Glucagon-like peptide 1 and gastric inhibitory polypeptide: potential applications in type 2 diabetes mellitus.
Although the insulinotropic actions of gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been known for almost 2 decades, the incretin hormones have not yet become available for clinical application. This can be explained by their unfavourable pharmacological properties. Both hormones are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP IV), yielding biologically inactive fragments. There have been several attempts to make use of the antidiabetogenic potential of the incretin hormones. Various analogues of GLP-1 and GIP have been generated in order to achieve resistance to DPP IV degradation. The natural GLP-1 receptor agonist exendin-4, found in the saliva of the Gila monster, has a longer biological half-life after subcutaneous injection than GLP-1, and inhibition of DPP IV using, for example, pyrrolidine derivatives provides elevated concentrations of intact, biologically active GIP and GLP-1 endogenously released from the gut. A continuous intravenous infusion of native GLP-1 for a limited time may be suitable in certain clinical situations. Numerous clinical studies are currently underway to evaluate these approaches. Therefore, an antidiabetic treatment based on incretin hormones may become available within the next 5 years.
Meier
Juris J
JJ
Medizinische Klinik I, St. Josef-Hospital, Klinikum der Ruhr-Universität Bochum, Bochum, Germany.
Gallwitz
Baptist
B
Nauck
Michael A
MA
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D000077270:Exenatide; D005749:Gastric Inhibitory Polypeptide / Q000502:physiology / Q000627:therapeutic use*; D005768:Gastrointestinal Hormones / Q000627:therapeutic use; D005934:Glucagon / Q000502:physiology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000502:physiology / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000627:therapeutic use; D011498:Protein Precursors / Q000502:physiology / Q000627:therapeutic use*; D014688:Venoms
D005768:Gastrointestinal Hormones; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D010455:Peptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D014688:Venoms; C055453:glucagon-like peptide 1 (7-36)amide; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4