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https://www.readbyqxmd.com/read/28342366/discovery-of-new-dual-ppar%C3%AE-gpr40-agonists-with-robust-antidiabetic-activity-design-synthesis-and-in-combo-drug-evaluation
#1
Sergio Hidalgo-Figueroa, Gabriel Navarrete-Vázquez, Samuel Estrada-Soto, Diana Giles-Rivas, Francisco J Alarcón-Aguilar, Ismael León-Rivera, Abraham Giacoman-Martínez, Elizabeth Miranda Pérez, Julio C Almanza-Pérez
The design of compounds 1 and 2 was based on the similar scaffold of pharmacophoric groups for PPARγ and GPR40 agonists. In order to find new compounds with improved biological activity, the current manuscript describes a new dual PPARγ-GPR40 agonist. We synthesized two compounds, which were prepared following a multistep synthetic route, and the relative mRNA expression levels of PPARγ, GLUT4, and GPR40 were quantified in cell culture, as well as insulin secretion and [Ca(2+)] intracellular levels. Compound 1 showed a 7-times increase in the mRNA expression of PPARγ, which in turn enhanced the expression levels of GLUT4 respect to control and pioglitazone...
March 22, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28333970/-epicatechin-3-o-%C3%AE-d-allopyranoside-from-davallia-formosana-prevents-diabetes-and-dyslipidemia-in-streptozotocin-induced-diabetic-mice
#2
Cheng-Hsiu Lin, Jin-Bin Wu, Jia-Ying Jian, Chun-Ching Shih
The objective of this study was to evaluate the effects and molecular mechanism of (-)-epicatechin-3-O-β-D-allopyranoside from Davallia formosana (BB) (also known as Gu-Sui-Bu) on type 1 diabetes mellitus and dyslipidemia in streptozotocin (STZ)-induced diabetic mice. This plant was demonstrated to display antioxidant activities and possess polyphenol contents. Diabetic mice were randomly divided into six groups and were given daily oral gavage doses of either BB (at three dosage levels), metformin (Metf) (at 0...
2017: PloS One
https://www.readbyqxmd.com/read/28325821/phosphorylation-of-the-exocyst-protein-exo84-by-tbk1-promotes-insulin-stimulated-glut4-trafficking
#3
Maeran Uhm, Merlijn Bazuine, Peng Zhao, Shian-Huey Chiang, Tingting Xiong, Sheelarani Karunanithi, Louise Chang, Alan R Saltiel
Insulin stimulates glucose uptake through the translocation of the glucose transporter GLUT4 to the plasma membrane. The exocyst complex tethers GLUT4-containing vesicles to the plasma membrane, a process that requires the binding of the G protein (heterotrimeric guanine nucleotide-binding protein) RalA to the exocyst complex. We report that upon activation of RalA, the protein kinase TBK1 phosphorylated the exocyst subunit Exo84. Knockdown of TBK1 blocked insulin-stimulated glucose uptake and GLUT4 translocation; knockout of TBK1 in adipocytes blocked insulin-stimulated glucose uptake; and ectopic overexpression of a kinase-inactive mutant of TBK1 reduced insulin-stimulated glucose uptake in 3T3-L1 adipocytes...
March 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28325730/glucose-oxidation-positively-regulates-glucose-uptake-and-improves-cardiac-function-recovery-after-myocardial-reperfusion
#4
Tingting Li, Jie Xu, Xinghua Qin, Zuoxu Hou, Yongzheng Guo, Zhenhua Liu, Jianjiang Wu, Hong Zheng, Xing Zhang, Feng Gao
Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia/reperfusion injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. Here we found that glucose uptake was remarkably diminished in myocardium following reperfusion in Sprague-Dawley rats as detected by 18F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by 3 folds and GLUT4 translocation remained unchanged compared with those of sham rats...
March 21, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28324027/follistatin-targets-distinct-pathways-to-promote-brown-adipocyte-characteristics-in-brown-and-white-adipose-tissues
#5
Rajan Singh, Melissa Braga, Srinivasa T Reddy, Se-Jin Lee, Meher Parveen, Victor Grijalva, Laurent Vergnes, Shehla Pervin
We previously demonstrated that Fst expression is highest in brown adipose tissue (BAT) and skeletal muscle, but is also present at substantial levels in epididymal (Epi) and subcutaneous (SC) white adipose tissues (WAT). Fst promotes mouse brown preadipocyte differentiation and promotes browning during differentiation of mouse embryonic fibroblasts (MEFs). Fst-transgenic (Fst-Tg) mouse show significant increase in circulating Fst levels and increased brown adipose mass. BAT of Fst-Tg mice had increased expression of brown adipose-associated markers including uncoupling protein 1 (UCP1), PRDM16, PGC-1α and Glut4...
January 16, 2017: Endocrinology
https://www.readbyqxmd.com/read/28322447/regulation-role-of-crtc3-in-skeletal-muscle-and-adipose-tissue
#6
REVIEW
Jiaqi Liu, Ziye Xu, Weiche Wu, Yizhen Wang, Tizhong Shan
The cyclic adenosine monophosphate (cAMP) - protein kinase A (PKA) signaling pathway plays important role in regulating energy homeostasis. Many of the effects of the cAMP-PKA signaling is mediated through the cAMP responsive element binding protein (CREB) and its coactivator CREB-regulated transcription coactivators (CRTCs). CRTC3 is a member of CRTCs family proteins and plays important roles in glucose and energy metabolism. Previous studies shown that global knockout of CRTC3 enhances oxygen consumption and energy expenditure and subsequently protects the knockout animal against obesity...
March 21, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28321925/effects-of-6-months-aerobic-interval-training-on-skeletal-muscle-metabolism-in-middle-aged-metabolic-syndrome-patients
#7
A Guadalupe-Grau, V E Fernández-Elías, J F Ortega, F Dela, J W Helge, R Mora Rodríguez
AIM: Aerobic interval training (AIT) improves the health of metabolic syndrome patients (MetS) more than moderate intensity continuous training. However, AIT has not been shown to reverse all metabolic syndrome risk factors, possibly due to the limited duration of the training programs. PURPOSE: To assess the effects of 6 months of AIT on cardio-metabolic health and muscle metabolism in middle aged MetS. METHODS: Eleven MetS (54.5 ± 0.7 yrs old) underwent 6 month of 3 days a week supervised AIT program on a cycle-ergometer...
March 21, 2017: Scandinavian Journal of Medicine & Science in Sports
https://www.readbyqxmd.com/read/28319810/inhibitors-of-glut-slc2a-enhance-the-action-of-bcnu-and-temozolomide-against-high-grade-gliomas
#8
Alberto Azzalin, Giulia Nato, Elena Parmigiani, Francesca Garello, Annalisa Buffo, Lorenzo Magrassi
Glucose transport across glioblastoma membranes plays a crucial role in maintaining the enhanced glycolysis typical of high-grade gliomas and glioblastoma. We tested the ability of two inhibitors of the glucose transporters GLUT/SLC2A superfamily, indinavir (IDV) and ritonavir (RTV), and of one inhibitor of the Na/glucose antiporter type 2 (SGLT2/SLC5A2) superfamily, phlorizin (PHZ), in decreasing glucose consumption and cell proliferation of human and murine glioblastoma cells. We found in vitro that RTV, active on at least three different GLUT/SLC2A transporters, was more effective than IDV, a specific inhibitor of GLUT4/SLC2A4, both in decreasing glucose consumption and lactate production and in inhibiting growth of U87MG and Hu197 human glioblastoma cell lines and primary cultures of human glioblastoma...
March 17, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28303117/expression-patterns-and-correlations-with-metabolic-markers-of-zinc-transporters-zip14-and-znt1-in-obesity-and-polycystic-ovary-syndrome
#9
Trine Maxel, Pernille Fog Svendsen, Kamille Smidt, Jesper Krogh Lauridsen, Birgitte Brock, Steen Bønlykke Pedersen, Jørgen Rungby, Agnete Larsen
Polycystic ovary syndrome (PCOS) is associated with infertility, increased androgen levels, and insulin resistance. In adipose tissue, zinc facilitates insulin signaling. Circulating zinc levels are altered in obesity, diabetes, and PCOS; and zinc supplementation can ameliorate metabolic disturbances in PCOS. In adipose tissue, expression of zinc influx transporter ZIP14 varies with body mass index (BMI), clinical markers of metabolic syndrome, and peroxisome proliferator-activated receptor gamma (PPARG). In this study, we investigated expression levels of ZIP14 and PPARG in subcutaneous adipose tissue of 36 PCOS women (17 lean and 19 obese women) compared with 23 healthy controls (7 lean and 16 obese women)...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28303003/effects-of-high-intensity-interval-training-and-moderate-intensity-continuous-training-on-glycaemic-control-and-skeletal-muscle-mitochondrial-function-in-db-db-mice
#10
Vivien Chavanelle, Nathalie Boisseau, Yolanda F Otero, Lydie Combaret, Dominique Dardevet, Christophe Montaurier, Geoffrey Delcros, Sébastien L Peltier, Pascal Sirvent
Physical activity is known as an effective strategy for prevention and treatment of Type 2 Diabetes. The aim of this work was to compare the effects of a traditional Moderate Intensity Continuous Training (MICT) with a High Intensity Interval Training (HIIT) on glucose metabolism and mitochondrial function in diabetic mice. Diabetic db/db male mice (N = 25) aged 6 weeks were subdivided into MICT, HIIT or control (CON) group. Animals in the training groups ran on a treadmill 5 days/week during 10 weeks...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28292758/feeding-influences-adipose-tissue-responses-to-exercise-in-overweight-men
#11
Yung-Chih Chen, Rebecca L Travers, Jean-Philippe Walhin, Javier T Gonzalez, Francoise Koumanov, James A Betts, Dylan Thompson
Feeding profoundly affects metabolic responses to exercise in various tissues but the effect of feeding status on human adipose tissue responses to exercise has never been studied. Ten healthy overweight men aged 26 ± 5 years (mean ± SD) with a waist circumference of 105 ± 10 cm walked at 60% of maximum oxygen uptake under either FASTED or FED conditions in a randomised, counterbalanced design. Feeding comprised 648 ± 115 kcal 2 h before exercise. Blood samples were collected at regular intervals to examine changes in metabolic parameters and adipokine concentrations...
March 14, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28282360/an-alpha7-nicotinic-acetylcholine-receptor-agonist-gts-21-promotes-c2c12-myonuclear-accretion-in-association-with-release-of-interleukin-6-il-6-and-improves-survival-in-burned-mice
#12
Mohammed A S Khan, Mohammed F Khan, Shizuka Kashiwagi, William R Kem, Shingo Yasuhara, Masao Kaneki, Ronald G Tompkins, J A Jeevendra Martyn
The role of interleukin-6 (IL-6) in physiological processes and disease is poorly understood. The hypothesis tested in this study was that selective alpha7 acetylcholine receptor (α7AChR) agonist, GTS-21, releases of IL-6 in association with myonuclear accretion and enhances insulin signaling in muscle cells, and improves survival of burn injured (BI) mice. The in vitro effects of GTS-21 were determined in C2C12 myoblasts and 7-day differentiated myotubes (myotubes). The in vivo effects of GTS-21 were tested in BI wild type (WT) and IL-6 knockout (IL6KO) mice...
March 9, 2017: Shock
https://www.readbyqxmd.com/read/28279980/glucose-transporter-4-glut4-is-not-necessary-for-overload-induced-glucose-uptake-or-hypertrophic-growth-in-mouse-skeletal-muscle
#13
Shawna L McMillin, Denise L Schmidt, Barbara B Kahn, Carol A Witczak
Glucose transporter 4 (GLUT4) is necessary for acute insulin- and contraction-induced skeletal muscle glucose uptake, but its role in chronic muscle loading (overload)-induced glucose uptake is unknown. Our goal was to determine if GLUT4 is required for overload-induced glucose uptake. Overload was induced in mouse plantaris muscle by unilateral synergist ablation. After 5 days, muscle weights and ex vivo [(3)H]-2-deoxy-D-glucose uptake were assessed. Overload-induced muscle glucose uptake and hypertrophic growth were not impaired in muscle-specific GLUT4 knockout mice, demonstrating that GLUT4 is not necessary for these processes...
March 9, 2017: Diabetes
https://www.readbyqxmd.com/read/28271502/trigonelline-and-vildagliptin-antidiabetic-effect-improvement-of-insulin-signalling-pathway
#14
Amat-Alrazaq A Aldakinah, Muhammad Y Al-Shorbagy, Dalaal M Abdallah, Hanan S El-Abhar
OBJECTIVES: Trigonelline (TRG) is known to have an antidiabetic efficacy; however, its mechanism is not entirely elucidated. METHODS: Hence, its effect on insulin signaling, besides its effectiveness in combination with vildagliptin (VLD) in a Type 2 diabetes model has been tested. KEY FINDINGS: TRG (50 mg/kg; p.o) lowered serum glucose, fructosamine, insulin, and HOMA-IR index and increased insulin sensitivity in soleus muscle via augmenting insulin receptor autophosphorylation (IR-PH), pT308-Akt, and glucose transporter 4 (GLUT4)...
March 8, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28263745/exercise-increases-hyper-acetylation-of-histones-on-the-cis-element-of-nrf-1-binding-to-the-mef2a-promoter-implications-on-type-2-diabetes
#15
Jitcy S Joseph, Ademola O Ayeleso, Emmanuel Mukwevho
Exercise brings changes on the chromatin ensuing the upregulation of many genes that confer protection from type 2 diabetes. In type-2 diabetes, critical genes are down-regulated such as those involved in glucose transport (GLUT4, MEF2A) and also oxidative phosphorylation (NRF-1 and its target genes). Recent reports have shown that NRF-1 not only regulate mitochondrial oxidative genes but also controls MEF2A, the main transcription factor for glucose transporter, GLUT4. Such dual control of the two pathways by NRF-1 place it as critical gene in the design of therapeutic modalities much needed to cure or better manage type 2 diabetes...
April 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28256118/treadmill-exercise-ameliorates-the-regulation-of-energy-metabolism-in-skeletal-muscle-of-nse-ps2m-transgenic-mice-with-alzheimer-s-disease
#16
Joon-Yong Cho, Jang-Soo Yook
Purpose: Alzheimer's disease (AD) is classified as a progressive neurological disorder, which not only causes cognitive impairment but also abnormal weight loss, with a reduction of muscle mass related to the accumulation of amyloid-β (Aβ) in skeletal muscle. Thus, we investigated the effect of treadmill exercise on Aβ deposition, and p-AMPK, p-ACC, BDNF, and GLUT4 protein levels the regulation of muscle energy metabolism using an AD mouse. Methods: At 13 months of age, NSE/PS2m mice (Tg) and control mice (non-Tg) were assigned to non-exercise control (Con) and exercise groups (Exe)...
March 2, 2017: Journal of Exercise Nutrition & Biochemistry
https://www.readbyqxmd.com/read/28251652/sirt1-may-play-a-crucial-role-in-overload-induced-hypertrophy-of-skeletal-muscle
#17
Erika Koltai, Zoltán Bori, Clovis Chabert, Hervé Dubouchaud, Hisashi Naito, Shuichi Machida, Kelvin Ja Davies, Zsolt Murlasits, Andrew C Fry, Istvan Boldogh, Zsolt Radak
Significant skeletal muscle mass guarantees functional wellbeing and is important for high level performance in many sports. Although the molecular mechanism for skeletal muscle hypertrophy has been well-studied, it still is not completely understood. In the present study, we used a functional overload model to induce plantaris muscle hypertrophy by surgically removing the soleus, and gastrocnemius muscles in rats. Two weeks of muscle ablation resulted in a 40% increase in muscle mass, which was associated with a significant increase in SIRT1 content and activity (P < 0...
March 2, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28244693/dapagliflozin-improves-insulin-resistance-and-glucose-intolerance-in-a-novel-transgenic-rat-with-chronic-glucose-overproduction-and-glucose-toxicity
#18
Christos N Joannides, Salvatore P Mangiafico, Matthew F Waters, Benjamin J Lamont, Sofianos Andrikopoulos
AIMS: Insulin resistance and impaired insulin secretion are cardinal defects that contribute to hyperglycemia in type 2 diabetes. Recently, a new class of drugs called sodium-glucose linked transporter 2 (SGLT2) inhibitors has been introduced that reduce blood glucose by inhibiting glucose reabsorption in the kidney and is not dependent on glucose metabolism or insulin action. The purpose of the present study was to determine whether the excretion of glucose would improve insulin resistance, impaired insulin secretion or both...
February 28, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28243863/effects-of-pterostilbene-in-brown-adipose-tissue-from-obese-rats
#19
Leixuri Aguirre, Iñaki Milton-Laskibar, Elizabeth Hijona, Luis Bujanda, Agnes M Rimando, María P Portillo
In recent years, much attention has been paid by the scientific community to phenolic compounds as active biomolecules naturally present in foods. Pterostilbene is a resveratrol dimethylether derivative which shows higher bioavailability. The aim of the present study was to analyze the effect of pterostilbene on brown adipose tissue thermogenic markers in a model of genetic obesity, which shows reduced thermogenesis. The experiment was conducted with 30 Zucker (fa/fa) rats that were distributed in three experimental groups: control and two groups orally administered with pterostilbene at 15 and 30 mg/kg body weight/day for 6 weeks...
February 27, 2017: Journal of Physiology and Biochemistry
https://www.readbyqxmd.com/read/28240264/overexpressing-the-novel-autocrine-endocrine-adipokine-wisp2-induces-hyperplasia-of-the-heart-white-and-brown-adipose-tissues-and-prevents-insulin-resistance
#20
John R Grünberg, Jenny M Hoffmann, Shahram Hedjazifar, Annika Nerstedt, Lachmi Jenndahl, Johannes Elvin, John Castellot, Lan Wei, Sofia Movérare-Skrtic, Claes Ohlsson, Louise Mannerås Holm, Fredrik Bäckhed, Ismail Syed, Fatima Bosch, Alan Saghatelian, Barbara B Kahn, Ann Hammarstedt, Ulf Smith
WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts...
February 27, 2017: Scientific Reports
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