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Daohua Shi, Tiancheng Xie, Jie Deng, Peiguang Niu, Weizhen Wu
PURPOSE: We intend to investigate the association between tacrolimus-induced new-onset diabetes after transplantation (NODAT) and polymorphisms of CYP3A4, CYP3A5, ATP-binding cassette transporter sub-family C member 8 (ABCC8), and glucokinase (GCK) in renal transplant recipients. METHODS: Polymorphisms of CYP3A4 *18B, CYP3A5 *3, ABCC8 T-3C, and GCK G-30A were genotyped in 169 renal transplant recipients. Trough concentrations of tacrolimus were detected by an ELISA kit...
March 15, 2018: European Journal of Clinical Pharmacology
Barbara Piccini, Caterina Coviello, Livia Drovandi, Artuso Rosangela, Francesca Monzali, Emilio Casalini, Sabrina Giglio, Sonia Toni, Carlo Dani
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes occurring within 6 months from birth. NDM can be permanent or transient (TNDM). We report the case of a preterm infant with TNDM due to an ABCC8 mutation identified by next-generation sequencing. The pancreatic adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channel is a key regulator of insulin secretion. Gain-of-function mutations in the genes encoding the Kir6.2 (KCNJ11) and SUR1 (ABCC8) subunits of the channel cause neonatal diabetes. The patient was successfully managed with insulin lispro at a 1:100 dilution, drawn up in an insulin pen injector with a 4-mm needle...
January 2018: American Journal of Perinatology Reports
Joanna Yuet-Ling Tung, Kara Boodhansingh, Charles A Stanley, Diva D De León
BACKGROUND: Dominant inactivating mutations in HNF1A and HNF4A have been described to cause hyperinsulinism (HI) before evolving to diabetes. However, information available in the literature regarding the clinical phenotype is limited. OBJECTIVE: To report the prevalence of HNF1A and HNF4A mutations in a large cohort of children with HI, and to describe their genotypes and phenotypes. DESIGN: Retrospective descriptive study. METHODS: Medical records were reviewed to extract clinical information...
March 1, 2018: Pediatric Diabetes
José M Vidal-Taboada, Marco Pugliese, Maria Salvadó, Josep Gámez, Nicole Mahy, Manuel J Rodríguez
The ATP-sensitive potassium (KATP ) channel directly regulates the microglia-mediated inflammatory response following CNS injury. To determine the putative role of the KATP channel in amyotrophic lateral sclerosis (ALS) pathology, we investigated whether ALS induces changes in KATP channel expression in the spinal cord and motor cortex. We also characterized new functional variants of human ABCC8, ABCC9, KCNJ8, and KCNJ11 genes encoding for the KATP channel and analyzed their association with ALS risk, rate of progression, and survival in a Spanish ALS cohort...
February 28, 2018: Molecular Neurobiology
Ewan R Pearson
In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11...
February 24, 2018: Current Opinion in Genetics & Development
Carolina I Ghanem, Jose E Manautou
Liver transporters play an important role in the pharmacokinetics and disposition of pharmaceuticals, environmental contaminants, and endogenous compounds. Among them, the family of ATP-Binding Cassette (ABC) transporters is the most important due to its role in the transport of endo- and xenobiotics. The ABCC sub-family is the largest one, consisting of 13 members that include the cystic fibrosis conductance regulator (CFTR/ABCC7); the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) and the multidrug resistance-associated proteins (MRPs)...
February 21, 2018: Current Medicinal Chemistry
Lisa R Letourneau, Siri Atma W Greeley
The majority of patients diagnosed with diabetes less than 6 months of age, and many cases diagnosed between 6 and 12 months of age, have a gene mutation that causes permanent or transient hyperglycemia. Recent research advances have allowed for the discovery of new causes of congenital diabetes, including genes involved in pancreatic development (GATA4, NKX2-2, MNX1) and monogenic causes of autoimmune dysregulation (STAT3, LRBA). Ongoing follow-up of patients with KCNJ11 and ABCC8 mutations has supported the safety and efficacy of sulfonylureas, as well as the use of insulin pumps and continuous glucose monitors in infants with insulin-requiring forms of monogenic diabetes...
February 14, 2018: Current Opinion in Genetics & Development
Viswanathan Mohan, Venkatesan Radha, Thong T Nguyen, Eric W Stawiski, Kanika Bajaj Pahuja, Leonard D Goldstein, Jennifer Tom, Ranjit Mohan Anjana, Monica Kong-Beltran, Tushar Bhangale, Suresh Jahnavi, Radhakrishnan Chandni, Vijay Gayathri, Paul George, Na Zhang, Sakthivel Murugan, Sameer Phalke, Subhra Chaudhuri, Ravi Gupta, Jingli Zhang, Sam Santhosh, Jeremy Stinson, Zora Modrusan, V L Ramprasad, Somasekar Seshagiri, Andrew S Peterson
BACKGROUND: Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. METHODS: In this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes...
February 13, 2018: BMC Medical Genetics
Makrina Karaglani, Georgia Ragia, Maria Panagopoulou, Ioanna Balgkouranidou, Evangelia Nena, George Kolios, Nikolaos Papanas, Vangelis G Manolopoulos, Ekaterini Chatzaki
Sulfonylureas are insulin secretagogues which act in pancreatic β cells by blocking the KATP channels encoded by KCNJ11 and ABCC8 genes. In the present study, a pharmacoepigenetic approach was applied for the first time, investigating the correlation of KCNJ11 and ABCC8 gene promoter methylation with sulfonylureas-induced mild hypoglycemic events as well as the KCNJ11 E23K genotype. Sodium bisulfite-treated genomic DNA of 171 sulfonylureas treated T2DM patients previously genotyped for KCNJ11 E23K, including 88 that had experienced drug-associated hypoglycemia and 83 that had never experienced hypoglycemia, were analyzed for DNA methylation of KCNJ11 and ABCC8 gene promoters via quantitative Methylation-Specific PCR...
February 2, 2018: Experimental and Clinical Endocrinology & Diabetes
Peter A Kropp, Jennifer C Dunn, Bethany A Carboneau, Doris A Stoffers, Maureen Gannon
The transcription factors Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA...
December 12, 2017: American Journal of Physiology. Endocrinology and Metabolism
Mary Ellen Vajravelu, Jinghua Chai, Bryan Krock, Samuel Baker, David Langdon, Craig Alter, Diva D De León
Context: Persistent hypoglycemia in the newborn period most commonly occurs due to hyperinsulinism. The phenotype of hypoketotic hypoglycemia can also result from pituitary hormone deficiencies, including growth hormone and adrenocorticotropic hormone deficiency. Forkhead box A2 (Foxa2) is a transcription factor shown in mouse models to influence insulin secretion by pancreatic beta cells. In addition, Foxa2 is involved in regulation of pituitary development, and deletions of FOXA2 have been linked to panhypopituitarism...
January 10, 2018: Journal of Clinical Endocrinology and Metabolism
Aisha Al Senani, Nishath Hamza, Hanan Al Azkawi, Manal Al Kharusi, Nashat Al Sukaiti, Maryam Al Badi, Moza Al Yahyai, Matthew Johnson, Elisa De Franco, Sarah Flanagan, Andrew Hattersley, Sian Ellard, Waad-Allah Mula-Abed
BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare disorder worldwide where diabetes is diagnosed in the first 6 months of life. However, Oman has a relatively high incidence of NDM. METHODS: In this study, we investigated the genetic etiologies underlying NDM and their prevalence in Oman. We collected a cohort of 24 NDM patients, with and without genetic diagnosis, referred to our center from 2007 to 2015. All patients without a genetic diagnosis were tested for mutations in 23 NDM-associated genes using a custom-targeted next-generation sequencing (NGS) panel and methylation analysis of the 6q24 locus...
January 26, 2018: Journal of Pediatric Endocrinology & Metabolism: JPEM
Hüseyin Demirbilek, Khalid Hussain
Pancreatic β-cells are finely tuned to secrete insulin so that plasma glucose levels are maintained within a narrow physiological range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is the inappropriate seretion of insulin in the presence of low plasma glucose levels and leads to severe and persistent hypoglycaemia in neonates and children. Mutations in 12 different key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1 and PMM2) that are involved in the regulation of insulin secretion from pancreatic β-cells have been described to be responsible for the underlying molecular mechanisms leading to congenital HH...
December 27, 2017: Journal of Clinical Research in Pediatric Endocrinology
Belma Haliloğlu, Heybet Tüzün, Sarah E Flanagan, Muhittin Çelik, Avni Kaya, Sian Ellard, Mehmet Nuri Özbek
BACKGROUND: Sirolimus has been described for the treatment of the diffuse form of congenital hyperinsulinism (CHI) unresponsive to diazoxide and octreotide without severe side effect. CASE REPORT: Two newborns with CHI due to homozygous ABCC8 gene mutations were started sirolimus due to unresponsive to medical treatment on day 21 and 17, and good response was observed. At follow-up, liver enzyme levels increased at 10 and 2 month of therapy in case 1 and 2, respectively (serum sirolimus level 1...
December 8, 2017: Journal of Clinical Research in Pediatric Endocrinology
Lydia Foucan, Laurent Larifla, Emmanuelle Durand, Christine Rambhojan, Christophe Armand, Carl-Thony Michel, Rachel Billy, Véronique Dhennin, Franck De Graeve, Iandry Rabearivelo, Olivier Sand, Jean-Marc Lacorte, Philippe Froguel, Amélie Bonnefond
Context: The population of Guadeloupe Island exhibits a high prevalence of obesity. Objective: We aimed to investigate whether rare genetic mutations in genes involved in monogenic obesity (or diabetes) might be causal in this population of Afro-Caribbean ancestry. Design and Setting: This was a secondary analysis of a study on obesity conducted in schoolchildren from Guadeloupe in 2013 that aimed to assess changes in children's profiles after a lifestyle intervention program...
February 1, 2018: Journal of Clinical Endocrinology and Metabolism
Vikas Bansal, Johann Gassenhuber, Tierney Phillips, Glenn Oliveira, Rebecca Harbaugh, Nikki Villarasa, Eric J Topol, Thomas Seufferlein, Bernhard O Boehm
BACKGROUND: Diagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1-2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes...
December 6, 2017: BMC Medicine
Anja Ludwig, Simone Enke, Janine Heindorf, Susann Empting, Thomas Meissner, Klaus Mohnike
BACKGROUND: Congenital hyperinsulinism (CHI) is hallmarked by persistent hypoketotic hypoglycemia in infancy. In the majority of all patients, CHI is caused by mutations in the KATP channel genes ABCC8 and KCNJ11, but other genes in the insulin-regulatory pathway have also been described. Repeated episodes of hypoglycemia include an increased risk of seizures and intellectual disability. So far, controlled psychometric studies on cognitive, motor, speech, and social-emotional outcome of CHI patients are missing...
November 17, 2017: Hormone Research in Pædiatrics
Klara Rozenkova, Azizun Nessa, Barbora Obermannova, Lenka Elblova, Petra Dusatkova, Zdenek Sumnik, Jan Lebl, Khalid Hussain, Stepanka Pruhova
BACKGROUND: Congenital hyperinsulinism (CHI) is frequently caused by mutations in one of the KATP channel subunits encoded by the genes ABCC8 and KCNJ11. The effect of simultaneous mutations in both of these genes on the pancreatic β-cell function is not known and patients with CHI carrying both ABCC8 and KCNJ11 mutations have not yet been reported. We questioned if a combination of heterozygous mutations in the ABCC8 and KCNJ11 genes could also lead to β-cell dysfunction presenting as CHI...
November 27, 2017: Journal of Pediatric Endocrinology & Metabolism: JPEM
Caroline Lenfant, Patrick Baz, Anne Degavre, Anne Philippi, Valérie Senée, Claire Vandiedonck, Céline Derbois, Marc Nicolino, Pierre Zalloua, Cécile Julier
Monogenic forms of diabetes may account for 1-5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her consanguineous parents and her four other siblings did not have diabetes or cataract, suggesting a recessive syndrome. Using whole exome sequencing of the affected proband, we identified a heterozygous p.R825Q ABCC8 mutation, located at the exact same amino-acid position as the p...
November 7, 2017: Genes
Balamurugan Kandasamy, Show-Ling Shyng
The ATP-sensitive potassium (KATP) channel formed by the inwardly rectifying potassium channel Kir6.2 and the sulfonylurea receptor 1 (SUR1) plays a key role in regulating insulin secretion. Genetic mutations in KCNJ11 or ABCC8 which encode Kir6.2 and SUR1 respectively are major causes of insulin secretion disorders: those causing loss of channel function lead to congenital hyperinsulinism, whereas those causing gain of channel function result in neonatal diabetes and in some cases developmental delay, epilepsy, and neonatal diabetes, referred to as the DEND syndrome...
2018: Methods in Molecular Biology
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