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https://www.readbyqxmd.com/read/28207836/tmg-123-a-novel-glucokinase-activator-exerts-durable-effects-on-hyperglycemia-without-increasing-triglyceride-in-diabetic-animal-models
#1
Yoshinori Tsumura, Yu Tsushima, Azusa Tamura, Makiko Hasebe, Masanobu Kanou, Hirotsugu Kato, Tsunefumi Kobayashi
Glucokinase (GK) plays a critical role for maintaining glucose homeostasis with regulating glucose uptake in liver and insulin secretion in pancreas. GK activators have been reported to decrease blood glucose levels in patients with type 2 diabetes mellitus. However, clinical development of GK activators has failed due to the loss of glucose-lowering effects and increased plasma triglyceride levels after chronic treatment. Here, we generated a novel GK activator, TMG-123, examined its in vitro and in vivo pharmacological characteristics, and evaluated its risks of aforementioned clinical issues...
2017: PloS One
https://www.readbyqxmd.com/read/28191470/effects-of-a-novel-glucokinase-activator-hms5552-on-glucose-metabolism-in-a-rat-model-of-type-2-diabetes-mellitus
#2
Ping Wang, Huili Liu, Li Chen, Yingli Duan, Qunli Chen, Shoumin Xi
Glucokinase (GK) plays a critical role in the control of whole-body glucose homeostasis. We investigated the possible effects of a novel glucokinase activator (GKA), HMS5552, to the GK in rats with type 2 diabetes mellitus (T2DM). Male Sprague-Dawley (SD) rats were divided into four groups: control group, diabetic group, low-dose (10 mg/kg) HMS5552-treated diabetic group (HMS-L), and high-dose (30 mg/kg) HMS5552-treated diabetic group (HMS-H). HMS5552 was administered intragastrically to the T2DM rats for one month...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/28163042/munc18b-increases-insulin-granule-fusion-restoring-deficient-insulin-secretion-in-type-2-diabetes-human-and-goto-kakizaki-rat-islets-with-improvement-in-glucose-homeostasis
#3
Tairan Qin, Tao Liang, Dan Zhu, Youhou Kang, Li Xie, Subhankar Dolai, Shuzo Sugita, Noriko Takahashi, Claes-Goran Ostenson, Kate Banks, Herbert Y Gaisano
Reduced pancreatic islet levels of Munc18a/SNARE complex proteins have been postulated to contribute to the deficient glucose-stimulated insulin secretion (GSIS) in type-2 diabetes (T2D). Whereas much previous work has purported Munc18a/SNARE complex (Syntaxin-1A/VAMP-2/SNAP25) to be primarily involved in predocked secretory granule (SG) fusion, less is known about newcomer SGs that undergo minimal docking time at the plasma membrane before fusion. Newcomer SG fusion has been postulated to involve a distinct SM/SNARE complex (Munc18b/Syntaxin-3/VAMP8/SNAP25), whose levels we find also reduced in islets of T2D humans and T2D Goto-Kakizaki (GK) rats...
January 22, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28122008/compromised-neurotrophic-and-angiogenic-regenerative-capability-during-tendon-healing-in-a-rat-model-of-type-ii-diabetes
#4
Aisha S Ahmed, Jian Li, Alim M D Abdul, Mahmood Ahmed, Claes-Göran Östenson, Paul T Salo, Carolyn Hewitt, David A Hart, Paul W Ackermann
Metabolic diseases such as diabetes mellitus type-II (DM-II) may increase the risk of suffering painful connective tissue disorders and tendon ruptures. The pathomechanisms, however, by which diabetes adversely affects connective tissue matrix metabolism and regeneration, still need better definition. Our aim was to study the effect of DM-II on expressional changes of neuro- and angiotrophic mediators and receptors in intact and healing Achilles tendon. The right Achilles tendon was transected in 5 male DM-II Goto-Kakizaki (GK) and 4 age-matched Wistar control rats...
2017: PloS One
https://www.readbyqxmd.com/read/28118732/relationship-between-pdk1-and-contraction-in-carotid-arteries-in-goto-kakizaki-rat-a-spontaneous-type-2-diabetic-animal-model
#5
Shun Watanabe, Takayuki Matsumoto, Kumiko Taguchi, Tsuneo Kobayashi
We studied the relationship between 3-phosphoinositide-dependent protein kinase 1 (PDK1) and contractions induced by serotonin, phenylephrine, and thromboxane A2 mimetic (U46619) in the presence of nitric oxide synthase inhibitor in the carotid arteries of Goto-Kakizaki (GK) rats, a spontaneous type 2 diabetic model, in the chronic stage of disease. Serotonin-induced contraction was greater in the GK rats than in the control Wistar rats. A specific PDK1 inhibitor (GSK2334470) decreased the serotonin-induced contraction in the GK rats but not in the Wistar rats, and the difference in such contraction was abolished with this treatment...
January 24, 2017: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/28116460/enhanced-vegf-signalling-mediates-cerebral-neovascularisation-via-downregulation-of-guidance-protein-robo4-in-a-rat-model-of-diabetes
#6
Mohammed Abdelsaid, Maha Coucha, Sherif Hafez, Abdul Yasir, Maribeth H Johnson, Adviye Ergul
AIMS/HYPOTHESIS: Diabetes promotes cerebral neovascularisation via increased vascular endothelial growth factor (VEGF) angiogenic signalling. Roundabout-4 (ROBO4) protein is an endogenous inhibitor of VEGF signalling that stabilises the vasculature. Yet, how diabetes affects ROBO4 function remains unknown. We hypothesised that increased VEGF signalling in diabetes decreases ROBO4 expression and function via binding of ROBO4 with VEGF-activated β3 integrin and that restoration of ROBO4 expression prevents/repairs cerebral neovascularisation in diabetes...
January 23, 2017: Diabetologia
https://www.readbyqxmd.com/read/28101124/reduced-up-regulation-of-the-nitric-oxide-pathway-and-impaired-endothelial-and-smooth-muscle-functions-in-the-female-type-2-diabetic-goto-kakizaki-rat-heart
#7
Martine Desrois, Carole Lan, Jamileh Movassat, Monique Bernard
BACKGROUND: Type 2 diabetes is associated with greater relative risk of cardiovascular diseases in women than in men, which is not well understood. Consequently, we have investigated if male and female displayed differences in cardiac function, energy metabolism, and endothelial function which could contribute to increased cardiovascular complications in type 2 diabetic female. METHODS: Male and female Control and type 2 diabetic Goto-Kakizaki (GK) isolated rat hearts were perfused during 28 min with a physiological buffer before freeze-clamping for biochemical assays...
2017: Nutrition & Metabolism
https://www.readbyqxmd.com/read/28042873/a-mini-network-balance-model-for-evaluating-the-progression-of-cardiovascular-complications-in-goto-kakizaki-rats
#8
Hao Jiang, Yu-Hao Wang, Chun-Xiang Wei, Xue Zhang, Hao-Chen Liu, Xiao-Quan Liu
Cardiovascular complications represent a leading cause of mortality in patients with type 2 diabetes mellitus (T2DM). During such complicated progression, subtle variations in the cardiovascular risk (CVR)-related biomarkers have been used to identify cardiovascular disease at the incipient stage. In this study we attempt to integrally characterize the progression of cardiovascular complications and to assess the beneficial effects of metformin combined with salvianolic acid A (Sal A), in Goto-Kakizaki (GK) rats with spontaneous T2DM...
January 2, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27995148/investigation-of-the-effects-and-mechanisms-of-mai-tong-formula-on-lower-limb-macroangiopathy-in-a-spontaneous-diabetic-rat-model
#9
Guangming Gong, Haipo Yuan, Ya Liu, Luguang Qi
A new Chinese herbal formula called Mai Tong Formulae (MTF) has recently been used to treat lower limb macroangiopathy in type 2 diabetes mellitus (T2DM) patients. In this study, we investigated the effect of MTF on lower limb macroangiopathy in a spontaneous diabetic rat model (GK rats). We found that MTF treatment significantly reduced serum fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), IL6, and VEGF and increased serum insulin in this model. Histological and ultrastructural observations showed that MTF treatment significantly reduced vascular endothelial cell shedding and improved endothelium injuries...
2016: Journal of Diabetes Research
https://www.readbyqxmd.com/read/27982676/lipasin-betatrophin-is-differentially-expressed-in-liver-and-white-adipose-tissue-without-association-with-insulin-resistance-in-wistar-and-goto-kakizaki-rats
#10
M Cahová, D Habart, T Olejár, Z Berková, Z Papáčková, H Daňková, A Lodererova, M Heczková, F Saudek
Lipasin is a recently identified lipokine expressed predominantly in liver and in adipose tissue. It was linked to insulin resistance in mice and to type 1 and type 2 diabetes (T1D, T2D) in humans. No metabolic studies concerning lipasin were performed yet in rats. Therefore, we used rat model of T2D and insulin resistance, Goto-Kakizaki (GK) rats, to determine changes of lipasin expression in liver and in white adipose tissue (WAT) over 52 weeks in the relation to glucose tolerance, peripheral tissue insulin sensitivity and adiposity...
December 16, 2016: Physiological Research
https://www.readbyqxmd.com/read/27904691/implantation-of-placenta-derived-mesenchymal-stem-cells-accelerates-murine-dermal-wound-closure-through-immunomodulation
#11
Haifeng Wang, Lianyu Chen, Yang Liu, Bangzhen Luo, Nanzi Xie, Tao Tan, Lige Song, Pei Erli, Ming Luo
BACKGROUND: Diabetic foot ulcer (DFU) is a major complication of diabetes mellitus. Although previous studies have established that inflammation, ischemia and neuropathy contribute to the development of DFU, it is still an unmet medical need due to lack knowledge of cellular and molecular mechanisms associated with DFU. In the present study, we tested our hypothesis that subcutaneous application of human placental mesenchymal stem cells (PMSCs) can accelerate diabetic dermal wound healing by modulating immunoresponse...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27804997/a-presenilin-notch1-pathway-regulated-by-mir-375-mir-30a-and-mir-34a-mediates-glucotoxicity-induced-pancreatic-beta-cell-apoptosis
#12
Yating Li, Tao Zhang, Yuncai Zhou, Yi Sun, Yue Cao, Xiaoai Chang, Yunxia Zhu, Xiao Han
The presenilin-mediated Notch1 cleavage pathway plays a critical role in controlling pancreatic beta cell fate and survival. The aim of the present study was to investigate the role of Notch1 activation in glucotoxicity-induced beta cell impairment and the contributions of miR-375, miR-30a, and miR-34a to this pathway. We found that the protein levels of presenilins (PSEN1 and PSEN2), and NOTCH1 were decreased in INS-1 cells after treatment with increased concentrations of glucose, whereas no significant alteration of mRNA level of Notch1 was observed...
November 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27780892/diabetes-negatively-affects-cortical-and-striatal-gabaergic-neurons-an-effect-that-is-partially-counteracted-by-exendin-4
#13
Martin Larsson, Grazyna Lietzau, David Nathanson, Claes-Göran Östenson, Carina Mallard, Maria E Johansson, Thomas Nyström, Cesare Patrone, Vladimer Darsalia
Type 2 diabetic (T2D) patients often develop early cognitive and sensorimotor impairments. The pathophysiological mechanisms behind these problems are largely unknown. Recent studies demonstrate that dysfunctional γ-aminobutyric acid (GABAergic) neurons are involved in age-related cognitive decline. We hypothesized that similar, but earlier dysfunction is taking place under T2D in the neocortex and striatum (two brain areas important for cognition and sensorimotor functions). We also hypothesized that the T2D-induced effects are pharmacologically reversible by anti-diabetic drugs targeting the glucagon-like peptide-1 receptor (GLP-1R)...
December 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27764176/a-novel-diphenylthiosemicarbazide-is-a-potential-insulin-secretagogue-for-anti-diabetic-agen
#14
Kenji Sugawara, Kohei Honda, Yoshie Reien, Norihide Yokoi, Chihiro Seki, Harumi Takahashi, Kohtaro Minami, Ichiro Mori, Akio Matsumoto, Haruaki Nakaya, Susumu Seino
Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue...
2016: PloS One
https://www.readbyqxmd.com/read/27756895/mpp2-is-a-postsynaptic-maguk-scaffold-protein-that-links-syncam1-cell-adhesion-molecules-to-core-components-of-the-postsynaptic-density
#15
Nils Rademacher, Bettina Schmerl, Jennifer A Lardong, Markus C Wahl, Sarah A Shoichet
At neuronal synapses, multiprotein complexes of trans-synaptic adhesion molecules, scaffold proteins and neurotransmitter receptors assemble to essential building blocks required for synapse formation and maintenance. Here we describe a novel role for the membrane-associated guanylate kinase (MAGUK) protein MPP2 (MAGUK p55 subfamily member 2) at synapses of rat central neurons. Through interactions mediated by its C-terminal SH3-GK domain module, MPP2 binds to the abundant postsynaptic scaffold proteins PSD-95 and GKAP and localises to postsynaptic sites in hippocampal neurons...
October 19, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27677945/rna-seq-analysis-of-the-hypothalamic-transcriptome-reveals-the-networks-regulating-physiopathological-progress-in-the-diabetic-gk-rat
#16
Yuhuan Meng, Yujia Guan, Wenlu Zhang, Yu-E Wu, Huanhuan Jia, Yu Zhang, Xiuqing Zhang, Hongli Du, Xiaoning Wang
The Goto-Kakizaki (GK) rat is an animal model of non-obese type 2 diabetes (T2D). The GK rat was generated through the introduction of various genetic mutations from continuous inbreeding; these rats develop diabetes spontaneously. The mutated genes in GK rats may play key roles in the regulation of diabetes. The hypothalamus plays a central role in systematic energy homeostasis. Here, the hypothalamic transcriptomes in GK and Wistar rats at 4, 8 and 12 weeks were investigated by RNA-seq, and multiple variants and gene expression profiles were obtained...
September 28, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27646706/transcriptome-profiling-in-rat-inbred-strains-and-experimental-cross-reveals-discrepant-genetic-architecture-of-genome-wide-gene-expression
#17
Pamela J Kaisaki, Georg W Otto, Karène Argoud, Stephan C Collins, Robert H Wallis, Steven P Wilder, Anthony C Y Yau, Christophe Hue, Sophie Calderari, Marie-Thérèse Bihoreau, Jean-Baptiste Cazier, Richard Mott, Dominique Gauguier
To test the impact of genetic heterogeneity on cis- and trans-mediated mechanisms of gene expression regulation, we profiled the transcriptome of adipose tissue in 20 inbred congenic strains derived from diabetic Goto-Kakizaki (GK) rats and Brown-Norway (BN) controls, which contain well-defined blocks (1Mb-183Mb) of genetic polymorphisms, and in 123 genetically heterogeneous rats of an (GKxBN)F2 offspring. Within each congenic we identified 73 to 1,351 differentially expressed genes (DEG), only 7.7% of which mapped within the congenic blocks, and which may be regulated in cis The remainder localised outside the blocks, and therefore must be regulated in trans Most trans-regulated genes exhibited approximately two-fold expression changes, consistent with mono-allelic expression...
September 19, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27632277/effect-of-nerve-growth-factor-on-osseointegration-of-titanium-implants-in-type-2-diabetic-rats
#18
Jing Zhang, Mai Shirai, Ryuji Yamamoto, Yasuo Yamakoshi, Shinichiro Oida, Chikahiro Ohkubo, Jianyu Zeng
PURPOSE: Compared with the general population, a poorer quality of bone-implant osseointegration occurs and at a higher failure rate in patients with type 2 diabetes mellitus. The aim of this study was to analyze the effects of local injection of nerve growth factor at the bone-implant interface after implantation in type 2 diabetic rats. MATERIALS AND METHODS: Goto-Kakizaki (GK) rats (n = 30) were used as a model of type 2 diabetes mellitus, and Wistar rats were used as a control (n = 15)...
September 2016: International Journal of Oral & Maxillofacial Implants
https://www.readbyqxmd.com/read/27623996/review-of-pharmacokinetic-data-of-different-drug-classes-in-goto-kakizaki-rats-a-non-obese-model-for-type-2-diabetes-mellitus-case-studies-and-perspectives
#19
Harilal Patel, Poonam Giri, Nuggehally R Srinivas
Goto-Kakizaki (GK) rats represent a unique non-obese and lean model with manifestation of type 2 diabetes (T2DM) broadly mimicking the human T2DM development. Therefore, in addition to the use of GK rats to test the efficacy of drugs, it may represent a great tool to study the influence of altered physiological process and/or organ specific pathophysiological changes (i.e., liver, kidney, etc.) on the disposition of drugs. The objectives of the review were: (a) to compile the published pharmacokinetic data of several drugs, such as cephalexin, cyclosporine, exendin-4, gliclazide, grepafloxacin, rosuvastatin, salsalate, salicylic acid, and theophylline, in GK rats relative to normal rats; and (b) critically evaluate the possible role of physiologically altered processes on the pharmacokinetics of reviewed drugs...
September 13, 2016: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27610615/oral-delivery-of-pentameric-glucagon-like-peptide-1-by-recombinant-lactobacillus-in-diabetic-rats
#20
Yin Lin, Kasper Krogh-Andersen, Julien Pelletier, Harold Marcotte, Claes-Göran Östenson, Lennart Hammarström
Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by intestinal cells and stimulates insulin secretion from the pancreas in a glucose-dependent manner. Exogenously supplied GLP-1 analogues are used in the treatment of type 2 diabetes. An anti-diabetic effect of Lactobacillus in lowering plasma glucose levels and its use as a vehicle for delivery of protein and antibody fragments has been shown previously. The aim of this study was to employ lactobacilli as a vehicle for in situ production and delivery of GLP-1 analogue to normalize blood glucose level in diabetic GK (Goto-Kakizaki) rats...
2016: PloS One
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