Drivers for the comorbidity of type 2 diabetes mellitus and epilepsy: A scoping review

Abstract

Epilepsy, a common neurologic condition, is associated with a greater prevalence of type 2 diabetes mellitus (T2DM). We examined potential drivers for the comorbidity of epilepsy and T2DM in an attempt to elucidate possible biological mechanisms underlying the development of processes in individuals. We searched PubMed and Medline up to December 2019. Our search yielded 3,361 articles, of which 82 were included in the scoping review. We reviewed articles with a focus on the association of epilepsy and T2DM, drivers, and biological mechanisms. Epilepsy is associated with obesity and obesity is associated with T2DM. Treatment with valproate (either sodium or acid) is associated with weight increase and hyperinsulinemia, while topiramate causes weight loss. People with epilepsy are less likely to exercise which is protective against obesity. Mitochondrial dysfunction and adiponectin deficiency are common to epilepsy and T2DM. One possible mechanism for the comorbidity is mitochondrial dysfunction and adiponectin deficiency which promotes epilepsy, obesity, and T2DM. Another possible mechanism is that people with epilepsy are more likely to be obese due to lack of exercise and the effects of some antiseizure medications, which makes them susceptible to T2DM due to the development of mitochondrial dysfunction and adiponectin deficiency. A third mechanism is that people with epilepsy have greater mitochondrial dysfunction and lower adiponectin levels than people without epilepsy at baseline, which may exacerbate after treatment with antiseizure medications. Future research involving a combined genetic and molecular pathway approach will likely yield valuable insight regarding the comorbidity of epilepsy and T2DM.

Metabolic Alterations Predispose to Seizure Development in High-Fat Diet-Treated Mice: the Role of Metformin

“…This is in agreement with previous observations indicating that cerebral glucose demand and its consumption are higher in epileptic brain, due to the increased neuronal excitability, than other brain activities [68,69]. This higher propensity to develop chronic seizures by PTZkindling are in keeping with both clinical [5,6] and preclinical evidence [7,9,70,71], reporting that T2DM and its main drivers, such as hyperglycemia and/or obesity, can often precipitate seizures [4]. Despite methodological differences, these findings are partially consistent with previous findings demonstrating that the increase in brain metabolic energy demands during seizures experimentally induced by kainate and PTZ administration, lead to an increased GLUT-1 and GLUT-3 protein abundance in several brain regions [72].…”

“…Despite this, to date, the relationship between epilepsy and T2DM is poorly understood and suffers from a lack of epidemiological evidence and continued biomedical research efforts [4].…”

“…Altogether, it seems reasonable to believe that insulin resistance, MetS and T2DM may have an influence on neuronal excitability and therefore on seizure development [4]. Therefore, we hypothesized that MetS linked to T2DM and obesity could increase seizure propensity and that metformin would be effective in reverting this phenomenon.…”

“…Recently, studies documented that patients with type 1 diabetes mellitus have a higher risk of developing epilepsy than the general population, although the underlying mechanisms remain unknown [2,3]. In contrast, little is known about the risk of epilepsy in patients with type 2 diabetes (T2DM) and/or metabolic syndrome (MetS) [4]. Interestingly, some clinical and preclinical studies reported that hyperglycemia and/or obesity, which represent risk factors for T2DM, can precipitate seizures, particularly those of focal onset [5][6][7][8][9].…”

Metformin Increases Protein Phosphatase 2A Activity in Primary Human Skeletal Muscle Cells Derived from Lean Healthy Participants

“…Metformin reduces glucose production by the liver and increases insulin sensitivity (i.e., decreased insulin resistance) in skeletal muscles [ 2 , 3 ]. In addition, links between insulin resistance, diabetes, and brain disorders have been reported [ 4 , 5 ], and metformin has been shown to have antiseizure effects in epilepsy animal models and is proposed as a potential candidate for drug repurposing for epilepsy patients [ 5 – 7 ]. Nonetheless, molecular mechanisms of metformin's action in skeletal muscle are incompletely understood.…”