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Acta Diabetologica

, Volume 50, Issue 6, pp 899–906 | Cite as

The MDM2 inhibitor Nutlin-3 attenuates streptozotocin-induced diabetes mellitus and increases serum level of IL-12p40

  • Paola Secchiero
  • Barbara Toffoli
  • Elisabetta Melloni
  • Chiara Agnoletto
  • Lorenzo Monasta
  • Giorgio ZauliEmail author
Original Article

Abstract

Besides its well-established oncosuppressor activity, a key function of p53 in regulating metabolic pathways has been recently identified. Nevertheless, the role of p53 with respect to diabetes mellitus (DM) appears highly controversial. To address this issue, we have used the cis-imidazoline compound Nutlin-3, an inhibitor of MDM2/p53 interaction, which represents a potent and selective non-genotoxic activator of the p53 pathway both in in vivo and in vitro experimental settings. Experimental DM was induced by intraperitoneal injections of low concentrations of streptozotocin (STZ) in C57BL/6N mice (n = 20). A group of control vehicle-injected mice (n = 10) and of STZ-treated mice (n = 10) was co-injected with Nutlin-3. Mice co-injected with STZ + Nutlin-3 exhibited attenuated features of DM with respect to animals treated with STZ alone. Indeed, STZ + Nutlin-3-treated mice were characterized by significantly (p < 0.05) lower levels of hyperglycemia, reduced weight loss, and increased spleen weight. In addition, STZ alone promoted a marked decrease in the levels of several circulating cytokines, including interleukin-12 (IL-12)p40. On the other hand, co-injection of STZ + Nutlin-3 significantly (p < 0.01) counteracted IL-12p40 down-modulation. In vitro experiments performed on the RAW264.7 macrophagic cell line model, used as cellular source of IL-12p40, demonstrated that Nutlin-3 treatment increased IL-12p40 release, strongly suggesting a direct effect of Nutlin-3 on the immune system. Overall, these data demonstrate that systemic administration of Nutlin-3 ameliorates the severity of STZ-induced DM and increases the levels of circulating IL-12p40.

Keywords

Nutlin-3 Diabetes mellitus Serum cytokines IL-12p40 

Notes

Acknowledgments

This work was supported by the grants from the Italian Ministry of Health to the IRCCS “Burlo Garofolo” of Trieste and by Italian Association for Cancer Research (AIRC) grant (IG 11465 to G. Zauli) and FIRB-MIUR grant (to G. Zauli). Chiara Agnoletto has been supported by a “Consorzio Spinner PhD Program.” We are extremely grateful to Riccardo Candido, M.D., PhD (Diabetological Centre ASS1 Trieste, Trieste, Italy), for the revision of the manuscript.

Conflict of interest

The authors have no conflicts of interest.

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Copyright information

© Springer-Verlag Italia 2013

Authors and Affiliations

  • Paola Secchiero
    • 1
  • Barbara Toffoli
    • 2
  • Elisabetta Melloni
    • 1
  • Chiara Agnoletto
    • 1
  • Lorenzo Monasta
    • 2
  • Giorgio Zauli
    • 2
    Email author
  1. 1.Department of Morphology, Surgery and Experimental Medicine and LTTA CentreUniversity of FerraraFerraraItaly
  2. 2.Institute for Maternal and Child HealthIRCCS “Burlo Garofolo”TriesteItaly

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