@article{bbfb70ffcc0044c8aee31492a94753c8,
title = "A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice",
abstract = "Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala2]palmitoyl-lamprey GLP-1 and [D-Ala2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal β-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet β-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.",
keywords = "Dual agonist, Insulinotropic, Lamprey GLP-1, Obesity, Paddlefish GLP-1, Type 2 diabetes",
author = "Graham, {Galyna V.} and Andrew McCloskey and Abdel-Wahab, {Yasser H.} and Conlon, {J. Michael} and Flatt, {Peter R.}",
note = "Funding Information: The authors wish to thank Bernard Thorens (University of Lausanne, Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University, USA) for glucagon receptor-transfected HEK293 cells, and Jaqueline Naylor (MedImmune, Cambridge, UK) for CRISPR/Cas9-engineered INS-1 cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang (Broad Institute, MIT) and pU6-(BbsI)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn (Broad Institute, MIT). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL), and Ulster University Strategic Funding. Funding Information: The authors wish to thank Bernard Thorens ( University of Lausanne , Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University , USA) for glucagon receptor-transfected HEK293 cells, and Jaqueline Naylor ( MedImmune , Cambridge, UK) for CRISPR/Cas9-engineered INS-1 cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang ( Broad Institute , MIT ) and pU6-(BbsI)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn ( Broad Institute , MIT ). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL) , and Ulster University Strategic Funding. Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",
year = "2020",
month = jan,
day = "1",
doi = "10.1016/j.mce.2019.110584",
language = "English",
volume = "499",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",
}