Neuronal nitric oxide synthase protects the pancreatic beta cell from glucolipotoxicity-induced endoplasmic reticulum stress and apoptosis

E. Bachar, Y. Ariav, E. Cerasi, N. Kaiser, G. Leibowitz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Aims/hypothesis Cytokines stimulate nitric oxide production in pancreatic beta cells, leading to endoplasmic reticulum (ER) stress and apoptosis. Treatment of beta cells with glucose and NEFA induces nitric oxide synthase (NOS) as well as ER stress. However, the role of NO in glucolipotoxicity-induced ER stress in beta cells is not clear. Methods We studied the effect of high glucose and palmitate levels on NOS isoform production in rat and Psammomys obesus islets and in insulinoma-1E beta cells. The effects of neuronal NOS (nNOS) inhibition by small interfering RNA or by Nω-nitro-l-arginine methyl ester (l-NAME) on beta cell function, ER stress and apoptosis under conditions of glucolipotoxicity were investigated. Results Overnight incubation of rat and P. obesus islets at 22.2 mmol/l glucose with 0.5 mmol/l palmitate induced the production of nNOS but not inducible NOS (iNOS), in contrast with the robust stimulation of iNOS by cytokines. NOS inhibition by l-NAME did not prevent the decrease in glucose-stimulated insulin secretion and proinsulin biosynthesis or the depletion of islet insulin content observed under conditions of glucolipotoxicity. Moreover, treatment of beta cells with palmitate and l-NAME together resulted in marked activation of the IRE1a and PERK pathways of the unfolded protein response. This was associated with increased JNK phosphorylation and apoptosis in islets and beta cells. Moreover, partial nNos knockdown increased JNK phosphorylation and CHOP production, leading to apoptosis. Conclusions/interpretation In beta cells subjected to glucolipotoxic conditions, chronic inhibition of NOS exacerbates ER stress and activates JNK. Therefore, induction of nNOS is an adaptive response to glucolipotoxicity that protects beta cells from stress and apoptosis.

Original languageAmerican English
Pages (from-to)2177-2187
Number of pages11
JournalDiabetologia
Volume53
Issue number10
DOIs
StatePublished - Oct 2010
Externally publishedYes

Keywords

  • Apoptosis
  • Beta cells
  • Endoplasmic reticulum stress
  • Islets
  • Nitric oxide synthase
  • Type 2 diabetes

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