Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I.
Interleukin-1beta is a potent pro-inflammatory cytokine that has been shown to inhibit islet beta 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 beta cell destruction in IDDM onset. The insulin-like growth factor I (IGF-I) has been shown to block IL-1beta actions in vitro. We hypothesized that gene transfer of the insulin-like growth factor I to intact human islets could prevent IL-1beta-induced beta cell dysfunction and sensitization to Fas-triggered apoptosis activation. Intact human islets were infected with adenoviral vectors encoding IGF-I as well as beta-galactosidase and enhanced green fluorescent protein as controls. Adenoviral gene transfer of human IGF-I prevented IL-1beta-mediated nitric oxide production from human islets in vitro as well as the suppression of beta cell function as determined by glucose-stimulated insulin production. Moreover, IGF-I gene transfer prevented IL-1beta-induced, Fas-mediated apoptosis. These results suggest that locally produced IGF-I from cultured islets may be beneficial in maintaining beta cell function and promoting islet survival before and following islet transplantation as a potential therapy for type I diabetes.
Giannoukakis
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Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Mi
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Rudert
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Gambotto
A
A
Trucco
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Robbins
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P
D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D017209:Apoptosis; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics; D009569:Nitric Oxide / Q000502:physiology; D014162:Transfection / Q000379:methods*; D001616:beta-Galactosidase / Q000235:genetics
D007328:Insulin; D007375:Interleukin-1; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D001616:beta-Galactosidase; D005947:Glucose