Duodenal enteroendocrine cells and GIP as treatment targets for obesity and type 2 diabetes

The duodenum is an important source of endocrine and paracrine signals controlling digestion and nutrient disposition, notably including the main incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Bariatric procedures that prevent nutrients from contact with the duodenal mucosa are particularly effective interventions to reduce body weight and improve glycaemic control in obesity and type 2 diabetes. These procedures take advantage of increased nutrient delivery to more distal regions of the intestine which enhances secretion of the other incretin hormone glucagon-like peptide-1 (GLP-1). Preclinical experiments have shown that either an increase or a decrease in the secretion or action of GIP can decrease body weight and blood glucose in obesity and non-insulin dependent hyperglycaemia, but clinical studies involving administration of GIP have been inconclusive. However, a synthetic dual agonist peptide (tirzepatide) that exerts agonism at receptors for GIP and GLP-1 has produced marked weight-lowering and glucose-lowering effects in people with obesity and type 2 diabetes. This appears to result from chronic biased agonism in which the novel conformation of the peptide triggers enhanced signalling by the GLP-1 receptor through reduced internalisation while reducing signalling by the GIP receptor directly or via functional antagonism through increased internalisation and degradation.