Extra-pancreatic effects of incretin-based therapies

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and inhibits glucagon secretion in the pancreatic islets of Langerhans under hyperglycaemia. In type 2 diabetes (T2DM), GLP-1 improves glycaemic control without a hypoglycaemia risk. GLP-1 receptors have also been found in extra-pancreatic tissues, e.g., the cardiovascular system, the gastrointestinal system, and the central nervous system. Since cardiovascular comorbidities and degenerative neurological changes are associated with T2DM, the interest in the extrapancreatic effects of GLP-1 has increased. GLP-1-based therapies with either GLP-1 receptor agonists (GLP-1 RA) or DPP-4 inhibitors (that delay the degradation of endogenous GLP-1) have become widely used therapeutic options in T2DM. In clinical studies, GLP-1 RA have demonstrated a significant lowering of blood pressure that is independent of body weight changes. Preclinical data and small short-term studies with GLP-1 and GLP-1 RA have shown cardioprotective effects in ischaemia models. GLP-1 as well as a treatment with GLP-1 RA also induces a stable body weight loss by affecting GLP-1 signaling in the hypothalamus and by slowing gastric emptying. Regarding neuroprotective actions in degenerative neurological disease models for Parkinson’s- or Alzheimer’s disease or neurovascular complications like stroke, animal studies have shown positive results. In this article, a summary of the extrapancreatic effects of GLP-1 and GLP-1-based therapies is presented.