Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes: Preclinical Biology and Mechanisms of Action

Daniel J. Drucker, MD


Diabetes Care. 2007;30(6):1335-1343. 

In This Article

DPP-4 Substrates and Reduced DPP-4 Enzyme Activity

Numerous endocrine peptides, chemokines, and neuropeptides contain an alanine or proline at position 2 and are putative DPP-4 substrates ( Table 1 ). An endogenous physiological DPP-4 substrate is defined as a peptide whose endogenous circulating levels of intact versus NH2-terminally cleaved forms are altered following reduction or elimination of DPP-4 activity in vivo. For the majority of peptides listed in Table 2, it is reasonable to assume that they may be pharmacological substrates, as DPP-4 produces NH2-terminal cleavage of the peptide(s) in vitro. In contrast, there is limited evidence that the majority of these peptides are physiological substrates. Moreover, even small changes in the ratios of intact to cleaved peptide for physiological DPP-4 substrates may not always be sufficient to produce predicted biological changes in specific target tissues, as discussed below.

Both GIP and GLP-1 are physiological substrates for DPP-4, as DPP-4 inhibition is associated with increased circulating levels of intact GIP and GLP-1 in vivo,[16,17] and levels of intact GIP and GLP-1 are increased, relative to their NH2-terminally cleaved forms in rats and mice with inactivating DPP-4 gene mutations.[37] Similarly, the chemokines SDF-1α and SDF-ß are cleaved by DPP-4 at the NH2-terminus, and plasma levels of intact SDF-1α[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67] are increased in DPP-4-/- mice.[42] Hence, endogenous levels of intact SDF-1 are clearly dependent on DPP-4 activity.

Substance P may also be a physiological substrate for DPP-4. Levels of tissue DPP-4 are reduced in nasal tissue of human subjects with chronic rhinosinusitis, and the vasodilatory effects of substance P are attenuated by DPP-4 in vivo.[45] Conversely, DPP-4 inhibition potentiates the vasodilatory effects of exogenous substance P, findings consistent with reports of nasopharyngitis in human subjects treated with DPP-4 inhibitors.[46,47] Moreover, plasma levels of substance P were more than twofold higher in DPP-4-/- versus DPP-4+/+ mice.[48] Hence, substance P fulfills the criteria for an endogenous substrate of DPP-4. Whether clinically meaningful increases in the levels of SDF-1 or substance P occur in humans following partial reduction of DPP-4 activity with selective DPP-4 inhibitors remains uncertain.

Although the majority of peptide hormones listed in Table 1 may be cleaved by DPP-4 in vitro, the endogenous levels of intact-to-cleaved peptide may not be significantly different in DPP-4-/- versus DPP-4+/+ mice or rats or following administration of DPP-4 inhibitors in vivo. For example, glucagon is cleaved by DPP-4 in vitro to yield glucagon,[3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29] and this cleavage is inhibited by the DPP-4 inhibitor isoleucine thiazolidide[49]; however, increased plasma levels of intact versus cleaved glucagon have not been reported following administration of DPP-4 inhibitors in vivo or in rats or mice with inactivating mutations of the DPP-4 gene.

GLP-2(1-33) is cleaved by DPP-4 at the position 2 alanine both in vitro and following exogenous administration in vivo, leading to the generation of GLP-2(3-33).[50,51] Moreover, DPP-4-resistant GLP-2 analogs exhibit much greater potency than native GLP-2 in vivo.[50] Nevertheless, although DPP-4 inhibition increased the plasma levels of intact nutrient-stimulated GLP-2[1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33] in rats, chronic administration of the DPP-4 inhibitor VP alone had no effect on intestinal growth, a key biological readout of enhanced GLP-2 activity in vivo.[52]

Growth hormone-releasing hormone (GHRH) was one of the first peptides demonstrated to be a substrate for DPP-4.[53] Circulating levels of GHRH are low and difficult to measure in plasma. Nevertheless, increased levels of intact bioactive GHRH in the hypothalamic-pituitary axis would be predicted to stimulate growth hormone secretion, leading to increased circulating levels of insulin-like growth factor (IGF)-1 and somatic growth. However, DPP-4-/- mice and F344 mutant rats do not exhibit increased body size or organ growth. Furthermore, treatment of young pigs for 72 h with a sitagliptin analog that produced 90% inhibition of plasma DPP-4 activity was not associated with alterations in the circulating concentrations of IGF-1.[54] Similarly, 10 days of sitagliptin administration to healthy nondiabetic male subjects did not produce significant elevations in IGF-1 or IGF binding protein-3 relative to placebo-treated control subjects.[55] Hence, DPP-4 inhibition may not always produce predictable changes in downstream biological pathways, despite altering the relative levels of intact-to-cleaved peptide substrates.

Neuropeptide Y (NPY) and peptide YY (PYY) exert opposing actions on control of food intake, and both peptides are cleaved by DPP-4 in vitro, resulting in the generation of NH2-terminally truncated peptides with different receptor affinities. Inhibition of DPP-4 activity prevents the generation of the anorectic PYY(3-36) from PYY(1-36), and reduced levels of PYY(3-36) have been detected following infusion of PYY(1-36) into rats treated with a DPP-4 inhibitor.[56] Although DPP-4 is clearly important for cleavage of exogenous PYY(1-36), biologically significant alterations in the levels of endogenous PYY(1-36)-to-PYY(3-36) have not yet been described in rodents or humans with reductions in DPP-4 activity. DPP-4 cleavage of NPY(1-36) in vitro leads to the generation of NPY(3-36), which exhibits a markedly reduced affinity for the orexigenic Y1 receptor but interacts with the Y2/Y5 receptor. Exogenous administration of NPY also exert effects on vasomotor activity, angiogenesis, and vascular remodeling; however, the importance of endogenous basal levels of NPY(1-36) and NPY(3-36) for control of these activities remains uncertain. Although administration of NPY produces potent anxiolytic and sedative-like effects in DPP-4-deficient F344 rats,[57] there is little evidence that endogenous circulating or tissue levels of NPY(1-36) versus NPY(3-36) are significantly altered following reduction of DPP-4 activity in vivo.


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