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.

Abstract:

: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 microM carbachol; however, it had no effect on phorbol ester- or alpha-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 ofphosphatidyinositol 3-kinase, that causes peripheral 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 insulin signaling pathways. This elegant biochemical control mechanism in beta-cells ensures the maintenance of glucose homeostasis despite a reduction in insulin action on peripheral tissues.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Zawalich WS,Zawalich KC

doi

10.1210/endo.141.9.7636

subject

Has Abstract

pub_date

2000-09-01 00:00:00

pages

3287-95

issue

9

eissn

0013-7227

issn

1945-7170

journal_volume

141

pub_type

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