Circulation and degradation of GIP and GLP-1.
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted from the intestinal K- and L-cells, respectively, but are immediately subject to rapid degradation. GLP-1 is found in two active forms, amidated GLP-1 (7-36) amide and glycine-extended GLP-1 (7-37), while GIP exists as a single 42 amino acid peptide. The aminopeptidase, dipeptidyl peptidase IV (DPP IV), which is found in the endothelium of the local capillary bed within the intestinal wall, is important for the initial inactivation of both peptides, with GLP-1 being particularly readily degraded. DPP IV cleavage generates N-terminally truncated metabolites (GLP-1 (9-36) amide / (9-37) and GIP (3-42)), which are the major circulating forms. Subsequently, the peptides may be degraded by other enzymes and extracted in an organ-specific manner. However, other endogenous metabolites have not yet been identified, possibly because existing assays are unable either to recognize them or to differentiate them from the primary metabolites. Neutral endopeptidase 24.11 has been demonstrated to be able to degrade GLP-1 in vivo, but its relevance in GIP metabolism has not yet been established. Intact GLP-1 and GIP are inactivated during passage across the hepatic bed by DPP IV associated with the hepatocytes, and further degraded by the peripheral tissues, while the kidney is important for the final elimination of the metabolites.
Deacon
C F
CF
Department of Medical Physiology, The Panum Institute, 2200 Copenhagen N, Denmark. deacon@mfi.ku.dk
D000243:Adenosine Deaminase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000378:metabolism*; D005934:Glucagon / Q000097:blood / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D015260:Neprilysin / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism*
D006023:Glycoproteins; D010446:Peptide Fragments; D011498:Protein Precursors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin; D000243:Adenosine Deaminase