The Endocrine Society Centennial: Cleavage Matters

Since its first discovery as a diaminopeptidase (1), the enzyme dipeptidylpeptidase IV (DPP IV) has been found to exert profound effects on the endocrine system. With relative specificity for N-terminal penultimate Ala and Pro residues, DPP IV hydrolyzes dozens of regulatory peptides and chemokines, resulting in the inactivation of some hormones and alteration of receptor specificity in the case of others. Most notably, the first report by Kieffer et al (2), published in Endocrinology, of the physiological importance of DPP IV to the incretin system of hormones has led not only to the development of two new classes of drugs for the treatment of patients with type 2 diabetes (T2D) but also to a novel therapeutic agent for patients with short bowel syndrome. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are peptide hormones released by proximal and distal enteroendocrine cells, respectively. Together these two peptides account for the ability of oral glucose to augment glucose-dependent insulin secretion by 30%–70% above that seen with isoglycemic iv glucose administration, the so-called incretin effect (3). Although great excitement was engendered by the possibility that one or both of these incretins might have therapeutic use to lower glycemia in patients with T2D, this hope was dampened by the realization that both of these peptides demonstrate extremely short half-lives in vivo. Mentlein et al (4) first used an in vitro assay to show that DPP IV in human serum removes the N-terminal dipeptide (Tyr1-Ala2 and His1-Ala2) from GIP and GLP-1, respectively, generating cleavage products that were functionally inactive as incretins. This report was followed shortly thereafter by the seminal study of Kieffer et al (2), demonstrating that GIP and GLP-1 have half-lives of less than 2 minutes in vivo in rats due to the actions of endogenous DPP IV. Within several years, a number of long-acting, DPP IV-resistant analogs of both GIP and GLP-1 had been reported (5–7), raising hope for the development of novel therapeutic peptides for the treatment of T2D. However, in parallel with these findings, a highly unusual source of a GLP-1 receptor agonist, exendin-4, was identified in the venom of the Gila lizard (Helderma suspectum) (8, 9). Exendin-4 was found to reduce glycemia in diabetic mice, rats, and monkeys as well as in both normal humans and those with T2D (10–13), an effect that is sustained to a greater extent than native GLP-1, at least in part, due to its resistance to DPP IV (His1-Gly2) (14). Recombinant exendin-4, exenatide, was thus approved by the Food and Drug Administration in 2005 as a first-in-class treatment for patients with T2D, with numerous other DPP IV-resistant GLP-1 receptor agonists following thereafter (15). The selected Centennial Paper was the first demonstration of the physiological importance of the enzyme, dipeptidylpeptidase IV, for the degradation of several intestinal peptide hormones. This finding led to the development of novel therapeutics for the treatment of patients with type 2 diabetes and short bowel syndrome. The importance of DPP IV in the inactivation of GIP and GLP-1 has also led to the development of DPP IV inhibitors as an alternate approach to raising the levels of incretin peptides in the circulation. Whereas Kieffer et al (2) demonstrated that a peptide-based DPP IV inhibitor could prevent the cleavage of GIP and GLP-1, it was not until the development of highly selective, orally available DPP IV inhibitors that this class of agents was also approved (in 2006) for the treatment of patients with T2D (16, 17). Most recently, therapeutic inhibition of the actions of DPP IV has also been applied to a GLP-1-related peptide that is cosecreted by the gut, GLP-2. First described as a potent intestinal growth factor, the actions of GLP-2 in vivo were also found to be limited by DPP IV-mediated removal of the N-terminal peptide, His1-Ala2 (18, 19). The development of a DPP IV-resistant analog of GLP-2 has recently led to approval (in 2012) for use of this peptide in patients with intestinal insufficiency consequent to short bowel syndrome (20). The wide array of proven and potential DPP IV substrates suggests the possibility of future therapeutic applications. Hence, although the pancreatic hormone glucagon (His1-Ser2) is only a poor substrate for DPP IV (21), the gut satiety factor, oxyntomodulin, which is a C-terminally extended form of glucagon, does appear to be inactivated by DPP IV (22). Conversely, cleavage of the N-terminal dipeptide from peptide YY (Tyr1-Pro2) actually enhances the binding of this peptide to the neuropeptide Y2 receptor, thus permitting induction of satiation (23). Finally, the chemokine stromal cell-derived factor-1α, and the tachykinin substance P, have been shown to be physiologically relevant DPP IV substrates, whereas other hormones appear to be cleaved by DPP IV under a variety of conditions (ie, gastrin releasing peptide, GHRH, IGF-1, secretin, etc [17]). The relevance of these findings remains uncertain. In summary, from a single publication more than 20 years ago using rats (2), the importance of DPP IV as a physiologically relevant and clinically important enzyme that cleaves multiple endocrine peptides has been repeatedly validated and is now widely accepted. However, several of the DPP IV-generated cleavage products have been reported to function as antagonists (ie, truncated GIP, GLP-1, and GLP-2 [24, 25]) or even as independent hormones (ie, satiety actions of truncated peptide YY, and cardiovascular effects of truncated GLP-1 [23, 26]). The physiological importance of some of these peptides and, thus the implications of their loss through the use of global DPP IV inhibitors, remains an outstanding question. Studies on GLP-1 and GLP-2 in the Brubaker laboratory are supported by operating grants from the Canadian Diabetes Association, the Canadian Institutes of Health Research, and the Natural Sciences and Engineering Research Council of Canada. P.L.B. is supported by the Canada Research Chairs Program. Disclosure Summary: The author has nothing to disclose. dipeptidylpeptidase IV glucose-dependent insulinotropic polypeptide glucagon-like peptide-1 type 2 diabetes

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