Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I

N. Giannoukakis, Z. Mi, W. A. Rudert, A. Gambotto, M. Trucco, P. Robbins

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Interleukin-1β is a potent pro-inflammatory cytokine that has been shown to inhibit islet β cell function as well as to activate Fas-mediated apoptosis in a nitric oxide-dependent manner. Furthermore, this cytokine is effective in recruiting lymphocytes that mediate β cell destruction in IDDM onset. The insulin-like growth factor I (IGF-I) has been shown to block IL-1β actions in vitro. We hypothesized that gene transfer of the insulin-like growth factor I to intact human islets could prevent IL-1β-induced β cell dysfunction and sensitization to Fas-triggered apoptosis activation. Intact human islets were infected with adenoviral vectors encoding IGF-I as well as β-galactosidase and enhanced green fluorescent protein as controls. Adenoviral gene transfer of human IGF-I prevented IL-1β-mediated nitric oxide production from human islets in vitro as well as the suppression of β cell function as determined by glucose-stimulated insulin production. Moreover, IGF-I gene transfer prevented IL-1β-induced, Fas-mediated apoptosis. These results suggest that locally produced IGF-I from cultured islets may be beneficial in maintaining β cell function and promoting islet survival before and following islet transplantation as a potential therapy for type I diabetes.

Original languageEnglish (US)
Pages (from-to)2015-2022
Number of pages8
JournalGene therapy
Volume7
Issue number23
DOIs
StatePublished - 2000
Externally publishedYes

Bibliographical note

Funding Information:
We would like to thank the Juvenile Diabetes Foundation International Islet Distribution Program; Elina Linetsky, Alessandra Ranuncoli and Jeff Ansite for the isolation and purification of human islets as well as Christy Bruton and Bruce Baldwin for technical assistance. This work was supported in part by Public Health Service grant AR-6–2225 (PDR) and a program project grant from the Juvenile Diabetes Foundation International (MT and PDR). NG is the recipient of a post-doctoral fellowship from the Juvenile Diabetes Foundation International and a prize from the Fonds pour la formation de chercheurs et a l’aide a la recherche (Fonds FCAR) from the provincial government of Quebec, Canada.

Keywords

  • Adenovirus
  • Gene therapy
  • IGF-I
  • IL-1β
  • Islets

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