N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

Finbarr O'Harte, MH Mooney, A Lawlor, Peter Flatt

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH2-terminally modified His(7)-glucitol tGLP-1 and its insulin-releasing and antihyperglycaemic activity in vivo, tGLP-1 was degraded by purified DPP IV after 4 h (43% intact) and after 12 hi 89% was converted to GLP-1(9-36)amide. In contrast > 99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administration of tGLP-1 and His7-glucitol tGLP-1 (36 and 49% less; AUC; 440 +/- 40 and 353 +/- 31 mM/min, respectively; P <0.01). This was associated with a significantly higher AUC for insulin (98-99% greater; AUC 834 +/- 6 and 838 +/- 39 ng/ml/min, respectively: P <0.01) after tGLP-1 and His7-glucitol tGLP-1 administration compared to controls (421 +/- 30 ng/ml/min). In conclusion, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo. (C) 2000 Elsevier Science B.V. All rights reserved.
LanguageEnglish
Pages13-22
JournalBIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume1474
Issue number1
Publication statusPublished - Mar 2000

Fingerprint

Hypoglycemic Agents
Sorbitol
Area Under Curve
Dipeptidyl Peptidase 4
Glucose
Insulin
glucagon-like peptide 1 (7-36)amide
glucagon-like peptide 1 (7-37)
Peptides
Dipeptides
Wistar Rats
Homeostasis
Injections

Cite this

@article{050c76dd2f7d4caa819340ee6cd40518,
title = "N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo",
abstract = "Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH2-terminally modified His(7)-glucitol tGLP-1 and its insulin-releasing and antihyperglycaemic activity in vivo, tGLP-1 was degraded by purified DPP IV after 4 h (43{\%} intact) and after 12 hi 89{\%} was converted to GLP-1(9-36)amide. In contrast > 99{\%} of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resistance to degradation in vivo (92{\%} intact) compared to tGLP-1 (27{\%} intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administration of tGLP-1 and His7-glucitol tGLP-1 (36 and 49{\%} less; AUC; 440 +/- 40 and 353 +/- 31 mM/min, respectively; P <0.01). This was associated with a significantly higher AUC for insulin (98-99{\%} greater; AUC 834 +/- 6 and 838 +/- 39 ng/ml/min, respectively: P <0.01) after tGLP-1 and His7-glucitol tGLP-1 administration compared to controls (421 +/- 30 ng/ml/min). In conclusion, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo. (C) 2000 Elsevier Science B.V. All rights reserved.",
author = "Finbarr O'Harte and MH Mooney and A Lawlor and Peter Flatt",
year = "2000",
month = "3",
language = "English",
volume = "1474",
pages = "13--22",
journal = "BBA - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - N-terminally modified glucagon-like peptide-1(7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo

AU - O'Harte, Finbarr

AU - Mooney, MH

AU - Lawlor, A

AU - Flatt, Peter

PY - 2000/3

Y1 - 2000/3

N2 - Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH2-terminally modified His(7)-glucitol tGLP-1 and its insulin-releasing and antihyperglycaemic activity in vivo, tGLP-1 was degraded by purified DPP IV after 4 h (43% intact) and after 12 hi 89% was converted to GLP-1(9-36)amide. In contrast > 99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administration of tGLP-1 and His7-glucitol tGLP-1 (36 and 49% less; AUC; 440 +/- 40 and 353 +/- 31 mM/min, respectively; P <0.01). This was associated with a significantly higher AUC for insulin (98-99% greater; AUC 834 +/- 6 and 838 +/- 39 ng/ml/min, respectively: P <0.01) after tGLP-1 and His7-glucitol tGLP-1 administration compared to controls (421 +/- 30 ng/ml/min). In conclusion, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo. (C) 2000 Elsevier Science B.V. All rights reserved.

AB - Glucagon-like peptide-1 (7-36)amide (tGLP-1) is inactivated by dipeptidyl peptidase (DPP) IV by removal of the NH2-terminal dipeptide His(7)-Ala(8). We examined the degradation of NH2-terminally modified His(7)-glucitol tGLP-1 and its insulin-releasing and antihyperglycaemic activity in vivo, tGLP-1 was degraded by purified DPP IV after 4 h (43% intact) and after 12 hi 89% was converted to GLP-1(9-36)amide. In contrast > 99% of His(7)-glucitol tGLP-1 remained intact at 12 h. His(7)-glucitol tGLP-1 was similarly resistant to plasma degradation in vitro. His7-glucitol tGLP-1 showed greater resistance to degradation in vivo (92% intact) compared to tGLP-1 (27% intact) 10 min after i.p. administration to Wistar rats. Glucose homeostasis was examined following i.p. injection of both peptides (12 nmol/kg) together with glucose (18 mmol/kg). Plasma glucose concentrations were significantly reduced and insulin concentrations elevated following peptides administration compared with glucose alone. The area under the curve (AUC) for glucose for controls (AUC 691 +/- 35 mM/min) was significantly lower after administration of tGLP-1 and His7-glucitol tGLP-1 (36 and 49% less; AUC; 440 +/- 40 and 353 +/- 31 mM/min, respectively; P <0.01). This was associated with a significantly higher AUC for insulin (98-99% greater; AUC 834 +/- 6 and 838 +/- 39 ng/ml/min, respectively: P <0.01) after tGLP-1 and His7-glucitol tGLP-1 administration compared to controls (421 +/- 30 ng/ml/min). In conclusion, His(7)-glucitol tGLP-1 resists plasma DPP IV degradation while retaining potent antihyperglycaemic and insulin-releasing activities in vivo. (C) 2000 Elsevier Science B.V. All rights reserved.

M3 - Article

VL - 1474

SP - 13

EP - 22

JO - BBA - General Subjects

T2 - BBA - General Subjects

JF - BBA - General Subjects

SN - 0304-4165

IS - 1

ER -