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https://www.readbyqxmd.com/read/29759973/enhanced-glucose-control-following-vertical-sleeve-gastrectomy-does-not-require-a-%C3%AE-cell-glucagon-like-peptide-1-receptor
#1
Jonathan D Douros, Alfor G Lewis, Eric P Smith, JingJing Niu, Megan Capozzi, April Wittmann, Jonathan Campbell, Jenny Tong, Constance Wagner, Parinaz Mahbod, Randy Seeley, David A D'Alessio
Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon-like peptide 1 (GLP-1), in great part because of the ∼10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct β-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of β-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, β-cell specific Glp1r knockdown ( Glp1r β-cell-ko )...
May 14, 2018: Diabetes
https://www.readbyqxmd.com/read/29746877/liraglutide-attenuates-the-migration-of-retinal-pericytes-induced-by-advanced-glycation-end-products
#2
Wen-Jian Lin, Xue-Fei Ma, Ming Hao, Huan-Ran Zhou, Xin-Yang Yu, Ning Shao, Xin-Yuan Gao, Hong-Yu Kuang
Retinal pericyte migration represents a novel mechanism of pericyte loss in diabetic retinopathy (DR), which plays a crucial role in the early impairment of the blood-retinal barrier (BRB). Glucagon-like peptide-1 (GLP-1) has been shown to protect the diabetic retina in the early stage of DR; however, the relationship between GLP-1 and retinal pericytes has not been discussed. In this study, advanced glycation end products (AGEs) significantly increased the migration of primary bovine retinal pericytes without influencing cell viability...
May 7, 2018: Peptides
https://www.readbyqxmd.com/read/29737015/therapeutic-agents-targeting-cardiometabolic-risk-for-preventing-and-treating-atherosclerotic-cardiovascular-diseases
#3
Benoit J Arsenault, Nicolas Perrot, Rishi Puri
Targeting atherogenic lipoprotein levels with statins remains the current cornerstone of atherosclerotic cardiovascular disease (ACVD) management. In patients at high ACVD risk who cannot achieve the desired low-density lipoprotein (LDL) cholesterol target, the addition of compounds such as ezetimibe and proprotein subtilisin/kexin type-9 (PCSK9) inhibitors incrementally lowers cardiovascular risk. New glucose-lowering drugs such as glucacon-like peptide-1 receptor (GLP1R) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors were also shown to improve cardiometabolic risk factors and provide cardiovascular benefits in patients with type 2 diabetes...
May 8, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29717107/exendin-4-ameliorates-high-glucose-induced-fibrosis-by-inhibiting-the-secretion-of-mir-192-from-injured-renal-tubular-epithelial-cells
#4
Yijie Jia, Zongji Zheng, Meiping Guan, Qian Zhang, Yang Li, Ling Wang, Yaoming Xue
Extracellular vesicles (EVs), which contain microRNA (miRNA), constitute a novel means of cell communication that may contribute to the inevitable expansion of renal fibrosis during diabetic kidney disease (DKD). Exendin-4 is effective for treating DKD through its action on GLP1R. However, the effect of exendin-4 on EV miRNA expression and renal cell communication during the development of DKD remains unknown. In this study, we found that EVs derived from HK-2 cells pre-treated with exendin-4 and high glucose (Ex-HG), which were taken up by normal HK-2 cells, resulted in decreased levels of FN and Col-I compared with EVs from HK-2 cells pre-treated with HG alone...
May 1, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29673577/profiling-of-g-protein-coupled-receptors-in-vagal-afferents-reveals-novel-gut-to-brain-sensing-mechanisms
#5
Kristoffer L Egerod, Natalia Petersen, Pascal N Timshel, Jens C Rekling, Yibing Wang, Qinghua Liu, Thue W Schwartz, Laurent Gautron
OBJECTIVES: G protein-coupled receptors (GPCRs) act as transmembrane molecular sensors of neurotransmitters, hormones, nutrients, and metabolites. Because unmyelinated vagal afferents richly innervate the gastrointestinal mucosa, gut-derived molecules may directly modulate the activity of vagal afferents through GPCRs. However, the types of GPCRs expressed in vagal afferents are largely unknown. Here, we determined the expression profile of all GPCRs expressed in vagal afferents of the mouse, with a special emphasis on those innervating the gastrointestinal tract...
April 3, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29650350/loss-of-dorsomedial-hypothalamic-glp-1-signaling-reduces-bat-thermogenesis-and-increases-adiposity
#6
Shin J Lee, Graciela Sanchez-Watts, Jean-Philippe Krieger, Angelica Pignalosa, Puck N Norell, Alyssa Cortella, Klaus G Pettersen, Dubravka Vrdoljak, Matthew R Hayes, Scott Kanoski, Wolfgang Langhans, Alan G Watts
OBJECTIVE: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function. METHODS: We investigate this possibility in adult male rats by using direct administration of GLP-1 (0...
March 21, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29531541/sitagliptin-accelerates-endothelial-regeneration-after-vascular-injury-independent-from-glp1-receptor-signaling
#7
Friederike Remm, Nicolle Kränkel, Daniela Lener, Daniel J Drucker, Sieghart Sopper, Christoph Brenner
Introduction: DPP4 inhibitors (gliptins) are commonly used antidiabetic drugs for the treatment of type 2 diabetes. Gliptins also act in a glucose-independent manner and show vasoregenerative effects. We have shown that gliptins can remarkably accelerate vascular healing after vascular injury. However, the underlying mechanisms remain unclear. Here, we examined potential signaling pathways linking gliptins to enhanced endothelial regeneration. Methods and Results: We used wild-type and GLP1 receptor knockout ( Glp1r -/- ) mice to investigate the underlying mechanisms of gliptin-induced reendothelialization...
2018: Stem Cells International
https://www.readbyqxmd.com/read/29510149/diversification-of-the-functions-of-proglucagon-and-glucagon-receptor-genes-in-fish
#8
David M Irwin, Svetlana Mojsov
The teleost fish-specific genome duplication gave rise to a great number of species inhabiting diverse environments with different access to nutrients and life histories. This event produced duplicated gcg genes, gcga and gcgb, for proglucagon-derived peptides, glucagon and GLP-1 and duplicated gcgr receptor genes, gcgra and gcgrb, which play key roles connecting the consumption of nutrients with glucose metabolism. We conducted a systematic survey of the genomes from 28 species of fish (24 bony (Superclass Osteichthyes), 1 lobe-finned (Class Sarcoperygii), 1 cartilaginous (Superclass Chondrichthyes), and 2 jawless (Superclass Agnatha)) and find that almost all surveyed ray-finned fish contain gcga and gcgb genes with different coding potential and duplicated gcgr genes, gcgra and gcgrb that form two separate clades in the phylogenetic tree consistent with the accepted species phylogeny...
May 15, 2018: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/29489747/hierarchical-neural-architecture-underlying-thirst-regulation
#9
Vineet Augustine, Sertan Kutal Gokce, Sangjun Lee, Bo Wang, Thomas J Davidson, Frank Reimann, Fiona Gribble, Karl Deisseroth, Carlos Lois, Yuki Oka
Neural circuits for appetites are regulated by both homeostatic perturbations and ingestive behaviour. However, the circuit organization that integrates these internal and external stimuli is unclear. Here we show in mice that excitatory neural populations in the lamina terminalis form a hierarchical circuit architecture to regulate thirst. Among them, nitric oxide synthase-expressing neurons in the median preoptic nucleus (MnPO) are essential for the integration of signals from the thirst-driving neurons of the subfornical organ (SFO)...
March 8, 2018: Nature
https://www.readbyqxmd.com/read/29488276/allelic-variant-in-the-glucagon-like-peptide-1-receptor-gene-associated-with-greater-effect-of-liraglutide-and-exenatide-on-gastric-emptying-a-pilot-pharmacogenetics-study
#10
V Chedid, P Vijayvargiya, P Carlson, K Van Malderen, A Acosta, A Zinsmeister, M Camilleri
BACKGROUND: Weight loss in response to the long-acting GLP-1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric-emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short-acting GLP-1 agonist, exenatide. METHODS: We evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5 μg BID for 30 days, or liraglutide, 3 mg daily for 5 weeks...
February 28, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/29444223/glp-1-receptor-expression-within-the-human-heart
#11
Laurie L Baggio, Bernardo Yusta, Erin E Mulvihill, Xiemin Cao, Catherine J Streutker, Jagdish Butany, Thomas P Cappola, Kenneth B Margulies, Daniel J Drucker
Glucagonlike peptide-1 receptor (GLP-1R) agonists, which are used to treat type 2 diabetes and obesity, reduce the rates of myocardial infarction and cardiovascular death. GLP-1R has been localized to the human sinoatrial node; however, its expression in ventricular tissue remains uncertain. Here we studied GLP-1R expression in the human heart using GLP-1R-directed antisera, quantitative polymerase chain reaction (PCR), reverse transcription PCR to detect full-length messenger RNA (mRNA) transcripts, and in situ hybridization (ISH)...
April 1, 2018: Endocrinology
https://www.readbyqxmd.com/read/29432213/regulation-of-intestinal-lipid-and-lipoprotein-metabolism-by-the-proglucagon-derived-peptides-glucagon-like-peptide-1-and-glucagon-like-peptide-2
#12
Erin E Mulvihill
PURPOSE OF REVIEW: The intestine is highly efficient at absorbing and packaging dietary lipids onto the structural protein apoB48 for distribution throughout the body. Here, we summarize recent advances into understanding the physiological and pharmacological actions of the proglucagon-derived peptides: glucagon like peptide 1 (GLP-1) and glucagon like peptide 2 (GLP-2) on intestinal lipoprotein secretion. RECENT FINDINGS: Several recent studies have elucidated mechanisms underlying the paradoxical effects of GLP-1 and GLP-2 on intestinal production of triglyceride-rich lipoproteins (TRLs)...
April 2018: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/29351810/identify-down-syndrome-transcriptome-associations-using-integrative-analysis-of-microarray-database-and-correlation-interaction-network
#13
Min Chen, Jiayan Wang, Yingjun Luo, Kailing Huang, Xiaoshun Shi, Yanhui Liu, Jin Li, Zhengfei Lai, Shuya Xue, Haimei Gao, Allen Chen, Dunjin Chen
BACKGROUND: Long non-coding RNAs (lncRNAs) have previously been emerged as key players in a series of biological processes. Dysregulation of lncRNA is correlated to human diseases including neurological disorders. Here, we developed a multi-step bioinformatics analysis to study the functions of a particular Down syndrome-associated gene DSCR9 including the lncRNAs. The method is named correlation-interaction-network (COIN), based on which a pipeline is implemented. Co-expression gene network analysis and biological network analysis results are presented...
January 19, 2018: Human Genomics
https://www.readbyqxmd.com/read/29335487/increased-expression-of-glp-1r-in-proliferating-islets-of-men1-mice-is-detectable-by-68-ga-ga-do3a-vs-cys-40-exendin-4-pet
#14
Azita Monazzam, Joey Lau, Irina Velikyan, Su-Chen Li, Masoud Razmara, Ulrika Rosenström, Olof Eriksson, Britt Skogseid
Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by heterozygous mutations in the MEN1 tumor suppressor gene. The MEN1 pancreas of the adolescent gene carrier frequently contain diffusely spread pre-neoplasias and microadenomas, progressing to macroscopic and potentially malignant pancreatic neuroendocrine tumors (P-NET), which represents the major death cause in MEN1. The unveiling of the molecular mechanism of P-NET which is not currently understood fully to allow the optimization of diagnostics and treatment...
January 15, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330364/polypharmacy-through-phage-display-selection-of-glucagon-and-glp-1-receptor-co-agonists-from-a-phage-displayed-peptide-library
#15
Anna Demartis, Armin Lahm, Licia Tomei, Elisa Beghetto, Valentina Di Biasio, Federica Orvieto, Francesco Frattolillo, Paul E Carrington, Sheena Mumick, Brian Hawes, Elisabetta Bianchi, Anandan Palani, Antonello Pessi
A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequentially selected on GCGR- and GLP1R-overexpressing cells...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29140125/diabetes-area-patent-participation-analysis-part-ii-years-2011-2016
#16
REVIEW
Markus Boehm, Matthew Crawford, Jamie E Moscovitz, Philip A Carpino
Diabetes is a metabolic disease characterized by elevated levels of plasma glucose. When untreated, diabetes increases the risk of developing co-morbidities such as cardiovascular disease. Several drugs, often used as part of combination therapies, have been approved to treat the disease, but these drugs will eventually fail to effectively control blood glucose levels, at which point insulin replacement therapy is required. A medical need exists for new antidiabetic drugs that exhibit good efficacy with improved safety/toleration profiles and can be added on top of existing therapies, or that can provide additional benefits beyond glucose lowering such as pancreatic beta (β)-cell protection...
February 2018: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29119245/development-and-characterisation-of-a-novel-glucagon-like-peptide-1-receptor-antibody
#17
Emma K Biggs, Lihuan Liang, Jacqueline Naylor, Shimona Madalli, Rachel Collier, Matthew P Coghlan, David J Baker, David C Hornigold, Peter Ravn, Frank Reimann, Fiona M Gribble
AIMS/HYPOTHESIS: Glucagon like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion by binding to GLP-1 receptors (GLP1Rs) on pancreatic beta cells. GLP-1 mimetics are used in the clinic for the treatment of type 2 diabetes, but despite their therapeutic success, several clinical effects of GLP-1 remain unexplained at a mechanistic level, particularly in extrapancreatic tissues. The aim of this study was to generate and characterise a monoclonal antagonistic antibody for the GLP1R for use in vivo...
March 2018: Diabetologia
https://www.readbyqxmd.com/read/29113813/altered-glucose-metabolism-after-bariatric-surgery-what-s-glp-1-got-to-do-with-it
#18
REVIEW
Eric P Smith, Georgina Polanco, Abid Yaqub, Marzieh Salehi
Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1)...
November 4, 2017: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29107282/the-autonomic-nervous-system-and-cardiac-glp-1-receptors-control-heart-rate-in-mice
#19
Laurie L Baggio, John R Ussher, Brent A McLean, Xiemin Cao, M Golam Kabir, Erin E Mulvihill, Alexandra S Mighiu, Hangjun Zhang, Andreas Ludwig, Randy J Seeley, Scott P Heximer, Daniel J Drucker
OBJECTIVES: Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice...
November 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29101219/mir-204-controls-glucagon-like-peptide-1-receptor-expression-and-agonist-function
#20
SeongHo Jo, Junqin Chen, Guanlan Xu, Truman B Grayson, Lance A Thielen, Anath Shalev
Glucagon-like peptide 1 receptor (GLP1R) agonists are widely used to treat diabetes. However, their function is dependent on adequate GLP1R expression, which is downregulated in diabetes. GLP1R is highly expressed on pancreatic β-cells, and activation by endogenous incretin or GLP1R agonists increases cAMP generation, which stimulates glucose-induced β-cell insulin secretion and helps maintain glucose homeostasis. We now have discovered that the highly β-cell-enriched microRNA, miR-204, directly targets the 3' UTR of GLP1R and thereby downregulates its expression in the β-cell-derived rat INS-1 cell line and primary mouse and human islets...
February 2018: Diabetes
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