Incretin-based therapies: mimetics versus protease inhibitors.
The physiological incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), lower blood glucose levels through multiple mechanisms, including enhancement of glucose-stimulated insulin secretion. Although of demonstrated benefit to glycemic control in patients with type 2 diabetes, particularly for GLP-1, the half-lives of these peptides are too short for practical therapeutic utility. Here, we discuss recent approaches to incretin-based therapy, including the use of long-acting GLP-1 receptor agonists, degradation-resistant GLP-1 analogs, GLP-1 analogs conjugated to albumin, non-peptide small molecules that bind to the GLP-1 receptor, and inhibitors of dipeptidyl peptidase IV, the enzyme that degrades both GIP and GLP-1.
Brubaker
Patricia L
PL
Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada. p.brubaker@utoronto.ca
D000595:Amino Acid Sequence; D000818:Animals; D032701:Biomimetics; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008954:Models, Biological; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000627:therapeutic use*; D017386:Sequence Homology, Amino Acid
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011480:Protease Inhibitors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1