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

Bo Ahrén, Linda J. Magrum, Peter J Havel, Stephanie F. Greene, Stephen D. Phinney, Patricia R. Johnson, Judith S. Stern

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Objective: The metabolism of arachidonic acid (AA) has been shown to be altered in severe insulin resistance that is present in obese (fa/fa) Zucker rats. We examined the effects and mechanism of action of AA on basal and glucose-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-old 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 lipoxygenase pathways. Medium insulin concentrations were measured by radioimmunoassay, and islet production of the 12-lipoxygenase metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), was measured by enzyme immunoassay. Results: In islets from lean animals, AA stimulated insulin secretion at submaximally stimulatory glucose levels (<11.1 mM) but not at 16.7 mM glucose. In contrast, in islets derived from obese rats, AA potentiated insulin secretion at all glucose concentrations. AA-induced insulin secretion was augmented 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-lipoxygenase, esculetin (0.5 μM), inhibited AA-stimulated insulin secretion 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 response to 16.7 mM glucose and to AA. Discussion: The insulin secretory response to AA is augmented in islets from obese Zucker rats by a mechanism related to enhanced activity of the 12-lipoxygenase pathway. Therefore, augmented action of AA may be a mechanism underlying the adaptation of insulin secretion to the increased demand caused by insulin resistance in these animals.

Original languageEnglish (US)
Pages (from-to)475-480
Number of pages6
JournalObesity Research
Volume8
Issue number6
StatePublished - Sep 2000

Keywords

  • Arachidonic acid
  • Insulin secretion
  • Lipoxygenase
  • Zucker rats

ASJC Scopus subject areas

  • Food Science
  • Endocrinology
  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism
  • Public Health, Environmental and Occupational Health

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    Ahrén, B., Magrum, L. J., Havel, P. J., Greene, S. F., Phinney, S. D., Johnson, P. R., & Stern, J. S. (2000). Augmented insulinotropic action of arachidonic acid through the lipoxygenase pathway in the obese zucker rat. Obesity Research, 8(6), 475-480.