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Glucokinase

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https://www.readbyqxmd.com/read/28525638/glucokinase-gene-may-be-a-more-suitable-target-than-the-insulin-gene-for-detection-of-beta-cell-death
#1
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
#2
Juliana 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...
May 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28512030/discovery-of-potent-and-orally-active-1-4-disubstituted-indazoles-as-novel-allosteric-glucokinase-activators
#3
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.
April 13, 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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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/28377501/the-transcription-factor-pax6-is-required-for-pancreatic-%C3%AE-cell-identity-glucose-regulated-atp-synthesis-and-ca2-dynamics-in-adult-mice
#13
Ryan K Mitchell, Marie-Sophie Nguyen-Tu, Pauline Chabosseau, Rebecca M Callingham, Timothy J Pullen, Rebecca Cheung, Isabelle Leclerc, David J Hodson, Guy A Rutter
Heterozygous mutations in the human paired box gene PAX6 lead to impaired glucose tolerance. Although embryonic deletion of the Pax6 gene in mice leads to the loss of most pancreatic islet cell types, the functional consequences of Pax6 loss in adults are poorly defined. Here, we developed a mouse line in which Pax6 was selectively inactivated in β cells by crossing animals with floxed Pax6 alleles to mice expressing the inducible Pdx1CreERT transgene. Pax6 deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia...
April 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28371533/preliminary-screening-of-mutations-in-the-glucokinase-gene-of-chinese-patients-with-gestational-diabetes
#14
Zhixin Wang, Fan Ping, Qian Zhang, Jia Zheng, Huabing Zhang, Miao Yu, Wenhui Li, Xinhua Xiao
Mutations in the glucokinase gene (GCK) are a pathogenetic cause of maturity-onset diabetes of the young (MODY). Studies have found that female patients with GCK-MODY often present with gestational diabetes during pregnancy. Our aim was to preliminarily assess the prevalence of mutations in the glucokinase gene in Chinese subjects with gestational diabetes MATERIALS AND METHODS: Chinese gestational subjects who underwent a 100 g oral glucose tolerance test in Peking Union Medical College Hospital (PUMCH) from July 2005 to May 2008 were retrospectively analyzed...
March 30, 2017: Journal of Diabetes Investigation
https://www.readbyqxmd.com/read/28338054/identification-of-hexose-kinase-genes-in-kluyveromyces-marxianus-and-thermo-tolerant-one-step-producing-glucose-free-fructose-strain-construction
#15
Guorong Zhang, Min Lu, Jichao Wang, Dongmei Wang, Xiaolian Gao, Jiong Hong
In yeast, the hexose assimilation is started at hexose phosphorylation. However, in Kluyveromyces marxianus, the hexokinase (HXK) and glucokinase (GLK) genes were not identified by experiments. Meanwhile, the glucose-free fructose product requires more cost-efficient method. In this study, the KmHXK1 and KmGLK1 genes were functionally identified through gene disruption, over-expression and recombinant enzymes characterization. Both glucose and fructose assimilation ability decreased significantly in KmHXK1 disrupted strain YLM001, however, this ability was not changed obviously in KmGLK1 disrupted strain YLM002...
March 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28332581/elevated-mir-130a-mir130b-mir-152-expression-reduces-intracellular-atp-levels-in-the-pancreatic-beta-cell
#16
Jones K Ofori, Vishal A Salunkhe, Annika Bagge, Neelanjan Vishnu, Mototsugu Nagao, Hindrik Mulder, Claes B Wollheim, Lena Eliasson, Jonathan L S Esguerra
MicroRNAs have emerged as important players of gene regulation with significant impact in diverse disease processes. In type-2 diabetes, in which impaired insulin secretion is a major factor in disease progression, dysregulated microRNA expression in the insulin-secreting pancreatic beta cell has been widely-implicated. Here, we show that miR-130a-3p, miR-130b-3p, and miR-152-3p levels are elevated in the pancreatic islets of hyperglycaemic donors, corroborating previous findings about their upregulation in the islets of type-2 diabetes model Goto-Kakizaki rats...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28331372/a-glucokinase-gene-mutation-in-a-young-boy-with-diabetes-mellitus-hyperinsulinemia-and-insulin-resistance
#17
Andrey O Emelyanov, Elena Sechko, Ekaterina Koksharova, Igor Sklyanik, Tamara Kuraeva, Alexander Mayorov, Valentina Peterkova, Ivan Dedov
We report the case of a 12-year-old boy with a glucokinase (GCK) mutation, and diabetes with hyperinsulinemia and insulin resistance. For 4 years, the patient intermittently received insulin medications Actrapid HM and Protaphane HM (total dose 5 U/day), with glycated hemoglobin (HbA1c) levels of 6.6%-7.0%. After extensive screening the patient was found to carry a heterozygous mutation (p.E256K) in GCK (MIM #138079, reference sequence NM_000162.3). Insulin therapy was replaced by metformin at 1,700 mg/day...
2017: International Medical Case Reports Journal
https://www.readbyqxmd.com/read/28327441/structure-based-design-synthesis-and-biological-evaluation-of-amino-phosphonate-derivatives-as-human-glucokinase-activators
#18
Nanda Kumar Yellapu, Ravendra Babu Kilaru, Nagaraju Chamarthi, Sarma Pvgk, Bhaskar Matcha
Glucokinase (GK) is a potential therapeutic target of type 2 diabetes and GK activators (GKAs) represent a promising class of small organic molecules which enhance GK activity. Based on the configuration and conformation of the allosteric site of GK, we have designed a novel class of amino phosphonate derivatives in order to develop potent GKAs. The QSAR model developed using numerous descriptors revealed its potential with the best effective statistical values of RMSE=1.52 and r(2)=0.30. Moreover, application of this model on the present test set GKAs proved to be worthy to predict their activities as a better linear relationship was observed with RMSE=0...
March 2, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28317897/identification-of-mangiferin-as-a-potential-glucokinase-activator-by-structure-based-virtual-ligand-screening
#19
Qiuxia Min, Xinpei Cai, Weiguang Sun, Fei Gao, Zhimei Li, Qian Zhang, Luo-Sheng Wan, Hua Li, Jiachun Chen
The natural product mangiferin (compound 7) has been identified as a potential glucokinase activator by structure-based virtual ligand screening. It was proved by enzyme activation experiment and cell-based assays in vitro, with potency in micromolar range. Meanwhile, this compound showed good antihyperglycemic activity in db/db mice without obvious side effects such as excessive hypoglycaemia.
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28284809/discovery-of-orally-active-hepatoselective-glucokinase-activators-for-treatment-of-type-ii-diabetes-mellitus
#20
Jiayi Xu, Songnian Lin, Robert W Myers, Maria E Trujillo, Michele J Pachanski, Sunita Malkani, Hsuan-Shen Chen, Zhesheng Chen, Brian Campbell, George J Eiermann, Nadine Elowe, Brian T Farrer, Wen Feng, Qinghong Fu, Roman Kats-Kagan, Michael Kavana, Daniel R McMasters, Kaushik Mitra, Xinchun Tong, Libo Xu, Fengqi Zhang, Rui Zhang, George H Addona, Joel P Berger, Bei Zhang, Emma R Parmee
Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic β-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk...
May 1, 2017: Bioorganic & Medicinal Chemistry Letters
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