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Mohamed Lotfy, Jaipaul Singh, Hameed Rashed, Saeed Tariq, Erika Zilahi and Ernest Adeghate

endocrine and an exocrine system with much interaction between the two parts ( Shetzline & Liddle 2002 ). The GI tract secretes a number of hormones including glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP1; Drucker 2003 b

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Eun-Young Lee, Xilin Zhang, Junki Miyamoto, Ikuo Kimura, Tomoaki Taknaka, Kenichi Furusawa, Takahito Jomori, Kosuke Fujimoto, Satoshi Uematsu and Takashi Miki

Introduction Oral ingestion of carbohydrate triggers secretion of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the major incretins that inhibit the rise in blood glucose levels by potentiating insulin

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C Y Shan, J H Yang, Y Kong, X Y Wang, M Y Zheng, Y G Xu, Y Wang, H Z Ren, B C Chang and L M Chen

-like peptide 1 (GLP1) and GLP2 may play key roles in these processes ( Tremaroli & Bäckhed 2012 ). For example, GLP2, which is secreted by intestine L cells, is a key regulator of intestinal permeability ( Cani et al . 2009 ). Therapeutic regimes that target

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Jia Fang Wang and David J Hill

endothelial cell CD31/PECAM-1 were obtained from Dako Corporation, Santa Barbara, CA, USA, and rabbit anti-human α amylase from Sigma Chemical Co. Rabbit anti-rat PDX-1 was provided by Dr C Wright, Vanderbilt University. Glucagon-like polypeptide 1 (GLP-1) and

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M-J Kim, J-H Kang, Y G Park, G R Ryu, S H Ko, I-K Jeong, K-H Koh, D-J Rhie, S H Yoon, S J Hahn, M-S Kim and Y-H Jo

Introduction Glucagon-like peptide-1 (GLP-1) has been of much interest due to its β-cell-proliferating effect and role as an incretin hormone in synergizing with glucose to enhance insulin release ( Ørskov 1992 , Egan et al. 2003

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Tao Xie, Min Chen and Lee S Weinstein

. 2003 ). In addition, type 2 diabetics also have increased glucagon (GCG) secretion from pancreatic α-cells and inappropriately increased serum levels of GCG ( Goke 2008 ). Glucagon-like peptide 1 (GLP1) and other incretin hormones promote glucose

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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

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

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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

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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

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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.