© 1999 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Dyslipidemia and Vascular Dysfunction in Diabetic Pigs Fed an Atherogenic Diet
From the Department of Food Science and Human Nutrition, College of Agriculture, Food and Natural Resources (J.L.D., J.D.S., G.A.W.), the Department of Veterinary Biomedical Sciences, School of Veterinary Medicine (M.H.L.), the Department of Biochemistry, College of Agriculture, Food and Natural Resources (G.A.W.), and the Dalton Cardiovascular Research Center and Department of Physiology, School of Medicine (J.L.P., M.H.L., M.S.), University of Missouri, Columbia.
Correspondence to Joseph L. Dixon, PhD, Dalton Cardiovascular Research Center, 122 Eckles Hall, University of Missouri, Columbia, MO 65211. E-mail dixonj{at}missouri.edu
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 F2
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.
Key Words: Sinclair miniature swine • animal model • lipids • VLDL • LDL • HDL • cholesterol • triglycerides • endothelium • vascular smooth muscle • atherosclerosis • coronary arteries
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