Incretin hormones: Their role in health and disease

Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycaemia. GIP (glucose‐dependent insulinotropic polypeptide) und GLP‐1 (glucagon‐like peptide‐1) are the known incretin hormones from the upper (GIP, K cells) and lower (GLP‐1, L cells) gut. Together, they are responsible for the incretin effect: a two‐ to three‐fold higher insulin secretory response to oral as compared to intravenous glucose administration. In subjects with type 2 diabetes, this incretin effect is diminished or no longer present. This is the consequence of a substantially reduced effectiveness of GIP on the diabetic endocrine pancreas, and of the negligible physiological role of GLP‐1 in mediating the incretin effect even in healthy subjects. However, the insulinotropic and glucagonostatic effects of GLP‐1 are preserved in subjects with type 2 diabetes to the degree that pharmacological stimulation of GLP‐1 receptors significantly reduces plasma glucose and improves glycaemic control. Thus, it has become a parent compound of incretin‐based glucose‐lowering medications (GLP‐1 receptor agonists and inhibitors of dipeptidyl peptidase‐4 or DPP‐4). GLP‐1, in addition, has multiple effects on various organ systems. Most relevant are a reduction in appetite and food intake, leading to weight loss in the long term. Since GLP‐1 secretion from the gut seems to be impaired in obese subjects, this may even indicate a role in the pathophysiology of obesity. Along these lines, an increased secretion of GLP‐1 induced by delivering nutrients to lower parts of the small intestines (rich in L cells) may be one factor (among others like peptide YY) explaining weight loss and improvements in glycaemic control after bariatric surgery (e.g., Roux‐en‐Y gastric bypass). GIP and GLP‐1, originally characterized as incretin hormones, have additional effects in adipose cells, bone, and the cardiovascular system. Especially, the latter have received attention based on recent findings that GLP‐1 receptor agonists such as liraglutide reduce cardiovascular events and prolong life in high‐risk patients with type 2 diabetes. Thus, incretin hormones have an important role physiologically, namely they are involved in the pathophysiology of obesity and type 2 diabetes, and they have therapeutic potential that can be traced to well‐characterized physiological effects.