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https://www.readbyqxmd.com/read/28327441/structure-based-design-synthesis-and-biological-evaluation-of-amino-phosphonate-derivatives-as-human-glucokinase-activators
#1
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/28325589/all-cause-mortality-in-patients-with-diabetes-under-glucagon-like-peptide-1-agonists-a-population-based-open-cohort-study
#2
K A Toulis, W Hanif, P Saravanan, B H Willis, T Marshall, B Kumarendran, K Gokhale, S Ghosh, K K Cheng, P Narendran, G N Thomas, K Nirantharakumar
AIM: The glucagon-like peptide-1 receptor agonist (GLP1a) liraglutide has been described to benefit patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk. However, there are still uncertainties relating to these cardiovascular benefits: whether they also apply to an unselected diabetic population that includes low-risk patients, represent a class-effect, and could be observed in a real-world setting. METHODS: We conducted a population-based, retrospective open cohort study using data derived from The Health Improvement Network database between Jan 2008 to Sept 2015...
March 18, 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28299616/promise-of-sglt2-inhibitors-in-heart-failure-diabetes-and-beyond
#3
REVIEW
Pieter Martens, Chantal Mathieu, Frederik H Verbrugge
This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents...
March 2017: Current Treatment Options in Cardiovascular Medicine
https://www.readbyqxmd.com/read/28295962/improving-glycemic-control-in-type-2-diabetes-stimulate-insulin-secretion-or-provide-beta-cell-rest
#4
REVIEW
Daniël H van Raalte, C Bruce Verchere
Type 2 diabetes (T2D) is characterized by a gradual decline of pancreatic beta cell function that determines the progressive course of the disease. While beta-cell failure is an important contributor to hyperglycemia, chronic hyperglycemia itself is also detrimental for beta-cell function, likely by inducing prolonged secretory stress on the beta cell as well as through direct glucotoxic mechanisms that have not been fully defined. For years, research has been carried out in search of therapies targeting hyperglycemia that preserve long-term beta-cell function in T2D, a quest that is still ongoing...
March 14, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28294635/maintenance-of-weight-loss-or-stability-in-subjects-with-obesity-a-retrospective-longitudinal-analysis-of-a-real-world-population
#5
Maral DerSarkissian, Rachel H Bhak, Joanna Huang, Sarah Buchs, Francis Vekeman, B Gabriel Smolarz, Jason Brett, Rahul Ganguly, Mei Sheng Duh
OBJECTIVES: Characterize patterns of weight change among subjects with obesity. METHODS: A retrospective observational longitudinal study of subjects with obesity was conducted using the General Electric Centricity electronic medical record database. Subjects who were ≥18 years old with BMI ≥30 kg/m(2) (first defining index BMI), had no medical conditions associated with unintentional weight loss, and had ≥4 BMI measurements/year for ≥2.5 years were included and categorized into groups (stable weight: within <5% of index BMI; modest weight loss: ≥5 to <10% of index BMI lost; moderate weight loss: ≥10 to <15% of index BMI lost; and high weight loss: ≥15% of index BMI lost) based on weight change during six months following index...
March 15, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28259008/glucose-patterns-during-the-ogtt-and-risk-of-future-diabetes-in-an-urban-indian-population-the-carrs-study
#6
Adam Hulman, Unjali P Gujral, K M Venkat Narayan, Rajendra Pradeepa, Deepa Mohan, Ranjit Mohan Anjana, Viswanathan Mohan, Kristine Færch, Daniel R Witte
AIMS: Traditionally, fasting and 2-hour post challenge plasma glucose have been used to diagnose diabetes. However, evidence indicates that clinically relevant pathophysiological information can be obtained by adding intermediate time-points to a standard oral glucose tolerance test (OGTT). METHODS: We studied a population-based sample of 3666 Asian Indians without diabetes from the CARRS-Chennai Study, India. Participants underwent a three-point (fasting, 30-min, and 2-h) OGTT at baseline...
February 17, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28254770/sglt2-inhibition-in-the-diabetic-kidney-from-mechanisms-to-clinical-outcome
#7
Erik J M van Bommel, Marcel H A Muskiet, Lennart Tonneijck, Mark H H Kramer, Max Nieuwdorp, Daniel H van Raalte
Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously...
March 2, 2017: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/28253317/development-of-the-diabetes-typology-model-for-discerning-type-2-diabetes-mellitus-with-national-survey-data
#8
Anna Bellatorre, Sharon H Jackson, Kelvin Choi
OBJECTIVE: To classify individuals with diabetes mellitus (DM) into DM subtypes using population-based studies. DESIGN: Population-based survey. SETTING: Individuals participated in 2003-2004, 2005-2006, or 2009-2010 the National Health and Nutrition Examination Survey (NHANES), and 2010 Coronary Artery Risk Development in Young Adults (CARDIA) survey (research materials obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center)...
2017: PloS One
https://www.readbyqxmd.com/read/28218739/suppression-of-islet-homeostasis-protein-thwarts-diabetes-mellitus-progression
#9
Seh-Hoon Oh, Marda L Jorgensen, Clive H Wasserfall, Altin Gjymishka, Bryon E Petersen
During progression to type 1 diabetes, insulin-producing β-cells are lost through an autoimmune attack resulting in unrestrained glucagon expression and secretion, activation of glycogenolysis, and escalating hyperglycemia. We recently identified a protein, designated islet homeostasis protein (IHoP), which specifically co-localizes within glucagon-positive α-cells and is overexpressed in the islets of both post-onset non-obese diabetic (NOD) mice and type 1 diabetes patients. Here we report that in the αTC1...
February 20, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28202628/effects-of-upgrade-versus-de-novo-cardiac-resynchronization-therapy-on-clinical-response-and-long-term-survival-results-from-a-multicenter-study
#10
Mate Vamos, Julia W Erath, Zsolt Bari, Denes Vagany, Sven P Linzbach, Tatsiana Burmistrava, Carsten W Israel, Gabor Z Duray, Stefan H Hohnloser
BACKGROUND: Benefits of cardiac resynchronization therapy (CRT) on morbidity and mortality in selected patients are well known. Although the number of upgrade procedures from single- or dual-chamber devices to CRT is increasing, there are only sparse data on the outcomes of upgrade procedures compared with de novo CRT. This study aimed to evaluate clinical response and survival in patients receiving de novo versus upgrade CRT defibrillator therapy. METHODS AND RESULTS: Prospectively collected outcome data were compared in patients undergoing de novo or upgrade CRT defibrillator implantation at 3 implant centers in Germany and Hungary...
February 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28191533/inhibition-of-cyst-growth-in-pck-and-wpk-rat-models-of-polycystic-kidney-disease-with-low-doses-of-peroxisome-proliferator-activated-receptor-%C3%AE-agonists
#11
Stephanie M Flaig, Vincent H Gattone, Bonnie L Blazer-Yost
BACKGROUND AND OBJECTIVES: The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD). MATERIALS AND METHODS: The PCK rat is a slowly progressing cystic model while the Wpk(-/-) rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4-28)...
September 1, 2016: Journal of Translational Internal Medicine
https://www.readbyqxmd.com/read/28168619/pure-endoscopic-management-of-epileptogenic-hypothalamic-hamartomas
#12
S Chibbaro, H Cebula, J Scholly, J Todeschi, I Ollivier, A Timofeev, M Ganau, P Di Emidio, M P Valenti, A M Staack, T Bast, B J Steinhoff, E Hirsch, P Kehrli, F Proust
Hypothalamic hamartomas (HH) are rare congenital malformations located in the region of the tuber cinereum and third ventricle. Their usual clinical presentation is characterized by gelastic/dacrystic seizures which often become pharmaco-resistant and progress to secondary focal/generalized intractable epilepsy causing mostly in children cognitive and behavioral problems (particularly in cases of progressive epileptic encephalopathy) and precocious puberty. Whereas gelastic seizures can be surgically controlled either by resection of the lesion or disconnection (tissue-destructive) procedures, aimed at functionally prevent the spreading of the epileptic burst; generalized seizures tend to respond better to HH excision rather than isolated neocortical resections, which generally fail to control them...
February 7, 2017: Neurosurgical Review
https://www.readbyqxmd.com/read/28138135/body-mass-index-as-a-predictor-of-healthy-and-disease-free-life-expectancy-between-ages-50-and-75-a-multicohort-study
#13
S Stenholm, J Head, V Aalto, M Kivimäki, I Kawachi, M Zins, M Goldberg, L G Platts, P Zaninotto, L L M Hanson, H Westerlund, J Vahtera
BACKGROUND: While many studies have shown associations between obesity and increased risk of morbidity and mortality, little comparable information is available on how body mass index (BMI) impacts health expectancy. We examined associations of BMI with healthy and chronic disease-free life expectancy in four European cohort studies. METHODS: Data were drawn from repeated waves of cohort studies in England, Finland, France and Sweden. BMI was categorized into four groups from normal weight (18...
January 31, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28121337/effects-of-sglt2-inhibitors-on-weight-loss-in-patients-with-type-2-diabetes-mellitus
#14
F A Ribola, F B Cançado, J H M Schoueri, V F De Toni, V H R Medeiros, D Feder
SGLT2 (sodium-glucose cotransporter type 2) inhibitors are a new class of drugs which reversibly block the glucose reabsorption that occurs in the kidneys. Since their mechanisms of action do not rely on insulin secretion, they constitute a complementary alternative to the classic treatment of type 2 diabetes mellitus. A glycemic level reduction in patients who used SGLT2 inhibitors due to the reversible block of their transporters could be observed. Associated with this, there was a reduction in body weight and blood pressure (BP) caused by osmotic diuresis...
January 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28110829/lipidomic-analysis-reveals-significant-lipogenesis-and-accumulation-of-lipotoxic-components-in-ob-ob-mouse-organs
#15
Jun Hayakawa, Miao Wang, Chunyan Wang, Rowland H Han, Zhen Y Jiang, Xianlin Han
To further understand the role of lipogenesis and lipotoxicity in the development of obesity and diabetes, lipidomes of various organs from ob/ob mice and their wild type controls were analyzed by shotgun lipidomics at 10, 12, and 16 weeks of age. We observed that the amounts of fatty acyl (FA) chains corresponding to those from de novo synthesis (e.g., 16:0, 16:1, and 18:1 FA) were substantially elevated in ob/ob mice, consistent with increased expression of genes and proteins involved in biosynthesis. Polyunsaturated fatty acid species were moderately increased in the examined tissues of ob/ob mice, since they can only be absorbed from diets or elongated from the ingested n-3 or n-6 FA...
January 11, 2017: Prostaglandins, Leukotrienes, and Essential Fatty Acids
https://www.readbyqxmd.com/read/28101643/polymorphisms-in-genes-encoding-mir-155-and-mir-146a-are-associated-with-protection-to-type-1-diabetes-mellitus
#16
Taís S Assmann, Guilherme C K Duarte, Letícia A Brondani, Pedro H O de Freitas, Égina M Martins, Luís H Canani, Daisy Crispim
AIMS: Type 1 diabetes mellitus (T1DM) is characterized by severe autoimmune destruction of pancreatic beta-cells. The triggering of autoimmunity against beta-cells is probably caused by a combination of environmental and genetic risk factors. Even though much is known about the genetic of T1DM, more information is needed to completely unravel this tangled disease. MicroRNAs (miRNAs) are a class of small noncoding RNAs molecules that negatively regulate gene expression by inducing target mRNA cleavage or by inhibiting protein translation...
January 19, 2017: Acta Diabetologica
https://www.readbyqxmd.com/read/28100340/-outcome-comparison-of-different-therapy-procedures-in-surgical-high-risk-elderly-patients-with-severe-aortic-stenosis
#17
Y Q Ye, Y T Wang, Z Li, M Y Wang, H Y Xu, W J Zhang, Q R Liu, G N Niu, Y J Wu
Objective: To compare the outcome of surgical high-risk elderly patients with severe aortic stenosis(SAS) treated by different therapy procedures, including transcatheter aortic valve implantation(TAVI), surgical aortic valve replacement(SAVR), and drug therapy. Methods: We retrospectively analyzed the clinical data of 242 surgical high-risk elderly (age ≥65 years old) SAS patients hospitalized in Fuwai Hospital between September 2012 and June 2015. According to the treatment method, patients were divided into TAVI group (81 cases), SAVR group (59 cases) and drug therapy group (102 cases)...
January 25, 2017: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/28086882/differential-effects-of-glucagon-like-peptide-1-receptor-agonists-on-heart-rate
#18
REVIEW
Martin Lorenz, Francesca Lawson, David Owens, Denis Raccah, Christine Roy-Duval, Anne Lehmann, Riccardo Perfetti, Lawrence Blonde
While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms)...
January 13, 2017: Cardiovascular Diabetology
https://www.readbyqxmd.com/read/27994747/discovery-and-optimization-of-a-novel-triazole-series-of-gpr142-agonists-for-the-treatment-of-type-2-diabetes
#19
Liangqin Guo, Dann L Parker, Yi Zang, Ramzi F Sweis, Weiguo Liu, Edward C Sherer, Nicole Buist, Jenna Terebetski, Terri Kelly, Randal Bugianesi, Birgit T Priest, Karen H Dingley, Xiaofang Li, Stan Mitelman, Gino Salituro, Maria E Trujillo, Michele Pachanski, Melissa Kirkland, Mary Ann Powles, George J Eiermann, Yue Feng, Jin Shang, Andrew D Howard, Feroze Ujjainwalla, Christopher J Sinz, John S Debenham, Scott D Edmondson, Ravi P Nargund, William K Hagmann, Derun Li
GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound 4 suffered from poor metabolic stability and poor solubility. Lead optimization strategies to improve potency, efficacy, metabolic stability, and solubility are described. This optimization led to compound 20e, which showed significant reduction of glucose excursion in wild-type but not in GPR142 deficient mice in an oral glucose tolerance test (oGTT) study...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27958378/large-scale-pharmacogenomic-study-of-sulfonylureas-and-the-qt-jt-and-qrs-intervals-charge-pharmacogenomics-working-group
#20
J S Floyd, C M Sitlani, C L Avery, R Noordam, X Li, A V Smith, S M Gogarten, J Li, L Broer, D S Evans, S Trompet, J A Brody, J D Stewart, J D Eicher, A A Seyerle, J Roach, L A Lange, H J Lin, J A Kors, T B Harris, R Li-Gao, N Sattar, S R Cummings, K L Wiggins, M D Napier, T Stürmer, J C Bis, K F Kerr, A G Uitterlinden, K D Taylor, D J Stott, R de Mutsert, L J Launer, E L Busch, R Méndez-Giráldez, N Sotoodehnia, E Z Soliman, Y Li, Q Duan, F R Rosendaal, P E Slagboom, K C Wilhelmsen, A P Reiner, Y-DI Chen, S R Heckbert, R C Kaplan, K M Rice, J W Jukema, A D Johnson, Y Liu, D O Mook-Kanamori, V Gudnason, J G Wilson, J I Rotter, C C Laurie, B M Psaty, E A Whitsel, L A Cupples, B H Stricker
Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals...
December 13, 2016: Pharmacogenomics Journal
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