Long-lasting antidiabetic effect of a dipeptidyl peptidase IV-resistant analog of glucagon-like peptide-1

Glucagon-like peptide-1(7-37) (GLP-1) is the most potent insulinotropic hor mone characterized thus far. Because its activity is preserved in non-insul in-dependent diabetes mellitus (NIDDM) patients, it is considered a potenti al new drug for the treatment of this disease. One limitation in its therap eutic use is a short half-life in vivo (5 minutes), due in part to a fast d egradation by the endoprotease dipeptidylpeptidase IV (DPPIV). Recently, it was reported that GLP-1 became resistant to DPPIV when the alanine residue at position 8 was replaced by a glycine (GLP-1-Gly8). We report here that this change slightly decreased the affinity of the peptide for its receptor (IC50, 0.41 +/- 0.14 and 1.39 +/- 0.61 nmol/L for GLP-1 and GLP-1-Gly8, re spectively) but did not change the efficiency to stimulate accumulation of intracellular cyclic adenosine monophosphate (cAMP) (EC50, 0.25 +/- 0.05 an d 0.36 +/- 0.06 nmol/L for GLP-1 and GLP-1-Gly8, respectively). Second, we demonstrate for the first time that this mutant has an improved insulinotro pic activity compared with the wild-type peptide when tested in vivo in an animal model of diabetes. A single injection of 0.1 nmol GLP-1-Gly8 in diab etic mice fed a high-fat diet can correct fasting hyperglycemia and glucose intolerance for several hours, whereas the activity of 1 nmol GLP-1 vanish es a few minutes after injection. These actions were correlated with increa sed insulin and decreased glucagon levels. Interestingly, normoglycemia was maintained over a period that was longer than the predicted peptide half-l ife, suggesting a yet undescribed long-term effect of GLP-1-Gly8. GLP-1-Gly 8 thus has a markedly improved therapeutic potential compared with GLP-1, s ince it can be used at much lower doses and with a more flexible schedule o f administration. Copyright (C) 1999 by W.B. Saunders Company.