Dipeptidyl peptidase-4, more commonly known as DPP4, is a protein that functions as an enzyme in the human body. It is expressed on the surface of most cell types and also circulates in a soluble form in blood plasma and other bodily fluids. This protein is a member of a specific family of enzymes called serine exopeptidases. Its structure allows it to cleave, or cut, certain types of peptides, which are short chains of amino acids, the building blocks of proteins.
Specifically, DPP4 targets and cuts peptides that have the amino acid proline or alanine in the second position of their chain. This action is specialized, as peptide bonds involving proline are resistant to being broken down by most other enzymes. Discovered in 1966, this enzyme is involved in a wide array of bodily processes, including immune regulation and signal transduction.
The Biological Role of DPP4
The primary function of DPP4 in metabolic regulation centers on its activity within the incretin system. After a meal, the digestive system releases hormones known as incretins, principally glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones signal the pancreas to release insulin, a process that helps manage the influx of glucose into the bloodstream from the food that was consumed.
DPP4 acts as the main regulator for inactivating these incretin hormones. The enzyme specifically recognizes and cleaves GLP-1 and GIP, rendering them inactive. For GLP-1, this degradation is rapid and efficient, effectively shutting down its insulin-stimulating signal once its task is complete. This process ensures that the hormonal response to a meal is temporary and tightly controlled, preventing prolonged or excessive insulin release.
The Connection to Type 2 Diabetes
In the context of type 2 diabetes, the body’s ability to manage blood glucose is impaired. This condition often involves a reduced insulin response to meals, a phenomenon linked to a diminished incretin effect. While GLP-1 activity is often preserved in individuals with type 2 diabetes, the overall system is less effective at controlling blood sugar levels after eating.
The enzyme’s natural role of breaking down incretin hormones like GLP-1 and GIP can be counterproductive when blood glucose levels are consistently high. By inactivating these hormones, DPP4 limits the body’s own mechanism for lowering blood sugar through glucose-dependent insulin secretion. Elevated activity or expression of DPP4 has been associated with increasing body mass index and high blood sugar, suggesting its involvement in the development of metabolic diseases. This direct influence on the lifespan of incretin hormones makes DPP4 a logical target for therapeutic intervention in type 2 diabetes.
DPP4 Inhibitors as Medication
A specific class of oral medications, known as DPP4 inhibitors or “gliptins,” has been developed to manage type 2 diabetes. These drugs work by selectively blocking the active site of the DPP4 enzyme. This inhibition prevents DPP4 from breaking down the incretin hormones GLP-1 and GIP. As a result, the active forms of these hormones remain in circulation for a longer period, potentiating their natural effects.
The extended activity of GLP-1 and GIP leads to several beneficial outcomes for glucose control. It enhances the pancreas’s ability to secrete insulin in a glucose-dependent manner, meaning more insulin is released only when blood sugar is high, such as after a meal. This mechanism also helps suppress the release of glucagon, a hormone that raises blood sugar levels by prompting the liver to produce glucose. Together, these actions lead to lower overall blood glucose levels.
This class of drugs is frequently prescribed for individuals with type 2 diabetes. Common medications in this category include sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta). These medications are taken orally and are considered effective for reducing key measures of blood sugar control.
While well-tolerated, DPP4 inhibitors can be associated with certain side effects. Some of the more commonly reported issues include headaches and an increased risk for nasopharyngitis (inflammation of the nose and pharynx) or urinary tract infections. The risk of hypoglycemia, or low blood sugar, is minimal when these drugs are used alone but can increase when they are combined with other diabetes medications like sulfonylureas or insulin.
Functions Beyond Glucose Control
The influence of the DPP4 enzyme extends beyond its well-known role in glucose metabolism. DPP4 is also known as CD26, a protein found on the surface of various immune cells, where it is involved in immune system activation and regulation. Its functions in the immune system appear to be independent of its enzymatic activity, meaning it can influence immune responses through protein-protein interactions without cleaving any peptides.
DPP4 participates in inflammatory processes by cleaving chemokines and cytokines, which are signaling molecules that mediate inflammation. Research has shown that soluble DPP4 can increase the secretion of pro-inflammatory cytokines in certain experimental settings. This connection suggests that DPP4 may act as a local mediator of inflammation in tissues like adipose (fat) and the liver, potentially linking obesity with insulin resistance.
Because of its broad involvement in immune function and inflammation, DPP4 is a subject of ongoing research for conditions other than diabetes. Its role in fibrosis, or scarring of organ tissue, has been suggested in animal studies involving the liver and kidneys. The enzyme’s multifaceted nature means it continues to be a molecule of interest for potential therapeutic applications in areas like autoimmune disorders and various inflammatory diseases.