Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet

Diabetic patients typically have not only hyperglycemia but also dyslipidem ia. Study of the pathogenic components of the diabetic milieu and mechanism s of accelerated atherosclerosis is hindered by inadequate animal models. A potentially suitable animal model for human diabetic dyslipidemia is the p ig, because it carries a large fraction of total cholesterol in low-density lipoprotein (LDL), similar to humans. In this study, male Sinclair miniatu re pigs were made diabetic by destroying the insulin-producing cells of the pancreas with alloxan and then were fed a high fat and high cholesterol di et for comparison with pigs fed a nondiabetic high fat and high cholesterol diet and control pigs. Diabetic pigs exhibited hyperglycemia, but plasma u rea nitrogen, creatinine, and transaminase levels were in the normal range, indicating no adverse effects on kidney and liver function. The lipoprotei n profile in diabetic pigs was similar to that found in human diabetic pati ents and was characterized by hypertriglyceridemia (2.8-fold increase versu s control and high fat-fed pigs) and a profound shift of cholesterol distri bution into the LDL fraction (81%) versus the distribution in high fat-fed (64%) and control (57%) pigs, LDL particles were lipid-enriched and more he terogeneous in diabetic pigs, Apolipoprotein B was distributed among a much broader spectrum of LDL particles, and apolipoprotein E was partially redi stributed from high-density lipoprotein to apolipoprotein B-containing lipo proteins in diabetic pigs. There was little change in apolipoprotein A-I di stribution. Diabetic pigs showed several early signs of excess vascular dis ease. In diabetic pigs, 75% of the coronary artery segments showed contract ile oscillations in response to prostaglandin F-2 alpha compared with 25% i n high fat-fed pigs and 10% in control pigs, Endothelium-dependent relaxati on of brachial arteries was nearly abolished in diabetic pigs but unchanged in high fat-fed versus control pigs, Carotid artery Sudan IV staining for fatty streaks was significantly increased only in diabetic pigs, This porci ne model should provide insights into the etiology of human diabetic dyslip idemia and facilitate study of peripheral vascular and coronary artery dise ase in diabetic patients.