Spontaneously diabetic Ins2+/Akita:apoE-deficient mice exhibit exaggerated hypercholesterolemia and atherosclerosis

Abstract

Type 1 diabetes (T1D) increases the risk of adverse coronary events. Among risk factors, dyslipidemia due to altered hepatic lipoprotein metabolism plays a central role in diabetic atherosclerosis. Nevertheless, the likely alterations in plasma lipid/lipoprotein profile remain unclear, especially in the context of spontaneously developed T1D and atherosclerosis. To address this question, we generated Ins2+/Akita:apoE−/−mouse by cross-breeding Ins2+/Akitamouse (which has Ins2 gene mutation, causing pancreatic β-cell apoptosis and insulin deficiency) with apoE−/−mouse. Ins2+/Akita:apoE−/−mice developed T1D spontaneously at 4–5 wk of age. At 25 wk of age and while on a standard chow diet, diabetic Ins2+/Akita:apoE−/−mice exhibited an approximately threefold increase in atherosclerotic plaque in association with an approximatelty twofold increase in plasma non-HDL cholesterol, predominantly in the LDL fraction, compared with nondiabetic controls. To determine factors contributing to the exaggerated hypercholesterolemia, we assessed hepatic VLDL secretion and triglyceride content, expression of hepatic lipoprotein receptors, and plasma apolipoprotein composition. Diabetic Ins2+/Akita:apoE−/−mice exhibited diminished VLDL secretion by ∼50%, which was accompanied by blunted Akt phosphorylation in response to insulin infusion and decreased triglyceride content in the liver. Although the expression of hepatic LDL receptor was not affected, there was a significant reduction in the expression of lipolysis-stimulated lipoprotein receptor (LSR) by ∼28%. Moreover, there was a marked decrease in plasma apoB-100 with a significant increase in apoB-48 and apoC-III levels. In conclusion, exaggerated hypercholesterolemia and atherosclerosis in spontaneously diabetic Ins2+/Akita:apoE−/−mice may be attributable to impaired lipoprotein clearance in the setting of diminished expression of LSR and altered apolipoprotein composition of lipoproteins.