Diabetes mellitus (DM) is associated with an increased risk of coronary artery disease (CAD) that could result, in part, from changes in lipoprotein profiles. The usual hyperlipoproteinemia found in both NIDDM and IDDM is hypertriglyceridemia.Whether this lipoprotein profile contributes to the accelerated atherogenesis in DM or whether the increased risk of CAD is due exclusively to other effects of defective insulin action and hyperglycemia are uncertain. We hypothesize that accelerated atherosclerosis in DM results from both a more atherogenic lipoprotein profile and effects of hyperglycemia, e.g. production of advanced glycosylation endproducts. Hypertriglyceridemia can, however, be associated with increases in small, remnant-like triglyceride-rich lipoproteins (TGRL) or larger nascent TGRL. Whether these two lipoprotein phenotypes are equally atherogenic will be studied using transgenic (tg) mice models of atherosclerosis.
Three specific aims are proposed to assess the effects of superimposing DM on several different lipoprotein profiles that mimic those in humans. Both an insulin deficient and insulin resistant DM model will be used. Preliminary data from investigators in this PPG have shown that streptozotocin (stz) increases atherosclerosis in the apoE knockout mice (Eo), but augmented hyperlipidemia due to the human (Hu) apoCIII transgene does not. These results have been used to design experiments in Aim 1 to test if DM will alter the atherogenicity of TGRL in the Eo mice.
Aim 2 will test if the amount of apoB produced by Hu apoB (HuB) tg mice, and the resulting type of TGRL, affects DM induced atherogenesis.
Aim 3 contains experiments to introduce both HuCIII and HuCI genes into control and diabetic HuB tg mice and determine if increases in large or small VLDL alter diabetes related increases in atherosclerosis. In addition, to prevent DM induced dyslipidemia, the Hu lipoprotein lipase transgene will be crossed onto the HuB tg mice, allowing the effects of DM to be assessed exclusive of alterations in lipoproteins. The experiments in this Project will be performed cooperatively with those in Project 2. These two Projects have a common objective, to demonstrate the lipoprotein versus non-lipoprotein-mediated atherogenic actions of DM in tg mice. Moreover, our second major objective, to define atherogenic and non-atherogenic DM induced lipoprotein changes, parallels that of the clinical studies in Project 3.
