Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes.
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.
Drucker
D J
DJ
Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Canada. d.drucker@utoronto.ca
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D000077270:Exenatide; D005934:Glucagon / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods; D014688:Venoms
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4