Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes.
The insulinotropic hormone, glucagon-like peptide 1 (GLP-1), which has been proposed as a new treatment for type 2 diabetes, is metabolized extremely rapidly by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP-IV), resulting in the formation of a metabolite, which may act as an antagonist at the GLP-1 receptor. Because of this, the effects of single injections of GLP-1 are short-lasting, and for full demonstration of its antidiabetogenic effects, continuous intravenous infusion is required. To exploit the therapeutic potential of GLP-1 clinically, we here propose the use of specific inhibitors of DPP-IV. We have demonstrated that the administration of such inhibitors may completely protect exogenous GLP-1 from DPP-IV-mediated degradation, thereby greatly enhancing its insulinotropic effect, and provided evidence that endogenous GLP-1 may be equally protected. Preliminary studies by others in glucose-intolerant experimental animals have shown that DPP-IV inhibition greatly ameliorates the condition. GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, trophic effects on the beta-cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and slowing of gastric emptying, all of which contribute to normalizing elevated glucose levels. Because of this, we predict that inhibition of DPP-IV, which will elevate the levels of active GLP-1 and reduce the levels of the antagonistic metabolite, may be useful to treat impaired glucose tolerance and perhaps prevent transition to type 2 diabetes. The actions of DPP-IV, other than degradation of GLP-1, particularly in the immune system are discussed, but it is concluded that side effects of inhibition therapy are likely to be mild. Thus, DPP-IV inhibition may be an effective supplement to diet and exercise treatment in attempts to prevent the deterioration of glucose metabolism associated with the Western lifestyle.
Holst
J J
JJ
Department of Medical Physiology, University of Copenhagen, Denmark. holst@mfi.ku.dk
Deacon
C F
CF
D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005934:Glucagon / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1; D006801:Humans; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011498:Protein Precursors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use
D010446:Peptide Fragments; D010455:Peptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4