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

S Patterson, M de Kort, Nigel Irwin, Charlotte Moffett, WH Dokter, ES Bos, AM Miltenburg, Peter Flatt

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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.
Original languageEnglish
Pages (from-to)760-770
Number of pages11
JournalDiabetes Obesity and Metabolism
Issue number8
Early online date30 Apr 2015
Publication statusPublished - 1 Aug 2015



  • GLP-1
  • glucagon-like peptide-1
  • glucose homeostasis
  • insulin secretion
  • liraglutide
  • pentasaccharide

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