Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review.
Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.
Baggio
Laurie L
LL
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Drucker
Daniel J
DJ
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism* / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism* / Q000627:therapeutic use*; D011498:Protein Precursors / Q000378:metabolism* / Q000627:therapeutic use*
D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon