Incretin Effects on β-Cell Function, Replication, and Mass

There is a progressive deterioration in β-cell function in patients with type 2 diabetes. At diagnosis, islet function may be reduced by up to 50% compared with healthy control subjects, and there is also likely to be a reduction in β-cell mass of up to 60%. The reduction in β-cell mass is due to accelerated apoptosis. Currently, few pharmacological therapies address this reduction in β-cell mass and function. This means that patients are generally subjected to an increasing polypharmacy to control their diabetes, with most eventually being treated by insulin. Incretin hormones, which are released from the gastrointestinal tract after a meal, enhance glucose-dependent insulin secretion from the pancreas, aiding the overall regulation of glucose homeostasis in healthy subjects. In addition, these hormones, especially glucagon-like peptide (GLP)-1, have a number of protective effects on the β-cells, including a reduction in apoptosis and enhancement of β-cell proliferation and neogenesis. These benefits are lost to a significant extent in patients with diabetes. The recently developed diabetes therapies, GLP-1 receptor agonists, such as exenatide and liraglutide, appear to have beneficial effects on β-cell function and hence offer promise for durable glycemic control as well as potentially reducing the micro- and macrovascular complications associated with type 2 diabetes. The clinical course of type 2 diabetes is characterized by a progressive decline in β-cell mass and function. Although the elevated levels of fasting glucose and impairment of insulin action in peripheral tissues may predate the diagnosis of type 2 diabetes, chronic hyperglycemia only results after a prolonged period of β-cell degeneration, a process that may begin as much as 12 years before diagnosis, involving a progressive reduction in functionality and mass (1,2). In the UK Prospective Diabetes Study, it was estimated that, at diagnosis, type 2 diabetic patients may have already lost up …