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Amichai Gutgold, David J Gross, Benjamin Glaser, Auryan Szalat
CONTEXT: Hypoglycemia is a rare event in healthy adults, and the differential diagnosis includes many diseases some of which are rare and easily missed. Description of the case: A 20 year-old male military paramedic was referred to our Emergency Department for the investigation of recurrent hypoglycemia episodes during the last months. Factitious hypoglycemia was excluded and organic hyperinsulinemic hypoglycemia was diagnosed by prolonged fast. Imaging studies (endoscopic ultrasound and triple-phase computed tomography) were normal...
October 18, 2016: Journal of Clinical Endocrinology and Metabolism
Katharina Warncke, Franziska Falco, Wolfgang Rabl, Ilse Engelsberger, Julia Saier, David Flores-Rodriguez, Stefan Burdach, Walter Bonfig
BACKGROUND: Congenital hyperinsulinism (CHI) is a rare disease with an estimated incidence of 1:40,000 live births. Here, we characterize 11 patients treated at Munich Children's Hospital Schwabing. METHODS: We analyzed data on birth, treatment and laboratory results including genetic testing and evaluated the long-term course with a follow-up visit. RESULTS: All patients had severe, diazoxide-(DZX)-resistant hypoglycemia, beginning immediately after birth...
October 1, 2016: Journal of Pediatric Endocrinology & Metabolism: JPEM
Yukiko Hashimoto, Sumito Dateki, Masakazu Hirose, Kenichi Satomura, Hirotake Sawada, Haruo Mizuno, Shigetaka Sugihara, Koichi Maruyama, Tatsuhiko Urakami, Hidenori Sugawara, Kenji Shirai, Tohru Yorifuji
BACKGROUND: There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM). OBJECTIVES: To elucidate the characteristics of Japanese patients with KATP-NDM. METHODS: By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM...
September 29, 2016: Pediatric Diabetes
Ruchira M Jha, Ava M Puccio, David O Okonkwo, Benjamin E Zusman, Seo-Young Park, Jessica Wallisch, Philip E Empey, Lori A Shutter, Robert S B Clark, Patrick M Kochanek, Yvette P Conley
OBJECTIVE: Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE...
September 27, 2016: Neurocritical Care
C Damon, M Luck, L Toullec, I Etienne, M Buchler, B Hurault de Ligny, G Choukroun, A Thierry, C Vigneau, B Moulin, A-E Heng, J-F Subra, C Legendre, A Monnot, A Yartseva, M Bateson, P Laurent-Puig, D Anglicheau, P Beaune, M A Loriot, E Thervet, N Pallet
Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0 ) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling...
September 6, 2016: American Journal of Transplantation
Gregory M Martin, Emily A Rex, Prasanna Devaraneni, Jerod S Denton, Kara E Boodhansingh, Diva D DeLeon, Charles A Stanley, Show-Ling Shyng
ATP-sensitive potassium (KATP) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of KATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects...
October 14, 2016: Journal of Biological Chemistry
Tomonori Shimbo, Takeshi Adachi, Susumu Fujisawa, Mai Hongoh, Takayoshi Ohba, Kyoichi Ono
The lower esophageal sphincter (LES) is a specialized region of the esophageal smooth muscle that allows the passage of a swallowed bolus into the stomach. Nitric oxide (NO) plays a major role in LES relaxation. Nicorandil possesses dual properties of a NO donor and an ATP-sensitive potassium channel (KATP channel) agonist, and is expected to reduce LES tone. This study investigated the mechanisms underlying the effects of nicorandil on the LES. Rat LES tissues were placed in an organ bath, and activities were recorded using an isometric force transducer...
August 2016: Journal of Pharmacological Sciences
Alla K Ovsyannikova, Oksana D Rymar, Elena V Shakhtshneider, Vadim V Klimontov, Elena A Koroleva, Natalya E Myakina, Mikhail I Voevoda
Maturity-onset diabetes of the young (MODY) is a heterogeneous group of diseases associated with gene mutations leading to dysfunction of pancreatic β-cells. Thirteen identified MODY variants differ from each other by the clinical course and treatment requirement. Currently, MODY subtypes 1-5 are best-studied, descriptions of the other forms are sporadic. This article reports a MODY12 clinical case, caused by a mutation in the gene of the ATP-binding cassette transporter sub-family C member 8 (ABCC8), encoding sulfonylurea receptor 1...
September 2016: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Valerio Costa, Antonio Federico, Carla Pollastro, Carmela Ziviello, Simona Cataldi, Pietro Formisano, Alfredo Ciccodicola
Type 2 diabetes (T2D) is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9) or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG)...
2016: International Journal of Molecular Sciences
Patricia Taberner, Sarah E Flanagan, Deborah J Mackay, Sian Ellard, Mariano J Taverna, Mabel Ferraro
AIMS: Neonatal diabetes mellitus (NDM) is a rare monogenic disorder, reported to affect less than 2 cases per 100,000 infants. There are two types, permanent (PNDM) and transient (TNDM). We describe our clinical experience in determining and comparing the genetic basis of diabetes in children with onset before 6months versus those diagnosed between 6 and 12months of age. METHODS: We reviewed medical records of children with diabetes diagnosed before 12months of age...
July 2016: Diabetes Research and Clinical Practice
David B Kurland, Volodymyr Gerzanich, Jason K Karimy, Seung Kyoon Woo, Rudi Vennekens, Marc Freichel, Bernd Nilius, Joseph Bryan, J Marc Simard
BACKGROUND: Harmful effects of activated microglia are due, in part, to the formation of peroxynitrite radicals, which is attributable to the upregulation of inducible nitric oxide (NO) synthase (NOS2). Because NOS2 expression is determined by Ca(2+)-sensitive calcineurin (CN) dephosphorylating nuclear factor of activated T cells (NFAT), and because Sur1-Trpm4 channels are crucial for regulating Ca(2+) influx, we hypothesized that, in activated microglia, Sur1-Trpm4 channels play a central role in regulating CN/NFAT and downstream target genes such as Nos2...
2016: Journal of Neuroinflammation
Domenico Tricarico, Maria Selvaggi, Giuseppe Passantino, Pasquale De Palo, Cataldo Dario, Pasquale Centoducati, Alessandra Tateo, Angela Curci, Fatima Maqoud, Antonietta Mele, Giulia M Camerino, Antonella Liantonio, Paola Imbrici, Nicola Zizzo
The ATP-sensitive K(+)-channels (KATP) are distributed in the tissues coupling metabolism with K(+) ions efflux. KATP subunits are encoded by KCNJ8 (Kir6.1), KCNJ11 (Kir6.2), ABCC8 (SUR1), and ABCC9 (SUR2) genes, alternative RNA splicing give rise to SUR variants that confer distinct physiological properties on the channel. An high expression/activity of the sarco-KATP channel is observed in various rat fast-twitch muscles, characterized by elevated muscle strength, while a low expression/activity is observed in the slow-twitch muscles characterized by reduced strength and frailty...
2016: Frontiers in Physiology
R Martínez, C Fernández-Ramos, A Vela, T Velayos, A Aguayo, I Urrutia, I Rica, L Castaño
CONTEXT: Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. OBJECTIVE: To characterize clinically and genetically CHI patients in Spain. DESIGN AND METHODS: We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes...
June 2016: European Journal of Endocrinology
Zeynep Şıklar, Merih Berberoğlu
Congenital Hyperinsulinism (CHI) is a rare disease and characterized by dysregulated insulin secretion from pancreatic β-cells. Recurrent hypoglycemia can lead to neurological insult and permenant brain injury. Recently, there are important advances in understanding the genetic mechanisms, histological characteristics, imaging and surgical techniques of Congenital Hyperinsulinaemic Hypoglycemia that could reflect to improvement of the clinical care of infants with this disorder. In Turkey, there is high rate of consanguinity, and the incidence of CHI expected to be high...
May 16, 2016: Journal of Clinical Research in Pediatric Endocrinology
Ivan Tkáč
Pharmacogenetics is the study of how genes (individual genotypes) affect a persons response to drugs. At present, recommendations made about the treatment of some monogenic forms of diabetes are based on genetic diagnostics. The first studies in the field of pharmacogenetics of oral antidiabetics have now been published which have identified associations of individual genetic variants with response to treatment. The response to sulfonylurea derivatives was significantly associated with the variants KCNJ11/ABCC8, TCF7L2 and CYP2C9...
March 2016: Vnitr̆ní Lékar̆ství
Pınar Kocaay, Zeynep Şiklar, Sian Ellard, Aydın Yagmurlu, Emine Çamtosun, Esra Erden, Merih Berberoglu, Sarah E Flanagan
BACKGROUND: Isolated hyperinsulinaemic hypoglycaemia (HH) commonly results from recessively inherited mutations in the ABCC8 and KCNJ11 genes that are located on chromosome 11p15.1. More rarely, HH can feature in patients with Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder, resulting from defects at a differentially methylated region telomeric to the K-ATP channel genes at chromosome 11p15.5. SUBJECT: We undertook genetic testing in a patient with diazoxide-unresponsive HH diagnosed at birth...
2016: Hormone Research in Pædiatrics
Hanna Huopio, Päivi J Miettinen, Jorma Ilonen, Päivi Nykänen, Riitta Veijola, Päivi Keskinen, Kirsti Näntö-Salonen, Jagadish Vangipurapu, Joose Raivo, Alena Stančáková, Jonna Männistö, Teemu Kuulasmaa, Mikael Knip, Timo Otonkoski, Markku Laakso
CONTEXT: Major advances have been made in the classification and genetics of monogenic diabetes in infancy. OBJECTIVE: The objective of the study was to characterize different forms of diabetes diagnosed during the first year of life. DESIGN: Patients diagnosed with diabetes before the age of 1 year in 10 Finnish hospitals from 1980 to 2014 were included. SETTING: The study was conducted at Kuopio University Hospital and University of Eastern Finland...
August 2016: Journal of Clinical Endocrinology and Metabolism
Anup K Nair, Leslie J Baier
Genetic studies in large outbred populations have documented a complex, highly polygenic basis for type 2 diabetes (T2D). Most of the variants currently known to be associated with T2D risk have been identified in large studies that included tens of thousands of individuals who are representative of a single major ethnic group such as European, Asian, or African. However, most of these variants have only modest effects on the risk for T2D; identification of definitive 'causal variant' or 'causative loci' is typically lacking...
October 2015: Review of Diabetic Studies: RDS
I Khurana, A Kaspi, M Ziemann, T Block, T Connor, B Spolding, A Cooper, P Zimmet, A El-Osta, K Walder
BACKGROUND/OBJECTIVE: The rising incidence of obesity is a major public health issue worldwide. Recent human and animal studies suggest that parental diet can influence fetal development and is implicated with risk of obesity and type 2 diabetes in offspring. The hypothalamus is central to body energy homoeostasis and appetite by controlling endocrine signals. We hypothesise that offspring susceptibility to obesity is programmed in the hypothalamus in utero and mediated by changes to DNA methylation, which persist to adulthood...
July 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Yanyan Zhao, Kun Shi, Xiaomei Su, Liqiang Xie, Yunjun Yan
Microcystins (MCs) are the most frequent cyanobacterial toxins observed in freshwater systems. Accumulating evidence suggests that MCs pose a serious threat to public health. However, the contributions of the exposure of MCs to the occurrence of human diseases remain largely unknown. This study provides the evidence of the effects of MC-LR on pancreatic β-cell function through the exposure of rat insulinoma (INS-1) cells to 0, 10, 20, or 40μM MC-LR for 72h and explores the underlying molecular mechanisms...
August 15, 2016: Journal of Hazardous Materials
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