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

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.

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).

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.