TABLE 2 Favorable Effects of GLP-1-Based Therapies In Type 2 Diabetes

Potential for normalizing glucose/HbA1c Glucose-dependent effect, no intrinsic hypoglycemias Various principles of action (e.g., glucagonostatic effect) No dose titration—"one size fits all" Moderate weight loss possible or weight neutral No severe side effects/broad therapeutic range

Results from animal and in vitro studies: positive effect on islet mass (neogenesis, proliferation, apotosis)

levels are produced by exogenous infusion, these have little or no effect on insulin secretion or glucose levels (22). This suggests that mediators other than GLP-1 may contribute to the therapeutic effect of DPP-4 inhibition. For instance, DPP-4 inhibition also blocks the inactivation of the other major incretin hormone GIP (81). Furthermore, various neuropeptides may contribute to the actions of DPP-4 inhibitors in diabetes like pituitary adenylate cyclase-activating peptide (PACAP), which is localized to islet nerves and has several actions relevant to glucose homeostasis (84). For example, PACAP is a powerful stimulator of insulin secretion and may, like GLP-1, be of importance for islet mass. PACAP may play a leading role in contributing to the prandial, neurally dependent cephalic phase of insulin secretion. Furthermore, it enhances glucose uptake in adipocytes and augments the antilipolytic action of insulin (81,85). Since PACAP is also a substrate for DPP-4, it is reasonable to speculate that this neuropeptide may contribute to the therapeutic benefits of DPP-4 inhibition. However, it is not yet known whether neuropeptides such as PACAP are substrates of DPP-4 in humans under physiological conditions, and this remains a weakness in this line of argument (81).

Because DPP-4 is involved in the degradation of many peptide hormones, the action of DPP-4 inhibitors is less specific than that of GLP-1 receptor agonists. Along with this, long-term immunological effects of DPP-4 inhibitors in humans are not known yet, since DPP-4 is also expressed on lymphocytes as CD26 (86,87). So far, however, DPP-4 inhibitor treatment did not show serious side effects and in human and animal studies no immunological changes have been observed.

In summary, the therapeutic principle of GLP-1 using incretin mimetics is a novel and attractive treatment option with multiple favorable actions for type 2 diabetes (Table 2) (55,56). Table 3 highlights the major differences between GLP-1 receptor agonists and DPP-4 inhibitors.

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