Dipeptidyl peptidase 4 (DPP-4) is an enzyme found throughout the human body, involved in various biological processes. Its presence and enzymatic activity contribute to the regulation of several bodily functions, including aspects of the immune system and metabolic control.
Understanding Dipeptidyl Peptidase 4
Dipeptidyl peptidase 4, also known as CD26 (Cluster of Differentiation 26), is a serine exopeptidase. This enzyme is present on the surface of various cells, including those in the kidney, intestine, liver, and immune system, and it also exists as a soluble form in the blood plasma and other bodily fluids.
The function of DPP-4 is cleaving dipeptides from the N-terminus of certain proteins and peptides. It targets peptide bonds where a proline or alanine amino acid is in the second position from the N-terminus. This specificity is notable because many other proteases cannot cleave bonds involving proline. DPP-4 inactivates its substrates through this cleavage, but it can also modify their biological activity, leading to altered receptor binding or novel functions.
The structure of DPP-4 is a homodimer, with each subunit containing an alpha/beta hydrolase domain and an eight-bladed beta-propeller domain that forms the substrate binding pocket. This enzyme is anchored to the cell membrane by a short N-terminal cytoplasmic extension and a single hydrophobic helix.
DPP-4’s Role in Blood Sugar Control
Dipeptidyl peptidase 4 plays a role in managing blood glucose levels by influencing incretin hormones. Incretins are gastrointestinal hormones, primarily Glucagon-Like Peptide-1 (GLP-1) and Glucose-Dependent Insulinotropic Polypeptide (GIP), released from the gut after a meal. These hormones signal the pancreas to increase insulin secretion in a glucose-dependent manner.
GLP-1 and GIP also contribute to glucose homeostasis by reducing glucagon secretion from the pancreas, decreasing glucose production by the liver. GLP-1 slows down the rate at which food empties from the stomach, regulating post-meal blood sugar spikes and promoting fullness. This combined action of stimulating insulin and suppressing glucagon helps to bring elevated blood glucose levels down.
DPP-4 rapidly inactivates these incretin hormones by cleaving off two amino acids from their N-terminus. This proteolytic processing limits the duration of GLP-1 and GIP’s action, as their half-lives in the bloodstream are less than two minutes. While this rapid inactivation is natural, in type 2 diabetes, increased DPP-4 activity contributes to persistently high blood sugar levels by prematurely degrading these hormones.
Targeting DPP-4 for Diabetes Management
The understanding of DPP-4’s role in incretin inactivation led to the development of a class of medications called DPP-4 inhibitors, known as “gliptins.” Examples of these oral medications include sitagliptin, saxagliptin, linagliptin, and alogliptin, which are prescribed for individuals with type 2 diabetes. Sitagliptin was the first agent in this class approved by the US Food and Drug Administration (FDA) in 2006.
These drugs work by blocking the activity of the DPP-4 enzyme. By inhibiting DPP-4, they prevent the rapid breakdown of naturally produced GLP-1 and GIP. This allows the active forms of these incretin hormones to remain in the bloodstream for a longer period and at higher concentrations.
The prolonged presence of active GLP-1 and GIP leads to enhanced glucose-dependent insulin secretion from the pancreatic beta cells. This means more insulin is released when blood glucose levels are elevated, helping to lower them. DPP-4 inhibitors contribute to improved blood sugar control by reducing the secretion of glucagon, a hormone that raises blood glucose, and also slow gastric emptying. These medications are generally taken orally once daily and are often well-tolerated. Common, mild side effects include nasopharyngitis (inflammation of the nose and pharynx), headache, and gastrointestinal symptoms like nausea or diarrhea.