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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3 Citations (Scopus)

Abstract

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.
LanguageEnglish
Pages760-770
JournalDiabetes Obesity and Metabolism
Volume17
Issue number8
DOIs
Publication statusPublished - 1 Aug 2015

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Glucagon-Like Peptide 1
Antithrombin III
Hypoglycemic Agents
Pharmacology
Insulin
Glucose
Islets of Langerhans
Half-Life
Glycols
Glycosylated Hemoglobin A
Glucose Tolerance Test
Pharmacokinetics
Fats
Cell Proliferation
Apoptosis

Keywords

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

Cite this

@article{5b773779612b4372b3c31a13e1515697,
title = "Pharmacological characterization and antidiabetic activity of a long-acting glucagon-like peptide-1 analogue conjugated to an antithrombin III-binding pentasaccharide.",
abstract = "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.",
keywords = "ATIII, GLP-1, glucagon-like peptide-1, glucose homeostasis, insulin secretion, liraglutide, pentasaccharide",
author = "S Patterson and {de Kort}, M and Nigel Irwin and Charlotte Moffett and WH Dokter and ES Bos and AM Miltenburg and Peter Flatt",
year = "2015",
month = "8",
day = "1",
doi = "10.1111/dom.12483",
language = "English",
volume = "17",
pages = "760--770",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "8",

}

TY - JOUR

T1 - Pharmacological characterization and antidiabetic activity of a long-acting glucagon-like peptide-1 analogue conjugated to an antithrombin III-binding pentasaccharide.

AU - Patterson, S

AU - de Kort, M

AU - Irwin, Nigel

AU - Moffett, Charlotte

AU - Dokter, WH

AU - Bos, ES

AU - Miltenburg, AM

AU - Flatt, Peter

PY - 2015/8/1

Y1 - 2015/8/1

N2 - 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.

AB - 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.

KW - ATIII

KW - GLP-1

KW - glucagon-like peptide-1

KW - glucose homeostasis

KW - insulin secretion

KW - liraglutide

KW - pentasaccharide

U2 - 10.1111/dom.12483

DO - 10.1111/dom.12483

M3 - Article

VL - 17

SP - 760

EP - 770

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 8

ER -