Dipeptidyl peptidase IV (DPPIV) is an enzyme found throughout the human body, existing both anchored to cell surfaces and in a soluble form circulating in various bodily fluids. This protein, also known as CD26, is important in biology and medicine due to its diverse properties. Its widespread presence and multifaceted actions make DPPIV a subject of ongoing research.
Understanding DPPIV in the Body
DPPIV is a type II transmembrane glycoprotein and a serine exopeptidase. As an enzyme, its primary function involves cleaving dipeptides from the N-terminus of certain proteins and peptides. This cleavage specifically occurs when proline or alanine is the second amino acid from the N-terminal end of the peptide. This unique specificity sets DPPIV apart from many other proteases.
DPPIV is widely distributed across various tissues, including the kidneys, liver, intestines, and on the surface of immune cells such as T lymphocytes, B cells, and macrophages. It is also highly expressed on endothelial and epithelial cells. Beyond its enzymatic activity, DPPIV acts as a binding glycoprotein, interacting with other molecules like adenosine deaminase.
DPPIV and Glucose Regulation
DPPIV’s primary role is its involvement in glucose metabolism. This enzyme inactivates incretin hormones, specifically Glucagon-Like Peptide-1 (GLP-1) and Glucose-Dependent Insulinotropic Polypeptide (GIP). These incretins are released from the gut after meals and play a role in stimulating insulin release from pancreatic beta-cells in a glucose-dependent manner. They also help suppress glucagon secretion, which prevents the liver from releasing stored glucose.
DPPIV rapidly cleaves GLP-1 and GIP, significantly limiting their duration of action in the bloodstream. By inactivating these hormones, DPPIV reduces their beneficial effects on blood sugar control. This action is particularly relevant in conditions like type 2 diabetes, where the body’s ability to regulate blood glucose is impaired.
Therapeutic Applications: DPPIV Inhibitors
Given DPPIV’s role in inactivating incretin hormones, a class of drugs known as DPPIV inhibitors, or gliptins, has been developed to manage type 2 diabetes. These oral medications work by blocking DPPIV activity. This prevents the rapid breakdown of naturally occurring GLP-1 and GIP, thereby prolonging their presence and action in the body.
This extended activity of incretins leads to increased glucose-dependent insulin secretion and decreased glucagon release, which collectively help lower blood sugar levels. Examples of DPPIV inhibitors include sitagliptin, saxagliptin, linagliptin, alogliptin, and vildagliptin. These drugs offer a way to improve glucose control in individuals with type 2 diabetes by enhancing the body’s natural blood sugar regulation.
Diverse Roles Beyond Glucose
Beyond its involvement in glucose metabolism, DPPIV exhibits a range of other physiological functions. It is recognized for its roles within the immune system. DPPIV is expressed on various immune cells, including T cells, B cells, natural killer cells, dendritic cells, and macrophages, and plays a part in their activation and function. It can act as a co-stimulatory molecule for T-cell activation and modulate the activity of various cytokines and chemokines.
DPPIV’s presence in the gut suggests a role in intestinal health, and its activity has been investigated in conditions like inflammatory bowel disease. DPPIV has also been linked to other processes such as inflammation and cell adhesion. Research explores its potential connections to cancer, where its levels on cell surfaces or in serum may be altered, and its involvement in tumor progression and immune responses against cancer.