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A comparison of the cellular and biological properties of DPP-IV-resistant N-glucitol analogues of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Green, BD, Gault, Victor, O'Harte, Finbarr and Flatt, Peter (2005) A comparison of the cellular and biological properties of DPP-IV-resistant N-glucitol analogues of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. DIABETES OBESITY AND METABOLISM, 7 (5). pp. 595-604. [Journal article]

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DOI: 10.1111/j.1463-1326.2004.00455.x

Abstract

Aim: The two major incretin hormones - glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) - are being actively researched by the pharmaceutical industry because of their glucose-lowering and potential anti-diabetic properties. Unfortunately, the inactivation of GLP-1 and GIP in the circulation brought about by dipeptidyl-peptidase-IV (DPP-IV) degradation makes their biological actions short-lived. This study directly compares the cellular and biological properties of GLP-1, GIP and their N-terminally modified counterparts, with glucitol extension at positions His(7) and Tyr(1), respectively, to confer DPP-IV resistance. Methods: Using both the glucose-responsive pancreatic beta-cell line, BRIN BD11, and the obese diabetic (ob/ob) mouse, we assessed adenosine 3',5'-cyclic monophosphate (cAMP) production and insulinotropic action in vitro as well as in vivo glucose-lowering and insulin-releasing actions. Results: The results reveal that glycation of the N-terminus of GLP-1 or GIP stabilized both peptides against DPP-IV degradation. However, N-glucitol-GLP-1 displayed reduced cAMP production, insulinotropic activity and glucose-lowering potency, compared to native GLP-1. By contrast, N-glucitol-GIP exhibited substantially improved biological activities, compared to native GIP, and possessed similar or enhanced in vivo potency to GLP-1. N-terminal extension by means of glucitol addition is more beneficial to bioactivity of GIP than it is to GLP-1. Conclusions: N-terminal glycation generates a super GIP agonist, which possesses acute in vivo glucose-lowering and insulinotropic actions superior to native GLP-1. Therefore, N-glucitol-GIP is a particularly attractive potential candidate molecule for drug therapy of type 2 diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:2997
Deposited By:Professor Peter Flatt
Deposited On:18 Dec 2009 09:53
Last Modified:11 Jun 2010 10:22

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