A link between insulin resistance and hyperinsulinemia: Inhibitors of phosphatidylinositol 3-kinase augment glucose-induced insulin secretion from islets of lean, but not obese, rats

Wortmannin (5-100 nM), a specific phosphatidyinositol 3-kinase inhibitor, a ugmented 8 mM glucose-induced insulin secretion from control Sprague Dawley rat islets in a dose-dependent manner. This effect persisted after its rem oval from the perifusion medium; however, this augmenting effect was reduce d by the calcium channel inhibitor nitrendipine or by lowering the glucose level to 3 mM. Wortmannin amplified insulin release induced by the combinat ion of 6-8 mM glucose plus 1 mu M carbachol; however, it had no effect on p horbol ester- or alpha-ketoisocaproate-induced insulin secretion. The poten tiating action of wortmannin on 8 mM glucose-induced release was duplicated by LY294002. Wortmannin had no effect on glucose usage rates or inositol p hosphate accumulation in [H-3] inositol-prelabeled islets. Of particular si gnificance, although 50 nM wortmannin potentiated 8 mM glucose-induced secr etion from islets of lean Zucker control rats, the fungal metabolite had li ttle effect on 8 mM glucose-induced release from islets of insulin-resistan t Zucker fatty rats. These findings support the concept that the same bioch emical process, inhibition of phosphatidyinositol 3-kinase, that causes per ipheral tissue insulin resistance enhances beta-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 i nsulin signaling pathways. This elegant biochemical control mechanism in be ta-cells ensures the maintenance of glucose homeostasis despite a reduction in insulin action on peripheral tissues.