A population-based study of epilepsy incidence in association with type 2 diabetes and severe hypoglycaemia
Introduction
Type 2 diabetes has been found to be associated with increased risks of various neurological disorders, including dementia [1], Parkinson’s disease [2], [3], and possibly multiple sclerosis [4]. Recent studies have found that type 1 diabetes could be associated with the incidence of epilepsy, though the underlying mechanisms exactly linking such a relationship remain unclear [5]. Previous studies noted that epilepsy or seizures are associated with various autoimmune or inflammatory disorders and are involved in the pro-inflammatory processes [6], [7]. Additionally, metabolic abnormalities of diabetes, such as hyperglycaemia and hypoglycaemia, may pose adverse effects on the central nervous system [5], thereby leading to seizure. It has been well documented that both hyperglycaemia and hypoglycaemia commonly occur in people with diabetes can alter the balance between the inhibition and excitation of neuronal networks and cause focal motor seizures [8], [9].
Epilepsy is a group of neurological diseases characterized by epileptic seizures. Mortality in people with epilepsy exceeds that in the general population, which is especially true for certain causes of death, including cerebrovascular disease (CVD), neoplastic disorders, and accidents [10]. In addition to some known risk factors for epilepsy including degenerative brain disorders and head injuries [11], several diseases associated with type 2 diabetes such as stroke and dementia have also been considered as predisposing factors to epilepsy [12].
Evidence concerning the association of diabetes with epilepsy was mainly derived from studies of type 1 diabetes [13], [14], [15]; little is known about the risk of epilepsy in association with type 2 diabetes. People with type 2 diabetes are also vulnerable to the occurrence of hypoglycaemia and some disorders that co-morbid epilepsy. While severe hypoglycaemia can lead to seizure, coma, and is even life-threatened in a relatively short period, some of the hypoglycaemia-induced changes in electrical activity may persist for a long period of time [16].
We conducted this population-based study to estimate the incidence of epilepsy in patients with type 2 diabetes, with particular interest in assessing whether severe hypoglycaemia may modify or mediate the association of type 2 diabetes with epilepsy incidence.
Section snippets
Data source
The study proposal was approved by the Institutional Review Board of National Cheng Kung University Hospital (A-EX-104-008). Data were retrieved from Taiwan’s NHI research database, a medical claim database that stores the medical records of beneficiaries that are uploaded by medical institutions to obtain reimbursement from NHI. Taiwan’s NHI program universally covers medical insurance for nearly all (>97%) Taiwanese citizens (prisoners and military personnel were exempted in our study period)
Results
Patients with type 2 diabetes and control subjects enrolled in this study are comparable with respect to age, sex, insurance premium, level of urbanization, and family income level. Prevalence rates of certain co-morbidities, including neurotic-anxiety disorder, sleep disorder, cerebral palsy, and cerebral vascular disorder were higher in type 2 diabetes than in controls. Patients with type 2 diabetes also had a higher frequency of ambulatory care visits than controls (Table 1). It shows that
Discussion
To our knowledge, this is the first population-based study reporting an elevated risk of epilepsy in patients with type 2 diabetes. Numerous studies have found that children and adolescents with type 1 diabetes were associated with three times higher incidence [13], [14] and 2–6-fold prevalence of epilepsy [15], [28] as compared to the general population. The possible mechanisms were reportedly involved in the common associations of type 1 diabetes and epilepsy with anti-glutamic acid
Acknowledgements
This study is based in part on data from the NHIRD provided by the National Health Insurance Administration, Ministry of Health and Welfare of Taiwan, and managed by the National Health Research Institutes. The interpretation and conclusions contained herein do not represent the views of the National Health Insurance Administration, Ministry of Health and Welfare of Taiwan or National Health Research Institutes.
Funding information
This study was supported by a grant from the Ministry of Science and Technology (
References (35)
- et al.
A population-based cohort study suggests an increased risk of multiple sclerosis incidence in patients with type 2 diabetes mellitus
J Epidemiol
(2017) - et al.
Risk of mortality among patients with epilepsy in southern Taiwan
Seizure
(2012) - et al.
Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study
Lancet Neurol
(2005) - et al.
Study of prevalence of epilepsy in children with type 1 diabetes mellitus
Seizure
(2012) - et al.
Survival analysis: time-dependent effects and time-varying risk factors
Kidney Int
(2008) - et al.
Type 2 diabetes as a risk factor for dementia in women compared with Men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia
Diabetes Care
(2016) - et al.
Diabetes and the risk of developing Parkinson’s disease in Denmark
Diabetes Care
(2011) - et al.
Risk of Parkinson disease onset in patients with diabetes: a 9-year population-based cohort study with age and sex stratifications
Diabetes Care
(2012) - et al.
Association between diabetes, severe hypoglycemia, and electroencephalographic abnormalities
Arch Dis Child
(1989) Autoantibodies in the patient with drug-resistant epilepsy: are we missing a treatable etiology?
Arch Neurol
(2012)
Diabetes and epilepsy in children and adolescents
Curr Diab Rep
Differential effects of low glucose concentrations on seizures and epileptiform activity in vivo and in vitro
Eur J Neurosci
Severe hypoglycaemia in a juvenile diabetic rat model: presence and severity of seizures are associated with mortality
PLoS ONE
Epilepsy in cerebrovascular diseases: review of experimental and clinical data with meta-analysis of risk factors
Epilepsia
Risk of epilepsy in type 1 diabetes mellitus: a population-based cohort study
Diabetologia
Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study
Diabetologia
Hypoglycaemia in diabetes mellitus: epidemiology and clinical implications
Nat Rev Endocrinol
Cited by (18)
Drivers for the comorbidity of type 2 diabetes mellitus and epilepsy: A scoping review
2020, Epilepsy and BehaviorCitation Excerpt :Data regarding the comorbid association of epilepsy and type 2 diabetes mellitus (T2DM) are sparser but exist. A cohort study of national health insurance claims in Taiwan found that people with T2DM had a higher incidence of epilepsy than controls independent of severe hypoglycemia [21]. A Bosnian retrospective study found an association of early and late seizures with T2DM after stroke [22].
The ‘epileptic diet’- ketogenic and/or slow release of glucose intervention: A review
2020, Clinical NutritionCitation Excerpt :Hypo-and hyperglycaemia can precede epileptic events after a stroke [64]. Severe hypoglycaemia may increase the risk of epilepsy [65]. However, the overall risk of seizures associated with hypoglycaemia generally is relatively low according to some authors [66].
Prevention of post-ischemic seizure by rapamycin is associated with deactivation of mTOR and ERK1/2 pathways in hyperglycemic rats
2019, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Rapamycin treatment in HG animals successfully prevented post-ischemic seizures in 7 out of 8 rats, substantially reduced the neuronal death, and partially or completely blocked the hyperglycemia-induced activations of mTOR and ERK1/2 signaling pathways. Clinical studies have revealed that patients with hyperglycemia have a higher incidence of seizure than those without hyperglycemia and the post-stroke seizure is inclined to occur more in diabetes mellitus patients than in those without diabetes [17,18]. We have previously observed that euglycemic animals rarely developed post-ischemic seizure after 10 min of forebrain ischemia, while about 50% of hyperglycemic ischemic animals developed seizures when plasma glucose increased to 10–16 mM and the post-ischemic seizure incidence reached to 100% when plasma glucose content surpassed 16 mM [18].
Envisioning the neuroprotective effect of Metformin in experimental epilepsy: A portrait of molecular crosstalk
2019, Life SciencesCitation Excerpt :Plethora of studies has reported the association of epilepsy with DM, which is mainly based on studies from T1DM [41,42]. However, a population based study from Taiwan reported that people with T2DM are at 1.5 times higher risk of developing epilepsy than matched controls [43]. The precise underlying mechanism relating DM and epilepsy is not well understood, however we can speculate blood-brain barrier (BBB) breakdown in DM might plays a role in epileptogenesis.
New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway
2023, Journal of Cellular and Molecular Medicine