Expression of islet iNOS and inhibition of glucose stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27.

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Abstract

Chronic exposure of pancreatic islets to elevated plasma lipids ( lipotoxicity) can lead to beta-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase ( iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide ( PACAP) 27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to beta-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive ( nc) NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in beta-cells.

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  • Physiology

Keywords

  • pituitary adenylate cyclase-activating polypeptide 27, pancreatic islets, synthase, isoforms of nitric oxide, insulin secretion
Original languageEnglish
Pages (from-to)E1447-E1455
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Volume292
Issue number5
Publication statusPublished - 2007
Publication categoryResearch
Peer-reviewedYes

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