Dyslipidemia and Vascular Dysfunction in Diabetic Pigs Fed an Atherogenic Diet

Abstract

Abstract —Diabetic patients typically have not only hyperglycemia but also dyslipidemia. Study of the pathogenic components of the diabetic milieu and mechanisms of accelerated atherosclerosis is hindered by inadequate animal models. A potentially suitable animal model for human diabetic dyslipidemia is the pig, because it carries a large fraction of total cholesterol in low-density lipoprotein (LDL), similar to humans. In this study, male Sinclair miniature 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 diet for comparison with pigs fed a nondiabetic high fat and high cholesterol diet and control pigs. Diabetic pigs exhibited hyperglycemia, but plasma urea nitrogen, creatinine, and transaminase levels were in the normal range, indicating no adverse effects on kidney and liver function. The lipoprotein profile in diabetic pigs was similar to that found in human diabetic patients and was characterized by hypertriglyceridemia (2.8-fold increase versus control and high fat–fed pigs) and a profound shift of cholesterol distribution into the LDL fraction (81%) versus the distribution in high fat–fed (64%) and control (57%) pigs. LDL particles were lipid-enriched and more heterogeneous in diabetic pigs. Apolipoprotein B was distributed among a much broader spectrum of LDL particles, and apolipoprotein E was partially redistributed from high-density lipoprotein to apolipoprotein B–containing lipoproteins in diabetic pigs. There was little change in apolipoprotein A-I distribution. Diabetic pigs showed several early signs of excess vascular disease. In diabetic pigs, 75% of the coronary artery segments showed contractile oscillations in response to prostaglandin F 2α compared with 25% in high fat–fed pigs and 10% in control pigs. Endothelium-dependent relaxation 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 porcine model should provide insights into the etiology of human diabetic dyslipidemia and facilitate study of peripheral vascular and coronary artery disease in diabetic patients.