Gut peptides in the treatment of diabetes mellitus.
It has been known for at least one century that agents secreted from the intestine during meal absorption regulates glucose assimilation. Extensive research during the past three decades has identified two gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory polypeptide) that are important in postprandial glucose metabolism. Both peptides are incretins; they are secreted during carbohydrate absorption and increase insulin secretion. Since they are potent insulin secretagogues, GIP and GLP-1 have received considerable attention as potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to the need to develop compounds that overcome this rapid inactivation. Two approaches have been taken to utilise the insulinotropic and glucose-lowering actions of GLP-1 as an antidiabetic agent: the development of DPP-IV-resistant analogues and the inhibition of DPP-IV. This review focuses on the physiology of GLP-1 and GIP and the advances that have been made thus far in developing treatments based on these physiological incretins for Type 2 diabetes.
Vahl
Torsten P
TP
University of Cincinnati, Department of Internal Medicine, OH 45220-0547, USA. torsten.vahl@uc.edu
D'Alessio
David A
DA
D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism / Q000627:therapeutic use; D005768:Gastrointestinal Hormones / Q000627:therapeutic use*; D005934:Glucagon / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use; D036361:Peptide Hormones / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use; D011498:Protein Precursors / Q000627:therapeutic use; D011964:Receptors, Gastrointestinal Hormone / Q000008:administration & dosage / Q000187:drug effects; D018027:Receptors, Glucagon / Q000008:administration & dosage / Q000187:drug effects
C000593833:GLP1R protein, human; D005768:Gastrointestinal Hormones; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D036361:Peptide Hormones; D011480:Protease Inhibitors; D011498:Protein Precursors; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D018819:Dipeptidyl Peptidase 4