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GLP-1 AND hepatocyte

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https://www.readbyqxmd.com/read/27377054/robust-anti-obesity-and-metabolic-effects-of-a-dual-glp-1-glucagon-receptor-peptide-agonist-in-rodents-and-non-human-primates
#1
S J Henderson, A Konkar, D C Hornigold, J L Trevaskis, R Jackson, M Fritsch Fredin, R Jansson-Löfmark, J Naylor, A Rossi, M A Bednarek, N Bhagroo, H Salari, S Will, S Oldham, G Hansen, M Feigh, T Klein, J Grimsby, S Maguire, L Jermutus, C M Rondinone, M P Coghlan
AIMS: To characterize the pharmacology of MEDI0382, a peptide dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors. MATERIALS AND METHODS: MEDI0382 was evaluated in vitro for its ability to stimulate cAMP accumulation in cell lines expressing transfected recombinant or endogenous GLP-1 or glucagon receptors, to potentiate glucose-stimulated insulin secretion (GSIS) in pancreatic β-cell lines and stimulate hepatic glucose output (HGO) by primary hepatocytes...
December 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27239734/c-ebp-homologous-protein-modulates-liraglutide-mediated-attenuation-of-non-alcoholic-steatohepatitis
#2
Khalidur Rahman, Yunshan Liu, Pradeep Kumar, Tekla Smith, Natalie E Thorn, Alton B Farris, Frank A Anania
The CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a major transcriptional regulator of endoplasmic reticulum (ER) stress-mediated apoptosis, is implicated in lipotoxicity-induced ER stress and hepatocyte apoptosis in non-alcoholic fatty liver disease (NAFLD). We have previously demonstrated that the glucagon-like peptide-1 (GLP-1) agonist, liraglutide, protects steatotic hepatocytes from lipotoxicity-induced apoptosis by improved handling of free fatty acid (FFA)-induced ER stress. In the present study, we investigated whether CHOP is critical for GLP-1-mediated restoration of ER homeostasis and mitigation of hepatocyte apoptosis in a murine model of NASH (non-alcoholic steatohepatitis)...
August 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/27208776/glp-1-analogue-improves-hepatic-lipid-accumulation-by-inducing-autophagy-via-ampk-mtor-pathway
#3
Qin He, Sha Sha, Lei Sun, Jing Zhang, Ming Dong
The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy...
August 5, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27178543/the-glucagon-like-peptide-1-analogue-exendin-4-reverses-impaired-intracellular-ca-2-signalling-in-steatotic-hepatocytes
#4
Eunüs S Ali, Jin Hua, Claire H Wilson, George A Tallis, Fiona H Zhou, Grigori Y Rychkov, Greg J Barritt
The release of Ca(2+) from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca(2+) by Ca(2+) entry through store-operated Ca(2+) channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca(2+) release and Ca(2+) entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood...
September 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/26741352/practical-prospects-for-boosting-hepatic-production-of-the-pro-longevity-hormone-fgf21
#5
Mark F McCarty
Fibroblast growth factor-21 (FGF21), produced mainly in hepatocytes and adipocytes, promotes leanness, insulin sensitivity, and vascular health while down-regulating hepatic IGF-I production. Transgenic mice overexpressing FGF21 enjoy a marked increase in median and maximal longevity comparable to that evoked by calorie restriction - but without a reduction in food intake. Transcriptional factors which promote hepatic FGF21 expression include PPARα, ATF4, STAT5, and FXR; hence, fibrate drugs, elevated lipolysis, moderate-protein vegan diets, growth hormone, and bile acids may have potential to increase FGF21 synthesis...
December 19, 2015: Hormone Molecular Biology and Clinical Investigation
https://www.readbyqxmd.com/read/26524624/control-of-liver-glucokinase-activity-a-potential-new-target-for-incretin-hormones
#6
Flavio Francini, María Laura Massa, Mónica Patricia Polo, Hernán Villagarcía, María Cecilia Castro, Juan José Gagliardino
We tested the exendin-4 and des-fluoro-sitagliptin effects on fructose-induced increase in liver glucokinase activity in rats with impaired glucose tolerance and the exendin-4 effect on glucokinase activity in HepG2 cells incubated with fructose in the presence/absence of exendin-9-39. After 3 weeks of in vivo fructose administration we measured: (1) serum glucose, insulin and triglyceride levels; (2) liver and HepG2 cells glucokinase activity and (3) liver glucokinase and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase mRNA and protein levels...
December 2015: Peptides
https://www.readbyqxmd.com/read/26324089/incretin-hormones-and-maturity-onset-diabetes-of-the-young-pathophysiological-implications-and-anti-diabetic-treatment-potential
#7
RANDOMIZED CONTROLLED TRIAL
Signe Harring Østoft
Maturity onset diabetes of the young (MODY) designates monogenic forms of non-autoimmune diabetes characterised by autosomal dominant inheritance, non-insulin dependent diabetes at onset and diagnosis often before 25 years of age. MODY constitutes genetically and clinically heterogeneous forms of diabetes. More than 8 different genes are known to cause MODY, among which hepatocyte nuclear factor 1 alpha (HNF1A) (MODY3) and glucokinase (GCK) (MODY2) mutations are the most common. Both forms of MODY are characterised by specific beta cell dysfunction, with patients with HNF1A-diabetes having a reduced insulin secretory capacity, while patients with GCK-diabetes have a glucose-sensing defect, but preserved insulin secretory capacity...
September 2015: Danish Medical Journal
https://www.readbyqxmd.com/read/26315270/glp-1-contributes-to-increases-in-pgc-1%C3%AE-expression-by-downregulating-mir-23a-to-reduce-apoptosis
#8
Chi Wang, Qiang Li, Wei Wang, Lin Guo, Chang Guo, Yiqiong Sun, Jinchao Zhang
GLP-1 can help to overcome problems of liver cells metabolism, not only pancreatic cell. But the explicit mechanism of this effect remains unclear. In recent years, microRNAs have received the attention of researchers and some microRNAs have important implications for diabetes. The mitochondrial protective gene PGC-1α is also closely related to diabetes, and UCP2 is related to anti-mitochondrial oxidative stress, but the mechanism of action of these genes is unclear. In this study, we used HepG2 cell line and used the cell counting kit (CCK) to measure the cell viability with GLP-1(7-36) and/or glucotoxicity...
October 9, 2015: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26072069/review-on-the-effect-of-glucagon-like-peptide-1-receptor-agonists-and-dipeptidyl-peptidase-4-inhibitors-for-the-treatment-of-non-alcoholic-fatty-liver-disease
#9
REVIEW
Chao-Lin Li, Lu-Jie Zhao, Xin-Li Zhou, Hui-Xiao Wu, Jia-Jun Zhao
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus (T2DM), dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors were widely used to treat T2DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor (GLP-1R) is present and functional in human and rat hepatocytes...
June 2015: Journal of Huazhong University of Science and Technology. Medical Sciences
https://www.readbyqxmd.com/read/25953829/postprandial-incretin-and-islet-hormone-responses-and-dipeptidyl-peptidase-4-enzymatic-activity-in-patients-with-maturity-onset-diabetes-of-the-young
#10
Signe Harring Østoft, Jonatan Ising Bagger, Torben Hansen, Bolette Hartmann, Oluf Pedersen, Jens Juul Holst, Filip Krag Knop, Tina Vilsbøll
OBJECTIVE: The role of the incretin hormones in the pathophysiology of maturity onset diabetes of the young (MODY) is unclear. DESIGN: We studied the postprandial plasma responses of glucagon, incretin hormones (glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)) and dipeptidyl-peptidase 4 (DPP4) enzymatic activity in patients with glucokinase (GCK) diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A) diabetes (MODY3) as well as in matched healthy individuals (CTRLs)...
August 2015: European Journal of Endocrinology
https://www.readbyqxmd.com/read/25506548/glp-1-receptor-agonism-ameliorates-hepatic-vldl-overproduction-and-de-novo-lipogenesis-in-insulin-resistance
#11
Jennifer Taher, Christopher L Baker, Carmelle Cuizon, Hassan Masoudpour, Rianna Zhang, Sarah Farr, Mark Naples, Celine Bourdon, Zdenka Pausova, Khosrow Adeli
BACKGROUND/OBJECTIVES: Fasting dyslipidemia is commonly observed in insulin resistant states and mechanistically linked to hepatic overproduction of very low density lipoprotein (VLDL). Recently, the incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in ameliorating dyslipidemia associated with insulin resistance and reducing hepatic lipid stores. Given that hepatic VLDL production is a key determinant of circulating lipid levels, we investigated the role of both peripheral and central GLP-1 receptor (GLP-1R) agonism in regulation of VLDL production...
December 2014: Molecular Metabolism
https://www.readbyqxmd.com/read/25280755/glucagon-like-peptide-2-improves-cholestasis-in-parenteral-nutrition-associated-liver-disease
#12
David W Lim, Paul W Wales, Jessica K Josephson, Patrick N Nation, Pamela R Wizzard, Consolato M Sergi, Catherine J Field, David L Sigalet, Justine M Turner
BACKGROUND: Parenteral nutrition-associated liver disease (PNALD) remains a significant cause of morbidity and mortality in neonates with intestinal failure. Although glucagon-like peptide-2 (GLP-2) is being advanced as therapy, the effect of GLP-2 treatment on PNALD is unknown. We aim to investigate the effect of exogenous GLP-2 administration on hepatic function in a neonatal piglet model of PNALD. METHODS: Neonatal piglets (aged 2-6 days) underwent jugular venous catheterization to receive isonitrogenous, isocaloric parenteral nutrition (PN)...
January 2016: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/25177166/exendin-4-improves-nonalcoholic-fatty-liver-disease-by-regulating-glucose-transporter-4-expression-in-ob-ob-mice
#13
Seok Kim, Jaehoon Jung, Hwajin Kim, Rok Won Heo, Chin-Ok Yi, Jung Eun Lee, Byeong Tak Jeon, Won-Ho Kim, Jong Ryeal Hahm, Gu Seob Roh
Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been known to reverse hepatic steatosis in ob/ob mice. Although many studies have evaluated molecular targets of Ex-4, its mechanism of action on hepatic steatosis and fibrosis has not fully been determined. In the liver, glucose transporter 4 (GLUT4) is mainly expressed in hepatocytes, endothelial cells and hepatic stellate cells (HSCs). In the present study, the effects of Ex-4 on GLUT4 expression were determined in the liver of ob/ob mice...
August 2014: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/25083081/potential-roles-of-glucagon-like-peptide-1-based-therapies-in-treating-non-alcoholic-fatty-liver-disease
#14
REVIEW
Ye Liu, Rui Wei, Tian-Pei Hong
Glucagon-like peptide-1 (GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease (NAFLD). Recent studies showed that glucose-induced GLP-1 secretion was decreased in patients with NAFLD and that the level of dipeptidyl peptidase-4, which inactivates intact GLP-1, was upregulated. Moreover, the expression of the GLP-1 receptor was downregulated in livers from patients with NAFLD, indicating an association of defective GLP-1 signalling with NAFLD...
July 21, 2014: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/25066109/glp-1-receptor-agonists-effects-on-the-progression-of-non-alcoholic-fatty-liver-disease
#15
REVIEW
Jia Liu, Guang Wang, Yumei Jia, Yuan Xu
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and its incidence has been increasing recently. In addition to hepatic complications, NAFLD is also recognized as an independent risk factor for cardiovascular disease. Unfortunately, the current therapies for NAFLD display variable efficacy; a novel and effective drug is urgently needed. Glucagon-like peptide-1 (GLP-1), a receptor agonist is a new drug approved for treating type 2 diabetes. Recently, these types of agents have shown a novel therapeutic effect on NAFLD...
May 2015: Diabetes/metabolism Research and Reviews
https://www.readbyqxmd.com/read/24998439/effect-of-glp-1-based-therapies-on-diabetic-dyslipidemia
#16
REVIEW
Vishal J Patel, Amit A Joharapurkar, Gaurang B Shah, Mukul R Jain
Glucagon-like peptide-1 (GLP-1), is a hormone secreted by small intestine. Consumption of food or glucose stimulates synthesis and secretion of GLP-1 in the bloodstream, which in turn stimulates insulin secretion from pancreas and delays gastric emptying. Owing to the favorable spectrum of effects on reduction of hyperglycemia and body weight, GLP-1 mimetics are intensely pursued as therapies for the treatment of type 2 diabetes (T2DM). Even after intensive control of hyperglycemia, the propensity for cardiovascular disease cannot be totally negated in diabetic patients...
2014: Current Diabetes Reviews
https://www.readbyqxmd.com/read/24966606/incretin-based-therapies-a-novel-treatment-approach-for-non-alcoholic-fatty-liver-disease
#17
REVIEW
Kristina Blaslov, Tomislav Bulum, Karin Zibar, Lea Duvnjak
Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome (MS). The current treatment of non-alcoholic fatty liver disease (NAFLD) principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment. Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion...
June 21, 2014: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/24947350/sirt1-mediates-the-effect-of-glp-1-receptor-agonist-exenatide-on-ameliorating-hepatic-steatosis
#18
Fen Xu, Zhuo Li, Xiaobin Zheng, Hongxia Liu, Hua Liang, Haixia Xu, Zonglan Chen, Kejing Zeng, Jianping Weng
GLP-1 and incretin mimetics, such as exenatide, have been shown to attenuate hepatocyte steatosis in vivo and in vitro, but the specific underlying mechanism is unclear. SIRT1, an NAD(+)-dependent protein deacetylase, has been considered as a crucial regulator in hepatic lipid homeostasis by accumulated studies. Here, we speculate that SIRT1 might mediate the effect of the GLP-1 receptor agonist exenatide (exendin-4) on ameliorating hepatic steatosis. After 8 weeks of exenatide treatment in male SIRT1(+/-) mice challenged with a high-fat diet and their wild-type (WT) littermates, we found that lipid deposition and inflammation in the liver, which were improved dramatically in the WT group, diminished in SIRT1(+/-) mice...
November 2014: Diabetes
https://www.readbyqxmd.com/read/24940046/glp-1-28-36-amide-the-glucagon-like-peptide-1-metabolite-friend-foe-or-pharmacological-folly
#19
REVIEW
Meng-Wong Taing, Felicity J Rose, Jonathan P Whitehead
The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes. GLP-1 mediates its key insulinotropic effects via a G-protein coupled receptor expressed on β-cells and other pancreatic cell types. The insulinotropic activity of GLP-1 is terminated via enzymatic cleavage by dipeptidyl peptidase-4. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive; however, accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor...
2014: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/24929431/glucose-lowering-effects-and-low-risk-of-hypoglycemia-in-patients-with-maturity-onset-diabetes-of-the-young-when-treated-with-a-glp-1-receptor-agonist-a-double-blind-randomized-crossover-trial
#20
RANDOMIZED CONTROLLED TRIAL
Signe H Østoft, Jonatan I Bagger, Torben Hansen, Oluf Pedersen, Jens Faber, Jens J Holst, Filip K Knop, Tina Vilsbøll
OBJECTIVE: The most common form of maturity-onset diabetes of the young (MODY), hepatocyte nuclear factor 1α (HNF1A diabetes: MODY3) is often treated with sulfonylureas that confer a high risk of hypoglycemia. We evaluated treatment with GLP-1 receptor agonists (GLP-1RAs) in patients with HNF1A diabetes. RESEARCH DESIGN AND METHODS: Sixteen patients with HNF1A diabetes (8 women; mean age 39 years [range 23-67 years]; BMI 24.9 ± 0.5 kg/m(2) [mean ± SEM]; fasting plasma glucose [FPG] 9...
July 2014: Diabetes Care
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