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

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 circula ting GLP-2-(1-33) levels in vivo, GLP-2-(1-33) or the DP IV-resistant analo g [Gly(2)] 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 G LP-2(1-33) in DP IV-negative rats and for [Gly(2)]GLP-2 in normal rats. To determine the role of the kidney in clearance of GLP-2-(1-33) from the circ ulation, normal rats were bilaterally nephrectomized, and plasma immunoreac tive 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 nephrectomi zed compared with nonnephrectomized rats (P < 0.01). In contrast to both GL P-2-(1-33) and [Gly2]GLP-2, GLP-2-(3-33) did not stimulate intestinal growt h in a murine assay in vivo. Thus the intestinotropic actions of GLP-2-(1-3 3) are determined both by the actions of DP IV and by the kidney in vivo in the rat.