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Melissa A Burmeister, Jennifer E Ayala, Hannah Smouse, Adriana Landivar-Rocha, Jacob D Brown, Daniel J Drucker, Doris A Stoffers, Darleen A Sandoval, Randy J Seeley, Julio E Ayala
Pharmacological activation of the hypothalamic glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD(ΔNkx2...
December 1, 2016: Diabetes
Eugene Han, Hye Sun Park, Obin Kwon, Eun Yeong Choe, Hye Jin Wang, Yong-Ho Lee, Sang-Hak Lee, Chul Hoon Kim, Lee-Kyung Kim, Soo Heon Kwak, Kyong Soo Park, Chul Sik Kim, Eun Seok Kang
Incretin hormone-based therapy in type 2 diabetes has been widely used, and dipepdityl peptidase-4 (DPP-4) inhibitors, which prevent incretin degradation, have become popular oral hypoglycemic agents. The efficacy of DPP-4 inhibitors varies from individuals, and factors determining responses to DPP-4 inhibitors have not been fully established. We aimed to investigate whether genetic variations in glucagon-like peptide (GLP-1) receptor are associated with responses to DPP-4 inhibitors in patients with type 2 diabetes...
November 2016: Medicine (Baltimore)
Sriparna Ghosal, Amy E B Packard, Parinaz Mahbod, Jessica M McKlveen, Randy J Seeley, Brent Myers, Yvonne Ulrich-Lai, Eric P Smith, David A D'Alessio, James P Herman
Organismal stress initiates a tightly orchestrated set of responses involving complex physiological and neurocognitive systems. Here, we present evidence for glucagon-like peptide 1 (GLP-1) mediated paraventricular hypothalamic circuit coordinating the global stress response. The GLP-1 receptor (Glp1r) in mice was knocked down in neurons expressing single-minded 1 (Sim1), a transcription factor abundantly expressed in the paraventricular nucleus (PVN) of the hypothalamus. Mice with Sim1-mediated Glp1r knockdown had reduced hypothalamic-pituitary-adrenal (HPA) axis responses to both acute and chronic stress and were protected against weight loss associated with chronic stress...
November 3, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Aine M McKillop, Brian M Moran, Yasser H A Abdel-Wahab, Noella M Gormley, Peter R Flatt
AIMS/HYPOTHESIS: Abnormal cannabidiol (Abn-CBD) and AS-1269574 are potent selective agonists for GPR55 and GPR119, respectively. The present study evaluated the actions and ability of these small-molecule agonists to counteract experimental diabetes in mice. METHODS: Diabetes was induced in NIH Swiss mice by five consecutive daily intraperitoneal injections of 40 mg/(kg body weight) streptozotocin. Diabetic mice received daily oral administration of Abn-CBD or AS-1269574 (0...
September 27, 2016: Diabetologia
Warapen Treekitkarnmongkol, Hiroshi Katayama, Kazuharu Kai, Kaori Sasai, Jennifer Carter Jones, Jing Wang, Li Shen, Aysegul A Sahin, Mihai Gagea, Naoto T Ueno, Chad J Creighton, Subrata Sen
Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition...
December 2016: Carcinogenesis
Satoru Takashima, Hiroki Fujita, Hiromi Fujishima, Tatsunori Shimizu, Takehiro Sato, Tsukasa Morii, Katsushi Tsukiyama, Takuma Narita, Takamune Takahashi, Daniel J Drucker, Yutaka Seino, Yuichiro Yamada
The role of stromal cell-derived factor-1 (SDF-1) in the pathogenesis of diabetic nephropathy and its modification by dipeptidyl peptidase-4 (DPP-4) inhibition are uncertain. Therefore, we studied this independent of glucagon-like peptide-1 receptor (GLP-1R) signaling using two Akita diabetic mouse models, the diabetic-resistant C57BL/6-Akita and diabetic-prone KK/Ta-Akita. Increased SDF-1 expression was found in glomerular podocytes and distal nephrons in the diabetic-prone mice, but not in kidneys from diabetic-resistant mice...
October 2016: Kidney International
Valentina Vellecco, Emma Mitidieri, Antonella Gargiulo, Vincenzo Brancaleone, Danilo Matassa, Thomas Klein, Franca Esposito, Giuseppe Cirino, Mariarosaria Bucci
AIM: To test the effect of linagliptin in non-obese diabetic (NOD) mice, a murine model of type 1 diabetes, to unveil a possible direct cardiovascular action of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond glycaemia control. METHODS: NOD mice were grouped according to glycosuria levels as NODI: none; NODII: high; NODIII: severe. Linagliptin treatment was initiated once they reached NODII levels. Vascular reactivity was assessed ex vivo on aorta harvested from mice upon reaching NODIII level...
December 2016: Diabetes, Obesity & Metabolism
Irene Fernández-Ruiz
No abstract text is available yet for this article.
August 2016: Nature Reviews. Cardiology
Robert A Scott, Daniel F Freitag, Li Li, Audrey Y Chu, Praveen Surendran, Robin Young, Niels Grarup, Alena Stancáková, Yuning Chen, Tibor V Varga, Hanieh Yaghootkar, Jian'an Luan, Jing Hua Zhao, Sara M Willems, Jennifer Wessel, Shuai Wang, Nisa Maruthur, Kyriaki Michailidou, Ailith Pirie, Sven J van der Lee, Christopher Gillson, Ali Amin Al Olama, Philippe Amouyel, Larraitz Arriola, Dominique Arveiler, Iciar Aviles-Olmos, Beverley Balkau, Aurelio Barricarte, Inês Barroso, Sara Benlloch Garcia, Joshua C Bis, Stefan Blankenberg, Michael Boehnke, Heiner Boeing, Eric Boerwinkle, Ingrid B Borecki, Jette Bork-Jensen, Sarah Bowden, Carlos Caldas, Muriel Caslake, L Adrienne Cupples, Carlos Cruchaga, Jacek Czajkowski, Marcel den Hoed, Janet A Dunn, Helena M Earl, Georg B Ehret, Ele Ferrannini, Jean Ferrieres, Thomas Foltynie, Ian Ford, Nita G Forouhi, Francesco Gianfagna, Carlos Gonzalez, Sara Grioni, Louise Hiller, Jan-Håkan Jansson, Marit E Jørgensen, J Wouter Jukema, Rudolf Kaaks, Frank Kee, Nicola D Kerrison, Timothy J Key, Jukka Kontto, Zsofia Kote-Jarai, Aldi T Kraja, Kari Kuulasmaa, Johanna Kuusisto, Allan Linneberg, Chunyu Liu, Gaëlle Marenne, Karen L Mohlke, Andrew P Morris, Kenneth Muir, Martina Müller-Nurasyid, Patricia B Munroe, Carmen Navarro, Sune F Nielsen, Peter M Nilsson, Børge G Nordestgaard, Chris J Packard, Domenico Palli, Salvatore Panico, Gina M Peloso, Markus Perola, Annette Peters, Christopher J Poole, J Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, Veikko Salomaa, María-José Sánchez, Naveed Sattar, Stephen J Sharp, Rebecca Sims, Nadia Slimani, Jennifer A Smith, Deborah J Thompson, Stella Trompet, Rosario Tumino, Daphne L van der A, Yvonne T van der Schouw, Jarmo Virtamo, Mark Walker, Klaudia Walter, Jean E Abraham, Laufey T Amundadottir, Jennifer L Aponte, Adam S Butterworth, Josée Dupuis, Douglas F Easton, Rosalind A Eeles, Jeanette Erdmann, Paul W Franks, Timothy M Frayling, Torben Hansen, Joanna M M Howson, Torben Jørgensen, Jaspal Kooner, Markku Laakso, Claudia Langenberg, Mark I McCarthy, James S Pankow, Oluf Pedersen, Elio Riboli, Jerome I Rotter, Danish Saleheen, Nilesh J Samani, Heribert Schunkert, Peter Vollenweider, Stephen O'Rahilly, Panos Deloukas, John Danesh, Mark O Goodarzi, Sekar Kathiresan, James B Meigs, Margaret G Ehm, Nicholas J Wareham, Dawn M Waterworth
Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia...
June 1, 2016: Science Translational Medicine
Martijn van de Bunt, Majlinda Lako, Amy Barrett, Anna L Gloyn, Mattias Hansson, Mark I McCarthy, Nicola L Beer, Christian Honoré
Directed differentiation of stem cells offers a scalable solution to the need for human cell models recapitulating islet biology and T2D pathogenesis. We profiled mRNA expression at 6 stages of an induced pluripotent stem cell (iPSC) model of endocrine pancreas development from 2 donors, and characterized the distinct transcriptomic profiles associated with each stage. Established regulators of endodermal lineage commitment, such as SOX17 (log2 fold change [FC] compared to iPSCs = 14.2, p-value = 4.9 × 10(-5)) and the pancreatic agenesis gene GATA6 (log2 FC = 12...
April 18, 2016: Islets
Erika K Williams, Rui B Chang, David E Strochlic, Benjamin D Umans, Bradford B Lowell, Stephen D Liberles
Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons)...
June 30, 2016: Cell
M Javorský, I Gotthardová, L Klimčáková, M Kvapil, J Židzik, Z Schroner, P Doubravová, I Gala, I Dravecká, I Tkáč
Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment...
September 2016: Diabetes, Obesity & Metabolism
Bosede O Owolabi, Opeolu O Ojo, Dinesh K Srinivasan, J Michael Conlon, Peter R Flatt, Yasser H A Abdel-Wahab
The frog skin host-defence peptide hymenochirin-1B has been shown to stimulate insulin release in vitro from isolated pancreatic islets and BRIN-BD11 clonal β-cells. This study examines the effects of 28-day administration of a more potent analogue [P5K]hymenochirin-1B ([P5K]hym-1B) (75 nmol·kg(-1) body weight) to high-fat-fed mice with obesity, glucose intolerance and insulin resistance. Treatment with [P5K]hym-1B significantly decreased plasma glucose concentrations and improved glucose tolerance, insulin secretion, insulin sensitivity and increased the magnitude of the incretin effect (difference in response to oral vs intraperitoneal glucose loads)...
July 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
Xiaochen Yao, Feng Wang
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are neoplasms presenting unpredictable and unusual biologic behavior that causes many clinical challenges. NETs can produce a variety of metabolically active substances (hormones and amines) leading to distinct clinical syndromes. This review will discuss the imaging techniques for the diagnosis of GEP-NETs including ultrasonography, CT, MRI and ultrasound endoscope. In this article, Gallium-68 labeled peptide binding to G protein coupled receptor including SSTR, CCKR1 and GLP1R is addressed, and the application of Gallium-68 labeled somatostin analogues and PET-CT for diagnosis of GEP-NETs is evaluated...
January 2016: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
Annalisa Natalicchio, Giuseppina Biondi, Nicola Marrano, Rossella Labarbuta, Federica Tortosa, Rosaria Spagnuolo, Rossella D'Oria, Emanuele Carchia, Anna Leonardini, Angelo Cignarelli, Sebastio Perrini, Luigi Laviola, Francesco Giorgino
The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA...
June 2016: Endocrinology
Alison Cameron-Vendrig, Adili Reheman, M Ahsan Siraj, Xiaohong Ruby Xu, Yiming Wang, Xi Lei, Talat Afroze, Eric Shikatani, Omar El-Mounayri, Hossein Noyan, Ralph Weissleder, Heyu Ni, Mansoor Husain
Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation...
June 2016: Diabetes
Ying Cui, Wen Chen, Jinfeng Chi, Lei Wang
OBJECTIVE: Diabetes mellitus type 2 (T2DM) is a metabolic disease that has become a pressing issue, with potential adverse impact on mental health. We aimed to explore the potential molecular mechanism of T2DM. MATERIAL AND METHODS: GSE38642 microarray data downloaded from gene expression omnibus was used to identify the differentially expressed genes (DEGs). Profiling of complex functionality (ProfCom) was used to analyze the complex function and mine T2DM signature genes...
February 2016: Annales D'endocrinologie
Fumiyo Kubo, Takeshi Miyatsuka, Shugo Sasaki, Mitsuyoshi Takahara, Yuichi Yamamoto, Naoki Shimo, Hirotaka Watada, Hideaki Kaneto, Maureen Gannon, Taka-aki Matsuoka, Iichiro Shimomura
Glucagon-like peptide 1 (GLP-1) has been shown to play important roles in maintaining β-cell functions, such as insulin secretion and proliferation. While expression levels of GLP-1 receptor (Glp1r) are compromised in the islets of diabetic rodents, it remains unclear when and to what degree Glp1r mRNA levels are decreased during the progression of diabetes. In this study, we performed real-time PCR with the islets of db/db diabetic mice at different ages, and found that the expression levels of Glp1r were comparable to those of the islets of nondiabetic db/misty controls at the age of four weeks, and were significantly decreased at the age of eight and 12 weeks...
February 26, 2016: Biochemical and Biophysical Research Communications
Xuemin Wang, Xiaolei Liu, Dadong Deng, Mei Yu, Xiaoping Li
BACKGROUND: Piglet birth weight variability, a trait also known as the within-litter homogeneity of birth weight, reflects the sow's prolificacy, because it is positively genetically correlated with preweaning mortality but negatively correlated with the mean growth of piglets during sucking. In addition, the maternal additive genetic variance and heritability has been found exist for this trait, thus, reduction in the variability of piglet birth weight to improve the sow prolificacy is possible by selective breeding...
2016: BMC Genetics
Naoki Shimo, Taka-aki Matsuoka, Takeshi Miyatsuka, Satomi Takebe, Yoshihiro Tochino, Mitsuyoshi Takahara, Hideaki Kaneto, Iichiro Shimomura
Alleviation of hyperglycaemia and hyperlipidemia improves pancreatic β-cell function in type 2 diabetes. However, the underlying molecular mechanisms are still not well clarified. In this study, we aimed to elucidate how the expression alterations of key β-cell factors are altered by the short-term selective alleviation of glucotoxicity or lipotoxicity. We treated db/db mice for one week with empagliflozin and/or bezafibrate to alleviate glucotoxicity and/or liptotoxicity, respectively. The gene expression levels of Pdx1 and Mafa, and their potential targets, insulin 1, Slc2a2, and Glp1r, were higher in the islets of empagliflozin-treated mice, and levels of insulin 2 were higher in mice treated with both reagents, than in untreated mice...
November 27, 2015: Biochemical and Biophysical Research Communications
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