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 ß-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.
Subject(s)
Genetic Association Studies , Genetic Variation , Insulin Resistance/genetics , Sulfonylurea Receptors/genetics , Thyrotoxicosis/genetics , Adult , Aged , Alleles , Case-Control Studies , Gene Frequency , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Thyrotoxicosis/diagnosis , Young AdultABSTRACT
Ion channels serve diverse cellular functions, mainly in cell signal transduction. In endocrine cells, these channels play a major role in hormonal secretion, Ca2+-mediated cell signaling, transepithelial transport, cell motility and growth, volume regulation and cellular ionic content and acidification of lysosomal compartments. Ion channel dysfunction can cause endocrine disorders or endocrine-related manifestations, such as pseudohypoaldosteronism type 1, Liddle syndrome, Bartter syndrome, persistent hyperinsulinemic hypoglycemia of infancy, neonatal diabetes mellitus, cystic fibrosis, Dent's disease, hypomagnesemia with secondary hipocalcemia, nephrogenic diabetes insipidus and, the most recently genetically identified channelopathy, thyrotoxic hypokalemic periodic paralysis. This review briefly recapitulates the membrane action potential in endocrine cells and offers a short overview of known endocrine channelopathies with focus on recent progress regarding the pathophysiological mechanisms and functional genetic defects.
Canais iônicos auxiliam diferentes funções celulares, principalmente na transdução de sinal. Nas células endócrinas, esses canais têm funções importantes na secreção hormonal, sinalização do Ca2+, transporte transepitelial, regulação da motilidade, volume e conteúdo iônico celular e da acidificação do compartimento lisossomal (pH). Como esperado, as alterações nos canais iônicos podem causar distúrbios endocrinológicos, como pseudo-hipoaldosteronismo tipo 1, síndrome de Liddle, síndrome de Bartter, hipoglicemia hiperinsulinêmica da infância, diabetes melito neonatal, fibrose cística, doença de Dent, hipomagnesemia com hipocalcemia secundária, diabetes insípido nefrogênico e paralisia periódica tirotóxica hipocalêmica. Este artigo propõe uma breve revisão das canalopatias endócrinas conhecidas, com foco particular nos recentes progressos no conhecimento dos mecanismos fisiopatológicos adquirido a partir das alterações funcionais encontradas.
Subject(s)
Humans , Channelopathies , Endocrine System Diseases , Ion Channels , Channelopathies/genetics , Channelopathies/physiopathology , Endocrine System Diseases/genetics , Endocrine System Diseases/physiopathology , Ion Channels/genetics , Ion Channels/physiologyABSTRACT
Ion channels serve diverse cellular functions, mainly in cell signal transduction. In endocrine cells, these channels play a major role in hormonal secretion, Ca(2+)-mediated cell signaling, transepithelial transport, cell motility and growth, volume regulation and cellular ionic content and acidification of lysosomal compartments. Ion channel dysfunction can cause endocrine disorders or endocrine-related manifestations, such as pseudohypoaldosteronism type 1, Liddle syndrome, Bartter syndrome, persistent hyperinsulinemic hypoglycemia of infancy, neonatal diabetes mellitus, cystic fibrosis, Dent's disease, hypomagnesemia with secondary hypocalcemia, nephrogenic diabetes insipidus and, the most recently genetically identified channelopathy, thyrotoxic hypokalemic periodic paralysis. This review briefly recapitulates the membrane action potential in endocrine cells and offers a short overview of known endocrine channelopathies with focus on recent progress regarding the pathophysiological mechanisms and functional genetic defects.
