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

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Concerning the potential mediators of the therapeutic effects of DPP-IV inhibition,
Nauck and El-Ouaghlidi (218) presented 5 arguments suggesting that GLP-1 is not the only
– or at least not the major – mediator of the glucose-lowering actions of DPP-IV inhibition
observed in clinical studies (219, 220, 215): DPP-IV inhibition - 1. causes little increase in
circulating endogenous GLP-; 2. has little effect on gastric emptying; 3. does not cause
nausea/vomiting as do GLP-1 and incretin mimetics; 4. meal-stimulated GLP-1 fall and 5.
has delayed effects on glucose homeostasis (218). In the same issue of Diabetologia, Holst
and Deacon acknowledge these arguments, but maintain that current evidence nonetheless
supports the dominant role of GLP-1 (221).
Table 5 summarizes the overlapping and distinct properties of GLP-1R agonists vs.
DPP-IV inhibitors for the treatment of DM 2 (222):
Table 5. GLP-1 Receptor agonists versus DPP-IV inhibitors
Ahrén (214) has suggested that neuropeptides, biologically active peptides localized
to islet nerve terminals and functioning as neurotransmitters, may be substrates for DPP-
IV (213), thus contributing to the actions of DPP-IV inhibitors in diabetes. Neuropeptides
that are stored in islet nerve terminals and affect islet function would be of particular
relevance in this regard, and the islet autonomic nervous system could be an important
regulator of islet function (223). One neuropeptide of potential importance is pituitary
adenylate cyclase–activating peptide (PACAP), which is localized to islet nerves and has
several actions relevant to glucose homeostasis (224). Since PACAP is also a substrate for
DPP-IV, it could contribute to the therapeutic benefits of DPP-IV inhibition recently shown
in mice whereby PACAP-induced insulin secretion increased following inhibition of DPP-
IV by valine pyrrolidide (225).
The potential risks associated with DPP-IV inhibitors include the prolongation of
the action of other peptide hormones, neuropeptides, growth factors, cytokines and
chemokines cleaved by the protease (213) along with their interaction with DPP-IV-related
proteases. Moreover, DPP-IV has effects beyond its proteolytic action, including T-cell