Incretin-based therapy for type 2 diabetes mellitus: pancreatic and extrapancreatic effects

The prevalence of type 2 diabetes mellitus has increased at an alarming rate in recent years. Recent estimations project that 366 million people could have diabetes by 2030. The incretin system emerges as a new target for type 2 diabetes therapy, and new molecules are being approved for its use in humans since the year 2005. These agents could be divided into 2 main groups, glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors. Endogenous GLP-1 is an incretin hormone composed by a 30-amino acid peptide and is secreted from L-cells in distal small intestine in response to calorie intake, causing a glucose-dependent β-cell response resulting in a restoration of the first-phase insulin response. Additionally, GLP-1 regulates glucagon production, which leads to inhibition of glucogenolysis and gluconeogenesis in the liver. Synthetic molecules such as exenatide and liraglutide have been developed to bind GLP-1 receptor and mimic GLP-1 effects in pancreatic cells and other target organs.