Permanent neonatal diabetes mellitus due to KCNJ11 mutation in a Portuguese family: transition from insulin to oral sulfonylureas

Dupont, Juliette; Pereira, Carla; Medeira, Ana; Duarte, Rui; Ellard, Sian; Sampaio, Lurdes

doi:10.1515/jpem-2011-0191

Cited by 16 publications

(14 citation statements)

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“…Heterozygous activation mutations in KCNJ11, encoding the Kir6.2 subunit of the KATP, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM (202). Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes diagnosed within the first 6 months of life.…”

Section: Diseases In Other Systemsmentioning

confidence: 99%

“…Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes diagnosed within the first 6 months of life. Heterozygous activation mutations in KCNJ11, encoding the Kir6.2 subunit of the KATP, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM (202). This channel plays a pivotal role in glucose-stimulated insulin release from the pancreatic beta cell.…”

Section: Diseases In Other Systemsmentioning

confidence: 99%

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Potassium Channels: Structures, Diseases, and Modulators

Tian

Zhu

et al. 2013

Chem Biol Drug Des

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Potassium channels participate in many critical biological functions and play important roles in a variety of diseases. In recent years, many significant discoveries have been made which motivate us to review these achievements. The focus of our review is mainly on three aspects. Firstly, we try to summarize the latest developments in structure determinants and regulation mechanism of all types of potassium channels. Secondly, we review some diseases induced by or related to these channels. Thirdly, both qualitative and quantitative approaches are utilized to analyze structural features of modulators of potassium channels. Our analyses further prove that modulators possess some certain natural-product scaffolds. And pharmacokinetic parameters are important properties for organic molecules. Besides, with in silico methods, some features that can be used to differentiate modulators are derived. There is no doubt that all these studies on potassium channels as possible pharmaceutical targets will facilitate future translational research. All the strategies developed in this review could be extended to studies on other ion channels and proteins as well.

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Section: Diseases In Other Systemsmentioning

confidence: 99%

Section: Diseases In Other Systemsmentioning

confidence: 99%

Potassium Channels: Structures, Diseases, and Modulators

Tian

Zhu

et al. 2013

Chem Biol Drug Des

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“…In addition, E23K variant was significantly associated with an increase of glycated hemoglobin A1c (HbA1c) level [47] and fasting glucose level that patients with the KK homozygous variant genotype had lower fasting glucose levels than those with the EE/EK heterozygous genotype [52]. Importantly, recent evidence demonstrated that patients with KCNJ11 variants responded more efficiently to sulfonylurea than insulin [64–66]. Another KCNJ11 polymorphism that was associated with sulfonylurea treatment responses is rs5210 which is located in 3’- untranslated region (UTR).…”

Section: Resultsmentioning

confidence: 99%

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment

et al. 2017

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BackgroundType 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects.MethodsBased on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl’s VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively.ResultsBased on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl’s VEP.ConclusionsOur study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy.

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“…These mutations prevent membrane depolarization in response to a decreased ATP:ADP ratio, resulting in decreased insulin secretion . Most patients with these mutations can be treated successfully with high‐dose sulfonylureas instead of the insulin that is the default treatment for neonatal diabetes and is more expensive, more invasive, less effective, and places individuals with these mutations at a greater risk for hypoglycemic episodes . Sulfonylureas close the same channels that become constitutively open owing to NDM mutations.…”

Section: Monogenic Diabetes Mellitus: Current Implementation Of Persomentioning

confidence: 99%

Personalized medicine in diabetes mellitus: current opportunities and future prospects

Kleinberger

Pollin

2015

Annals of the New York Academy of Sciences

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Diabetes mellitus affects approximately 382 million individuals worldwide and is a leading cause of morbidity and mortality. Over 40 and nearly 80 genetic loci influencing susceptibility to type 1 and type 2 diabetes, respectively, have been identified. Additionally, there is emerging evidence that some genetic variants help to predict response to treatment. Other variants confer apparent protection from diabetes or its complications and may lead to development of novel treatment approaches. Currently, there is clear clinical utility to genetic testing to find the at least 1% of diabetic individuals who have monogenic diabetes (e.g., maturity onset diabetes of the young and KATP channel neonatal diabetes). Diagnosing many of these currently underdiagnosed types of diabetes enables personalized treatment, resulting in improved and less invasive glucose control, better prediction of prognosis, and enhanced familial risk assessment. Efforts to enhance the rate of detection, diagnosis, and personalized treatment of individuals with monogenic diabetes should set the stage for effective clinical translation of current genetic, pharmacogenetic, and pharmacogenomic research of more complex forms of diabetes.

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Permanent neonatal diabetes mellitus due to KCNJ11 mutation in a Portuguese family: transition from insulin to oral sulfonylureas

Cited by 16 publications

References 0 publications

Potassium Channels: Structures, Diseases, and Modulators

Potassium Channels: Structures, Diseases, and Modulators

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment

Personalized medicine in diabetes mellitus: current opportunities and future prospects

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