Probucol was given to rats made diabetic by streptozotodn. Compared with diabetic rats not receiving probucol or with nondiabetic rats, probucol lowered the plasma concentrations of trigrycerkies, phospholipids, cholesterol, and apolipoproteln B. The concentrations of serum chylomicrons and very low density lipoprotein (VLDL) were also reduced. In control and diabetic rats, probucol enhanced the clearance of endogenoushy radiolabeled VLDL from the plasma. Clearances from the plasma of rat lymph chylomicrons or chylomicronlike lipkJ emulsions were slow in diabetic rats. Probucol normalized chyiomicron clearance in diabetic rats primarily by restoring hepatic uptake of remnants, which was decreased in diabetes. In diabetic rats, uptake of chyiomicron remnants was increased in a number of extrahepatic tissues, including the heart and kidney. Probucol significantly decreased uptake in some extrahepatic tissues. Increased plasma clearance of VLDL and chylomicrons was associated with an increase in the apolipoprotein CH/Clll and apolipoprotein E/C ratios. Orally administered probucol was specifically incorporated into lymph chylomicrons, and clearance of probucol from the plasma exactly paralleled the clearance of chyiomicron remnants, as traced with radiolabeled cholesteiyl esters. Chylomicron-like emulsions incorporating probucol were exclusively cleared from the plasma by the liver in normal rats. We conclude that in streptozotodn diabetic rats, probucol is an effective hypolipidemic agent because it promotes the clearance of the trigiyceride-rich lipoproteins. are frequently found in patients with diabetes mellitus. The hyperlipidemia primarily reflects slow clearance of plasma lipoproteins, although overproduction of lipoproteins may also be a contributing factor in non-insulin-dependent diabetes.1 A defective clearance from the plasma of chylomicrons and very low density lipoproteins (VLDLs) has been reported in human diabetic patients (for a review, see Howard 1 ) and in animal models of this disease.2 " 4 Hydrolysis of triglycerides may be compromised by severe insulin deficiency because insulin maintains the synthesis and secretion of lipoprotein lipase in some tissues.5 Posthydrolysis clearance of the remnant particles is also delayed, 6 although the reasons for this are unclear. Elevated plasma concentrations of triglycerides and cholesterol are thought to contribute to the high incidence of atherosclerosis in diabetic patients, and so it is desirable to reduce the concentrations of these lipids. Probucol is a potent hypolipidemic agent that reduces serum cholesterol level principally by increasing the fractional catabolic rate of low density lipoprotein (LDL). 7 ? Probucol is an effective lipid antioxidant, but it is not clear whether its pharmacological actions on the metabolism of LDL are related to the prevention of oxidation. Lipoproteins from diabetic donors show increased amounts of oxidative products compared with lipoproteins of nondiabetic origin. Probucol has been shown to decrease oxidation of...