Dipeptidyl peptidase 4 (DPP4) is an ubiquitous enzyme that regulates incretins (a hormone that stimulates insulin secretion). DPP4 is mainly secreted by endothelial cells and acts as a regulatory protease for cytokines, chemokines, and neuropeptides involved in inflammation, immunity, and vascular function. DPP4 (also known as adenosine deaminase binding protein), is a serine exopeptidase able to inactivate various oligopeptides through the removal of N-terminal dipeptides. Human white preadipocyte and adipocyte cells express DPP4 in high amounts. In humans, the DPP4 gene is located on chromosome 2q23, encoding a protein of 766 amino acids.
DPP4 degrades incretin peptides (e.g. GLP1/glucagon-like peptide 1) and is known for its regulatory effect in glucose metabolism [1]. Recent study found a connection of DPP4 with obesity and the metabolic syndrome or insulin resistance. DPP4 expression and release are higher in obese patients with metabolic syndrome and type 2 diabetes. Researches on DPP4 knockout mice revealed that absence of this enzyme improves glycemic control and leads to reduced fat mass which made DPP4 inhibitors promising candidates for treating human Type 2 diabetes (T2DM). So DPP4 inhibitors are in clinical use as antidiabetic drugs to improve glycemic control by stimulating pancreatic insulin secretion and suppressing glucagon production. Recent research found that adipocytes release DPP4 in a differentiation-dependent manner. Circulating DPP4 concentrations are increased in obese subjects and correlate with fasting plasma insulin, leptin, and adipocyte size in subcutaneous adipose tissue (SAT). DPP4 overexpression in visceral adipose tissue (VAT) is a marker of adipose tissue inflammation, which is known to be associated with insulin resistance and the metabolic syndrome [2].
Several DPP4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, and alogliptin) have been launched in the market and are now being used for the treatment of T2DM. All of them have proved efficacy in glycemic control with impressive safety and tolerance profiles. Gliptins (small molecular inhibitors of the peptidase DPP4) can be used as monotherapy or in combination with other oral agents (in dual or triple therapy) and even with insulin [3]. The adipose tissue is a major endocrine and energy storage organ that plays an important role in metabolic systems and insulin action which make this a target for another class of antidiabetics, the glitazones. DPP4 plays a functional role within adipose tissue, because DPP4 inhibition has been seen to prevent adipose tissue inflammation and development of glucose intolerance in high fat diet induced obesity in mice.
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