Enzymatic- and renal-dependent catabolism of the intestinotropic hormone glucagon-like peptide-2 in rats

Abstract

The intestinotropic hormone glucagon-like peptide (GLP)-2-(1—33) is cleaved in vitro to GLP-2-(3—33) by dipeptidyl peptidase IV (DP IV). To determine the importance of DP IV versus renal clearance in the regulation of circulating GLP-2-(1—33) levels in vivo, GLP-2-(1—33) or the DP IV-resistant analog [Gly2]GLP-2 was injected in normal or DP IV-negative rats and assayed by HPLC and RIA. Normal rats showed a steady degradation of GLP-2-(1—33) to GLP-2-(3—33) over time, whereas little or no conversion was detected for GLP-2-(1—33) in DP IV-negative rats and for [Gly2]GLP-2 in normal rats. To determine the role of the kidney in clearance of GLP-2-(1—33) from the circulation, normal rats were bilaterally nephrectomized, and plasma immunoreactive GLP-2 levels were measured. The slope of the disappearance curves for both GLP-2-(1—33) and [Gly2]GLP-2 were significantly reduced in nephrectomized compared with nonnephrectomized rats ( P < 0.01). In contrast to both GLP-2-(1—33) and [Gly2]GLP-2, GLP-2-(3—33) did not stimulate intestinal growth in a murine assay in vivo. Thus the intestinotropic actions of GLP-2-(1—33) are determined both by the actions of DP IV and by the kidney in vivo in the rat.