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 language | English (US) |
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Pages (from-to) | 298-308 |
Number of pages | 11 |
Journal | Diabetologia |
Volume | 51 |
Issue number | 2 |
DOIs | |
State | Published - Feb 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