Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Aims/hypothesis: The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. Materials and methods: The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). Results: Metabolism of GLP-1 (C-terminal RIA; t(1/2) 2.0 +/- 0.2 min, metabolic clearance rate [MCR] 23.2 +/- 2.8 ml min(-1) kg(-1); N-terminal RIA; t(1/2) 1.5 +/- 0.2 min, MCR 88.1 +/- 10.6 ml min(-1) kg(-1)) was significantly faster than the metabolism of exendin-4 (t(1/2) 22.0 +/- 2.1 min, p < 0.0001; MCR 1.7 +/- 0.3 ml min(-1) kg(-1), p < 0.01). Differences in arteriovenous concentrations revealed organ extraction of GLP-1 by the kidneys (C-terminal 56.6 +/- 2.6%; N-terminal 48.3 +/- 5.9%), liver (N-terminal 41.4 +/- 3.8%), and peripheral tissues (C-terminal 42.3 +/- 6.0%; N-terminal 33.0 +/- 7.8%), whereas organ extraction of exendin-4 was limited to the kidneys (21.3 +/- 4.9%). While the renal extraction of exendin-4 (6.9 +/- 2.5 pmol/min) did not differ significantly from the amount undergoing glomerular filtration (8.4 +/- 2.0 pmol/min), the renal extraction of C-terminal GLP-1 (9.0 +/- 1.1 pmol/min), exceeded the amount which could be accounted for by glomerular filtration (4.2 +/- 0.5 pmol/min, p < 0.0005). Conclusions/interpretation: In addition to an increased resistance to enzymatic degradation, the increased stability of exendin-4 is the result of reduced differential organ extraction compared to GLP-1. The data suggest that in the anaesthetised pig, extraction occurs only in the kidney and can be fully accounted for by glomerular filtration.