Chronic exposure to high leucine impairs glucose-induced insulin release by lowering the ATP-to-ADP ratio

Exposure of rat pancreatic islets to 20 mM leucine for 24 h reduced insulin release in response to glucose (16.7 and 22.2 mM). Insulin release was nor mal when the same islets were stimulated with leucine (40 mM) or glyburide (1 muM). To investigate the mechanisms responsible for the different effect of these secretagogues, we studied several steps of glucose-induced insuli n secretion. Glucose utilization and oxidation rates in leucine-precultured islets were similar to those of control islets. Also, the ATP-sensitive K channel-independent pathway of glucose-stimulated insulin release, studied in the presence of 30 mM K+ and 250 muM diazoxide, was normal. In contrast , the ATP-to-ADP ratio after stimulation with 22.2 mM glucose was reduced i n leucine-exposed islets with respect to control islets. The decrease of th e ATP-to-ADP ratio was due to an increase of ADP levels. In conclusion, pro longed exposure of pancreatic islets to high leucine levels selectively imp airs glusoce-induced insulin release. This secretory abnormality is associa ted with (and might be due to) a reduced ATP-to-ADP ratio. The abnormal pla sma amino acid levels often present in obesity and diabetes may, therefore, affect pancreatic islet insulin secretion in these patients.