THERAPEUTIC STRATEGIES BASED ON GLP-1

Activation of GLP-1 receptor is an important determinant for cell survival , particularly following organ and tissue damage. This makes GLP-1 as an attractive therapeutic agent. But GLP-1 is very susceptible to proteolytic degradation.(plasma half life of 1-2 min).
In this context, two separate approaches can be envisaged.
The development of analogs of GLP-1 that are not susceptible to enzymatic degradation.
The use of selective enzyme inhibitors to prevent degradation and enhance the levels of biologically active peptides.

Enzyme resistant GLP-1 analogs
Exedine-4 is a GLP-1 receptor agonist, originally isolated from the venom of the Gila monster lizard, which shares 53%sequence homology with native GLP-1. It is resistance to DPP-IV (because of the penultimate nh2 terminal is glycine instead of alanine as in GLP-1). It survives longer in the circulation (plasma half life -26 min) Repeated administration of exendin-4 for 13 weeks increased plasma concentration and reduces blood glucose.

Enzyme inhibitors
A DPP-IV inhibitor, valine-pyrrolidide, eliminated NH2­ terminal degradation of
GLP-1, improving the metabolic stability of the intact biologically active peptide and potentiating its insulinotropic and antihyperglycemic effects.
Other inhibitor, isoleucine-thiazolidide, improve glucose tolerance.