Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation

Frontiers in Endocrinology

Endocrinology

Charles C. N. Wang¹  Ni Tien²  Fang-Yi Chu³  Yun-Ping Lim⁴  Chung Y. Hsu⁵  Tien-Yuan Wu⁶  Cheng-Li Lin⁷  Yi-Jen Fang⁸  Fuu-Jen Tsai⁹ 

[1] Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan;Center for Precision Health Research, Asia University, Taichung, Taiwan;Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan;Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan;Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan;Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan;Department of Medical Research, China Medical University Hospital, Taichung, Taiwan;Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan;Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan;Graduate Institute of Clinical Pharmacy, College of Medicine, Tzu Chi University, Hualien, Taiwan;Department of Pharmacy, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan;Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan;School of Chinese Medicine, College of Medicine, China Medical University, Taichung, Taiwan;Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University and National Health Research Institutes, Kaohsiung, Taiwan;Department of Environmental Health, Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Post-Baccalaureate Medicine, College of Medicine, National Chung-Hsing University, Taichung, Taiwan;Digestive Disease Center, Show Chwan Memorial Hospital, Changhua, Taiwan;School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan;Department of Medical Research, China Medical University Hospital, Taichung, Taiwan;Division of Medical Genetics, China Medical University Children’s Hospital, Taichung, Taiwan;Department of Biotechnology and Bioinformatics, Asia University, Taichung, Taiwan;

关键词: epilepsy;    anti-epileptic drugs;    type 2 diabetes mellitus;    next-generation RNA sequencing;    peroxisome proliferator-activated receptor γ;   

DOI  :  10.3389/fendo.2023.1156952

 received in 2023-02-02, accepted in 2023-05-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionA 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.MethodsWe 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.ResultsAfter 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.DiscussionOur 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 relationshipbetween epilepsy and T2DM.

【 授权许可】

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Copyright © 2023 Tien, Wu, Lin, Chu, Wang, Hsu, Tsai, Fang and Lim