Novel DPP-IV-resistant Analogs of GLP-1: The N-terminal Extension of GLP-1 by a Single Amino Acid

摘要

Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced from intestinal L cells of the gut and plays an important role in glucose-dependent insulin secretion, suppression of glucagon secretion, proliferation of pancreatic β-cells, and inhibition of food intake. The short half-life of GLP-1 (t_(1/2) < 2 minutes) resulted from degradation by dipeptidyl peptidase IV (DPP-IV), however, has stymied the application of GLP-1 for the treatment of insulin-resistant type 2 diabetes. Exendin-4, which is derived from saliva of a lizard Gila monster with ～53% sequence homology with GLP-1, has Gly in position 2 rather than Ala, as is the case in GLP-1. Thus, exendin-4 is resistant to the cleavage by DPP-IV and has a half-life of approximately 30 minutes after intravenous administration and 2-3 hours after subcutaneous administration in humans.'