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https://www.readbyqxmd.com/read/28783164/effect-of-sequence-variants-on-variance-in-glucose-levels-predicts-type-2-diabetes-risk-and-accounts-for-heritability
#1
Erna V Ivarsdottir, Valgerdur Steinthorsdottir, Maryam S Daneshpour, Gudmar Thorleifsson, Patrick Sulem, Hilma Holm, Snaevar Sigurdsson, Astradur B Hreidarsson, Gunnar Sigurdsson, Ragnar Bjarnason, Arni V Thorsson, Rafn Benediktsson, Gudmundur Eyjolfsson, Olof Sigurdardottir, Isleifur Olafsson, Sirous Zeinali, Fereidoun Azizi, Unnur Thorsteinsdottir, Daniel F Gudbjartsson, Kari Stefansson
Sequence variants that affect mean fasting glucose levels do not necessarily affect risk for type 2 diabetes (T2D). We assessed the effects of 36 reported glucose-associated sequence variants on between- and within-subject variance in fasting glucose levels in 69,142 Icelanders. The variant in TCF7L2 that increases fasting glucose levels increases between-subject variance (5.7% per allele, P = 4.2 × 10(-10)), whereas variants in GCK and G6PC2 that increase fasting glucose levels decrease between-subject variance (7...
August 7, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28727166/hepatocytes-contribute-to-residual-glucose-production-in-a-mouse-model-for-glycogen-storage-disease-type-ia
#2
Brenda S Hijmans, Andreas Boss, Theo H van Dijk, Maud Soty, Henk Wolters, Elodie Mutel, Albert K Groen, Terry G J Derks, Gilles Mithieux, Arend Heerschap, Dirk-Jan Reijngoud, Fabienne Rajas, Maaike H Oosterveer
It is a longstanding enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production (EGP) despite the loss of glucose-6-phosphatase (G6Pase) activity. Insight into the source of residual EGP is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated G6Pase-independent EGP in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc(-/-) mice), and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc(-/-) mice using state-of-the-art stable isotope methodologies...
July 20, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28726111/glucokinase-mutations-in-pediatric-patients-with-impaired-fasting-glucose
#3
C Aloi, A Salina, N Minuto, R Tallone, F Lugani, A Mascagni, O Mazza, M Cassanello, M Maghnie, G d'Annunzio
AIMS: Our aim was to detect the frequency of glucokinase (GCK) gene mutations in a cohort of patients with impaired fasting glucose and to describe the clinical manifestations of identified variants. We also aimed at predicting the effect of the novel missense mutations by computational approach. METHODS: Overall 100 unrelated Italian families with impaired fasting glucose were enrolled and subdivided into two cohorts according to strict and to mild criteria for diagnosis of maturity-onset diabetes of the young (MODY)...
July 19, 2017: Acta Diabetologica
https://www.readbyqxmd.com/read/28688303/effect-of-styrene-exposure-on-plasma-parameters-molecular-mechanisms-and-gene-expression-in-rat-model-islet-cells
#4
Kamal Niaz, Fatima Ismail Hassan, Faheem Mabqool, Fazlullah Khan, Saeideh Momtaz, Maryam Baeeri, Mona Navaei-Nigjeh, Mahban Rahimifard, Mohammad Abdollahi
Styrene is an aromatic hydrocarbon compound present in the environment and have primary exposure through plastic industry. The current study was designed to evaluate styrene-induced toxicity parameters in rat plasma fasting blood glucose (FBG) level, oral glucose tolerance, insulin secretion, oxidative stress, and inflammatory cytokines in cellular and molecular levels. Styrene was dissolved in corn oil and administered at different doses (250, 500, 1000, 1500, 2000mg/kg/day and control) to each rat, for 42days...
June 23, 2017: Environmental Toxicology and Pharmacology
https://www.readbyqxmd.com/read/28678435/molecular-mechanisms-of-action-of-styrene-toxicity-in-blood-plasma-and-liver
#5
Kamal Niaz, Faheem Mabqool, Fazlullah Khan, Fatima Ismail Hassan, Maryam Baeeri, Mona Navaei-Nigjeh, Shokoufeh Hassani, Mahdi Gholami, Mohammad Abdollahi
Styrene is an aromatic colorless hydrocarbon available in liquid form and highly volatile. In its pure form, it gives a sweet smell. The primary source of exposure in the environment is from plastic materials, rubber industries, packaging materials, insulations, and fiber glass and carpet industry. Natural sources of styrene include: few metabolites in plants which are transferred through food chain. The current study was designed to evaluate styrene toxicity, including: superoxide dismutase (SOD) and protein carbonyl, oxidative stress, glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK) activities, adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio, and changes in gene expressions such as glutamate dehydrogenase 1 (GLUD1), glucose transporter 2 (GLUT2), and glucokinase (GCK) in the rat liver tissue...
July 5, 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/28663157/phenotype-heterogeneity-in-glucokinase-maturity-onset-diabetes-of-the-young-gck-mody-patients-single-pediatric-centre-observation
#6
Anna Wedrychyowicz, Ewa Tobor, Magdalena Wilk, Ewa Ziolkowska-Ledwith, Anna Rams, Katarzyna Wzorek, Barbara Sabal, Małgorzata Stelmach, Jerzy B Starzyk
OBJECTIVE: The aim of the study was to evaluate the clinical phenotypes of Glucokinase - Maturity Onset Diabetes of the Young (GCK-MODY) pediatric patients from South-West Poland and to search for phenotype-genotype correlations. METHODS: We performed retrospective analysis of data of all 37 CGK-MODY patients, 21 girls, age 1.9-20.1, mean 12.5±5.2 years, treated in our centre. A retrospective analysis of clinical data from years 2002-2013 was performed. RESULTS: GCK-MODY carriers were found among 1043 diabetes mellitus (DM) patients (3%), they were second the most numerous groups of DM patients, following type 1 DM, in our centre...
June 30, 2017: Journal of Clinical Research in Pediatric Endocrinology
https://www.readbyqxmd.com/read/28597946/comprehensive-screening-for-monogenic-diabetes-in-89-japanese-children-with-insulin-requiring-antibody-negative-type-1-diabetes
#7
Kikumi Ushijima, Maki Fukami, Tadayuki Ayabe, Satoshi Narumi, Misako Okuno, Akie Nakamura, Toshikazu Takahashi, Kenji Ihara, Kazuhiro Ohkubo, Emiko Tachikawa, Shoji Nakayama, Junichi Arai, Nobuyuki Kikuchi, Toru Kikuchi, Tomoyuki Kawamura, Tatsuhiko Urakami, Kenichiro Hata, Kazuhiko Nakabayashi, Yoichi Matsubara, Shin Amemiya, Tsutomu Ogata, Ichiro Yokota, Shigetaka Sugihara
BACKGROUND: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D). OBJECTIVES: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. METHODS: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification...
June 9, 2017: Pediatric Diabetes
https://www.readbyqxmd.com/read/28593615/a-single-dose-of-dapagliflozin-an-sglt-2-inhibitor-induces-higher-glycosuria-in-gck-and-hnf1a-mody-than-in-type-2-diabetes-mellitus
#8
J Hohendorff, M Szopa, J Skupien, M Kapusta, B Zapala, T Platek, S Mrozinska, T Parpan, W Glodzik, A Ludwig-Galezowska, B Kiec-Wilk, T Klupa, M T Malecki
AIMS: SGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes. METHODS: We examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes...
August 2017: Endocrine
https://www.readbyqxmd.com/read/28580277/expression-and-functional-assessment-of-candidate-type-2-diabetes-susceptibility-genes-identify-four-new-genes-contributing-to-human-insulin-secretion
#9
Fatou K Ndiaye, Ana Ortalli, Mickaël Canouil, Marlène Huyvaert, Clara Salazar-Cardozo, Cécile Lecoeur, Marie Verbanck, Valérie Pawlowski, Raphaël Boutry, Emmanuelle Durand, Iandry Rabearivelo, Olivier Sand, Lorella Marselli, Julie Kerr-Conte, Vikash Chandra, Raphaël Scharfmann, Odile Poulain-Godefroy, Piero Marchetti, François Pattou, Amar Abderrahmani, Philippe Froguel, Amélie Bonnefond
OBJECTIVES: Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells...
June 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28575730/novel-glucokinase-gene-mutation-in-the-first-macedonian-family-tested-for-mody
#10
M Kocova, L Elblova, S Pruhova, J Lebl, P Dusatkova
We present a boy with mild hyperglycemia detected during an upper respiratory infection. Novel splicing mutation in the intron 1 of the GCK gene (c.45+1G>A) was detected, and was subsequently confirmed in his father. This is the first case of genetically confirmed Macedonian family with MODY.
May 10, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28555465/identification-of-maturity-onset-diabetes-of-the-young-caused-by-glucokinase-mutations-detected-using-whole-exome-sequencing
#11
Eun Hee Cho, Jae Woong Min, Sun Shim Choi, Hoon Sung Choi, Sang Wook Kim
Glucokinase maturity-onset diabetes of the young (GCK-MODY) represents a distinct subgroup of MODY that does not require hyperglycemia-lowering treatment and has very few diabetes-related complications. Three patients from two families who presented with clinical signs of GCK-MODY were evaluated. Whole-exome sequencing was performed and the effects of the identified mutations were assessed using bioinformatics tools, such as PolyPhen-2, SIFT, and in silico modeling. We identified two mutations: p.Leu30Pro and p...
June 2017: Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28525638/glucokinase-gene-may-be-a-more-suitable-target-than-the-insulin-gene-for-detection-of-beta-cell-death
#12
J Sklenarova, L Petruzelkova, S Kolouskova, J Lebl, Z Sumnik, O Cinek
Detection and quantification of unmethylated circulating insulin (INS) DNA presumably released from beta cells has been previously used for assessing their destruction. As the targets within the INS gene suffer from suboptimal specificity, we sought to improve the assay parameters by using the glucokinase gene (GCK) tissue-specific pancreatic promoter.The amount of methylated and unmethylated GCK DNA was measured using a droplet PCR assay, and compared with the previously published INS-targeted assay. The method was tested using synthetic target sequences and DNA from pancreatic islets, blood, brain, kidney, large intestine, liver, lung, small intestine and stomach...
May 18, 2017: Endocrinology
https://www.readbyqxmd.com/read/28516783/antidiabetic-disruptors-of-the-glucokinase-glucokinase-regulatory-protein-complex-reorganize-a-coulombic-interface
#13
Juliana A Martinez, Qing Xiao, Armen Zakarian, Brian G Miller
The glucokinase regulatory protein (GKRP) plays an essential role in glucose homeostasis by acting as a competitive inhibitor of glucokinase (GCK) and triggering its localization to the hepatocyte nucleus upon glucose deprivation. Metabolites such as fructose 6-phosphate and sorbitol 6-phosphate promote assembly of the GCK-GKRP complex, whereas fructose 1-phosphate and functionalized piperazines with potent in vivo antidiabetic activity disrupt the complex. Here, we establish the molecular basis by which these natural and synthetic ligands modulate the GCK-GKRP interaction...
June 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28466490/local-and-regional-control-of-calcium-dynamics-in-the-pancreatic-islet
#14
REVIEW
Guy A Rutter, David J Hodson, Pauline Chabosseau, Elizabeth Haythorne, Timothy J Pullen, Isabelle Leclerc
Ca(2+) is the key intracellular regulator of insulin secretion, acting in the beta cell as the ultimate trigger for exocytosis. In response to high glucose, ATP-sensitive K(+) channel closure and plasma membrane depolarisation engage a sophisticated machinery to drive pulsatile cytosolic Ca(2+) changes. Voltage-gated Ca(2+) channels, Ca(2+) -activated K(+) channels and Na(+) /Ca(2+) exchange all play important roles. The use of targeted Ca(2+) probes has revealed that during each cytosolic Ca(2+) pulse, uptake of Ca(2+) by mitochondria, endoplasmic reticulum (ER), secretory granules and lysosomes fine-tune cytosolic Ca(2+) dynamics and control organellar function...
May 3, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28458896/octreotide-therapy-and-restricted-fetal-growth-pregnancy-in-familial-hyperinsulinemic-hypoglycemia
#15
Marianne Geilswijk, Lise Lotte Andersen, Morten Frost, Klaus Brusgaard, Henning Beck-Nielsen, Anja Lisbeth Frederiksen, Dorte Møller Jensen
SUMMARY: Hypoglycemia during pregnancy can have serious health implications for both mother and fetus. Although not generally recommended in pregnancy, synthetic somatostatin analogues are used for the management of blood glucose levels in expectant hyperinsulinemic mothers. Recent reports suggest that octreotide treatment in pregnancy, as well as hypoglycemia in itself, may pose a risk of fetal growth restriction. During pregnancy, management of blood glucose levels in familial hyperinsulinemic hypoglycemia thus forms a medical dilemma...
2017: Endocrinology, Diabetes & Metabolism Case Reports
https://www.readbyqxmd.com/read/28451822/a-novel-heterozygous-deletion-in-the-intron-8-exon-9-boundary-of-the-glucokinase-gene-in-a-chinese-pedigree-of-gck-mody
#16
Min Chen, Hua Liang, Weibin Zhou, Chengjiang Li, Jianping Weng
No abstract text is available yet for this article.
April 27, 2017: Acta Diabetologica
https://www.readbyqxmd.com/read/28436179/monogenic-diabetes-prevalence-among-polish-children-summary-of-11%C3%A2-years-long-nationwide-genetic-screening-program
#17
Beata Małachowska, Maciej Borowiec, Karolina Antosik, Arkadiusz Michalak, Anna Baranowska-Jaźwiecka, Grażyna Deja, Przemysława Jarosz-Chobot, Agnieszka Brandt, Małgorzata Myśliwiec, Małgorzata Stelmach, Joanna Nazim, Jadwiga Peczyńska, Barbara Głowińska-Olszewska, Anita Horodnicka-Józwa, Mieczysław Walczak, Maciej T Małecki, Agnieszka Zmysłowska, Agnieszka Szadkowska, Wojciech Fendler, Wojciech Młynarski
BACKGROUND: Estimated monogenic diabetes (MD) prevalence increases as screening programs proceeds. OBJECTIVE: To estimate prevalence of MD among Polish children. SUBJECTS: Patients and their family members suspected of suffering from MD (defined as causative mutation in one of the Maturity Onset Diabetes of the Young or permanent neonatal diabetes mellitus genes) were recruited between January 2005 and December 2015. METHODS: Nationwide prevalence was estimated based on data from 6 administrative provinces (out of 16 in Poland) with high referral rates of patients (>10 per 100 000 children)...
April 24, 2017: Pediatric Diabetes
https://www.readbyqxmd.com/read/28387648/dysmorphic-features-frontal-cerebral-cavernoma-and-hyperglycemia-in-a-girl-with-a-de-novo-deletion-of-7-23-mb-in-region-7p13-p12-1
#18
Gilberto Pérez López, Beatriz Villafuerte Quispe, María José Cabrejas Núñez, Luis Castaño, Raquel Barrio
We describe the case of a 7 year old girl referred to our Diabetes Unit for hyperglycemia associated to facial dysmorphic features, intellectual disability and cerebral cavernomas, who was initially diagnosed with type 1 diabetes mellitus (positive anti-IA2 antibody and HLA DR3/DR4/DQ2). In follow up, due to the evolution of the diabetes (very good metabolic control with low insulin dose and negative IA-2 antibodies - samples analyzed in two different laboratories-), first clinical suspicion was GCK-related Maturity-Onset Diabetes of the Young (MODY 2) by persistent mild hyperglycemia in the fasting state, which was substantiated in Multiplex Ligation-dependent Probe Amplification (MLPA)...
April 7, 2017: Journal of Clinical Research in Pediatric Endocrinology
https://www.readbyqxmd.com/read/28385800/an-exome-chip-association-analysis-in-chinese-reveals-a-functional-missense-variant-of-gckr-that-regulates-fgf21-levels
#19
Chloe Yy Cheung, Clara S Tang, Aimin Xu, Chi-Ho Lee, Ka-Wing Au, Lin Xu, Carol Hy Fong, Kelvin Hm Kwok, Wing-Sun Chow, Yu-Cho Woo, Michele Yuen, Stacey S Cherny, JoJo Hai, Bernard My Cheung, Kathryn Tan, Tai-Hing Lam, Hung-Fat Tse, Pak-Chung Sham, Karen Sl Lam
Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian Exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, GCKR, significantly associated with circulating FGF21 levels at genome-wide significance...
April 6, 2017: Diabetes
https://www.readbyqxmd.com/read/28385506/divergent-synthesis-of-kinase-inhibitor-derivatives-leading-to-discovery-of-selective-gck-inhibitors
#20
Takanori Matsumaru, Makoto Inai, Kana Ishigami, Toshiki Iwamatsu, Hiroshi Maita, Satoko Otsuguro, Takao Nomura, Akira Matsuda, Satoshi Ichikawa, Masahiro Sakaitani, Satoshi Shuto, Katsumi Maenaka, Toshiyuki Kan
We accomplished divergent synthesis of potent kinase inhibitor BAY 61-3606 (1) and 27 derivatives via conjugation of imidazo[1,2-c]pyrimidine and indole ring compounds with aromatic (including pyridine) derivatives by means of palladium-catalyzed cross-coupling reaction. Spleen tyrosine kinase (Syk) and germinal center kinase (Gck, MAP4K2) inhibition assays showed that some of the synthesized compounds were selective Gck inhibitors.
March 23, 2017: Bioorganic & Medicinal Chemistry Letters
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