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

Front Endocrinol (Lausanne). 2023 Jun 2:14:1156952. doi: 10.3389/fendo.2023.1156952. eCollection 2023.

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticonvulsants / adverse effects
  • Cohort Studies
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / epidemiology
  • Epilepsy* / complications
  • Epilepsy* / drug therapy
  • Epilepsy* / epidemiology
  • Humans
  • PPAR gamma / genetics
  • Retrospective Studies
  • Transcriptional Activation

Substances

  • Anticonvulsants
  • PPAR gamma

Grants and funding

This study was supported by the Ministry of Science and Technology, Taiwan, R.O.C. (MOST110-2320-B-039-016-MY3), China Medical University, Taichung, Taiwan (CMU111-MF-34), China Medical University Hospital, Taichung, Taiwan (DMR-111-105), partially supported by the Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW110-TDU-B-212-124004), Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (TTCRD112-28), Show Chwan Memorial Hospital, Changhua, Taiwan (SRD-111024).