Augmented insulinotropic action of arachidonic acid through the lipoxygenase pathway in the obese Zucker rat

Objective: The metabolism of arachidonic acid (AA) has been shown to be alt ered in severe insulin resistance that is present in obese (fa/fa) Zucker r ats. We examined the effects and mechanism of action of AA on basal and glu cose stimulated insulin secretion in pancreatic islets isolated from obese (fa/fa) Zucker rats and their homozygous lean (Fa/Fa) littermates. Research Methods and Procedures: Islets were isolated from 10- to 12-week-o ld rats and incubated for 45 minutes in glucose concentrations ranging from 3.3 to 16.7 mM with or without inhibitors of the cyclooxygenase or lipoxyg enase pathways. Medium insulin concentrations were measured by radioimmunoa ssay, and islet production of the 12-lipoxygenase metabolite, 12-hydroxyeic osatetraenoic acid (12-HETE), was measured by enzyme immunoassay. Results: In islets from lean animals, AA stimulated insulin secretion at su bmaximally stimulatory glucose levels (<11.1 mM) but not at 16.7 mM glucose . In contrast, in islets derived from obese rats, AA potentiated insulin se cretion at all glucose concentrations. AA-induced insulin secretion was aug mented in islets from obese compared with lean rats at high concentrations of AA in the presence of 3.3 mM glucose. Furthermore, the inhibitor of 12-l ipoxygenase, esculetin (0.5 mu M), inhibited AA-stimulated insulin secretio n in islets from obese but not lean rats. Finally, the islet production of the 12-HETE was markedly enhanced in islets from obese rats, both in respon se to 16.7 mM glucose and to AA. Discussion: The insulin secretory response to AA is augmented in islets fro m obese Zucker rats by a mechanism related to enhanced activity of the 12-l ipoxygenase pathway. Therefore, augmented action of AA may be a mechanism u nderlying the adaptation of insulin secretion to the increased demand cause d by insulin resistance in these animals.