1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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Dipeptidyl peptidase-IV (DPP-IV) inhibitors (“incretin enhancers”)
The major therapeutic drawback using native GLP-1 is its very short half-life of less
than 2 minutes, following exogenous administration, as previously indicated due in part to
the protease DDP-IV (157) a result, preventing the degradation of native GLP-1 by
inhibiting the activy of the DDP-IV enzyme has emerged as a therapeutic strategy for
enhancing endogenous GLP-1 action in vivo.
DPP-IV is an ubiquitously expressed serine protease that exhibits postproline or
alanine peptidase activity (213). The requisite for cleavage is that an alanine or a proline
must be present as the second amino acid from the N-terminal end, in which case the two
N-terminal amino acids are cleaved from the rest of the peptide. When this cleavage results
in a loss of activity, such as with GLP-1 and GIP, DPP-IV acts as an inactivation enzyme.
However, because exogenous GIP is comparatively less effective than GLP-1 at stimulating
insulin secretion in DM2, whereas the insulinotropic action of GP-1 is well preserved, as
shown earlier, much of the current research has focused on enhancing GLP-1 action for the
treatment of DM2. However, it is possible that the effects of DPP-IV inhibition in diabetes
are mediated by inhibition of bioactive peptides other than GLP-1. One puzzling finding
might support this, as indicated by Ahrén (214): in patients with DM2, concentrations of
active GLP-1 after meal ingestion are doubled by DPP-IV inhibition (compared with
placebo) while glucose control improves (215). In contrast, when similar increases in GLP-
1 levels are produced by exogenous infusion, there is little or no effect on insulin secretion
or glucose levels (216). This suggests that mediators other than GLP-1 may contribute to
the therapeutic effect of DPP-IV inhibition. Alternatively, recent findings indicate that
GLP-1 may work indirectly through activation of autonomic nervous system (217), an
effect possibly mediated by local activation of afferent nerve terminals. If this proves to be
an important mechanism, comparison of circulating levels of GLP-1 under different
conditions becomes less relevant, since the key factor would be the local concentration of
active GLP-1 in the vicinity of nerve terminals rather than the concentration in the
circulation (218).