Mode of action of DPP-IV inhibitors

DPP-4 cleaves an N-terminal dipeptide from susceptible peptides, and early in vitro kinetic studies revealed that both GLP-1 and GIP are substrates. The extremely rapid and extensive degradation of GLP-1 by DPP-4 gave rise to the proposal that inhibitors of the enzyme could be used as a therapy for type 2 diabetes, by protecting and thereby enhancing the circulating levels of GLP-1. Early experiments documented that administration of an already existing inhibitor to pigs completely protected both endogenous and exogenous GLP-1, which furthermore greatly enhanced insulin responses to glucose. The idea was quickly accepted by the pharmaceutical industry and numerous companies embarked on development of DPP-4 inhibitors for clinical use. The DPP-4 inhibitors are all orally available and are rapidly absorbed, with significant inhibition of plasma DPP-4 activity within 5 min of administration.

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