AbstractPrevious studies have revealed that thyroid hormone (TH) levels are associated with the risk of diabetic peripheral neuropathy (DPN) in euthyroid patients with type 2 diabetes mellitus (T2DM). However, the relationship between TH sensitivity, a complementary method for assessing thyroid function, and DPN remains unclear.

摘要先前的研究表明，甲状腺功能正常的2型糖尿病（T2DM）患者甲状腺激素（TH）水平与糖尿病周围神经病变（DPN）的风险相关。然而，评估甲状腺功能的补充方法TH敏感性与DPN之间的关系仍不清楚。

This study aimed to investigate the correlation between DPN and TH sensitivity in euthyroid patients with T2DM. Exactly 708 euthyroid adults with T2DM were retrospectively enrolled. The FT3/FT4 ratio was used to estimate peripheral TH sensitivity. Central TH sensitivity was assessed using the Thyrotroph T4 Resistance Index (TT4RI), Thyroid-Stimulating Hormone Index (TSHI), Thyroid Feedback Quantile-based Index (TFQI), and Parametric TFQI (PTFQI).

本研究旨在探讨甲状腺功能正常的T2DM患者DPN与TH敏感性之间的相关性。回顾性分析了708名甲状腺功能正常的T2DM成人。FT3/FT4比率用于估计外周TH敏感性。使用促甲状腺激素T4抵抗指数（TT4RI），促甲状腺激素指数（TSHI），甲状腺反馈分位数指数（TFQI）和参数TFQI（PTFQI）评估中枢TH敏感性。

DPN was assessed using neurologic symptoms, signs, and nerve conduction velocity tests. The relationship between DPN and TH sensitivity was examined using logistic regression analysis. We observed that an elevated FT3/FT4 ratio was associated with DPN (OR = 1.36, 95%CI: 1.13–1.63, p = 0.0012). For each standard deviation (SD) increase in the TT4RI, TSHI, TFQI, and PTFQI, the OR of DPN was 0.80 (95%CI: 0.68–0.94, p = 0.0078), 0.72 (95%CI: 0.60–0.86, p = 0.0002), 0.69 (95%CI: 0.58–0.83, p < 0.0001), and 0.69 (95%CI: 0.58–0.82, p < 0.0001), respectively.

使用神经系统症状，体征和神经传导速度测试评估DPN。使用逻辑回归分析检查DPN和TH敏感性之间的关系。我们观察到FT3/FT4比值升高与DPN相关（OR=1.36，95%CI:1.13-1.63，p=0.0012）。。

These results suggested that reduced central and peripheral TH sensitivity is associated with a decreased risk of developing DPN..

这些结果表明，中枢和外周TH敏感性降低与发生DPN的风险降低有关。。

IntroductionBased on the World Health Organization (WHO) standards, the prevalence of diabetes mellitus has reached as high as 12.4% in China, with type 2 diabetes mellitus (T2DM) accounting for over 90% of the cases1. As diabetes progresses, many patients develop complications, which are the leading cause of disability and death.

引言根据世界卫生组织（WHO）的标准，中国糖尿病的患病率高达12.4%，其中2型糖尿病（T2DM）占病例的90%以上1。随着糖尿病的进展，许多患者会出现并发症，这是导致残疾和死亡的主要原因。

Diabetic peripheral neuropathy (DPN), a condition characterized by peripheral nerve injury and dysfunction caused by prolonged hyperglycemia, is a common complication of T2DM, affecting approximately 30% of patients with the condition2. It mainly presents as symmetrical sensory abnormalities in the lower limbs, including burning and pins-and-needles sensations, which can lead to diabetic foot and may require amputation in severe cases3.

糖尿病周围神经病变（DPN）是一种以长时间高血糖引起的周围神经损伤和功能障碍为特征的疾病，是T2DM的常见并发症，约30%的患者受到影响2。它主要表现为下肢对称的感觉异常，包括烧灼感和针刺感，这可能导致糖尿病足，严重时可能需要截肢3。

Managing DPN involves optimizing glycemic control and addressing various risk factors such as hypertension and dyslipidemia. Still, there is currently no disease-modifying treatment for DPN4. Therefore, identifying new risk factors for DPN is important for improving prevention and treatment strategies.Thyroid hormones (THs) are crucial in regulating glucose and lipid metabolism.

管理DPN涉及优化血糖控制和解决各种风险因素，如高血压和血脂异常。尽管如此，目前还没有针对DPN4的疾病缓解治疗方法。因此，确定DPN的新危险因素对于改进预防和治疗策略很重要。甲状腺激素（THs）在调节葡萄糖和脂质代谢中至关重要。

Earlier studies have identified specific correlations between TH levels and diabetes and its complications. Previous studies revealed that in euthyroid patients with T2DM, serum-free triiodothyronine (FT3) and free thyroxine (FT4) levels were negatively correlated with the prevalence of DPN, and thyroid-stimulating hormone (TSH) levels were positively correlated5,6.

早期的研究已经确定了TH水平与糖尿病及其并发症之间的特定相关性。先前的研究表明，在甲状腺功能正常的T2DM患者中，血清游离三碘甲状腺原氨酸（FT3）和游离甲状腺素（FT4）水平与DPN的患病率呈负相关，促甲状腺激素（TSH）水平呈正相关5,6。

Some studies also suggested that elevated FT4 levels increase the risk of developing DPN and that there is no correlation between TSH and DPN occurrence7.As TH levels alone do not stably reflect thyroid function, TH sensitivity can be used as a complementary index to assess .

一些研究还表明，FT4水平升高会增加发生DPN的风险，TSH和DPN发生之间没有相关性7。由于TH水平本身不能稳定反映甲状腺功能，因此TH敏感性可以作为评估的补充指标。

(1)

(1)

FT3/FT4 = FT3 (pmol/L)/FT4 (pmol/L), which represents the efficiency of converting FT4 to FT3, reflecting peripheral sensitivity to THs. Elevated ratios reflect increased peripheral TH sensitivity13.

FT3/FT4=FT3（pmol/L）/FT4（pmol/L），表示将FT4转换为FT3的效率，反映了对TH的外围敏感性。升高的比率反映了外周TH敏感性的增加13。

(2)

(2)

TT4RI = FT4 (pmol/L) × TSH (mIU/L), which relates TSH to FT4 without introducing an additional coefficient. Higher TT4RI values indicate lower central TH sensitivity14.

TT4RI = FT4（pmol/L）× TSH（mIU/L），它将TSH与FT4联系起来，而不引入额外的系数。较高的TT4RI值表明较低的中央TH敏感性14。

(3)

(3)

TSHI = lnTSH (mIU/L) + 0.1345 × FT4 (pmol/L), which reflects the feedback inhibition of FT4 for TSH. Higher TSHI values reflect lower central TH sensitivity15.

TSHI=lnTSH（mIU/L）+0.1345×FT4（pmol/L），这反映了FT4对TSH的反馈抑制。较高的TSHI值反映出较低的中央TH敏感性15。

(4)

(4)

TFQI = cdfFT4 − (1 − cdfTSH). The index varies within the range of -1 to 1, with a negative value suggesting increased central TH sensitivity and a positive value suggesting decreased central TH sensitivity.

。该指数在-1至1的范围内变化，负值表明中枢TH敏感性增加，正值表明中枢TH敏感性降低。

(5)

(5)

PTFQI has the same scope and interpretation as TFQI. It can be applied to different populations. In this study, we used the Chinese-referenced PTFQI9,16.

PTFQI的范围和解释与TFQI相同。它可以应用于不同的人群。在这项研究中，我们使用了中文参考的PTFQI9,16。

Definition of DPNNeurological symptoms, signs, and nerve conduction velocities were used to diagnose DPN. The Toronto Clinical Scoring System (TCSS) was used to assess neurological signs and symptoms17. The patients were asked if they had symptoms such as numbness, pins and needles, weakness, and unsteady gait.

DPN神经学症状，体征和神经传导速度的定义用于诊断DPN。多伦多临床评分系统（TCSS）用于评估神经系统体征和症状17。询问患者是否有麻木、针扎、虚弱和步态不稳等症状。

Knee and ankle reflexes were examined. Pain, touch, temperature, vibration, and position sensations were evaluated. The TCSS score ranged from 0 to 19, with scores of 0–5 indicating no DPN and scores above 6 indicating DPN.Nerve conduction velocity (NCV) was detected using electromyography. The patients were awake and relaxed, ensuring the local skin temperature was > 31℃.

检查膝关节和踝关节反射。评估疼痛，触摸，温度，振动和位置感觉。TCSS评分范围为0至19，0-5分表示无DPN，6分以上表示DPN。使用肌电图检测神经传导速度（NCV）。患者清醒放松，确保局部皮肤温度>31℃。

Electrical stimulation was applied to the patients, and the motor and sensory NCV, terminal latency, and wave amplitude were recorded from the ulnar, median, common peroneal, and tibial nerves. The NCV decline threshold was determined based on the Chinese NCV reference standard18.Statistical analysisThe associations between FT3/FT4, PTFQI, TFQI, TSHI, TT4RI, and DPN were investigated using multivariable regression models.

对患者进行电刺激，并记录尺神经，正中神经，腓总神经和胫神经的运动和感觉NCV，终末潜伏期和波幅。根据中国NCV参考标准18确定NCV下降阈值。统计分析使用多变量回归模型研究FT3/FT4，PTFQI，TFQI，TSHI，TT4RI和DPN之间的关联。

Model 1 was adjusted for sex and age. Model 2 was additionally adjusted for BMI, FPG, HbA1c, TyG index, smoking status, drinking status, diabetes duration, hypertension, dyslipidemia, and use of antihyperglycemic, antihypertensive, and lipid-lowering agents. Stratified analyses were conducted based on BMI, age, HbA1c, and diabetes course.

模型1根据性别和年龄进行了调整。模型2还针对BMI，FPG，HbA1c，TyG指数，吸烟状况，饮酒状况，糖尿病持续时间，高血压，血脂异常以及抗高血糖，抗高血压和降脂药的使用进行了调整。根据BMI，年龄，HbA1c和糖尿病病程进行分层分析。

We further fitted the data using smoothing and generalized additive models to investigate the potential non-linear relationship.Statistical analyses were conducted using the R package and Empower Stats (http://www.Rproject.org and http://www.empowerstats.com). The level of statistical significance was set at P < 0.05 (two-sided).Statement of .

我们使用平滑和广义加性模型进一步拟合数据，以研究潜在的非线性关系。使用R软件包和Empower Stats进行统计分析(http://www.Rproject.org和http://www.empowerstats.com)。统计学显着性水平设定为P<0.05（双侧）。的声明。

Data availability

数据可用性

The data analyzed and generated in this study are available from the corresponding author on reasonable request.

。

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Download referencesAcknowledgementsWe would like to thank Editage (www.editage.cn) for English language editing.FundingThis work was supported by the First Hospital of Jilin University (2021-zl-01 and JDYYCB-2023010 to Xue Zhao; JDYYZH-2102030 to Guixia Wang), the Department of Science and Technology of Jilin Province (20210101439JC to Xue Zhao; YDZJ202202CXJD042, 20210303001SF, and 20190901006JC to Guixia Wang), and grants from the National Natural Science Foundation of China (82270850 and 81970687 to Guixia Wang).Author informationAuthor notesThese authors contributed equally: Meixin Sun and Lu Yu.Authors and AffiliationsDepartment of Endocrinology and Metabolism, The First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, 130021, ChinaMeixin Sun, Xue Zhao, Linan Ren, Xinming Liu, Xiaokun Gang & Guixia WangDepartment of Endocrinology and Metabolism, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, ChinaLu YuAuthorsMeixin SunView author publicationsYou can also search for this author in.

下载参考文献致谢我们要感谢Editage（www.Editage.cn）进行英语编辑。资助这项工作得到了吉林大学第一医院（2021-zl-01和JDYYCB-2023010给薛昭；JDYYZH-2102030给王桂霞）、吉林省科学技术厅（20210101439JC给薛昭；YDZJ202202CXJD04220210303001SF和20190901006JC给王桂霞）的支持，以及国家自然科学基金（82270850和81970687给王桂霞）的资助。作者信息作者注意到这些作者做出了同样的贡献：孙美欣和陆雨。作者和附属机构吉林大学第一医院内分泌与代谢科，长春市朝阳区新民街71号，130021，中国孙美新，薛昭，任林楠，刘新明，肖昆刚和王桂霞华中科技大学同济医学院附属协和医院内分泌与代谢科，武汉，430000，中国陆宇作者孙美新观点作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsM.S. reviewed relevant literature and wrote the manuscript. L.Y. collected and analyzed data. X.Z. generated relevant charts and graphs. L.R. and X.L. reviewed and revised the manuscript. X.G. and G.W. were responsible for financial support. All the authors have read and approved the manuscript.

PubMed谷歌学术贡献。S、 。五十、 Y.收集和分析数据。十、 Z.生成相关图表。五十、 R.和X.L.审查并修订了手稿。十、 G.和G.W.负责财务支持。所有作者都阅读并批准了手稿。

M.S. and L.Y. contributed equally to this work and should be considered co-first authors.Corresponding authorsCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleSun, M., Yu, L., Zhao, X. et al. Correlation between thyroid hormone sensitivity and diabetic peripheral neuropathy in euthyroid patients with type 2 diabetes mellitus.

转载和许可本文引用本文Sun，M.，Yu，L.，Zhao，X。等人。甲状腺功能正常的2型糖尿病患者甲状腺激素敏感性与糖尿病周围神经病变的相关性。

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KeywordsDiabetic peripheral neuropathyThyroid hormonePeripheral thyroid hormone sensitivityCentral thyroid hormone sensitivity

关键词糖尿病周围神经甲状腺激素外周甲状腺激素敏感性中心甲状腺激素敏感性

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