Atherosclerotic vascular disease is a major cause of the increased morbidity and mortality associated with diabetes mellitus. Although the etiology of antherosclerosis is unknown, there is a strong correlation between the plasma cholesterol concentrations and atherosclerosis. Plasma cholesterol levels are increased in diabetic patients and recent studies have demonstrated that plasma cholesterol concentrations are directly correlated with the degree of hyperglycemia. Diabetics with """"""""loose"""""""" metabolic control have been noted to have elevated plasma cholesterol concentrations in comparison to diabetics with """"""""tight"""""""" control. The etiology of the elevations in plasma cholesterol concentrations in diabetics is unknown, but recently we have demonstrated that in rats, diabetes results in a 2 to 3 fold stimulation of cholesterol synthesis in the small intestine. Insulin therapy, which results in the normalization of blood glucose, decreases cholesterol synthesis to levels only slightly greater than in the controls. Most importantly, this increase in intestinal cholesterol synthesis results in a 4 fold increase in the transport of cholesterol from the intestines to the bloodstream. This suggests that the increase in intestinal cholesterol synthesis contributes to the elevations in plasma cholesterol concentrations observed in diabetics. The present proposal plans to determine: 1) if other animal models of diabetes also have increased intestinal cholesterol synthesis; 2) the factors that regulate intestinal cholesterol synthesis in diabetic animals; and 3) if chylomicrons obtained from control and diabetic animals are metabolized differently. Understanding the factors that regulate cholesterol synthesis in diabetic animals is essential to unraveling the basis for the stimulation of intestinal cholesterol synthesis observed in diabetes.
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