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 hormones on the oxidation of low density lipoproteins (LDL) and superoxide anion production by peripheral blood mononuclear cells (MC). LDL oxidation was measured by the production of thiobarbituric acid reactive substances (TBARS). Insulin and IGF-I at 10(-7) M caused a 33% and 48% increase in TBARS production, respectively. At 10(-6) M the corresponding values were 63% and 67%. Proinsulin and IGF-II at 10(-6) M had no effect. Glucose caused a concentration dependent (up to 10 mM) stimulation 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 electrophoretic mobility. Insulin-stimulated LDL oxidation was inhibited by superoxide dismutase (SOD), but insulin had no effect on MC superoxide production. MC were isolated from five subjects before and after a 5 h hyperinsulinemic, euglycemic clamp. Insulin infusion had no effect on TBARS or superoxide production by MC. Our in vitro experiments suggest that high levels of insulin and IGF-I stimulate MC-mediated oxidation of LDL, an effect that is potentially atherogenic.