EVIDENCE FOR A GLUTAMATE RECEPTOR OF THE AMPA SUBTYPE WHICH MEDIATES INSULIN RELEASE FROM RAT PERFUSED PANCREAS

1 The effect of L-glutamate has been studied on insulin secretion by the isolated perfused pancreas of the rat. The glutamate receptor subtype involved has been characterized. 2 In the presence of a slightly stimulating glucose concentration (8.3 mM), L-glutamate (5 x 10(-5) - 4 x 10(-3) M) induced an immediate, transient and concentration-dependent insulin response. On the other hand, in the presence of a non stimulating glucose concentration (2.8 mM), L-glutamate (10(-3) M) did not modify the basal insulin secretion. 3 The three non-NMDA receptor agonists, kainate (10(-4) - 10(-3) M), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 5 x 10(-5) - 10(-4) M) and quisqualate (5 x 10(-6) - 5 x 10(-5) M) all provoked a transient and concentration-dependent insulin response from pancreas perfused with 8.3 mm glucose. Compared with glutamate, kainate exhibited a similar efficacy, whereas AMPA and quisqualate elicited only a 3 fold lower maximal insulin response. In contrast, NMDA (10(-4) - 10(-3) M) was ineffective. 4 An antagonist of non-NMDA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 5 x 10(-5) M) totally prevented the stimulatory effect of L-glutamate (4 x 10(-4) M) and kainate (2 x 10(-4) M). In contrast, the NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+) MK801) was without effect. 5 The insulin secretory effect of glutamate (4 x 10(-4) M) was not affected by atropine (3 x 10(-7) M) or tetrodotoxin (3 x 10(-6) M). 6 Quisqualate at a high maximally effective concentration (4 x 10(-4) M) inhibited glutamate (10(-3) M) or kainate (4 x 10(-4) M)-induced insulin release. 7 This study shows that L-glutamate stimulates insulin secretion in rat pancreas, by acting on an excitatory amino acid receptor of the AMPA subtype.