Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

A. Fornoni, Antonello Pileggi, R. D. Molano, N. Y. Sanabria, T. Tejada, J. Gonzalez-Quintana, H. Ichii, L. Inverardi, C. Ricordi, R. L. Pastori

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Aims/hypothesis: Activation of c-jun N-terminal kinase (JNK) has been described in islet isolation and engraftment, making JNK a key target in islet transplantation. The objective of this study was to investigate if JNK inhibition with a cell-permeable TAT peptide inhibitor (L-JNKI) protects functional beta cell mass in human islets and affects AKT and its substrates in islet cells. Methods: The effect of L-JNKI (10 μmol/l) on islet count, mitochondrial membrane potential, glucose-stimulated insulin release and phosphorylation of both AKT and its substrates, as well as on reversal of diabetes in immunodeficient diabetic Nu/Nu mice was studied. Results: In vitro, L-JNKI reduced the islet loss in culture and protected from cell death caused by acute cytokine exposure. In vivo, treatment of freshly isolated human islets and diabetic Nu/Nu mice recipients of such islets resulted in improved functional beta cell mass. We showed that L-JNKI activates AKT and downregulates glycogen synthase kinase-3 beta (GSK-3B) in human islets exposed to cytokines, while other AKT substrates were unaffected, suggesting that a specific AKT/GSK-3B regulation by L-JNKI may represent one of its mechanisms of cytoprotection. Conclusions/interpretation: In conclusion, we have demonstrated that targeting JNK in human pancreatic islets results in improved functional beta cell mass and in the regulation of AKT/GSK3B activity.

Original languageEnglish (US)
Pages (from-to)298-308
Number of pages11
JournalDiabetologia
Volume51
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • AKT
  • Beta cell viability
  • C-jun N terminal kinase
  • Inflammation
  • Insulin production
  • Islet transplantation
  • Mitogen activated protein kinase
  • Pancreatic islets

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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