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Joan Serrano, Àngela Casanova-Martí, Mayte Blay, Ximena Terra, Anna Ardévol, Montserrat Pinent
Food intake depends on homeostatic and non-homeostatic factors. In order to use grape seed proanthocyanidins (GSPE) as food intake limiting agents, it is important to define the key characteristics of their bioactivity within this complex function. We treated rats with acute and chronic treatments of GSPE at different doses to identify the importance of eating patterns and GSPE dose and the mechanistic aspects of GSPE. GSPE-induced food intake inhibition must be reproduced under non-stressful conditions and with a stable and synchronized feeding pattern...
October 20, 2016: Nutrients
Zhu Zeng, Rui Yu, Fanglei Zuo, Bo Zhang, Deju Peng, Huiqin Ma, Shangwu Chen
Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, is an excellent therapeutic peptide drug for type 2 diabetes due to longer lasting biological activity compared to GLP-1. This study explored the feasibility of using probiotic Lactobacillus paracasei as an oral vector for recombinant exendin-4 peptide delivery, an alternative to costly chemical synthesis and inconvenient administration by injection. L. paracasei transformed with a plasmid encoding the exendin-4 gene (L. paracasei L14/pMG76e-exendin-4) with a constitutive promotor was successfully constructed and showed efficient secretion of exendin-4...
2016: PloS One
Mohammad Massumi, Farzaneh Pourasgari, Amarnadh Nalla, Battsetseg Batchuluun, Kristina Nagy, Eric Neely, Rida Gull, Andras Nagy, Michael B Wheeler
The ability to yield glucose-responsive pancreatic beta-cells from human pluripotent stem cells in vitro will facilitate the development of the cell replacement therapies for the treatment of Type 1 Diabetes. Here, through the sequential in vitro targeting of selected signaling pathways, we have developed an abbreviated five-stage protocol (25-30 days) to generate human Embryonic Stem Cell-Derived Beta-like Cells (ES-DBCs). We showed that Geltrex, as an extracellular matrix, could support the generation of ES-DBCs more efficiently than that of the previously described culture systems...
2016: PloS One
Giulia Cantini, Alessandra Di Franco, Edoardo Mannucci, Michaela Luconi
Glucagon-like peptide 1(9-36) [GLP-1(9-36)] is generated by dipeptidyl peptidase-4 (DPP4) cleavage of the gut incretin hormone, GLP-1(7-36). Since GLP-1(9-36) has a very low affinity for the GLP-1 receptor (GLP-1R), it has so far been considered an inactive form of GLP-1. Here we show GLP-1(9-36) activity in human adipose stem cells (ASC) in vitro. GLP-1(9-36) inhibits human ASC proliferation, glucose uptake and adipogenesis, as well as induces cell apoptosis, to a similar extent as GLP-1(7-36) and liraglutide...
October 13, 2016: Molecular and Cellular Endocrinology
Yan Liu, Ying Wang, Yong Zhang, Tao Liu, Haiqun Jia, Huafei Zou, Qiangwei Fu, Yuhan Zhang, Lucy Lu, Elizabeth Chao, Holly Parker, Van Nguyen-Tran, Weijun Shen, Danling Wang, Peter G Schultz, Feng Wang
Recent studies have suggested that modulation of two or more signaling pathways can achieve substantial weight loss and glycemic stability. We have developed an approach to the generation of bifunctional antibody agonists that activate leptin receptor and GLP-1 receptor. Leptin was fused into the complementarity determining region 3 loop of the light chain alone, or in combination with exendin-4 (EX4) fused at the N-terminus of the heavy chain of Herceptin. The antibody fusions exhibit similar or increased in vitro activities on their cognate receptors, but 50-100-fold longer circulating half-lives in rodents compared to the corresponding native peptides/proteins...
October 5, 2016: ACS Chemical Biology
Marina Basalay, Svetlana Mastitskaya, Aleksander Mrochek, Gareth L Ackland, Ana Gutierrez Del Arroyo, Jenifer Sanchez, Per-Ove Sjoquist, John Pernow, Alexander V Gourine, Andrey Gourine
AIMS: Although the nature of the humoral factor which mediates cardioprotection established by remote ischaemic conditioning (RIc) remains unknown, parasympathetic (vagal) mechanisms appear to play a critical role. As the production and release of many gut hormones is modulated by the vagus nerve, here we tested the hypothesis that RIc cardioprotection is mediated by the actions of glucagon-like peptide-1 (GLP-1). METHODS AND RESULTS: A rat model of myocardial infarction (coronary artery occlusion followed by reperfusion) was used...
October 4, 2016: Cardiovascular Research
Zengbing Lu, Chi-Kong Yeung, Ge Lin, David T W Yew, P L R Andrews, John A Rudd
BACKGROUND: GLP-1 receptor agonists are utilised for the treatment of Type-2 diabetes but can be associated with undesirable effects of nausea and vomiting. OBJECTIVES: To investigate the role of GLP-1 receptors in mechanisms of emesis, behaviours indicative of nausea (BIN) and food intake in the ferret. RESULTS: Exendin-4 (10 and 30nmol, i.c.v.) induced emesis, inhibited food intake, and increased the frequency of BIN. Increases in c-Fos in the brainstem, midbrain and forebrain occurred in animals exhibiting emesis; no activation of the brainstem occurred in animals not vomiting...
September 14, 2016: Autonomic Neuroscience: Basic & Clinical
Ioannis Christakis, Rebecca Scott, James Minnion, Joyceline Cuenco, Tricia Tan, Fausto Palazzo, Stephen Bloom
PURPOSE/AIM OF THE STUDY: The pharmacokinetic (PK) parameters in animal models can help optimize novel candidate drugs prior to human trials. However, due to the complexity of pharmacokinetic experiments, their use is limited in academia. We present a novel surgical rat model for investigation of pharmacokinetic parameters and its use in an anti-obesity drug development program. MATERIALS AND METHODS: The model uses anesthetized male Wistar rats, a jugular, a femoral catheter, and an insulin pump for peptide infusion...
September 30, 2016: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
Imre Farkas, Csaba Vastagh, Erzsébet Farkas, Flóra Bálint, Katalin Skrapits, Erik Hrabovszky, Csaba Fekete, Zsolt Liposits
Glucagon-like peptide-1 (GLP-1), a metabolic signal molecule, regulates reproduction, although, the involved molecular mechanisms have not been elucidated, yet. Therefore, responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the GLP-1 analog Exendin-4 and elucidation of molecular pathways acting downstream to the GLP-1 receptor (GLP-1R) have been challenged. Loose patch-clamp recordings revealed that Exendin-4 (100 nM-5 μM) elevated firing rate in hypothalamic GnRH-GFP neurons of male mice via activation of GLP-1R...
2016: Frontiers in Cellular Neuroscience
Chen Qiu, Yan-Ping Wang, Xiao-Dong Pan, Xiao-Ying Liu, Zhou Chen, Li-Bin Liu
BACKGROUND: Type 2 diabetes mellitus (T2DM) increases the risk of developing Alzheimer's disease. Most recently, GLP-1 analogs have been shown to have a significant neuroprotective role in several neurodegenerative diseases. However, few are known on its potential mechanism. OBJECTIVE: In this study, we report the effect of exendin-4 (Ex-4), a GLP-1 receptor agonist, on amyloid-β(1-42) peptide oligomer-induced apoptosis in a PC12 neuronal cell model. METHODS: MTT, DAPI and Annexin-V/PI assays revealed that the viability of PC12 cells decreased in a dose- and time-dependent manner after exposure to amyloid-β(1-42) oligomers...
2016: American Journal of Translational Research
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
Anneli Rydén, Görel Nyman, Lovisa Nalin, Susanne Andreasson, Olle Korsgren, Olof Eriksson, Marianne Jensen-Waern
No abstract text is available yet for this article.
September 7, 2016: Nuclear Medicine and Biology
Gunnar Sørensen, S Barak Caine, Morgane Thomsen
BACKGROUND: Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to decrease ethanol (EtOH) drinking in rodent assays. The GLP-1 system also powerfully modulates food and fluid intake, gastrointestinal functions, and metabolism. To begin to understand the neurobiological mechanisms by which GLP-1 receptor ligands may be able to control EtOH intake, it is important to ascertain whether they can modulate the direct reinforcing effects of EtOH, without the confound of effects on ingestive behaviors generally...
October 2016: Alcoholism, Clinical and Experimental Research
Xiaosi Hong, Heng Zhang, Hongbin Liang, Danjie Li, Jiana Huang, Zhi Li, Sibo Jiang, Weizhen Zhang, Geyang Xu
Exendin-4 (EX-4), a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, regulates feeding behavior through its ability to inhibit gastric emptying. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate appetite. Here, we report that EX-4 suppresses ghrelin production through the mTORC1-dependent mechanism. Central administration of EX-4 reduces gastric, hypothalamic and plasma ghrelin in both C57BL/6J mice and diet induced obese mice. These changes were associated with a significant increase in mTORC1 activity...
December 5, 2016: Molecular and Cellular Endocrinology
Fangzhe Chen, Weifeng Wang, Hongyan Ding, Qi Yang, Qiang Dong, Mei Cui
BACKGROUND: As the number of patients with cardioembolic ischemic stroke is predicted to be double by 2030, increased burden of warfarin-associated hemorrhagic transformation (HT) after cerebral ischemia is an expected consequence. However, thus far, no effective treatment strategy is available for HT prevention in routine clinical practice. While the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is known to protect against oxidative stress and neuronal cell death caused by ischemic brain damage, its effect on preventing warfarin-associated HT after cerebral ischemia is yet unknown...
2016: Journal of Neuroinflammation
Azazul Islam Chowdhury, Peter Bergsten
Elevated circulating palmitate levels have been connected with type 2 diabetes mellitus. GLP-1 has favorable effects on beta-cells function. The aim was to identify mechanisms for decreased GSIS after long-term palmitate exposure and restoration by GLP-1 by analyzing changes in G-protein coupled receptor (GPCR) pathway signaling. Insulin secretory response to 20 mM glucose was attenuated after 7 days in islets exposed to palmitate but inclusion of exendin-4 restored secretion. Palmitate treatment altered genes of several GPCR signaling pathways including inflammatory pathways with up-regulated IL-1B, SOCS1 and SOCS2 transcript levels...
August 23, 2016: Molecular and Cellular Endocrinology
Yoshinori Iba, Koji Yokoi, Itsuka Eitoku, Masaki Goto, Seiko Koizumi, Fumihito Sugihara, Hiroshi Oyama, Tadashi Yoshimoto
The aim of this study was to evaluate the antidiabetic properties of collagen hydrolysates (CHs). CHs exhibited dipeptidyl peptidase-IV inhibitory activity and stimulated glucagon-like-peptide-1 (GLP-1) secretion in vitro. We also determined whether CHs improve glucose tolerance in normal mice. Oral administration of CHs suppressed the glycemic response during the oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT), but the effects were weaker in IPGTT than in OGTT. CHs had no effect on the gastric emptying rate...
September 2016: Journal of Medicinal Food
Inge van der Kroon, Lieke Joosten, Berthold A Nock, Theodosia Maina, Otto C Boerman, Maarten Brom, Martin Gotthardt
OBJECTIVE: Accurate assessment of the (111)In-exendin-3 uptake within the pancreas requires exact delineation of the pancreas, which is highly challenging by MRI and CT in rodents. In this study, the pancreatic tracer (99m)Tc-demobesin-4 was evaluated for accurate delineation of the pancreas to be able to accurately quantify (111)In-exendin-3 uptake within the pancreas. METHODS: Healthy and alloxan-induced diabetic Brown Norway rats were injected with the pancreatic tracer (99m)Tc-demobesin-4 ([(99m)Tc-N4-Pro(1),Tyr(4),Nle(14)]bombesin) and the beta cell tracer (111)In-exendin-3 ([(111)In-DTPA-Lys(40)]exendin-3)...
October 3, 2016: Molecular Pharmaceutics
Anna Sowa-Staszczak, Małgorzata Trofimiuk-Müldner, Agnieszka Stefańska, Monika Tomaszuk, Monika Buziak-Bereza, Aleksandra Gilis-Januszewska, Agata Jabrocka-Hybel, Bogusław Głowa, Maciej Małecki, Tomasz Bednarczuk, Grzegorz Kamiński, Aldona Kowalska, Renata Mikołajczak, Barbara Janota, Alicja Hubalewska-Dydejczyk
INTRODUCTION: The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma. MATERIALS AND METHODS: Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions...
2016: PloS One
Hiroyuki Sato, Naoto Kubota, Tetsuya Kubota, Iseki Takamoto, Kaito Iwayama, Kumpei Tokuyama, Masao Moroi, Kaoru Sugi, Keizo Nakaya, Moritaka Goto, Takahito Jomori, Takashi Kadowaki
AIMS/HYPOTHESIS: Recently, incretin-related agents have been reported to attenuate insulin resistance in animal models, although the underlying mechanisms remain unclear. In this study, we investigated whether anagliptin, the dipeptidyl peptidase 4 (DPP-4) inhibitor, attenuates skeletal muscle insulin resistance through endothelial nitric oxide synthase (eNOS) activation in the endothelial cells. We used endothelium-specific Irs2-knockout (ETIrs2KO) mice, which show skeletal muscle insulin resistance resulting from a reduction of insulin-induced skeletal muscle capillary recruitment as a consequence of impaired eNOS activation...
November 2016: Diabetologia
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