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Journal of Clinical Endocrinology & Metabolism, Vol 80, 952-957, Copyright © 1995 by Endocrine Society

ARTICLES

Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo

CF Deacon, AH Johnsen and JJ Holst
Department of Medical Physiology, Panum Institute, University of Copenhagen, Denmark.

The metabolism of glucagon-like peptide-1 (GLP-1) has not been studied in detail, but it is known to be rapidly cleared from the circulation. Measurement by RIA is hampered by the fact that most antisera are side- viewing or C-terminally directed, and recognize both intact GLP-1 and biologically inactive. N-terminally truncated fragments. Using high pressure liquid chromatography in combination with RIAs, methodology allowing specific determination of both intact GLP-1 and its metabolites was developed. Human plasma was shown to degrade GLP-1-(7- 36)amide, forming an N-terminally truncated peptide with a t1/2 of 20.4 +/- 1.4 min at 37 C (n = 6). This was unaffected by EDTA or aprotinin. Inhibitors of dipeptidyl peptidase-IV or low temperature (4 C) completely prevented formation of the metabolite, which was confirmed to be GLP-1-(9-36)amide by mass spectrometry and sequence analysis. High pressure liquid chromatography revealed the concentration of GLP-1- (9-36)amide to be 53.5 +/- 13.7% of the concentration of endogenous intact GLP-1 in the fasted state, which increased to 130.8 +/- 10.0% (P < 0.01; n = 6) 1 h postprandially. Metabolism at the C-terminus was not observed. This study suggests that dipeptidyl peptidase-IV is the primary mechanism for GLP-1 degradation in human plasma in vitro and may have a role in inactivating the peptide in vivo.


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Endocrinology, February 1, 2001; 142(2): 521 - 527.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
C. F. Deacon, M. A. Nauck, J. Meier, K. Hücking, and J. J. Holst
Degradation of Endogenous and Exogenous Gastric Inhibitory Polypeptide in Healthy and in Type 2 Diabetic Subjects as Revealed Using a New Assay for the Intact Peptide
J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3575 - 3581.
[Abstract] [Full Text]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
B. Balkan and X. Li
Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2000; 279(4): R1449 - R1454.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
B. Hartmann, M. B. Harr, P. B. Jeppesen, M. Wojdemann, C. F. Deacon, P. B. Mortensen, and J. J. Holst
In Vivo and in Vitro Degradation of Glucagon-Like Peptide-2 in Humans
J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2884 - 2888.
[Abstract] [Full Text]

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 Am. J. Physiol. Endocrinol. Metab.Home page
L. Hansen, B. Hartmann, T. Bisgaard, H. Mineo, P. N. Jorgensen, and J. J. Holst
Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum
Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1010 - E1018.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
Q. Xiao, R. P. Boushey, M. Cino, D. J. Drucker, and P. L. Brubaker
Circulating levels of glucagon-like peptide-2 in human subjects with inflammatory bowel disease
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2000; 278(4): R1057 - R1063.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
W. Tavares, D. J. Drucker, and P. L. Brubaker
Enzymatic- and renal-dependent catabolism of the intestinotropic hormone glucagon-like peptide-2 in rats
Am J Physiol Endocrinol Metab, January 1, 2000; 278(1): E134 - E139.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
T. J. Kieffer and J. Francis Habener
The Glucagon-Like Peptides
Endocr. Rev., December 1, 1999; 20(6): 876 - 913.
[Abstract] [Full Text]

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 EndocrinologyHome page
L. Hansen, C. F. Deacon, C. Ørskov, and J. J. Holst
Glucagon-Like Peptide-1-(7-36)Amide Is Transformed to Glucagon-Like Peptide-1-(9-36)Amide by Dipeptidyl Peptidase IV in the Capillaries Supplying the L Cells of the Porcine Intestine
Endocrinology, November 1, 1999; 140(11): 5356 - 5363.
[Abstract] [Full Text]

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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
E. Naslund, J. Bogefors, S. Skogar, P. Gryback, H. Jacobsson, J. J. Holst, and P. M. Hellstrom
GLP-1 slows solid gastric emptying and inhibits insulin, glucagon, and PYY release in humans
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 1999; 277(3): R910 - R916.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
A. S. Ryan, J. M. Egan, J. F. Habener, and D. Elahi
Insulinotropic Hormone Glucagon-Like Peptide-1-(7-37) Appears Not to Augment Insulin-Mediated Glucose Uptake in Young Men during Euglycemia
J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2399 - 2404.
[Abstract] [Full Text]

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 Proc. Natl. Acad. Sci. USAHome page
H. Li, H. Wang, K. M. Schegg, and D. A. Schooley
Metabolism of an insect diuretic hormone by Malpighian tubules studied by liquid chromatography coupled with electrospray ionization mass spectrometry
PNAS, December 9, 1997; 94(25): 13463 - 13468.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
P. L. Brubaker, A. Crivici, A. Izzo, P. Ehrlich, C.-H. Tsai, and D. J. Drucker
Circulating and Tissue Forms of the Intestinal Growth Factor, Glucagon-Like Peptide-2
Endocrinology, November 1, 1997; 138(11): 4837 - 4843.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
H. J. Balks, J. J. Holst, A. von zur Muhlen, and G. Brabant
Rapid Oscillations in Plasma Glucagon-Like Peptide-1 (GLP-1) in Humans: Cholinergic Control of GLP-1 Secretion via Muscarinic Receptors
J. Clin. Endocrinol. Metab., March 1, 1997; 82(3): 786 - 790.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
R. P. Pauly, F. Rosche, M. Wermann, C. H.S. McIntosh, R. A. Pederson, and H.-U. Demuth
Investigation of Glucose-dependent Insulinotropic Polypeptide(1-42) and Glucagon-like Peptide-1-(7-36) Degradation in Vitro by Dipeptidyl Peptidase IV Using Matrix-assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry. A NOVEL KINETIC APPROACH
J. Biol. Chem., September 20, 1996; 271(38): 23222 - 23229.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
L. Baggio, F. Adatia, T. Bock, P. L. Brubaker, and D. J. Drucker
Sustained Expression of Exendin-4 Does Not Perturb Glucose Homeostasis, beta -Cell Mass, or Food Intake in Metallothionein-Preproexendin Transgenic Mice
J. Biol. Chem., October 27, 2000; 275(44): 34471 - 34477.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
C. F. Deacon, A. Plamboeck, S. Moller, and J. J. Holst
GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion
Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E873 - E879.
[Abstract] [Full Text] [PDF]


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