Isolated pancreatic islets from mice were perifused with media containing maximally effective concentrations of glibenclamide (0.1-10 mumol/l) or glipizide (1 mumol/l). In these islets an increase of the glucose concentration from 10 mmol/l to 40 mmol/l or addition of D-glyceraldehyde (20 mmol/l) caused a temporary decrease in insulin release which was followed by a sustained enhancement of release. alpha-Ketoisocaproate (3 or 20 mmol/l) did not inhibit insulin release; at high concentration it was an even stronger secretagogue than D-glucose or D-glyceraldehyde. It is concluded that high energy phosphates couple B-cell fuel metabolism and insulin release by acting both on the ATP-dependent K+ channel and on other targets not yet identified.
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