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National Centre for Food Quality and Risk Assessment, Section of Nutrition, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
¹ Department of Drug Research and Evaluation, Section of Cell Aging and Degeneration, Istituto Superiore di Sanità, Rome, Italy
² Department of Clinical Sciences University ‘La Sapienza’, Rome, Italy
³ Division of Endocrinology and Metabolism Cedars-Sinai Medical Center, University of California, Los Angeles, California, USA

(Requests for offprints should be addressed to C Santangelo; Email: c.santan{at}iss.it)

Type 2 diabetes is characterized by peripheral insulin resistance, pancreatic ß-cells dysfunction, and decreased ß-cell mass with increased rate of apoptosis. Chronic exposure to high levels of free fatty acids (FFAs) has detrimental effects on ß-cell function and survival. FFAs have adverse effects on mitochondrial function, with a consequent increase in the production of reactive oxygen species. Hepatocyte growth factor (HGF) plays a critical role in promoting ß-cell survival. In the present study, we investigated whether HGF was capable of protecting ß-cells from death induced by prolonged exposure to FFAs. RINm5F cell line was cultured in the presence of FFAs (oleate:palmitate 2:1) for 72 h in order to induce apoptosis. Simultaneous administration of HGF and FFAs significantly suppressed the impaired insulin secretion and FFA-induced apoptosis. Specifically, HGF exerted its protective effect by counteracting: (i) the overproduction of either hydrogen peroxide and superoxide anion, (ii) the reduction of intracellular -glutamylcysteinylglycine level, and (iii) the depolarization of mitochondrial membrane, induced by prolonged FFAs exposure. These effects appear to be mediated by bcl-2 and phosphatidylinositol 3 kinase (PI3K)/Akt pathways. Indeed, HGF increased mRNA and protein expression of bcl-2 downregulated by FFAs-treatment; moreover, pre-treatment with the specific PI3-kinase inhibitor LY294002, significantly abolished the protective effect of HGF. In conclusion, in rat insulin-producing RINm5F cells, HGF exerts its prosurvival effect by counteracting the increased intracellular oxidative stress and, consequently, by inhibiting apoptosis induced by chronic exposure to FFAs.

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