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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/28197316/design-and-synthesis-of-novel-selective-gpr40-agopams
#2
Christopher W Plummer, Matthew J Clements, Helen Chen, Murali Rajagopalan, Hubert Josien, William K Hagmann, Michael Miller, Maria E Trujillo, Melissa Kirkland, Daniel Kosinski, Joel Mane, Michele Pachanski, Boonlert Cheewatrakoolpong, Andrew F Nolting, Robert Orr, Melodie Christensen, Louis-Charles Campeau, Michael J Wright, Randal Bugianesi, Sarah Souza, Xiaoping Zhang, Jerry Di Salvo, Adam B Weinglass, Richard Tschirret-Guth, Ravi Nargund, Andrew D Howard, Steven L Colletti
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs...
February 9, 2017: ACS Medicinal Chemistry Letters
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/27982676/lipasin-betatrophin-is-differentially-expressed-in-liver-and-white-adipose-tissue-without-association-with-insulin-resistance-in-wistar-and-goto-kakizaki-rats
#9
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
#10
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/27881924/rodent-models-of-diabetic-nephropathy-their-utility-and-limitations
#11
REVIEW
Munehiro Kitada, Yoshio Ogura, Daisuke Koya
Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes...
2016: International Journal of Nephrology and Renovascular Disease
https://www.readbyqxmd.com/read/27875385/effects-of-linagliptin-on-vessel-wall-healing-in-the-rat-model-of-arterial-injury-under-normal-and-diabetic-conditions
#12
Linnea Eriksson, Samuel Röhl, Robert Saxelin, Mariette Lengquist, Malin Kronqvist, Kenneth Caidahl, Claes-Göran Östenson, Anton Razuvaev
Diabetic patients suffer an increased risk of restenosis and late stent thrombosis after angioplasty, complications that are related to a defective re-endothelialization. Dipeptidyl peptidase-4 inhibitors have been suggested to exert direct effect on endothelial and smooth muscle cells (SMCs). Therefore the objective was to study if the dipeptidyl peptidase-4 inhibitor linagliptin could influence vascular repair and accelerate re-endothelialization after arterial injury in healthy and diabetic animals. Diabetic Goto-Kakizaki and healthy Wistar rats were subjected to arterial injury and treated with linagliptin or vehicle...
November 17, 2016: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/27832863/endothelial-progenitor-cells-from-human-fetal-aorta-cure-diabetic-foot-in-a-rat-model
#13
Wan-Ni Zhao, Shi-Qing Xu, Jian-Feng Liang, Liang Peng, Hong-Lin Liu, Zai Wang, Qing Fang, Meng Wang, Wei-Qin Yin, Wen-Jian Zhang, Jin-Ning Lou
OBJECTIVE: Recent evidence has suggested that circulating endothelial progenitor cells (EPCs) can repair the arterial endothelium during vascular injury. However, a reliable source of human EPCs is needed for therapeutic applications. In this study, we isolated human fetal aorta (HFA)-derived EPCs and analyzed the capacity of EPCs to differentiate into endothelial cells. In addition, because microvascular dysfunction is considered to be the major cause of diabetic foot (DF), we investigated whether transplantation of HFA-derived EPCs could treat DF in a rat model...
December 2016: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/27826468/digital-analysis-of-eyelid-features-and-eyebrow-position-following-co2-laser-assisted-blepharoptosis-surgery
#14
Xiaodong Zheng, Hirohiko Kakizaki, Tomoko Goto, Atsushi Shiraishi
BACKGROUND: To compare the margin reflex distance of the upper (MRD-1) and lower (MRD-2) eyelids and the eyebrow height (EBH) in patients with involutional and hard contact lens wear--induced blepharoptosis before and after ptosis surgery. METHODS: Sixty patients with acquired blepharoptosis were studied. Group 1 consisted of 30 patients with involutional ptosis (age, 75.8 ± 6.4 years), and group 2 consisted of 30 patients with hard contact lens wear-induced ptosis (age, 50...
October 2016: Plastic and Reconstructive Surgery. Global Open
https://www.readbyqxmd.com/read/27790925/hepatic-and-skeletal-muscle-mitochondrial-toxicity-of-chitosan-oligosaccharides-of-normal-and-diabetic-rats
#15
João Soeiro Teodoro, Ana Patrícia Gomes, Ana Teresa Varela, Filipe Valente Duarte, Anabela Pinto Rolo, Carlos Marques Palmeira
Diabetes and associated conditions are now considered a worldwide epidemic, with increasing costs and burdens with no cure yet developed. The chitin-derived glucosamine biopolymer chitosan has shown promising results when supplied to diabetic patients. However, no study has investigated the possible toxic side effects of chitosan treatments, in particular when regarding the most important bioenergetic organelle, mitochondria. As such, we aimed to understand if supplementation of chitosan to the diet of normal and diabetic rats could compromise mitochondrial function on two of the major organs involved in diabetes, obesity, and metabolic regulation, the liver and skeletal muscle...
November 2016: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/27780892/diabetes-negatively-affects-cortical-and-striatal-gabaergic-neurons-an-effect-that-is-partially-counteracted-by-exendin-4
#16
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
#17
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/27724997/rice-endosperm-protein-slows-progression-of-fatty-liver-and-diabetic-nephropathy-in-zucker-diabetic-fatty-rats
#18
Masatoshi Kubota, Reiko Watanabe, Miki Yamaguchi, Michihiro Hosojima, Akihiko Saito, Mikio Fujii, Shinobu Fujimura, Motoni Kadowaki
We previously reported that rice endosperm protein (REP) has renoprotective effects in Goto-Kakizaki rats, a non-obese diabetic model. However, whether these effects occur in obese diabetes remains unclear. This study aimed to clarify the effects of REP on obese diabetes, especially on fatty liver and diabetic nephropathy, using the obese diabetic model Zucker diabetic fatty (ZDF) rats. In total, 7-week-old male ZDF rats were fed diets containing 20 % REP or casein (C) for 8 weeks. Changes in fasting blood glucose levels and urinary markers were monitored during the experimental period...
October 2016: British Journal of Nutrition
https://www.readbyqxmd.com/read/27713282/combating-combination-of-hypertension-and-diabetes-in-different-rat-models
#19
REVIEW
Talma Rosenthal, Firas Younis, Ariela Alter
Rat experimental models are used extensively for studying physiological mechanisms and treatments of hypertension and diabetes co-existence. Each one of these conditions is a major risk factor for cardiovascular disease (CVD), and the combination of the two conditions is a potent enhancer of CVD. Five major animal models that advanced our understanding of the mechanisms and therapeutic approaches in humans are discussed in this review: Zucker, Goto-Kakizaki, SHROB, SHR/NDmcr-cp and Cohen Rosenthal diabetic hypertensive (CRDH) rats...
March 26, 2010: Pharmaceuticals
https://www.readbyqxmd.com/read/27677945/rna-seq-analysis-of-the-hypothalamic-transcriptome-reveals-the-networks-regulating-physiopathological-progress-in-the-diabetic-gk-rat
#20
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
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