The Dipeptidyl Peptidase Family, Prolyl Oligopeptidase, and Prolyl Carboxypeptidase in the Immune System and Inflammatory Disease, Including Atherosclerosis

The American Heart Association (AHA) and the American Diabetes Association (ADA) have each published guidelines for cardiovascular disease prevention: The ADA has issued separate recommendations for each of the cardiovascular risk factors in patients with diabetes, and the AHA has shaped primary and secondary guidelines that extend to patients with diabetes. This statement will attempt to harmonize the recommendations of both organizations where possible but will recognize areas in which AHA and ADA recommendations differ.

The dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antihyperglycaemic agents which were developed for the treatment of type 2 diabetes by rational drug design, based on an understanding of the underlying mechanism of action and knowledge of the structure of the target enzyme. Although they differ in terms of their chemistry, they are all small molecules which are orally available. There are some differences between them in terms of their absorption, distribution, metabolism and elimination, as well as in their potency and duration of action, but their efficacy, both in terms of inhibiting plasma DPP-4 activity and as antidiabetic agents, appears to be similar. They improve glycaemic control, reducing both fasting and postprandial glucose levels to lower HbA1c levels, without weight gain and with an apparently benign adverse event profile. At present, there seems to be little to distinguish between the different inhibitors in terms of their efficacy as antidiabetic agents and their safety. Long-term accumulated clinical experience will reveal whether compound-related characteristics lead to any clinically relevant differences. © 2010 Blackwell Publishing Ltd.

The combined actions of glucose-dependent insulinotropic polypeptide (GIP) and truncated glucagon-like peptide-1 (tGLP-1) may fully account for the incretin effect. These hormones are released from the small intestine in response to oral glucose and stimulate insulin release. Recently, evidence has been provided demonstrating the degradation of GIP-(1-42) and GLP-1-(7-36)NH2 by the serum enzyme dipeptidyl peptidase IV (DPP IV) into the biologically inactive products GIP-(3-42) and GLP-1-(9-36)NH2. The objective of the current investigation was to develop a method to monitor the degradation of these hormones in vivo. Synthetic peptides were radiolabeled and purified by HPLC. Subsequent degradation of the peptides under various conditions was then monitored by further HPLC analysis. Incubation of [125I]GIP-(1-42) or [125I]GLP-1-(7-36)NH2 with Wistar rat serum or purified DPP IV resulted in the major N-terminal-truncated products [125I]GIP-(3-42) and [125I]GLP-1-(9-36)NH2. These products were significantly reduced when the specific DPP IV inhibitor diprotin A was included in the incubation mixture and were absent when serum from DPP IV-deficient rats was used. When the labeled peptides were infused into rats at hormone levels within the physiological range, over 50% was metabolized to the truncated forms within 2 min. These products were absent when the tracers were infused into DPP IV-deficient animals. It is concluded that DPP IV may be a primary inactivating enzyme of both GIP and tGLP-1 in vivo. As the N-terminal-truncated products of the DPP IV cleavage may not be distinguished from the biologically active hormone by currently employed assays, reports of circulating hormone levels should be reconsidered. The method described in this manuscript may be useful for investigating the durations of action of GIP and tGLP-1 in normal and pathophysiological conditions.