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The DPP-4 enzyme

Discovered in 1967, the DPP-4 enzyme has attracted a great deal of
interest because of its role in a number of important cellular processes,
not least of all its function in blood sugar homeostasis. This enzyme oc-
curs as a membrane bound form abundant in several body tissues (e.g.
kidney, heart and liver) and a free form that circulates in the blood
stream. It is classed as a glycoprotein and a serine exopeptidase that
cleaves peptides with proline and alanine in the pen-ultimate N-term-
inal position in a diverse range of substrates, including regulatory pep-
tides (e.g. GLP-1 and GIP), chemokines, neuropeptides, and vasoactive
peptides. Especially intact GLP-1 (sequence [7-36 amide] or [7-37]) is
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avidly attacked and degraded (products [9-36 amide] or [9-37]). Even
during a continuous intravenous infusion, only 15 % of GLP-1 remains in
its intact, biologically active state. DPP-4 thus limits and terminates the
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biological activity of GLP-1 (and, to a lesser degree, GIP).

DPP-4 inhibitors

Background and mode of action

The DPP-4 enzyme is very important in the incretin system as it rapidly
inactivates the incretin hormones, GLP-1 and GIP, thereby regulating
their effects (Figure 4). Following the discovery that GLP-1 and GIP
2
are degraded various inhibitors of the DPP-4 enzyme were identified.
These findings paved the way for a novel means of reducing blood
glucose levels via modulation of the incretin effect; namely prolonging
the effect of native GLP-1, the biological activity of which is limited by
a half-life of less than 2 minutes. Inhibition of DPP-4 has been shown
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to increase endogenous GLP-1 levels by 2-to-3 fold, thereby improving
insulin secretion, suppressing glucagon, and lowering blood sugar.

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