Epilepsy is one of the most common serious diseases of the central nervous system (CNS) affecting more than 70 million people worldwide (1). Although antiepileptic drugs can suppress up to two-thirds of seizures, they do not change the long-term prognosis, and even patients who do not have seizures often experience adverse drug reactions (2, 3). Therefore, from the perspective of primary prevention, identifying modifiable risk factors is essential to prevent the onset of epilepsy and reduce the disease burdens.

Diabetes mellitus (DM), including type 1 diabetes mellitus (T1DM) and T2DM, is a chronic metabolic disease characterized by high blood glucose (BG), caused by complete/partial insufficiency of insulin secretion and insulin action, which is a major health problem contributing to the global burden of disease (4, 5). Recent evidence suggested DM may promote the occurrence of epilepsy and other neurological diseases through mechanisms, such as inflammation, immune imbalance, and cerebrovascular injury, caused by metabolic abnormalities (6–8). Several cohort studies have shown that patients with T1DM and T2DM have a significantly increased risk of subsequent epilepsy compared with non-T1DM and non-T2DM and that severe hypoglycemia may also increase the risk of epilepsy (9–12). However, evidence for the effects of DM and BG on the risk of epilepsy is still limited at present. In addition, traditional epidemiological studies are susceptible to confounding factors and causal inversion that the true associations of DM and BG with the onset of epilepsy are unclear.

Mendelian randomization (MR) is a burgeoning approach that exploits single nucleotide polymorphisms (SNPs) as unconfounded instrumental variants (IVs) to investigate the potential causal associations between exposures and diseases (13). Meanwhile, genetic code is not affected by environmental factors or preclinical diseases, thus MR analysis is less susceptible to bias resulting from reverse causation. More recently, MR analysis has also been utilized to investigate the potential causes of epilepsy (14, 15). Nevertheless, no study has discussed the causal associations of DM or BG with the onset of epilepsy based on MR methods.

In this study, we conducted a two-sample MR study to explore the potential causal associations between DM and BG-related indexes with epilepsy, aiming to provide an evidence-based foundation for the prevention of epilepsy and screening for high-risk populations.

This two-sample MR analysis explored the potential causal associations between DM and BG-related indexes with epilepsy. The study results showed that patients with T1DM seemed to have a potential risk of developing epilepsy and generalized epilepsy. In addition, no reverse causal association was found between T1DM and epilepsy or generalized epilepsy.

To the best of our knowledge, this is the first study to discuss potential causal associations between DM and BG with epilepsy based on the MR approach. Some observational studies have explored the relationship between DM and subsequent epilepsy risk, which may provide some pathological evidence for further causal association investigation, but the causal inference is limited. A meta-analysis conducted involved the aggregation of data from ten datasets, which were obtained from six observational studies and found that individuals with T1DM exhibited a significantly heightened susceptibility to epilepsy when compared with those with normoglycemia (19). Falip et al. (20) recruited adult onset T1DM patients who were seen consecutively in the Diabetes Unit of the Hospital Universitari de Bellvitge, calculated the prevalence of epilepsy and/or seizures, and showed that patients with high titers of glutamic acid decarboxylase antibody were more likely to develop temporal lobe epilepsy. A population-based cohort study of Danish citizens suggested T2DM was associated with several psychiatric and neurological disorders, including epilepsy, and most associations were consistently found for both temporal order of disorders (9). In addition, another cohort study included patients with T2DM and matched controls in Taiwan in 2002–2003, following the incidence of epilepsy or by the end of 2011, which supported that severe hypoglycemia may increase the risk of epilepsy and that T2DM increased the risk of epilepsy independent of severe hypoglycemia (10). In the current study, although no significant association was found between T2DM or BG with epilepsy, similar to Falip's results, T1DM had a potential unidirectional causal association with epilepsy and generalized epilepsy. MR design can make causal inferences compared with previous observational studies so that our findings relatively provided some reference for further clarification on the true association between DM and epilepsy. Nevertheless, the study population of this MR research was only European, and due to the limitation of the GWAS database, we could not obtain data on the exact location of epilepsy as well. Therefore, further studies are still needed to reveal correlations between DM and BG with epilepsy onset risk.

Several studies have explored the etiology of epilepsy, from which we can speculate about the possible mechanisms of the association between T1DM and epilepsy. T1DM is a T-cell-mediated autoimmune disease whose etiology is not fully understood. During T1DM pathogenesis, mitochondrial dysfunction due to impaired mitophagy with the release of reactive oxygen species contributes to initiating an inflammatory response by elevating pro-inflammatory cytokines (21). Meanwhile, clinical and animal studies have shown a complex role of inflammation in the development and progression of epilepsy (22). An elevated inflammatory response increases the secretion of pro-inflammatory cytokines and markers of inflammation and impairs neural circuits (23, 24). Recently, an MR study conducted by Sun et al. (25) showed that three inflammatory cytokines were associated with epilepsy, five were associated with generalized epilepsy, and four were linked to focal epilepsy. Herein, inflammation plays a key role in the underlying link between T1DM and epilepsy. Besides, hypothalamus-pituitary-adrenal (HPA) axis dysfunction may also be involved in the pathway that DM had a causal association with epilepsy. Patients with T2DM showed an impaired cortisol or growth hormone response, which is mainly regulated through the CNS (26, 27). Circadian rhythms of plasma cortisol concentrations instructed by the HPA axis may alter the balance between neuronal excitability and inhibition and modify neuronal excitability and epilepsy through gamma-aminobutyric acid levels (28, 29). However, more evidence should be proposed to clarify the exact mechanisms of the causal association between T1DM and epilepsy in the future.

MR is a relatively superior study design to observational studies on inferring the causal effect of potential risk factors on diseases of interest as mentioned before. Through investigating the roles of DM and BG in epilepsy risk, the present MR study may facilitate the recommendation of public health policies and clinical interventions that effectively reduce the incidence and social burden of epilepsy among the European population. We performed reverse causal association analysis and sensitivity analyses of significant results and found there was no reverse causal association of T1DM with epilepsy, focal epilepsy, or generalized epilepsy. In addition, although the causal association between BG and epilepsy was not significant, in fact, seizures usually improve with the control of glycaemic status in patients with T1DM and T2DM (30). Therefore, in clinical practice, the BG fluctuations need to be reduced timely among both patients with DM and those who had abnormal BG indexes, and at the same time, symptomatic treatment must be administered to avoid severe hypoglycemia or hyperglycemia, thereby reducing the potential risk of epilepsy.

This two-sample MR research explored the causal associations between DM and BG with epilepsy, which could overcome the influence resulting from common confounding factors and reverse causal association. Based on publicly available large-sample GWASs, IVs associated with study exposures and outcomes were highly explanatory and representative. In addition, sensitivity analyses were carried out by IVW-radial and leave-one-out methods, and the results indicated the potential causal association between T1DM and epilepsy was relatively robust. However, there are still some limitations that limited the interpretation of study results. Involved GWASs only included the European population, which limited these potential causal associations extrapolated to other populations. Aggregated data of GWASs limited further exploration of the potential causal associations of DM and BG with epilepsy in individuals with different characteristics. In addition, lacking individual data prevented the assessment of potential non-linear associations between them.

T1DM had a potential causal association with epilepsy. Patients with DM should be treated symptomatically and monitored timely to reduce the potential risk of epilepsy in clinical practice. However, the true relationship between DM and epilepsy needs to be further clarified.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent from the patients/participants or patients/participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

MZ: Conceptualization, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. SL: Data curation, Formal analysis, Investigation, Methodology, Writing – review & editing.