Pharmacological characterization and antidiabetic activity of a long-acting glucagon-like peptide-1 analogue conjugated to an antithrombin III-binding pentasaccharide.

Autor: Patterson S; SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.; Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK., de Kort M; MSD, Oss, The Netherlands., Irwin N; SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK., Moffett RC; SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK., Dokter WH; MSD, Oss, The Netherlands., Bos ES; MSD, Oss, The Netherlands., Miltenburg AM; MSD, Oss, The Netherlands., Flatt PR; SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2015 Aug; Vol. 17 (8), pp. 760-70. Date of Electronic Publication: 2015 Jun 16.
DOI: 10.1111/dom.12483
Abstrakt: Aims: To examine the biological characteristics of a novel glucagon-like peptide-1 (GLP-1) conjugate, in which an antithrombin III (ATIII)-binding pentasaccharide is conjugated to d-Ala(8) GLP-1 using a tetraethylene glycol linker.
Methods: We assessed GLP-1 receptor binding, cAMP generation and insulin secretory activity of the GLP-1 conjugate in vitro. Circulating half-life, glucose homeostatic and subchronic therapeutic effectiveness were then examined in vivo.
Results: The half-life of the GLP-1 conjugate in mice was ∼11 h. In vitro insulin secretion from clonal β cells and islets was increased (p < 0.001) by the conjugate. The conjugate had half maximum effective concentration values of 1.3 × 10(-7) and 9.9 × 10(-8)  M for displacement of (125) I-GLP-1 in competitive GLP-1 receptor binding and cAMP generation, respectively. Glucose tolerance in normal mice, immediately and 4 h after conjugate injection, resulted in significant (p < 0.001) improvements in blood glucose. These effects persisted for >48 h after administration. Daily treatment (21 days) of high-fat-fed and ob/ob mice with 25 nmol/kg conjugate resulted in significant improvement in glucose tolerance (p < 0.001) and reductions in glycated haemoglobin (HbA1c; p < 0.01) equivalent to or better than with exenatide or liraglutide. Treatment of C57BL/KsJ db/db mice for 15 days with 100 nmol/kg conjugate significantly (p < 0.001) reduced glucose and raised plasma insulin. Oral glucose tolerance was significantly (p < 0.001) improved and both 24-h glucose profile (p < 0.001) and HbA1c levels (p < 0.001) were reduced. Islet size (p < 0.001) and pancreatic insulin content were increased without change of islet cell proliferation or apoptosis.
Conclusion: These data show that d-Ala(8) GLP-1(Lys(37) ) pentasaccharide exerts significant antidiabetic actions and has a projected pharmacokinetic/pharmacodynamic profile that merits further evaluation in humans for a possible once-weekly dosing regimen.
(© 2015 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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