Dipeptidyl Peptidase 4 (DPP-4) is a widely distributed enzyme that functions primarily by regulating the activity of various signaling molecules. The discovery of its potent enzymatic action on specific metabolic hormones established a direct link between this enzyme and the regulation of blood sugar. This understanding subsequently led to the development of a new class of pharmaceutical agents designed to modulate its activity for therapeutic benefit.
The Molecular Identity of Dipeptidyl Peptidase 4
DPP-4 is classified as a serine exopeptidase. This molecule exists as a type II transmembrane glycoprotein, anchored to the exterior surface of cell membranes in many tissues. Due to its presence on immune cells, DPP-4 is also recognized by its alternate designation, Cluster of Differentiation 26 (CD26).
The enzyme is found abundantly on the surfaces of endothelial cells, immune cells, and epithelial cells within the liver and kidneys. Its structure includes a short cytoplasmic tail, a membrane-spanning segment, and a large extracellular domain where the catalytic action occurs. DPP-4 functions specifically as a dipeptidyl peptidase, cleaving off a two-amino-acid segment (dipeptide) from the N-terminus of a larger peptide chain.
This cleavage action is highly selective, targeting peptide chains that have either proline or alanine situated in the second position. Cleaving this dipeptide often leads to the inactivation of the original signaling molecule, terminating its biological message. In addition to its membrane-bound form, a soluble version (sDPP-4) is shed from the cell surface and circulates freely in the bloodstream.
Central Role in Glucose Metabolism
The primary metabolic function of DPP-4 centers on its interaction with incretins, a family of gut hormones, specifically Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP). These hormones are released by intestinal cells following a meal and play a significant part in the body’s response to ingested nutrients. Incretins enhance the secretion of insulin from pancreatic beta cells in a glucose-dependent manner, meaning they only stimulate insulin release when blood sugar levels are high.
DPP-4 acts as the body’s natural off-switch for these incretin hormones, rapidly degrading them upon their release into the circulation. Active GLP-1 is quickly broken down by DPP-4, resulting in a half-life of approximately one minute in the bloodstream. This swift inactivation ensures the hormonal signal is brief and tightly controlled, preventing prolonged insulin release when glucose levels normalize.
The enzyme’s activity also indirectly influences the secretion of glucagon, a hormone that raises blood sugar, from pancreatic alpha cells. Active GLP-1 normally suppresses glucagon release, limiting the liver’s production of glucose after eating. By inactivating GLP-1, DPP-4 diminishes this suppressive effect, contributing to higher blood glucose levels. In Type 2 Diabetes, where incretin signaling is often impaired, this rapid degradation by DPP-4 exacerbates the underlying metabolic dysfunction.
Therapeutic Inhibition in Diabetes Management
Understanding the role of DPP-4 led to the pharmacological strategy of inhibiting the enzyme to improve glucose control in Type 2 Diabetes. This approach uses medications known as DPP-4 inhibitors, a class of oral anti-diabetic drugs commonly referred to as “gliptins.” These compounds work by binding to the enzyme’s active site, blocking its ability to cleave and inactivate the incretin hormones.
Inhibition of DPP-4 significantly prolongs the lifespan of naturally secreted GLP-1 and GIP, leading to a two- to four-fold increase in active incretins in the circulation. This sustained presence results in greater stimulation of insulin secretion from beta cells and more effective suppression of glucagon release from alpha cells. The net result is an improvement in post-meal blood sugar levels and a reduction in long-term glucose markers, such as HbA1c.
A significant benefit of this therapeutic mechanism is the low risk of hypoglycemia when these medications are used alone. Since the incretin hormones only stimulate insulin release when glucose concentrations are elevated, the effect of the inhibitor is self-limiting and glucose-dependent. DPP-4 inhibitors are typically taken orally, are generally well-tolerated, and are often used alongside other standard diabetes treatments like metformin. The first drug in this class, sitagliptin, received approval in 2006.
Diverse Biological Activities Beyond Metabolism
While its role in glucose control is the most widely recognized, DPP-4 possesses a range of functions extending beyond metabolic regulation. As the T-cell activation antigen CD26, the protein is involved in the body’s immune response. It modulates T-cell function and is implicated in the co-stimulation required for immune cell activation.
The enzyme acts on a broad spectrum of substrates besides GLP-1 and GIP, including various chemokines and neuropeptides. For instance, DPP-4 cleaves stromal cell-derived factor-1 alpha (SDF-1\(\alpha\)), a chemokine involved in the migration of immune cells and tissue repair. It also targets neuropeptides like Neuropeptide Y and Brain Natriuretic Peptide, which are involved in blood pressure regulation and fluid balance.
The presence of DPP-4 on various cell types means its activity can affect processes such as inflammation, cell adhesion, and cell signaling. Researchers have noted its involvement in inflammation, certain cancers, and bone metabolism. These non-metabolic activities highlight the enzyme’s complex and multi-faceted nature as a regulator of systemic communication.