Pharmacological characterisation and antidiabetic activity of a long-acting GLP-1 analogue conjugated to an ATIII-binding pentasaccharide

S. Patterson, M. de Kort, N. Irwin, R.C. Moffett, W.H.A. Dokter, E.S. Bos, A.M.M. Miltenburg, P.R. Flatt

Research output: Contribution to journalArticle

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‐Ala8GLP‐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 125I‐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‐Ala8GLP‐1(Lys37) 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
Volume17
Issue number8
Early online date30 Apr 2015
DOIs
Publication statusPublished - Aug 2015

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Glucagon-Like Peptide 1
Antithrombin III
Hypoglycemic Agents
Pharmacology
Insulin
Glucose
Islets of Langerhans
Half-Life
Cyclic AMP Receptors
Glycols
Glycosylated Hemoglobin A
Glucose Tolerance Test
Pharmacokinetics
Cell Proliferation
Apoptosis
In Vitro Techniques
Therapeutics

Keywords

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

Cite this

Patterson, S. ; de Kort, M. ; Irwin, N. ; Moffett, R.C. ; Dokter, W.H.A. ; Bos, E.S. ; Miltenburg, A.M.M. ; Flatt, P.R. / Pharmacological characterisation and antidiabetic activity of a long-acting GLP-1 analogue conjugated to an ATIII-binding pentasaccharide. In: Diabetes, Obesity and Metabolism. 2015 ; Vol. 17, No. 8. pp. 760-770.
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Pharmacological characterisation and antidiabetic activity of a long-acting GLP-1 analogue conjugated to an ATIII-binding pentasaccharide. / Patterson, S.; de Kort, M.; Irwin, N.; Moffett, R.C.; Dokter, W.H.A.; Bos, E.S.; Miltenburg, A.M.M.; Flatt, P.R.

In: Diabetes, Obesity and Metabolism, Vol. 17, No. 8, 08.2015, p. 760-770.

Research output: Contribution to journalArticle

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T1 - Pharmacological characterisation and antidiabetic activity of a long-acting GLP-1 analogue conjugated to an ATIII-binding pentasaccharide

AU - Patterson, S.

AU - de Kort, M.

AU - Irwin, N.

AU - Moffett, R.C.

AU - Dokter, W.H.A.

AU - Bos, E.S.

AU - Miltenburg, A.M.M.

AU - Flatt, P.R.

N1 - Details from accepted version of article - add reference information when available. ET 15-6-15

PY - 2015/8

Y1 - 2015/8

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‐Ala8GLP‐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 125I‐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‐Ala8GLP‐1(Lys37) 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‐Ala8GLP‐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 125I‐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‐Ala8GLP‐1(Lys37) 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 - glucagon-like peptide-1 (GLP-1)

KW - glucose homeostasis

KW - insulin secretion

KW - pentasaccharide

KW - liraglutide

KW - GLP-1

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DO - 10.1111/dom.12483

M3 - Article

VL - 17

SP - 760

EP - 770

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

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