1748-P: NMDA Receptor Is Involved in Amplification Effects of Glycine on Insulin Secretion

The NMDA receptor plays a crucial role in the central nervous system. Glutamate acts as its agonist, while glycine and D-serine play a co-agonist role. Recent studies have indicated that β-cells express the NMDA receptor, and it regulates insulin secretion, but the detailed mechanism is still unclear. Mouse islets were perifused in response to 10 mM glucose stimulation, a ramp of glutamate and glycine (0 to 10 mM) was administered either alone or on top of glucose. The ramp of glutamate and glycine alone have no effects on insulin secretion in perifused mouse islets. However, glycine ramp, not glutamate and D-serine ramp, can potentiate the 10 mM glucose-stimulated insulin secretion (GSIS). Glycine transporter 1, 2 and glycine receptor inhibitors, such as strychnine (5 µM), org25543 (10 µM), and the combination of org25543 (10 µM) and org24598 (10 µM), cannot block the potentiation effects of glycine to GSIS. The NMDA receptor inhibitor, MK801 (10 µM), enhanced the ability of glycine to augment GSIS, resulting in a leftward shift of the glycine amplification curve. Remarkably, D-serine and MK801 significantly enhanced the insulin secretion driven by 10 mM glucose, although glycine no longer exhibited its enhancing effects on GSIS. The synergistic effects of D-serine and MK801 on glucose ramp (0 to 25 mM) stimulated insulin secretion were examined. The combination resulted in an increase in the maximum insulin secretion induced by the glucose ramp, while the threshold remained unchanged. In vivo tests demonstrated that glycine improved glucose tolerance by increasing baseline insulin secretion. Our study has shown that glycine enhances GSIS through the involvement of the NMDA receptor pathway. In contrast to the central nervous system, the NMDA receptor in islets is no longer responsive to stimulation by glutamate. However, it still exhibits a robust response to glycine. While the NMDA receptor is present in islets, it may be regulated and sensed differently compared to the central nervous system.