Favorable Effects of GLP-1 Receptor Agonist against Pancreatic ß-Cell Glucose Toxicity and the Development of Arteriosclerosis: "The Earlier, the Better" in Therapy with Incretin-Based Medicine.

Fundamental pancreatic ß-cell function is to produce and secrete insulin in response to blood glucose levels. However, when ß-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic ß-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the ß-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of ß-cells. However, GLP-1R expression in ß-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on ß-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of ß-cells against glucose toxicity in routine medical care.