Pharmacological characterization and antidiabetic activity of a long‐acting glucagon‐like peptide‐1 analogue conjugated to an antithrombin III‐binding pentasaccharide. Issue 8 (16th June 2015)

• Record Type: Journal Article
• Authors: Patterson, S.; de Kort, M.; Irwin, N.; Moffett, R. C.; Dokter, W. H. A.; Bos, E. S.; Miltenburg, A. M. M.; Flatt, P. R.
• Is Part Of: Diabetes, obesity & metabolism. Volume 17:Issue 8(2015:Aug.)
• Page Start: 760
• Page End: 770
• Publication Date: 2015-06-16
• Subjects: Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.12483
• Languages: English
• ISSNs: 1462-8902

Abstract

<abstract abstract-type="main" id="dom12483-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="dom12483-sec-0001" sec-type="section"> <title>Aims</title> <p id="dom12483-para-0001">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 <sc>d</sc>‐Ala<sup>8</sup>GLP‐1 using a tetraethylene glycol linker.</p> </sec> <sec id="dom12483-sec-0002" sec-type="section"> <title>Methods</title> <p id="dom12483-para-0002">We assessed GLP‐1 receptor binding, cAMP generation and insulin secretory activity of the GLP‐1 conjugate <italic>in vitro</italic>. Circulating half‐life, glucose homeostatic and subchronic therapeutic effectiveness were then examined <italic>in vivo</italic>.</p> </sec> <sec id="dom12483-sec-0003" sec-type="section"> <title>Results</title> <p id="dom12483-para-0003">The half‐life of the GLP‐1 conjugate in mice was ∼11 h. <italic>In vitro</italic> 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<sup>−7</sup> and 9.9 × 10<sup>−8</sup> M for displacement of <sup>125</sup>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 <italic>ob/ob</italic> 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 <italic>db/db</italic> 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.</p> </sec> <sec id="dom12483-sec-0004" sec-type="section"> <title>Conclusion</title> <p id="dom12483-para-0004">These data show that <sc>d</sc>‐Ala<sup>8</sup>GLP‐1(Lys<sup>37</sup>) 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.</p> </sec> </abstract>