or reduce iNOS expression may be necessary for the prevention or inhibition of β-cell damage. Glucagon-like peptide-1 (GLP-1) and its potent agonist exendin-4 (EX-4) have received great attention because of their insulinotropic and β
Jung-Hoon Kang, Seo-Yoon Chang, Hyun-Jong Jang, Dong-Bin Kim, Gyeong Ryul Ryu, Seung Hyun Ko, In-Kyung Jeong, Yang-Hyeok Jo, and Myung-Jun Kim
Srilaxmi Kalavalapalli, Fernando Bril, Joy Guingab, Ariana Vergara, Timothy J Garrett, Nishanth E Sunny, and Kenneth Cusi
under investigation for NASH, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown a significant promise for the treatment of NAFLD ( Ding et al. 2006 , Blonde & Russell-Jones 2009 , Cusi 2012 , Armstrong et al. 2013 , 2016 a , b
BD Green, MH Mooney, VA Gault, N Irwin, CJ Bailey, P Harriott, B Greer, FP O'Harte, and PR Flatt
Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid inactivation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1(9-36)amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC(50) values 32.9 and 6.7 nM, respectively) compared with native GLP-1 (IC(50) 0.37 nM). Similarly, both analogues stimulated cAMP production with EC(50) values of 16.3 and 27 nM respectively compared with GLP-1 (EC(50) 4.7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5.6 mM glucose (P<0.05 to P<0.001) similar to native GLP-1. Both analogues (25 nM/kg body weight) lowered plasma glucose and increased plasma insulin levels when administered in conjunction with glucose (18 nM/kg body weight) to adult obese diabetic (ob/ob) mice. N-pyroglutamyl-GLP-1 was substantially better at lowering plasma glucose compared with the native peptide, while N-acetyl-GLP-1 was significantly more potent at stimulating insulin secretion. These studies indicate that N-terminal modification of GLP-1 results in DPP IV-resistant and biologically potent forms of GLP-1. The particularly powerful antihyperglycaemic action of N-pyroglutamyl-GLP-1 shows potential for the treatment of type 2 diabetes.
Hamzeh Karimkhanloo, Stacey N Keenan, Emily W Sun, David A Wattchow, Damien J Keating, Magdalene K Montgomery, and Matthew J Watt
insulin injection. In separate experiments, the GLP1 receptor antagonist Exendin (9–39) amide (Abcam) was administered to mice (i.p. 4 µg/g body weight) in the presence or absence of CTSS (i.p. 1.0 mg/kg body weight), and a GTT was performed as described
Li Zhao, Chunfang Zhu, Meng Lu, Chi Chen, Xiaomin Nie, Buatikamu Abudukerimu, Kun Zhang, Zhiyuan Ning, Yi Chen, Jing Cheng, Fangzhen Xia, Ningjian Wang, Michael D Jensen, and Yingli Lu
. 2010 ). Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by gastrointestinal L cells in response to oral nutrient ingestion ( Wan et al . 2017 ) and is an ideal therapy for obesity and T2DM ( Rajeev & Wilding 2016 ). However, native
Adrian Holliday and Andrew Blannin
–tyrosine (PYY) and glucagon-like peptide 1 (GLP-1) have been observed with continuous, high-intensity aerobic bouts of exercise lasting as little as 30 min ( Ueda et al . 2009 a ), and with intermittent exercise bouts yielding energy expenditure values of as
Tianru Jin
cDNAs from these species further revealed that it encodes not only glucagon but also two glucagon-like peptide hormones, namely glucagon-like peptide-1 (GLP-1) and GLP-2 ( Lund et al . 1982 ). Glucagon is produced and released from the pancreatic α
Sandra Steensels, Matthias Lannoo, Bert Avau, Jorien Laermans, Laurien Vancleef, Ricard Farré, Kristin Verbeke, and Inge Depoortere
considered as one of the possible mechanisms for the postsurgical metabolic improvements ( Svane et al. 2015 ). RYGB surgery enhances the secretion of the anorexigenic hormones glucagon-like peptide 1 (GLP1) and peptide YY (PYY), and although more
Shou-Si Lu, Yun-Li Yu, Hao-Jie Zhu, Xiao-Dong Liu, Li Liu, Yao-Wu Liu, Ping Wang, Lin Xie, and Guang-Ji Wang
play is an important role in the regulation of endocrine pancreatic secretion. The intestinal products of the proglucagon gene, glucagon-like peptide-1 (GLP-1), has been shown to contribute significantly to the overall insulin response to oral glucose
Ashley I Taylor, Nigel Irwin, Aine M McKillop, Steven Patterson, Peter R Flatt, and Victor A Gault
has examined the plasma stability and satiety effects of xenin, and further characterised the glucose-lowering and insulinotropic effects of xenin both alongside GIP, glucagon-like peptide-1 (GLP1) and neurotensin. Materials and Methods Degradation of
