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

Metabolism. 1999 Feb;48(2):252-8. doi: 10.1016/s0026-0495(99)90043-4.


Glucagon-like peptide-1(7-37) (GLP-1) is the most potent insulinotropic hormone characterized thus far. Because its activity is preserved in non-insulin-dependent diabetes mellitus (NIDDM) patients, it is considered a potential new drug for the treatment of this disease. One limitation in its therapeutic use is a short half-life in vivo (5 minutes), due in part to a fast degradation 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, respectively) but did not change the efficiency to stimulate accumulation of intracellular cyclic adenosine monophosphate (cAMP) (EC50, 0.25 +/- 0.05 and 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 insulinotropic 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 diabetic mice fed a high-fat diet can correct fasting hyperglycemia and glucose intolerance for several hours, whereas the activity of 1 nmol GLP-1 vanishes a few minutes after injection. These actions were correlated with increased insulin and decreased glucagon levels. Interestingly, normoglycemia was maintained over a period that was longer than the predicted peptide half-life, suggesting a yet undescribed long-term effect of GLP-1-Gly8. GLP-1-Gly8 thus has a markedly improved therapeutic potential compared with GLP-1, since it can be used at much lower doses and with a more flexible schedule of administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • Blood Glucose / metabolism
  • Cells, Cultured
  • Diet
  • Dipeptidyl Peptidase 4 / metabolism*
  • Glucagon / blood
  • Glucagon / metabolism
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Glucose Tolerance Test
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Insulin / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Protein Precursors / metabolism
  • Protein Precursors / pharmacology*


  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Peptide Fragments
  • Protein Precursors
  • Glucagon-Like Peptide 1
  • Glucagon
  • Dipeptidyl Peptidase 4