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Douglas Marcotte, Mia Rushe, Robert M Arduini, Christine Lukacs, Kateri Atkins, Xin Sun, Kevin Little, Michael Cullivan, Murugan Paramasivam, Thomas A Patterson, Thomas Hesson, Timothy D McKee, Tricia L May-Dracka, Zhili Xin, Andrea Bertolotti-Ciarlet, Govinda R Bhisetti, Joseph P Lyssikatos, Laura F Silvian
Germinal-center kinase-like kinase (GLK, Map4k3), a GCK-I family kinase, plays multiple roles in regulating apoptosis, amino acid sensing, and immune signaling. We describe here the crystal structure of an activation loop mutant of GLK kinase domain bound to an inhibitor. The structure reveals a weakly associated, activation-loop swapped dimer with more than 20 amino acids of ordered density at the carboxy-terminus. This C-terminal PEST region binds intermolecularly to the hydrophobic groove of the N-terminal domain of a neighboring molecule...
October 11, 2016: Protein Science: a Publication of the Protein Society
Barbara Piccini, Rosangela Artuso, Lorenzo Lenzi, Monica Guasti, Giulia Braccesi, Federica Barni, Emilio Casalini, Sabrina Giglio, Sonia Toni
Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family...
September 19, 2016: European Journal of Medical Genetics
Amanda J Brahm, Grace Wang, Jian Wang, Adam D McIntyre, Henian Cao, Matthew R Ban, Robert A Hegele
OBJECTIVES: Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, reportedly accounting for 2% to 5% of all cases of diabetes. In samples from Canadian patients referred for molecular genetic confirmation of a clinically suspected MODY, we determined the prevalence of likely disease-causing DNA variants in known MODY genes. METHODS: Between 1999 and 2015, our centre received requests from colleagues for DNA sequencing of 96 samples from unrelated Canadian patients with clinically suspected MODY...
September 12, 2016: Canadian Journal of Diabetes
O Tsave, M P Yavropoulou, M Kafantari, C Gabriel, J G Yovos, A Salifoglou
Insulin resistance is identified through numerous pathophysiological conditions, such as Diabetes mellitus II, obesity, hypertension and other metabolic syndromes. Enhancement of insulin action and\or its complete replacement by insulin-enhancing or insulin-mimetic agents seems to improve treatment of metabolic diseases. Over the last decades, intensive research has targeted the investigation of such agents, with chromium emerging as an important inorganic cofactor involved in the requisite metabolic chemistry...
July 27, 2016: Journal of Inorganic Biochemistry
Jacob A Galan, Joseph Avruch
The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1-6 and Sav1/WW45...
October 4, 2016: Biochemistry
Jeffrey W Kleinberger, Kristin A Maloney, Toni I Pollin
The genetic architecture of diabetes mellitus in general and in pregnancy is complex, owing to the multiple types of diabetes that comprise both complex/polygenic forms and monogenic (largely caused by a mutation in a single gene) forms such as maturity-onset diabetes of the young (MODY). Type 1 diabetes (T1D) and type 2 diabetes (T2D) have complex genetic etiologies, with over 40 and 90 genes/loci, respectively, implicated that interact with environmental/lifestyle factors. The genetic etiology of gestational diabetes mellitus has largely been found to overlap that of T2D...
August 29, 2016: American Journal of Perinatology
Mauren Isfer Anghebem-Oliveira, Susan Webber, Dayane Alberton, Emanuel Maltempi de Souza, Giseli Klassen, Geraldo Picheth, Fabiane Gomes de Moraes Rego
BACKGROUND: The glucokinase regulatory protein (GCKR) regulates the activity of the glucokinase (GCK), which plays a key role in glucose homeostasis. Genetic variants in GCK have been associated with diabetes and gestational diabetes (GDM). Due to the relationship between GCKRP and GCK, polymorphisms in GCKR are also candidates for genetic association with GDM. The aim of this study was to evaluate the association between the GCKR rs780094 polymorphism and GDM in a Brazilian population...
August 24, 2016: Journal of Clinical Laboratory Analysis
Steffi F Baldini, Agata Steenackers, Stéphanie Olivier-Van Stichelen, Anne-Marie Mir, Marlène Mortuaire, Tony Lefebvre, Céline Guinez
Blood glucose fluctuates with the fasting-feeding cycle. One of the liver's functions is to maintain blood glucose concentrations within a physiological range. Glucokinase (GCK) or hexokinase IV, is the main enzyme that regulates the flux and the use of glucose in the liver leading to a compensation of hyperglycemia. In hepatocytes, GCK catalyzes the phosphorylation of glucose into glucose-6-phosphate. This critical enzymatic reaction is determinant for the metabolism of glucose in the liver which includes glycogen synthesis, glycolysis, lipogenesis and gluconeogenesis...
September 16, 2016: Biochemical and Biophysical Research Communications
Rinki Murphy
Monogenic diabetes is frequently mistakenly diagnosed as either type 1 or type 2 diabetes, yet accounts for approximately 1-2% of diabetes. Identifying monogenic forms of diabetes has practical implications for specific therapy, screening of family members and genetic counselling. The most common forms of monogenic diabetes are due to glucokinase (GCK), hepatocyte nuclear factor (HNF)-1A and HNF-4A, HNF-1B, m.3243A>G gene defects. Practical aspects of their recognition, diagnosis and management are outlined, particularly as they relate to pregnancy...
September 2015: Obstetric Medicine
Laura K M Steinbusch, Alexandre Picard, Marion S Bonnet, Davide Basco, Gwenaël Labouèbe, Bernard Thorens
Glucokinase (Gck) is a critical regulator of glucose-induced insulin secretion by pancreatic β-cells. It has been suggested to also play an important role in glucose signaling in neurons of the ventromedial hypothalamic nucleus (VMN), a brain nucleus involved in the control of glucose homeostasis and feeding. To test the role of Gck in VMN glucose sensing and physiological regulation, we studied mice with genetic inactivation of the Gck gene in Sf1 neurons of the VMN (Sf1Gck(-/-) mice). Compared with control littermates, Sf1Gck(-/-) mice displayed increased white fat mass and adipocyte size, reduced lean mass, impaired hypoglycemia-induced glucagon secretion, and a lack of parasympathetic and sympathetic nerve activation by neuroglucopenia...
October 2016: Diabetes
Chrysi Koliaki, Birgit Knebel, Fausto Machicao, Michael Roden, Karsten Müssig
UNLABELLED: Medical history and clinical examination: We report on a 52-year-old lean female patient with diabetes mellitus, treated with various glucose-lowering medications including insulin for 6 years. Both her mother and great-grandmother were also diagnosed with diabetes. At admission, she presents with good glycemic control and no signs of diabetes-related comorbidities. LABORATORY TESTS: HbA1c is 6 %. On the basis of positive family history for diabetes, normal body weight and negative antibodies against islet-cell antigens, we perform blood molecular genetic analyses with the suspicion of a genetic form of diabetes...
July 2016: Deutsche Medizinische Wochenschrift
Su Yon Jung, Eric M Sobel, Jeanette C Papp, Carolyn J Crandall, Alan N Fu, Zuo-Feng Zhang
PURPOSE: Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. METHODS: With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP-glucose variations...
September 2016: Genetic Epidemiology
R von Hahn, A Becker, F Berg, K Blaum, C Breitenfeldt, H Fadil, F Fellenberger, M Froese, S George, J Göck, M Grieser, F Grussie, E A Guerin, O Heber, P Herwig, J Karthein, C Krantz, H Kreckel, M Lange, F Laux, S Lohmann, S Menk, C Meyer, P M Mishra, O Novotný, A P O'Connor, D A Orlov, M L Rappaport, R Repnow, S Saurabh, S Schippers, C D Schröter, D Schwalm, L Schweikhard, T Sieber, A Shornikov, K Spruck, S Sunil Kumar, J Ullrich, X Urbain, S Vogel, P Wilhelm, A Wolf, D Zajfman
An electrostatic cryogenic storage ring, CSR, for beams of anions and cations with up to 300 keV kinetic energy per unit charge has been designed, constructed, and put into operation. With a circumference of 35 m, the ion-beam vacuum chambers and all beam optics are in a cryostat and cooled by a closed-cycle liquid helium system. At temperatures as low as (5.5 ± 1) K inside the ring, storage time constants of several minutes up to almost an hour were observed for atomic and molecular, anion and cation beams at an energy of 60 keV...
June 2016: Review of Scientific Instruments
Lei Yang, Jin Xin, Zhenhai Zhang, Hongmei Yan, Jing Wang, E Sun, Jian Hou, Xiaobin Jia, Huixia Lv
OBJECTIVE: This work aimed at preparing ginsenoside compound K (GCK)-loaded liposomes modified with TPGS (GCKT-liposomes) to enhance solubility and targeting capability of GCK, as well as inhibit the efflux of GCK from tumour cells. METHODS: GCKT-liposomes were prepared by the thin-film hydration method and characterized by particle size, polydispersity, zeta potential and drug encapsulation efficiency. A549 cells were used as antitumour cell model to access the cellular uptake of the GCK and perform its antitumour function...
September 2016: Journal of Pharmacy and Pharmacology
Eray Kemahli, Mevlüt Yildiz, Tülin Firat, Mehmet Emin Özyalvaçli, Uğur Üyetürk, Burak Yilmaz, Adnan Gücük
INTRODUCTION: The aim of this experimental study was to investigate the histopathological and biochemical effects of pyrrolidine dithiocarbamate, an antioxidant and inhibitor of NF-kβ, on ischemiareperfusion injury in rats. METHODS: A total of 21 male Wistar-Albino rats were randomly distributed into three groups as sham group (Group 1), ischemia-reperfusion (I/R) group (Group 2) and I/R with pyrrolidine dithiocarbamate (PDTC) group (Group 3). Left testicles of rats in Groups 2 and 3 underwent testicular torsion of 720° for four hours and 100 mg/kg of PDTC was administered intraperitoneally prior to detorsion in Group 3...
March 2016: Canadian Urological Association Journal, Journal de L'Association des Urologues du Canada
H Heuvel-Borsboom, H W de Valk, M Losekoot, J Westerink
Maturity onset diabetes of the young (MODY) is a monogenic, autosomal dominant form of diabetes characterised by mutations in genes resulting in dysfunction of pancreatic β-cells and subsequent insulin production. We present a family with HNF1A-MODY due to a likely pathogenic mutation in HNF1A (c.59G>A, p.Gly20Glu), diagnosed a long time after the first diagnosis of diabetes. Currently 13 MODY subtypes caused by mutations in 13 genes, are known. We describe the four most prevalent forms in more detail, i...
June 2016: Netherlands Journal of Medicine
Renata P Dotto, Fernando M A Giuffrida, Luciana Franco, Andreia L G Mathez, Leticia S Weinert, Sandra P Silveiro, Joao R Sa, Andre F Reis, Magnus R Dias-da-Silva
Thirty-two patients with diabetes negative for point mutations in GCK and HNF1A underwent further molecular screening of GCK, HNF1A, HNF4A, and HNF1B by MLPA analysis. We described the first Brazilian case of MODY5 due to a heterozygous whole-gene deletion in HNF1B, who developed rapidly progressive renal failure and death.
June 2016: Diabetes Research and Clinical Practice
Ariel Pablo Lopez, Alejandro de Dios, Ignacio Chiesa, Maria Silvia Perez, Gustavo Daniel Frechtel
BACKGROUND: Maturity-onset diabetes of the young 2 (MODY2) is a form of diabetes that is clinically characterized by early age at onset and mild hyperglycemia, and has a low risk of late complications. It is often underdiagnosed due to its mild symptoms. To date, over 600 different GCK/MODY2 mutations have been reported. Despite only a few de novo mutations having been described, recent studies have reported the detection of a higher frequency of this kind of mutation. Therefore, de novo mutations could be more frequent than previously described...
August 2016: Diabetes Research and Clinical Practice
Yu Ping Xiao, Xiao Hua Xu, Yan Lan Fang, LiQiong Jiang, Chun Chen, Li Liang, Chun Lin Wang
BACKGROUND: Maturity-onset diabetes of the young type 2 (MODY2) is caused by mutations in the glucokinase (GCK) gene and is rare in the Chinese population. We report three Chinese families with MODY2 and the sequencing of the GCK gene. METHODS: Three unrelated Chinese families with MODY2 and their pedigrees were investigated. In Family 1, the proband was a 7-year-old girl with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Her mother and maternal grandfather had IFG...
August 1, 2016: Journal of Pediatric Endocrinology & Metabolism: JPEM
Belma Haliloglu, Gerald Hysenaj, Zeynep Atay, Tulay Guran, Saygın Abalı, Serap Turan, Abdullah Bereket, Sian Ellard
OBJECTIVE: Inactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort. DESIGN AND PATIENTS: Fifty-four unrelated probands were selected based on the following criteria: age of diagnosis ≤17 years, family history of diabetes in at least two generations, anti-GAD/ICA negative, BMI<95...
September 2016: Clinical Endocrinology
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