Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan.
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.
Front Endocrinol (Lausanne). 2023 Jun 2;14:1156952. doi: 10.3389/fendo.2023.1156952. eCollection 2023.
A potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship.
We extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated.
After adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ.
Our study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM.
最近的研究表明，癫痫与随后发生的 2 型糖尿病（T2DM）之间存在潜在关联。然而，癫痫、抗癫痫药物（AEDs）与 T2DM 发病风险之间的关联仍存在争议。我们旨在进行一项全国性、基于人群的回顾性队列研究，以评估这种关系。
我们从台湾新发性癫痫患者的纵向世代追踪数据库中提取数据，并将其与无癫痫的对照组进行比较。使用 Cox 比例风险回归模型分析两组患者发生 T2DM 的风险差异。使用下一代 RNA 测序来描述 AED 诱导的与 T2DM 相关的分子变化及其改变的 T2DM 相关途径。还评估了 AED 诱导过氧化物酶体增殖物激活受体 γ（PPARγ）反式激活的潜力。
在调整了合并症和混杂因素后，病例组（N=14089）发生 T2DM 的风险高于对照组（N=14089）[校正后的风险比（aHR），1.27]。未用 AED 治疗的癫痫患者发生 T2DM 的风险明显高于非癫痫对照组（aHR，1.70）。在用 AED 治疗的患者中，发生 T2DM 的风险明显低于未用 AED 治疗的患者（所有 aHR≤0.60）。然而，苯妥英（PHE）的定义日剂量增加（但不是丙戊酸（VPA））会增加 T2DM 发病风险（aHR，2.28）。差异表达基因的功能富集分析表明，与 PHE 相比，VPA 诱导了与葡萄糖稳态相关的多种有益基因。在 AED 中，VPA 诱导了 PPARγ的特异性反式激活。
我们的研究表明，癫痫会增加 T2DM 发病的风险，但某些 AED（如 VPA）可能对其具有保护作用。因此，需要对癫痫患者进行血糖筛查，以探讨 AED 在 T2DM 发病中的具体作用和影响。未来对 VPA 治疗 T2DM 的可能性进行深入研究，将为癫痫与 T2DM 之间的关系提供有价值的见解。
