Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes

Curr Pharm Des. 2001 Sep;7(14):1399-412. doi: 10.2174/1381612013397401.


Glucagon-like peptide-1 (GLP-1) is released from gut endocrine cells following nutrient ingestion and acts to regulate nutrient assimilation via effects on gastrointestinal motility, islet hormone secretion, and islet cell proliferation. Exogenous administration of GLP-1 lowers blood glucose in normal rodents and in multiple experimental models of diabetes mellitus. Similarly, GLP-1 lowers blood glucose in normal subjects and in patients with type 2 diabetes. The therapeutic utility of the native GLP-1 molecule is limited by its rapid enzymatic degradation by the serine protease dipeptidyl peptidase IV. This review highlights recent advances in our understanding of GLP-1 physiology and GLP-1 receptor signaling, and summarizes current pharmaceutical strategies directed at sustained activation of GLP-1 receptor-dependent actions for glucoregulation in vivo. Given the nutrient-dependent control of GLP-1 release, neutraceuticals or modified diets that enhance GLP-1 release from the enteroendocrine cell may exhibit glucose-lowering properties in human subjects. The utility of GLP-1 derivatives engineered for sustained action and/or DP IV-resistance, and the biological activity of naturally occurring GLP-1-related molecules such as exendin-4 is reviewed. Circumventing DP IV-mediated incretin degradation via inhibitors that target the DP IV enzyme represents a complementary strategy for enhancing GLP-1-mediated actions in vivo. Finally, the current status of alternative GLP-1-delivery systems via the buccal and enteral mucosa is briefly summarized. The findings that the potent glucose-lowering properties of GLP-1 are preserved in diabetic subjects, taken together with the potential for GLP-1 therapy to preserve or augment beta cell mass, provides a powerful impetus for development of GLP-1-based human pharmaceuticals.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Dipeptidyl Peptidase 4 / metabolism
  • Drug Delivery Systems / methods
  • Exenatide
  • Glucagon / chemistry
  • Glucagon / metabolism
  • Glucagon / therapeutic use*
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Peptide Fragments / chemistry
  • Peptide Fragments / metabolism
  • Peptide Fragments / therapeutic use*
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Protein Precursors / chemistry
  • Protein Precursors / metabolism
  • Protein Precursors / therapeutic use*
  • Receptors, Glucagon / metabolism
  • Technology, Pharmaceutical* / methods
  • Venoms*


  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Peptide Fragments
  • Peptides
  • Protein Precursors
  • Receptors, Glucagon
  • Venoms
  • Glucagon-Like Peptide 1
  • Glucagon
  • Exenatide
  • Dipeptidyl Peptidase 4