STIMULATION OF LOW-DENSITY-LIPOPROTEIN OXIDATION BY INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I

Hyperinsulinemia has been implicated as an independent risk factor for atherosclerosis. We measured the effect of insulin and related hormon es on the oxidation of low density lipoproteins (LDL) and superoxide a nion production by peripheral blood mononuclear cells (MC). LDL oxidat ion was measured by the production of thiobarbituric acid reactive sub stances (TBARS). Insulin and IGF-I at 10(-7) M caused a 33% and 48% in crease in TBARS production, respectively. At 10(-6) M the correspondin g values were 63% and 67%. Proinsulin and IGF-II at 10(-6) M had no ef fect. Glucose caused a concentration dependent (up to 10 mM) stimulati on of LDL oxidation reaching 85% and 77% at insulin concentrations of 10(-7) M and 10(-6) M, respectively. The stimulatory effect of insulin was confirmed by measurements of other indices of LDL oxidation, i.e. absorbance at 234 nm, trinitrobenzene sulfonic acid reactivity and el ectrophoretic mobility. Insulin-stimulated LDL oxidation was inhibited by superoxide dismutase (SOD), but insulin had no effect on MC supero xide production. MC were isolated from five subjects before and after a 5 h hyperinsulinemic, euglycemic clamp. Insulin infusion had no effe ct on TBARS or superoxide production by MC. Our in vitro experiments s uggest that high levels of insulin and IGF-I stimulate MC-mediated oxi dation of LDL, an effect that is potentially atherogenic.