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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2392.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Selective Insulin Resistance Affecting Nitric Oxide Release But Not Plasminogen Activator Inhibitor-1 Synthesis in Fibroblasts From Insulin-Resistant Individuals

Assunta Pandolfi; Anna Solini; Giuliana Pellegrini; Gabriella Mincione; Sara Di Silvestre; Paola Chiozzi; Annalisa Giardinelli; Maria Carmela Di Marcantonio; Alessandro Piccirelli; Fabio Capani; Agostino Consoli

From Aging Research Center (A. Pandolfi; S.D.S., A.G., F.C., A.C.), Ce.S.I., "Gabriele D’Annunzio" University Foundation, Chieti-Pescara, Italy; Department of Biomorphology (A. Pandolfi), University of "G. D’Annunzio," Chieti-Pescara, Italy; Department of Internal Medicine (A.S.), University of Pisa, Italy; Department of Medicine and Aging Sciences (G.P., F.C., A.C.), University of "G. D’Annunzio," Chieti-Pescara, Italy; Department of Oncology and Neurosciences (G.M., M.C.D.M., A. Piccirelli), University of "G. D’Annunzio," Chieti-Pescara, Italy; Section of General Pathology (P.C.), University of Ferrara, Italy.

Correspondence to Agostino Consoli, MD, Department of Medicine and Aging Sciences, Edificio Ce.S.I., room 271, University of Chieti, Via dei Vestini, 1 66100 CHIETI, Italy. E-mail consoli{at}unich.it

Objectives— Insulin activates several processes potentially dangerous for the arterial wall and hyperinsulinemia might be atherogenic. However, other insulin effects are protective for the vessel wall and thus anti-atherogenic. Aim of this study was to investigate whether insulin effects on potentially pro-atherogenic and anti-atherogenic processes were differently affected in cells from insulin-resistant individuals.

Methods and Results— We determined insulin effect on nitric oxide (NO) production and plasminogen activator inhibitor (PAI)-1 synthesis in 12 fibroblast strains obtained from skin biopsy samples of 6 insulin-sensitive (IS) (clamp M >7 mg/kg body weight per minute) and 6 insulin-resistant (IR) (clamp M <5 mg/kg body weight per minute) healthy volunteers. Insulin effects on NO release and Akt phosphorylation were significantly impaired in fibroblasts from IR as compared with IS individuals. Conversely, there was not any difference between IR and IS strains in insulin ability to increase PAI-1 antigen levels and, after 24-hour insulin incubation, PAI-1 mRNA increase in IR strains was only slightly less than in IS strains. Insulin ability to induce MAPK activation was also comparable in IR and IS cells.

Conclusions— We conclude that in cells from IR individuals, insulin action on anti-atherogenic processes, such as NO release, is impaired, whereas the hormone ability to stimulate atherogenic processes, such as PAI-1 release, is preserved.

We investigated insulin pro- and antiatherogenic properties in fibroblasts derived from insulin-resistant (IR) subjects. In IR fibroblasts, insulin-dependent NO release and Akt phosphorylation were impaired, whereas insulin ability to stimulate MAPK activity and PAI-1 release was unaffected.

Key Words: diabetes mellitus • fibroblasts • insulin resistance • nitric oxide • plasminogen activator inhibitor type 1