Evidence that acute insulin administration enhances LDL cholesterol susceptibility to oxidation in healthy humans

Increased free radical production and hyperinsulinemia are thought to play a role in experimental and human atherosclerosis, but the relation between the 2 abnormalities has not been studied. In 23 healthy volunteers, we meas ured the susceptibility of circulating low-density lipoprotein (LDL) choles terol particles to in vitro copper sulfate oxidation (measured as the lag p hase) and cell-mediated oxidative modification (measured as malondialdehyde generation in LDL during incubation with human umbilical vein endothelial cells), as well as the vitamin E content of LDL cholesterol at baseline and after 2 hours of physiological hyperinsulinemia (euglycemic insulin clamp) . The lag time of LDL oxidation decreased from control values of 108+/-3 an d 107+/-3 minutes (at baseline and after 2 hours of saline infusion) to 101 +/-3 minutes after 2 hours of clamping (P<0.0001). At corresponding times, cell-mediated malondialdehyde generation in LDL rose from 4.96+/-0.11 and 4 .98+/-0.10 to 5.28+/-0.10 nmol/L (P=0.0006), whereas the LDL vitamin E cont ent decreased from 6.78+/-0.06 and 6.77+/-0.06 to 6.64+/-0.06 mu g/mg (P<0. 04). The insulin-induced shortening of the lag phase was directly related t o the decrement of vitamin E in LDL; furthermore, in subjects with higher b aseline serum triglyceride levels, insulin induced a greater shortening of the lag phase than in subjects with low baseline triglycerides. We conclude that in healthy humans acute physiological hyperinsulinemia enhances the o xidative susceptibility of LDL cholesterol particles. This effect may have pathogenic significance for atherogenesis in insulin resistant states.