>Indeed, smoking is a critical risk factor. As stated, individual smoking status is not recorded in the Disease Analyzer database. We therefore followed established practice in using COPD as a proxy, recognizing its limitations. As noted in the literature, around 90% of patients with COPD are current or former smokers [<span>5</span>]. However, not all smokers develop COPD, so COPD cannot fully replace smoking status, but provides an approximate indicator. We clearly acknowledged this limitation in the manuscript. Importantly, smoking prevalence in Germany has declined over the study period, which may have contributed to overall cardiovascular improvements. However, as these trends would influence both diabetic and nondiabetic populations alike, our interpretation focused on diabetes-specific outcomes in a matched T2D cohort.</p><p>We agree that socioeconomic status and medication use are important factors. Although these data were not available in sufficient detail in our database, our large, matched cohorts and adjustment for key comorbidities offer valuable insights into temporal patterns. The unchanged MI and IS incidence, despite improvements in CHD and TIA, likely reflects a balance between earlier vascular damage and therapeutic progress. Although we did not stratify events by time since diagno

我们真诚地感谢评论的作者，并感谢有机会回应澄清我们研究的具体方面。首先，我们同意实验室参数是代谢控制和心血管风险的关键指标。尽管疾病分析数据库包括来自实践子集的实验室数据，但实验室值在我们的队列中并不是始终如一地可用。因此，我们选择不将它们包括在我们的分析中。为了解决这一局限性，我们调整了已知与代谢控制不良相关的慢性合并症，如高血压、血脂异常和肥胖（编码诊断）。先前的研究证实了疾病分析数据库的有效性，特别是针对糖尿病的病例对照研究。此外，通过关注明确的T2D队列中没有CVD的首次心血管事件，我们旨在减少混淆并提高内部有效性，尽管缺乏统一可用的实验室标记。正如我们在手稿中所述，我们承认仅依赖ICD-10代码的潜在局限性。然而，Disease Analyzer数据库已被广泛验证，并显示出对主要心血管诊断的高阳性预测价值，包括心肌梗塞[1-3]。我们赞赏Tsai等人[4]的参考文献，该文献强调了ICD-10-CM代码在识别AMI亚型方面的强大有效性。虽然他们的工作证实了出色的表现指标，但我们的兴趣不是亚型，而是总体心肌梗死发病率的趋势。事实上，吸烟是一个关键的风险因素。如前所述，个人吸烟状况未记录在疾病分析数据库中。因此，在认识到COPD的局限性后，我们遵循了使用COPD作为替代指标的既定做法。如文献所述，约90%的COPD患者是当前或曾经的吸烟者。然而，并非所有吸烟者都会发展为慢性阻塞性肺病，因此慢性阻塞性肺病不能完全取代吸烟状态，但提供了一个近似的指标。我们在手稿中清楚地承认了这一局限性。重要的是，在研究期间，德国的吸烟率有所下降，这可能有助于整体心血管疾病的改善。然而，由于这些趋势会影响糖尿病和非糖尿病人群，我们的解释集中在匹配的T2D队列中糖尿病特异性结果。我们同意社会经济地位和药物使用是重要因素。虽然这些数据在我们的数据库中没有足够的细节，但我们的大型匹配队列和关键合并症的调整为时间模式提供了有价值的见解。尽管冠心病和TIA有所改善，但心肌梗死和心肌梗死发生率不变，可能反映了早期血管损伤和治疗进展之间的平衡。虽然我们没有根据诊断后的时间对事件进行分层，但我们的5年随访捕获了总体发病率模式。高血压和肥胖症的增加可能抵消了改善护理的一些好处。我们没有推断因果关系，而是将我们的发现解释为时间趋势，承认冠心病和TIA的下降可能是由临床改善和人口水平变化驱动的多因素。尽管存在局限性，但我们的研究为T2D事件的心血管趋势提供了新的见解。我们欢迎进一步的研究纳入生活方式、生物标志物和社会经济地位数据来扩展这些发现。向特蕾西娅·萨拉巴伊和卡雷尔·科斯特夫致以诚挚的问候。根据ICMJE指南，个人贡献如下：T.S.和K.K.手稿起草，以及响应协调。所有作者都已阅读并批准了回复的最终版本，并同意对工作的各个方面负责。作者没有什么可报告的。作者声明无利益冲突。

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