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Exp Clin Endocrinol Diabetes 2002; 110(3): 113-118
DOI: 10.1055/s-2002-29087
Articles

© Johann Ambrosius Barth

Endoproteolysis by isolated membrane peptidases reveal metabolic stability of glucagon-like peptide-1 analogs, exendins-3 and -4

A. Thum 1 , K. Hupe-Sodmann 1 , R. Göke 2 , K. Voigt 1 , B. Göke 3 , G. P. McGregor 1
  • 1 Institute of Physiology, Philipps-University, Marburg, Germany
  • 2 Clinical Research Unit for Gastrointestinal Endocrinology, University of Marburg, Germany
  • 3 Department of Medicine II, University of Munich, Klinikum Grosshadern, Munich, Germany
Further Information

Publication History

received 21 September 2001 first decision 26 October 2001

accepted 07 February 2002

Publication Date:
15 May 2002 (online)

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Summary

These in vitro studies aimed to characterize the pattern and the kinetics of endoproteolysis of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) and related peptides by native ectopeptidases. Peptides were incubated with isolated rat or pig kidney brush-border microvilli membranes, which are a rich source of the ectopeptidases that are responsible for the post-secretory metabolism of peptide hormones. The proteolytic products were separated by reversed-phase HPLC column chromatography and characterised by molecular mass and primary structure. The relative importance of specific peptidases was established by measuring the effects of specific peptidase inhibitors on the kinetics of proteolysis. Dipeptidyl-peptidase-IV was found to be rate-limiting in the endoproteolysis of GLP-1. GLP-1 homologs, exendins-3 and -4, exhibited exceptional stability in the presence of isolated kidney microvilli membranes. Our finding that exendin-4 is several orders of magnitude more stable than GLP-1 and Ser-8-GLP-1 is especially noteworthy given this peptide's widely reported insulinotropic potency.

Key words:

Glucagon-like peptide-1 - Exendin-3 - Exendin-4 - Membrane ectopeptidases - Endoproteolysis

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Prof. G. P. McGregor

Institute of Physiology

Philipps-University Marburg

Deutschhausstr. 2

D-35037 Marburg

Germany

Phone: +49-6421-285353

Fax: +49-6421-282306

Email: prof.mcgregor@pascoe.de

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