The insulin-sensitivity sulphonylurea receptor variant is associated with thyrotoxic paralysis

Abstract

Thyrotoxicosis is the most common cause of the acquired flaccid muscle paralysis in adults called thyrotoxic periodic paralysis (TPP) and is characterised by transient hypokalaemia and hypophosphataemia under high thyroid hormone levels that is frequently precipitated by carbohydrate load. The sulphonylurea receptor 1 (SUR1 (ABCC8)) is an essential regulatory subunit of the β-cell ATP-sensitive K+ channel that controls insulin secretion after feeding. Additionally, the SUR1 Ala1369Ser variant appears to be associated with insulin sensitivity. We examined the ABCC8 gene at the single nucleotide level using PCR-restriction fragment length polymorphism (RFLP) analysis to determine its allelic variant frequency and calculated the frequency of the Ala1369Ser C-allele variant in a cohort of 36 Brazilian TPP patients in comparison with 32 controls presenting with thyrotoxicosis without paralysis (TWP). We verified that the frequency of the alanine 1369 C-allele was significantly higher in TPP patients than in TWP patients (61.1 vs 34.4%, odds ratio (OR)=3.42, P=0.039) and was significantly more common than the minor allele frequency observed in the general population from the 1000 Genomes database (61.1 vs 29.0%, OR=4.87, P<0.005). Additionally, the C-allele frequency was similar between TWP patients and the general population (34.4 vs 29%, OR=1.42, P=0.325). We have demonstrated that SUR1 alanine 1369 variant is associated with allelic susceptibility to TPP. We suggest that the hyperinsulinaemia that is observed in TPP may be linked to the ATP-sensitive K+/SUR1 alanine variant and, therefore, contribute to the major feedforward precipitating factors in the pathophysiology of TPP.