Streptozotocin-induced increase in cholesterol ester transfer protein (CETP) and its reversal by insulin in transgenic mice expressing human CETP

High plasma triacylglycerol and low high-density lipoprotein levels are risk factors for cardiovascular disease in diabetes. Plasma high-density lipoprotein levels are regulated by cholesterol ester transfer protein (CETP). The regulation of CETP under diabetic conditions is not clear, and this is due to a lack of appropriate models. We used transgenic mice expressing human CETP to study the regulation of this protein under type-1 diabetic conditions and further investigated whether insulin reverses the effect of diabetes. Mice expressing human CETP under the control of its natural flanking region and age-matched littermates not expressing this protein were made diabetic by injecting streptozotocin, and the reversal of diabetes was assessed by injecting insulin. The plasma total cholesterol, low-density lipoprotein-cholesterol, and triacylglycerol concentrations were elevated, whereas high-density lipoprotein-cholesterol concentrations were reduced after the onset of diabetes. Insulin injection partially recovered this effect. The plasma cholesterol ester transfer activity, CETP mass, and hepatic CETP mRNA abundance were significantly higher in diabetic mice that were partially restored by insulin administration. There was a strong correlation between high-density lipoprotein-cholesterol concentrations and cholesterol ester transfer activity. These results suggest that an increase in CETP under diabetic conditions might be a major factor responsible for increased incidence of diabetes-induced atherosclerosis.