Incretin-based therapies in prediabetes: Current evidence and future perspectives

Figure 1 Glucagon-like peptide-1 and the β-cell: Amplification of the glucose-stimulated insulin secretion. Increased glucose levels are transported into the β-cell by GLUT-2. They are phosphorylated by GK to glucose-6-P, promoting an increased rate of aerobic glycolysis. Pyruvate is the main substrate for mitochondrial oxidative metabolism. Increased cytosolic ATP/ADP concentration is the major cellular metabolic signal between the glucose stimulus and insulin secretion. It promotes the closure of K_ATP channels, thereby initiating plasma membrane depolarization, activation of VDCCs, Ca²⁺ influx and an increase in the intracellular Ca²⁺ concentration. This in turn stimulates the granules that contain insulin and promotes their release into the blood compartment. Repolarization of β-cells is mainly mediated by K_Ca and K_v channels. GLP-1 binds to GLP-1R, a class 2 G protein-coupled receptor, in the cell membrane of the pancreatic cells. Through this receptor it mainly exerts its insulinotropic activity. It promotes increased levels of cAMP through stimulation of adenylate cyclase. Downstream effectors of cAMP are PKA and Epac. Through the activation of these two important cellular pathways GLP-1 amplifies insulin secretion via its effects on ATP/ADP concentration ratio, K_ATP channels, K_v and K_Ca channels, VDCCs, Ca²⁺ influx and insulin granule exocytosis. GLU: Glucose; GLUT-2: Type 2 facillitative glucose transporter; GK: Glucokinase; Glucose-6-P: Glucose-6-phosphate; K_ATP: ATP-sensitive K⁺ channels; VDCCs: Voltage-dependent Ca²⁺ channels; K_Ca: Ca²⁺-sensitive voltage-depended K⁺ channels; K_v: Voltage-dependent K⁺ channels; GLP-1: Glucagon-like peptide-1; GLP-1R: Glucagon-like peptide-1 receptor; cAMP: Cyclic adenosine 3’,5’-monophosphate; PKA: Protein kinase A; ATP: Adenosine triphosphate; ADP: Adenosine diphosphate.