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monogenic diabetes

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https://www.readbyqxmd.com/read/29141982/a-partial-loss-of-function-variant-in-akt2-is-associated-with-reduced-insulin-mediated-glucose-uptake-in-multiple-insulin-sensitive-tissues-a-genotype-based-callback-positron-emission-tomography-study
#1
Aino Latva-Rasku, Miikka-Juhani Honka, Alena Stančáková, Heikki A Koistinen, Johanna Kuusisto, Li Guan, Alisa K Manning, Heather Stringham, Anna L Gloyn, Cecilia M Lindgren, Francis S Collins, Karen L Mohlke, Laura J Scott, Tomi Karjalainen, Lauri Nummenmaa, Michael Boehnke, Pirjo Nuutila, Markku Laakso
Rare fully penetrant mutations in AKT2 are an established cause of monogenic disorders of glucose metabolism. Recently, a novel partial loss-of-function AKT2 coding variant (p.Pro50Thr) was identified that is nearly specific to Finns (frequency 1.1%), with the low-frequency allele associated with an increase in fasting plasma insulin level and risk of type 2 diabetes. The effects of p.Pro50Thr on insulin-stimulated glucose uptake (GU) in the whole body and in different tissues have not previously been investigated...
November 15, 2017: Diabetes
https://www.readbyqxmd.com/read/29120028/precision-medicine-for-monogenic-diabetes-from-a-survey-to-the-development-of-a-next-generation-diagnostic-panel
#2
Sakina Kherra, Jean-Louis Blouin, Federico Santoni, Valerie Schwitzgebel
Monogenic diabetes (MD) accounts for 1-2% of all diabetes cases. Because of its wide phenotypic spectrum, MD is often misdiagnosed as type 1 or type 2 diabetes. While clinical and biochemical parameters can suggest MD, a definitive diagnosis requires genetic analysis. We conducted a survey among clinicians specialising in diabetes to document the cases with MD. Of 74 clinically suspected MD patients, 46% had undergone genetic analysis, which was mostly conducted using Sanger's classical sequencing method. The most common recorded mutations were located in the GCK gene, followed by the mitochondrial genome (m...
November 9, 2017: Swiss Medical Weekly
https://www.readbyqxmd.com/read/29112131/juvenile-onset-diabetes-and-congenital-cataract-double-gene-mutations-mimicking-a-syndromic-diabetes-presentation
#3
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
https://www.readbyqxmd.com/read/29107594/genes-associated-with-pancreas-development-and-function-maintain-open-chromatin-in-ipscs-generated-from-human-pancreatic-beta-cells
#4
Matthias Thurner, Liraz Shenhav, Agata Wesolowska-Andersen, Amanda J Bennett, Amy Barrett, Anna L Gloyn, Mark I McCarthy, Nicola L Beer, Shimon Efrat
Current in vitro islet differentiation protocols suffer from heterogeneity and low efficiency. Induced pluripotent stem cells (iPSCs) derived from pancreatic beta cells (BiPSCs) preferentially differentiate toward endocrine pancreas-like cells versus those from fibroblasts (FiPSCs). We interrogated genome-wide open chromatin in BiPSCs and FiPSCs via ATAC-seq and identified ∼8.3k significant, differential open chromatin sites (DOCS) between the two iPSC subtypes (false discovery rate [FDR] < 0.05). DOCS where chromatin was more accessible in BiPSCs (Bi-DOCS) were significantly enriched for known regulators of endodermal development, including bivalent and weak enhancers, and FOXA2 binding sites (FDR < 0...
November 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29099273/dna-methylation-profiles-in-sibling-pairs-discordant-for-intrauterine-exposure-to-maternal-gestational-diabetes
#5
Eunae Kim, Soo Heon Kwak, Hye Rim Chung, Jung Hun Ohn, Jae Hyun Bae, Sung Hee Choi, Kyong Soo Park, Joon-Seok Hong, Joohon Sung, Hak Chul Jang
Intrauterine exposure to hyperglycemia is reported to confer increased metabolic risk in later life, supporting the 'developmental origins of health and disease' hypothesis. Epigenetic alterations are suggested as one of the possible underlying mechanisms. In this study, we compared pairwise DNA methylation differences between siblings whose intrauterine exposure to maternal gestational diabetes (GDM) were discordant. Methylation of peripheral blood DNA of 18 sibling pairs was measured using Infinium HumanMethylation450 BeadChip assays...
November 3, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/29059180/diverse-type-2-diabetes-genetic-risk-factors-functionally-converge-in-a-phenotype-focused-gene-network
#6
Cynthia Sandor, Nicola L Beer, Caleb Webber
Type 2 Diabetes (T2D) constitutes a global health burden. Efforts to uncover predisposing genetic variation have been considerable, yet detailed knowledge of the underlying pathogenesis remains poor. Here, we constructed a T2D phenotypic-linkage network (T2D-PLN), by integrating diverse gene functional information that highlight genes, which when disrupted in mice, elicit similar T2D-relevant phenotypes. Sensitising the network to T2D-relevant phenotypes enabled significant functional convergence to be detected between genes implicated in monogenic or syndromic diabetes and genes lying within genomic regions associated with T2D common risk...
October 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/29056535/analysis-of-the-gck-gene-in-79-mody-type-2-patients-a-multicenter-turkish-study-mutation-profile-and-description-of-twenty-novel-mutations
#7
Ayça Aykut, Emin Karaca, Hüseyin Onay, Damla Gökşen, Şevki Çetinkalp, Erdal Eren, Betül Ersoy, Esra Papatya Çakır, Muammer Büyükinan, Cengiz Kara, Ahmet Anık, Birgül Kırel, Samim Özen, Tahir Atik, Şükran Darcan, Ferda Özkınay
Maturity onset diabetes is a genetic form of diabetes mellitus characterized by an early age at onset and several etiologic genes for this form of diabetes have been identified in many patients. Maturity onset diabetes type 2 [MODY2 (#125851)] caused by mutations in the glucokinase gene (GCK). Although its prevalence is not clear, it is estimated that 1%-2% of patients with diabetes have the monogenic form. The aim of this study was to evaluate the molecular spectrum of GCK gene mutations in 177 Turkish MODY type 2 patients...
October 19, 2017: Gene
https://www.readbyqxmd.com/read/29044799/insulin-secretory-defect-in-familial-partial-lipodystrophy-type-2-and-successful-long-term-treatment-with-a-glucagon-like-peptide-1-receptor-agonist
#8
F Banning, M Rottenkolber, I Freibothe, J Seissler, A Lechner
BACKGROUND: Familial partial lipodystrophies are rare monogenic disorders that are often associated with diabetes. In such cases, it can be difficult to achieve glycaemic control. CASE REPORT: We report a 34-year old woman with familial partial lipodystrophy type 2 (Dunnigan) and diabetes; her hyperglycaemia persisted despite metformin treatment. A combined intravenous glucose tolerance-euglycaemic clamp test showed severe insulin resistance, as expected, but also showed strongly diminished first-phase insulin secretion...
October 17, 2017: Diabetic Medicine: a Journal of the British Diabetic Association
https://www.readbyqxmd.com/read/29044608/nutrient-sensing-in-pancreatic-islets-lessons-from-congenital-hyperinsulinism-and-monogenic-diabetes
#9
REVIEW
Ming Lu, Changhong Li
Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose-stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM))...
October 16, 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29026101/heterozygous-rfx6-protein-truncating-variants-are-associated-with-mody-with-reduced-penetrance
#10
Kashyap A Patel, Jarno Kettunen, Markku Laakso, Alena Stančáková, Thomas W Laver, Kevin Colclough, Matthew B Johnson, Marc Abramowicz, Leif Groop, Päivi J Miettinen, Maggie H Shepherd, Sarah E Flanagan, Sian Ellard, Nobuya Inagaki, Andrew T Hattersley, Tiinamaija Tuomi, Miriam Cnop, Michael N Weedon
Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10(-4))...
October 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29020906/the-prevalence-of-monogenic-diabetes-in-australia-the-fremantle-diabetes-study-phase-ii
#11
Timothy Me Davis, Ashley E Makepeace, Sian Ellard, Kevin Colclough, Kirsten Peters, Andrew Hattersley, Wendy A Davis
OBJECTIVE: To determine the prevalence of monogenic diabetes in an Australian community. DESIGN: Longitudinal observational study of a cohort recruited between 2008 and 2011. SETTING: Urban population of 157 000 people (Fremantle, Western Australia). PARTICIPANTS: 1668 (of 4639 people with diabetes) who consented to participation (36.0% participation). MAIN OUTCOME MEASURES: Prevalence of maturity-onset diabetes of the young (MODY) and permanent neonatal diabetes in patients under 35 years of age, from European and non-European ethnic backgrounds, who were at risk of MODY according to United Kingdom risk prediction models, and who were then genotyped for relevant mutations...
October 16, 2017: Medical Journal of Australia
https://www.readbyqxmd.com/read/28993341/insights-from-molecular-characterization-of-adult-patients-of-families-with-multigenerational-diabetes-mellitus
#12
Serena Pezzilli, Ornella Ludovico, Tommaso Biagini, Luana Mercuri, Federica Alberico, Eleonora Lauricella, Hamza Dallali, Daniele Capocefalo, Massimo Carella, Elide Miccinilli, Pamela Piscitelli, Maria Giovanna Scarale, Tommaso Mazza, Vincenzo Trischitta, Sabrina Prudente
Multigenerational diabetes of the adulthood is a mostly overlooked entity, simplistically comprised in the large basin of type 2 diabetes. The general aim we are pursuing in last years is to unravel the genetic causes of such form of diabetes. Identifying among families with multigenerational diabetes those carrying mutations in known monogenic diabetes genes is the first step to then concentrate on remaining pedigrees where to unravel new diabetogenes.Targeted Next Generation Sequencing of 27 monogenic diabetes-genes has been carried out in 55 family probands and identified mutations verified among their relatives by Sanger sequencing...
October 9, 2017: Diabetes
https://www.readbyqxmd.com/read/28992123/whole-exome-sequencing-identifies-a-novel-ins-mutation-causative-of-maturity-onset-diabetes-of-the-young-10
#13
Jing Yan, Feng Jiang, Rong Zhang, Tongfu Xu, Zhou Zhou, Wei Ren, Danfeng Peng, Yong Liu, Cheng Hu, Weiping Jia
Monogenic diabetes is often misdiagnosed with type 2 diabetes due to overlapping characteristics. This study aimed to discover novel causative mutations of monogenic diabetes in patients with clinically diagnosed type 2 diabetes and to explore potential molecular mechanisms. Whole-exome sequencing was performed on 31 individuals clinically diagnosed with type 2 diabetes. One novel heterozygous mutation (p.Ala2Thr) in INS was identified. It was further genotyped in an additional case-control population (6523 cases and 4635 controls), and this variant was observed in 0...
August 23, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28951986/evaluation-of-the-informational-content-readability-and-comprehensibility-of-online-health-information-on-monogenic-diabetes
#14
Yue Guan, Kristin A Maloney, Debra L Roter, Toni I Pollin
The purpose of this study was to assess the informational content, readability, suitability and comprehensibility of websites offering educational information about monogenic diabetes available to patients. The top 20 results from 15 queries in four search engines were screened. Content analysis was performed by two independent coders. Readability was determined using Flesch-Kincaid grade level (FKGL) and Simplified Measure of Goobledygook (SMOG). The Comprehensibility Assessment of Materials (SAM + CAM) scale was utilized to evaluate website suitability and comprehensibility...
September 26, 2017: Journal of Genetic Counseling
https://www.readbyqxmd.com/read/28951826/endoplasmic-reticulum-stress-and-eif2%C3%AE-phosphorylation-the-achilles-heel-of-pancreatic-%C3%AE-cells
#15
REVIEW
Miriam Cnop, Sanna Toivonen, Mariana Igoillo-Esteve, Paraskevi Salpea
BACKGROUND: Pancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches. SCOPE OF REVIEW: Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes...
September 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28948172/incidence-and-mortality-rates-and-clinical-characteristics-of-type-1-diabetes-among-children-and-young-adults-in-cochabamba-bolivia
#16
Elizabeth Duarte Gómez, Gabriel Andrew Gregory, Miriam Castrati Nostas, Angela Christine Middlehurst, Alicia Josephine Jenkins, Graham David Ogle
OBJECTIVES: To determine incidence, mortality, and clinical status of youth with diabetes at the Centro Vivir con Diabetes, Cochabamba, Bolivia, with support from International Diabetes Federation Life for a Child Program. METHODS: Incidence/mortality data analysis of all cases (<25 year (y)) diagnosed January 2005-February 2017 and cross-sectional data (December 2015). RESULTS: Over 12.2 years, 144 cases with type 1 diabetes (T1D) were diagnosed; 43...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/28943514/a-novel-kcnj11-mutation-associated-with-transient-neonatal-diabetes
#17
Evangelia Gole, Stavroula Oikonomou, Sian Ellard, Elisa De Franco, Kyriaki Karavanaki
BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare type of monogenic diabetes that presents in the first 6 months of life. Activating mutations in the KCNJ11 gene encoding for the Kir6.2 subunit of the KATP channel can lead to transient (TNDM) or permanent neonatal diabetes mellitus (PNDM). CASE REPORT: A female infant presented at the 22nd day of life with severe hyperglycemia and ketoacidosis (glucose: 907mg/dl, blood gas pH: 6.84, HCO3: 6mmol/l). She was initially managed with intravenous (IV) fluids and IV insulin...
September 25, 2017: Journal of Clinical Research in Pediatric Endocrinology
https://www.readbyqxmd.com/read/28943513/neonatal-diabetes-two-cases-with-isolated-pancreas-agenensis-due-to-homozygous-ptf1a-enhancer-mutations-and-one-with-dend-syndrome-due-to-kcnj11-mutation
#18
Olcay Evliyaoğlu, Oya Ercan, Emel Ataloğlu, Ümit Zübarioğlu, Bahar Özcabı, Aydilek Dağdeviren, Hande Erdoğan, Elisa De Franco, Sian Ellard
Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first 6 months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the PTF1A enhancer and one with DEND syndrome (developmental delay, epilepsy, and neonatal diabetes) due to a KCNJ11 mutation. The two cases with mutations in the distal enhacer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analysis showed that these mutations can decrease expression of PTF1A which is involved in pancreas development...
September 25, 2017: Journal of Clinical Research in Pediatric Endocrinology
https://www.readbyqxmd.com/read/28940958/a-novel-neurog3-mutation-in-neonatal-diabetes-associated-with-a-neuro-intestinal-syndrome
#19
Suna Hancili, Amélie Bonnefond, Julien Philippe, Emmanuel Vaillant, Franck De Graeve, Olivier Sand, Kanetee Busiah, Jean-Jacques Robert, Michel Polak, Philippe Froguel, Ayla Güven, Martine Vaxillaire
Neonatal diabetes mellitus (NDM) is a rare form of non-autoimmune diabetes usually diagnosed in the first 6 months of life. Various genetic defects have been shown to cause NDM with diverse clinical presentations and variable severity. Among transcriptional factor genes associated with isolated or syndromic NDM, a few cases of homozygous mutations in the NEUROG3 gene have been reported, all mutated patients presenting with congenital malabsorptive diarrhea with or without diabetes at a variable age of onset from early life to childhood...
September 22, 2017: Pediatric Diabetes
https://www.readbyqxmd.com/read/28938416/pancreatic-histopathology-of-human-monogenic-diabetes-due-to-causal-variants-in-kcnj11-hnf1a-gata6-and-lmna
#20
May Sanyoura, Laura Jacobsen, David Carmody, Daniela Del Gaudio, Gorka Alkorta-Aranburu, Kelly Arndt, Ying Ying Hu, Frances Kobiernicki, Irina Kusmartseva, Mark A Atkinson, Louis H Philipson, Desmond Schatz, Martha Campbell-Thompson, Siri Atma W Greeley
Context: Monogenic diabetes is thought to account for 2% of all diabetes cases but most patients are misdiagnosed as type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreases from patients with monogenic diabetes. Objective: Retrospective study of the JDRF Network for Pancreatic Organ donors with Diabetes biorepository was used to identify possible cases with monogenic diabetes and to compare effects of genetic variants on pancreas histology...
August 16, 2017: Journal of Clinical Endocrinology and Metabolism
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