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Glucokinase

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https://www.readbyqxmd.com/read/28626777/long-term-efficacy-and-safety-of-insulin-and-glucokinase-gene-therapy-for-diabetes-8-year-follow-up-in-dogs
#1
Maria Luisa Jaén, Laia Vilà, Ivet Elias, Veronica Jimenez, Jordi Rodó, Luca Maggioni, Rafael Ruiz-de Gopegui, Miguel Garcia, Sergio Muñoz, David Callejas, Eduard Ayuso, Tura Ferré, Iris Grifoll, Anna Andaluz, Jesus Ruberte, Virginia Haurigot, Fatima Bosch
Diabetes is a complex metabolic disease that exposes patients to the deleterious effects of hyperglycemia on various organs. Achievement of normoglycemia with exogenous insulin treatment requires the use of high doses of hormone, which increases the risk of life-threatening hypoglycemic episodes. We developed a gene therapy approach to control diabetic hyperglycemia based on co-expression of the insulin and glucokinase genes in skeletal muscle. Previous studies proved the feasibility of gene delivery to large diabetic animals with adeno-associated viral (AAV) vectors...
September 15, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28623340/adenovirus-mediated-suppression-of-hypothalamic-glucokinase-affects-feeding-behavior
#2
Romina María Uranga, Carola Millán, María José Barahona, Antonia Recabal, Magdiel Salgado, Fernando Martinez, Patricio Ordenes, Roberto Elizondo-Vega, Fernando Sepúlveda, Elena Uribe, María de Los Ángeles García-Robles
Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28615161/high-glucose-increases-action-potential-firing-of-catecholamine-neurons-in-the-nucleus-of-the-solitary-tract-by-increasing-spontaneous-glutamate-inputs
#3
Brandon L Roberts, Mingyan Zhu, Huan Zhao, Crystal Dillon, Suzanne M Appleyard
Glucose is a crucial substrate essential for cell survival and function. Changes in glucose levels impact neuronal activity and glucose deprivation increases feeding. Several brain regions have been shown to respond to glucoprivation, including the nucleus of the solitary tract (NTS) in the brainstem. The NTS is the primary site in the brain that receives visceral afferent information from the gastrointestinal tract. The catecholaminergic (CA) subpopulation within the NTS modulates many homeostatic functions including cardiovascular reflexes, respiration, food intake, arousal and stress...
June 14, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
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
#4
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...
June 7, 2017: Endocrine
https://www.readbyqxmd.com/read/28584574/increased-glucose-metabolism-and-alpha-glucosidase-inhibition-in-cordyceps-militaris-water-extract-treated-hepg2-cells
#5
Dae Jung Kim, Yun Hwan Kang, Kyoung Kon Kim, Tae Woo Kim, Jae Bong Park, Myeon Choe
BACKGROUND/OBJECTIVES: Recent living condition improvements, changes in dietary habits, and reductions in physical activity are contributing to an increase in metabolic syndrome symptoms including diabetes and obesity. Through such societal developments, humankind is continuously exposed to metabolic diseases such as diabetes, and the number of the victims is increasing. This study investigated Cordyceps militaris water extract (CMW)-induced glucose uptake in HepG2 cells and the effect of CMW treatment on glucose metabolism...
June 2017: Nutrition Research and Practice
https://www.readbyqxmd.com/read/28575730/novel-glucokinase-gene-mutation-in-the-first-macedonian-family-tested-for-mody
#6
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
#7
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...
May 29, 2017: Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28539593/identification-of-the-matricellular-protein-fibulin-5-as-a-target-molecule-of-glucokinase-mediated-calcineurin-nfat-signaling-in-pancreatic-islets
#8
Tomoko Okuyama, Jun Shirakawa, Hiromi Yanagisawa, Mayu Kyohara, Shunsuke Yamazaki, Kazuki Tajima, Yu Togashi, Yasuo Terauchi
Glucokinase-mediated glucose signaling induces insulin secretion, proliferation, and apoptosis in pancreatic β-cells. However, the precise molecular mechanisms underlying these processes are not clearly understood. Here, we demonstrated that glucokinase activation using a glucokinase activator (GKA) significantly upregulated the expression of Fibulin-5 (Fbln5), a matricellular protein involved in matrix-cell signaling, in isolated mouse islets. The islet Fbln5 expression was induced by ambient glucose in a time- and dose-dependent manner and further enhanced by high-fat diet or the deletion of insulin receptor substrate 2 (IRS-2), whereas the GKA-induced increase in Fbln5 expression was diminished in Irs-2-deficient islets...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28525638/glucokinase-gene-may-be-a-more-suitable-target-than-the-insulin-gene-for-detection-of-beta-cell-death
#9
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
#10
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/28512030/discovery-of-potent-and-orally-active-1-4-disubstituted-indazoles-as-novel-allosteric-glucokinase-activators
#11
Zacharia S Cheruvallath, Stephen L Gwaltney, Mark Sabat, Mingnam Tang, Haixia Wang, Andy Jennings, David Hosfield, Bumsup Lee, Yiqin Wu, Petro Halkowycz, Charles E Grimshaw
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28487991/blood-glycemia-modulating-effects-of-melanian-snail-protein-hydrolysates-in-mice-with-type%C3%A2-ii-diabetes
#12
Jae-Suk Choi, Joo-Wan Kim, Jeong Been Park, Sang Eun Pyo, Yong-Ki Hong, Sae Kwang Ku, Mi-Ryung Kim
Freshwater animal proteins have long been used as nutrient supplements. In this study, melanian snail (Semisulcospira libertina) protein hydrolysates (MPh) were found to exert anti-diabetic and protective effects against liver and kidney damage in mice with type II diabetes adapted to a 45% kcal high-fat diet (HFD). The hypoglycemic, hepatoprotective and nephroprotective effects of MPh were analyzed after 12 weeks of the continuous oral administration of MPh at 125, 250 and 500 mg/kg. Diabetic control mice exhibited an increase in body weight, and blood glucose and insulin levels, with a decrease in serum high-density lipoprotein (HDL) levels...
June 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28483921/lack-of-liver-glycogen-causes-hepatic-insulin-resistance-and-steatosis-in-mice
#13
Jose M Irimia, Catalina M Meyer, Dyann M Segvich, Sneha Surendran, Anna A DePaoli-Roach, Nuria Morral, Peter J Roach
Disruption of the Gys2 gene that encodes the liver isoform of glycogen synthase generates a mouse (LGSKO mouse) with an almost complete lack of hepatic glycogen, impaired glucose disposal and a pre-disposition to enter the fasted state. This study explores how the lack of liver glycogen increases fat accumulation and the development of liver insulin resistance. Insulin signaling in LGSKO mice is reduced in liver, but not in muscle, suggesting an organ specific defect. Phosphorylation of several components of the hepatic insulin signaling pathway, IRS1, Akt, and GSK3, were decreased in LGSKO mice and, after insulin stimulation, their responses were significantly suppressed, both temporally and in an insulin dose response...
May 8, 2017: Journal of Biological Chemistry
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/28451822/a-novel-heterozygous-deletion-in-the-intron-8-exon-9-boundary-of-the-glucokinase-gene-in-a-chinese-pedigree-of-gck-mody
#15
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/28449056/plant-hexokinases-are-multifaceted-proteins
#16
Giovanna P Aguilera-Alvarado, Sobeida Sánchez-Nieto
Sugars are the main carbon and energy source in cells, but they can also act as signaling molecules that affect the whole plant life cycle. Certain tissues can produce sugars and supply them to others, and this plant tissue heterogeneity makes sugar signaling a highly complex process that requires elements capable of perceiving changes in sugar concentrations among different tissues, cell compartments and developmental stages. In plants, the regulatory effects of Glucose (Glc) have been the most studied to date...
April 25, 2017: Plant & Cell Physiology
https://www.readbyqxmd.com/read/28432632/tryptophan-fluorescence-yields-and-lifetimes-as-a-probe-of-conformational-changes-in-human-glucokinase
#17
Bogumil Zelent, Chris Bialas, Ignacy Gryczynski, Pan Chen, Rahul Chib, Karina Lewerissa, Maria G Corradini, Richard D Ludescher, Jane M Vanderkooi, Franz M Matschinsky
Five variants of glucokinase (ATP-D-hexose-6-phosphotransferase, EC 2.7.1.1) including wild type and single Trp mutants with the Trp residue at positions 65, 99, 167 and 257 were prepared. The fluorescence of Trp in all locations studied showed intensity changes when glucose bound, indicating that conformational change occurs globally over the entire protein. While the fluorescence quantum yield changes upon glucose binding, the enzyme's absorption spectra, emission spectra and fluorescence lifetimes change very little...
April 22, 2017: Journal of Fluorescence
https://www.readbyqxmd.com/read/28405188/compound-19e-a-novel-glucokinase-activator-protects-against-cytokine-induced-beta-cell-apoptosis-in-ins-1-cells
#18
Yoon Sin Oh, Eunhui Seo, Kaapjoo Park, Hee-Sook Jun
Previously, compound 19e, a novel heteroaryl-containing benzamide derivative, was identified as a potent glucokinase activator (GKA) and showed a glucose-lowering effect in diabetic mice. In this study, the anti-apoptotic actions of 19e were evaluated in INS-1 pancreatic beta-cells co-treated with TNF-α and IL-1β to induce cell death. Compound 19e protected INS-1 cells from cytokine-induced cell death, and the effect was similar to treatment with another GKA or exendin-4. Compound 19e reduced annexin-V stained cells and the expression of cleaved caspase-3 and poly (ADP-ribose) polymerase protein, as well as upregulated the expression of B-cell lymphoma-2 protein...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28390958/discovery-of-liver-directed-glucokinase-activator-having-anti-hyperglycemic-effect-without-hypoglycemia
#19
Anil M Deshpande, Debnath Bhuniya, Siddhartha De, Bhavesh Dave, Vinod P Vyavahare, Santosh H Kurhade, Sachin R Kandalkar, Keshav P Naik, Balasaheb S Kobal, Rahul D Kaduskar, Sujay Basu, Vaibhav Jain, Pratima Patil, Sandhya Chaturvedi Joshi, Ganesh Bhat, Amol A Raje, Satyanarayana Reddy, Jayasagar Gundu, Vamsi Madgula, Suhas Tambe, Prasad Shitole, Dhananjay Umrani, Anita Chugh, Venkata P Palle, Kasim A Mookhtiar
Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development...
March 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28385800/an-exome-chip-association-analysis-in-chinese-reveals-a-functional-missense-variant-of-gckr-that-regulates-fgf21-levels
#20
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
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