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A Link between Insulin Resistance and Hyperinsulinemia: Inhibitors of Phosphatidylinositol 3-Kinase Augment Glucose-Induced Insulin Secretion from Islets of Lean, But Not Obese, Rats¹

Yale University School of Nursing, New Haven, Connecticut 06536-0740

Address all correspondence and requests for reprints to: Dr. Walter S. Zawalich, Yale University School of Nursing, 100 Church Street South, New Haven, Connecticut 06536-0740. E-mail: walter.zawalich{at}yale.edu

Wortmannin (5–100 nM), a specific phosphatidyinositol 3-kinase inhibitor, augmented 8 mM glucose-induced insulin secretion from control Sprague Dawley rat islets in a dose-dependent manner. This effect persisted after its removal from the perifusion medium; however, this augmenting effect was reduced by the calcium channel inhibitor nitrendipine or by lowering the glucose level to 3 mM. Wortmannin amplified insulin release induced by the combination of 6–8 mM glucose plus 1 µM carbachol; however, it had no effect on phorbol ester- or -ketoisocaproate-induced insulin secretion. The potentiating action of wortmannin on 8 mM glucose-induced release was duplicated by LY294002. Wortmannin had no effect on glucose usage rates or inositol phosphate accumulation in [³H]inositol-prelabeled islets. Of particular significance, although 50 nM wortmannin potentiated 8 mM glucose-induced secretion from islets of lean Zucker control rats, the fungal metabolite had little effect on 8 mM glucose-induced release from islets of insulin-resistant Zucker fatty rats. These findings support the concept that the same biochemical process, inhibition of phosphatidyinositol 3-kinase, that causes peripheral tissue insulin resistance enhances ß-cell sensitivity to glucose and produces a compensatory increase in insulin secretion from these cells. The efficacy of wortmannin depends on the in vivo status of the donor’s insulin signaling pathways. This elegant biochemical control mechanism in ß-cells ensures the maintenance of glucose homeostasis despite a reduction in insulin action on peripheral tissues.

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