Perifused islets from rats infused for 7 days with 40% glucose exhibited an altered secretory response to selected stimuli. Both phases of insulin release were blunted when 20 mM L-leucine was tested; the secretory response to a subsequent leucine stimulation was also blunted compared with the control group. The ability of 20 mM α-ketoisocaproate to stimulate the release of insulin was also greatly diminished in islets from glucose-infused rats. The secretory response to 50 μM tolbutamide plus 7 mM glucose by perifused islets from glucose-infused rats was 45% lower than in the control group. In addition, the response to a subsequent 10 mM glucose stimulation was lost. On the other hand, islets from glucose-infused rats responded to 20 μM forskolin plus 16.7 mM glucose with no significant change in the amount of insulin released during both phases of stimulation compared with the control group. The response to 100 nM phorbol 12-mirystate 13-acetate was 3.1-fold higher in islets from glucose-infused compared with saline-infused rats. The finding that chronic infusions of glucose lead to selective impairment of the secretory response to fuel stimuli and agents such as tolbutamide that act on metabolically regulated K+ channels gives support to the notion that alterations in the generation of metabolic coupling signals might be involved in the phenomenon described here.

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