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 measured the susceptibility of circulating low-density lipoprotein (LDL) cholesterol particles to in vitro copper sulfate oxidation (measured as the lag phase) 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 and 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 content decreased from 6.78+/-0.06 and 6.77+/-0.06 to 6.64+/-0.06 microg/mg (P<0.04). The insulin-induced shortening of the lag phase was directly related to the decrement of vitamin E in LDL; furthermore, in subjects with higher baseline 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 oxidative susceptibility of LDL cholesterol particles. This effect may have pathogenic significance for atherogenesis in insulin resistant states.
Quiñones-Galvan
A
A
CNR Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa, Pisa, Italy.
Sironi
A M
AM
Baldi
S
S
Galetta
F
F
Garbin
U
U
Fratta-Pasini
A
A
Cominacini
L
L
Ferrannini
E
E
D000328:Adult; D001786:Blood Glucose; D008076:Cholesterol, HDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D005230:Fatty Acids, Nonesterified; D005609:Free Radicals; D007004:Hypoglycemic Agents; D007328:Insulin; D008077:Lipoproteins, LDL; D014280:Triglycerides; C099252:oxidized low density lipoprotein