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GLP-1 diabetes obesity

Xuejing Li, Suhui Qie, Xianying Wang, Yingying Zheng, Yang Liu, Guoqiang Liu
OBJECTIVES: To investigate the safety and efficacy of once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide as monotherapy or add-on to other antihyperglycaemic agents (AHAs) in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, Embase, Cochrane library and were searched from the inception to January 18, 2018. Randomised controlled trials (RCTs) comparing semaglutide with placebo or other AHAs in T2DM patients were included in our meta-analysis...
August 12, 2018: Endocrine
Joachim Tillner, Maximilian G Posch, Frank Wagner, Lenore Teichert, Youssef Hijazi, Christine Einig, Stefanie Keil, Torsten Haack, Michael Wagner, Martin Bossart, Philip J Larsen
AIMS: To evaluate the safety, pharmacokinetics, and pharmacodynamics of SAR425899, a novel polypeptide active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1 R) and the glucagon receptor, in healthy volunteers and in patients with overweight/obesity and type 2 diabetes. METHODS: Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (BMI: 25─30 kg/m2 ; n = 32) received single-ascending doses (0...
August 8, 2018: Diabetes, Obesity & Metabolism
Jing Han, Yue Huang, Xinyu Chen, Feng Zhou, Yingying Fei, Junjie Fu
The main disadvantages of glucagon-like peptide 1 (GLP-1) are its rapid degradation and excretion. These bottlenecks can be overcome by lipidation or other structural modification. The aim of this study was to design a series of long-acting GLP-1 analogues based on our previously discovered Xenopus GLP-1 analogs (1-3). The structure-activity relationship around lipidated 1-3 derivatives (1a-3l) with respect to in vitro potency as well as protraction was firstly explored. Compound 3g was selected for further modification...
July 20, 2018: European Journal of Pharmaceutical Sciences
N M Pathak, V Pathak, V A Gault, S McClean, N Irwin, P R Flatt
Glucose-dependent insulinotropic hormone (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that exert an array of beneficial actions on metabolism and cognitive function. GLP-1-based therapeutics have been highly successful in terms of obesity and diabetes management, however GIP therapies have found no clinical utility to date. In the present study we describe, for the first time, the therapeutic effectiveness of a novel GIP/GLP-1 hybrid peptide based on the amino acid sequences of GIP, GLP-1 and the clinically approved GLP-1 mimetic, exendin-4...
July 18, 2018: Biochemical Pharmacology
Mehmet Akif Camkurt, Luca Lavagnino, Xiang Y Zhang, Antonio L Teixeira
Obesity and diabetes are both risk factors and consequences of psychiatric disorders. Glucagon like peptide 1 (GLP-1) receptor agonists such as liraglutide are widely used in the treatment of diabetes and obesity. There are considerable amounts of preclinical studies showing the effects of liraglutide on promotion of neurogenesis, while preventing apoptosis and oxidation. Preliminary clinical evidence has suggested that liraglutide could decrease weight gain, improve cognition and prevent cognitive decline...
July 18, 2018: Hormone Molecular Biology and Clinical Investigation
Ann A Coulter, Candida J Rebello, Frank L Greenway
For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term...
July 2018: Drugs
Junling Liu, Kun Yang, Wenhua Xiao, Yunyi Le, Shan Lang, Jingjing Zhang, Rui Wei, Jin Yang, Tianpei Hong
The level of serum angiopoietin-like protein 8 (ANGPTL8), a novel hepatokine, is associated with obesity and type 2 diabetes mellitus (T2DM). The aims of this study were to investigate whether serum ANGPTL8 level in patients with T2DM was affected by treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, and to determine whether and how GLP-1R agonists regulated ANGPTL8 production in hepatocytes. A multiple-center trial was conducted in China. Among 240 patients with T2DM enrolled in this trial, 195 patients adhered to a 16-week exenatide treatment and follow-up...
August 2018: Peptides
Ralf Elvert, Martin Bossart, Andreas W Herling, Tilo Weiss, Baohong Zhang, Aimo Kannt, Michael Wagner, Torsten Haack, Andreas Evers, Angela Dudda, Stefanie Keil, Martin Lorenz, Katrin Lorenz, Michela Riz, Wolfgang Hennerici, Philip J Larsen
We assessed the therapeutic contribution of the individual components of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonists alone and in combination upon energy homeostasis and glycemic control in diet-induced obese, diabetic nonhuman primates. The pharmacological active dose ranges of selective agonists were established through a dose-finding study, followed by a 6-week chronic study. Repeated subcutaneous administration of a selective GCGR agonist (30 µg/kg once daily) did not affect food intake or body weight, whereas the selective GLP-1R agonist (3 µg/kg once daily) alone decreased energy intake by 18% and body weight by 3...
August 1, 2018: Endocrinology
Christian Seerup Frandsen, Thomas Fremming Dejgaard, Sten Madsbad, Jens Juul Holst
Despite intensified insulin treatment, many persons with type 1 diabetes (T1D) do not achieve glycemic and metabolic targets. Consequently, non-insulin chemical therapies that improve glycemic control and metabolic parameters without increasing the risk of adverse events (including hypoglycemia) are of interest as adjunct therapies to insulin. Areas covered: In this review, the authors discuss the efficacy and safety of non-insulin therapies, including pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4), sodium-glucose cotransporter (SGLT1 and SGLT2) inhibitors, metformin, sulfonylureas, and thiazolidinediones as add-on therapies to insulin in T1D...
June 2018: Expert Opinion on Pharmacotherapy
Vishal J Patel, Amit A Joharapurkar, Samadhan G Kshirsagar, Brijesh K Sutariya, Maulik S Patel, Hiren M Patel, Dheerendra K Pandey, Rajesh H Bahekar, Mukul R Jain
AIM: To investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS: Chronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc ) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 μg/kg, sc ) treatment was continued for forty weeks...
June 15, 2018: World Journal of Diabetes
Lee Kallenbach, Amy M Shui, Wendy Y Cheng, Tao Fan, Wenli Hu, Miriam L Zichlin, Mei Sheng Duh, Fen Ye, Philip A Levin
OBJECTIVE: To understand factors associated with intensification of basal insulin therapy and treatment impact on clinical outcomes in patients with type 2 diabetes (T2D). METHODS: In this retrospective, observational study of the Practice Fusion electronic health record database, eligible patients were adults with T2D, ≥1 basal insulin prescription and office visit in the 6 months before an A1C test >7.0% (index date), and no other injectable prescriptions in the 12 months before index date...
July 5, 2018: Endocrine Practice
Yuka Kinoshita
Incretins are gastro-intestinal hormones released from enteroendocrine cells in response to food intake. Incretins such as glucose-dependent insulinotropic peptide(GIP)and glucagon-like peptide 1(GLP-1)modulate glucose homeostasis by regulating glucose-dependent insulin release from pancreatic βcells. Dipeptidyl peptidase-4(DPP-4)inhibitors and GLP-1 receptor agonists are incretin-based drugs that have been used for the management of hyperglycemia and obesity in patients with type 2 diabetes mellitus. Although experimental studies have shown that incretin improves bone quality and increases bone mass in rodents, further studies are necessary to clarify the effect of incretin-based drugs on bone mineral density and risk of fractures in humans...
2018: Clinical Calcium
Maria J Pereira, Per Lundkvist, Prasad G Kamble, Joey Lau, Julian G Martins, C David Sjöström, Volker Schnecke, Anna Walentinsson, Eva Johnsson, Jan W Eriksson
INTRODUCTION: The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes. METHODS: In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m2 ] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment...
June 13, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Yung-Chih Chen, Robert M Edinburgh, Aaron Hengist, Harry A Smith, Jean-Philippe Walhin, James A Betts, Dylan Thompson, Javier T Gonzalez
NEW FINDINGS: What is the central question of this study? Glucagon-like peptide-1 (GLP-1) is an important obesity/diabetes target, with effects dependent on circulating GLP-1 concentrations. Peripheral tissues extract GLP-1; therefore, sampling venous versus arterialized blood might provide different GLP-1 concentrations. This study examined whether arterialization alters GLP-1 concentrations during fasting and feeding. What is the main finding and its importance? This study demonstrates that venous blood provides lower postprandial but not fasting GLP-1 concentrations versus arterialized blood...
June 27, 2018: Experimental Physiology
Philip Ambery, Victoria E Parker, Michael Stumvoll, Maximilian G Posch, Tim Heise, Leona Plum-Moerschel, Lan-Feng Tsai, Darren Robertson, Meena Jain, Marcella Petrone, Cristina Rondinone, Boaz Hirshberg, Lutz Jermutus
BACKGROUND: Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes. METHODS: This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany...
June 30, 2018: Lancet
Henri Honka, Jukka Koffert, Saila Kauhanen, Nobuyuki Kudomi, Saija Hurme, Andrea Mari, Andreas Lindqvist, Nils Wierup, Riitta Parkkola, Leif Groop, Pirjo Nuutila
AIMS/HYPOTHESIS: The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance. METHODS: A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI...
July 2018: Endocrine Connections
Ralf Elvert, Andreas W Herling, Martin Bossart, Tilo Weiss, Baohong Zhang, Pierre Wenski, Jörn Wandschneider, Sabrina Kleutsch, Uwe Butty, Aimo Kannt, Michael Wagner, Torsten Haack, Andreas Evers, Angela Dudda, Martin Lorenz, Stefanie Keil, Philip J Larsen
AIM: We performed acute and chronic studies in healthy and diet-induced obese animals using mouse-specific or monkey-specific dual GLP-1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP-1R agonist liraglutide was used as comparator. METHODS: The mouse-specific dual agonist and liraglutide were tested in lean wild type, GLP-1R knockout and diet-induced obese mice at different doses...
August 2018: Diabetes, Obesity & Metabolism
K S Weber, K Straßburger, M Fritsch, A Bierwagen, C Koliaki, E Phielix, G Pacini, J-H Hwang, D F Markgraf, V Burkart, K Müssig, J Szendroedi, M Roden
AIM: Type 2 diabetes (T2D) alters glucagon, glucagon-like peptide (GLP)-1, glucose-dependent insulinotropic polypeptide (GIP) and hepatic energy metabolism, yet the possible relationships remain unclear. METHODS: In this observational study, lean insulin-sensitive control subjects (BMI: 23.2±1.5kg/m2 ), age-matched insulin-resistant obese subjects (BMI: 34.3±1.7kg/m2 ) and similarly obese elderly T2D patients (BMI: 32.0±2.4kg/m2 ) underwent mixed-meal tolerance tests (MMTTs), and assessment of hepatic γATP, inorganic phosphate (Pi ) and lipids using 31 P/1 H magnetic resonance spectroscopy...
June 2, 2018: Diabetes & Metabolism
Andreas Evers, Martin Bossart, Stefania Pfeiffer-Marek, Ralf Elvert, Herman Schreuder, Michael Kurz, Siegfried Stengelin, Martin Lorenz, Andreas Herling, Anish Konkar, Ulrike Lukasczyk, Anja Pfenninger, Katrin Lorenz, Torsten Haack, Dieter Kadereit, Michael Wagner
Novel peptidic dual agonists of the glucagon-like peptide 1 (GLP-1) and glucagon receptor are reported to have enhanced efficacy over pure GLP-1 receptor agonists with regard to treatment of obesity and diabetes. We describe novel exendin-4 based dual agonists designed with an activity ratio favoring the GLP-1 versus the glucagon receptor. As result of an iterative optimization procedure that included molecular modeling, structural biological studies (X-ray, NMR), peptide design and synthesis, experimental activity, and solubility profiling, a candidate molecule was identified...
July 12, 2018: Journal of Medicinal Chemistry
Helena W Rodbard
GLP-1 receptor agonists (GLP-1 RAs), introduced for clinical use in 2005, have excellent potency in reducing HbA1c and mean glucose, improving fasting plasma glucose, inducing weight loss or protecting against the weight gain associated with insulin therapy, reducing appetite, and delaying gastric emptying. Two of these medications, liraglutide and semaglutide, appear to have cardioprotective effects as reflected in cardiovascular outcomes studies. The GLP-1 RAs are associated with gastrointestinal side effects that tend to diminish over time...
June 2018: Diabetes Technology & Therapeutics
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