title: PPARgamma-dependent and -independent effects of rosiglitazone on lipotoxic human pancreatic islets.
abstract: We explored the in vitro effects of Rosiglitazone (RZG), a PPARgamma agonist, on human pancreatic islet dysfunctions induced by chronic free fatty acid exposure. We demonstrated that RZG beneficial effects on insulin secretion and apoptosis did not imply PDX-1 or insulin gene modulation. It rather involved, through a PPARgamma-dependent mechanism, a reduction of iNOS overexpressed in lipotoxic islets. This reduction likely led to the restoration of ATP level and insulin secretion as well as the decrease in apoptosis. More interestingly, we also demonstrated that RZG beneficial effects involved PPARgamma-independent mechanisms. RZG treatment led to a limitation of oxidative stress exemplified by an increase of GPx and SOD expression. It also increased UCP2 expression that seemed to display antioxidant action in this model. Thus, RZG did not appear to exert a direct action on insulin expression but rather an indirect action on insulin secretion and apoptosis, through PPARgamma-dependent and -independent mechanisms, via regulation of nitrogen and oxygen reactive species injury.
authors.affiliation: INSERM U859, Diabetes Cell Therapy, Faculty of Medicine, Lille2 University, Place de Verdun, 59045 Lille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vandewalle
authors.forename: Ericka
authors.initials: E
authors.lastname: Moerman
authors.forename: Bruno
authors.initials: B
authors.lastname: Lefebvre
authors.forename: Frédérique
authors.initials: F
authors.lastname: Defrance
authors.forename: Valéry
authors.initials: V
authors.lastname: Gmyr
authors.forename: Bruno
authors.initials: B
authors.lastname: Lukowiak
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr Conte
authors.forename: François
authors.initials: F
authors.lastname: Pattou
mesh_terms: D000328:Adult; D005230:Fatty Acids, Nonesterified / Q000633:toxicity*; D020869:Gene Expression Profiling; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D005230:Fatty Acids, Nonesterified; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D019308:Palmitic Acid