Insulin Receptor Polymorphisms; Predictors Of Pharmaco-resistance

Introduction: Current antiepileptic drugs (AEDs) are ineffective in around one third of patients [1]. The reason why these drugs fail to control seizures in this sizeable population is unclear but numerous hypotheses have been proposed involving multiple biological processes and pathways. The insulin receptor (INSR) has an important role in controlling blood glucose levels but is also involved in regulation of neuronal growth and survival, proliferation of astrocytes, synaptic plasticity and apoptosis in the CNS [2]. Recent evidence suggests that a polymorphism (H1085H) in the INSR gene can act as a biomarker of treatment outcome in epilepsy. Patients carrying either CT or TT genotype at this locus were significantly less likely to respond to AED therapy than those with a CC genotype [3]. The current study aimed to validate this observation and confirm the involvement of the INSR H1085H polymorphism in drug resistant epilepsy.

Method: Deoxyribonucleic acid (DNA) samples were obtained from 325 Caucasian patients with epilepsy. Of these, 120 patients had been free from seizures for at least 12 months at last recorded follow-up and were considered drug-responsive. The remaining 205 patients had continued to experience in the 12 months prior to last recorded follow-up despite exposure to otherwise appropriate AEDs at adequate dosage; these patients were considered drug resistant. Genotyping of the H1085H polymorphism was performed by polymerase chain reaction, followed by restriction enzyme digest with PmlI for 4 hours. Digest products were electrophoresed on a 2% agarose gel and visualised by ethidium bromide staining and ultraviolet trans-illumination. Genotypes were identified according to DNA fragment length; the CC genotype gave bands of 274bp and 43bp, the CT genotype gave bands of 317bp, 274bp and 43bp, while the TT genotype gave a single band at 317bp.

Results: The frequency of INSR H1085H genotypes in patients with drug-responsive epilepsy (n=120) was 62.5% CC, 31.7% CT and 5.8% TT. In patients with drug-resistant epilepsy (n=205), the corresponding genotype frequencies were 63.4% CC, 30.2% CT, and 6.3% TT. There was no statistically significant difference in genotype distribution between patients with drug-responsive and drug-resistant epilepsy (chi-sq = 0.092; p=0.955). Likewise, genotypes did not segregate on the basis of multiple clinical and demographic variables, including age, sex, epilepsy type and outcome of diagnostic investigations.

Discussion: This study failed to confirm a previous report suggesting that the INSR H1085H polymorphism might act as a biomarker for treatment outcome in epilepsy (3). We failed to find any association between INSR genotype and multiple demographic variables, including drug response, in a cohort of over 300 epilepsy patients. The reasons for this are unclear but ethnicity may be an important factor as the original observation was made in an Asian population. The role of insulin in the CNS remains to be fully explored but the diversity of its effects, including those on neuronal plasticity and neuronal survival [4,5], might suggest that this key signalling molecule has a potentially important influence in epilepsy and in other neurological disorders.

(1) Engel Jr. Annals of Indian Academy of Neurology 2014; 17: S12-S17;

(2) Van Der Heide et al. Progress in Neurobiology 2006; 79, 205-221;

(3) Che et al. Seizure 2015; 25: 178-180;

(4) Wang et al. Journal of the Neurological Sciences 2010; 296: 64-68;

(5) Timofeev et al. The Neuroscientist 2010; 16: 19-27.