Abstract Diabetic patients have 2~4-fold increased risk of developing atherosclerotic vascular disease and its complications compared to non-diabetic individuals, and individuals with atherosclerosis frequently have type 2 diabetes mellitus (T2DM). Although genetic factors have been well documented as a major determinant of cardiovascular events in type 2 diabetic patients, identification of causal variants has been confounded by both environmental and genetic heterogeneity. We have observed that Apoe-/- mice, a commonly used model for atherosclerosis research, develop T2DM on certain genetic backgrounds after prolonged exposure to a Western diet but become resistant after being transferred on certain other backgrounds. The Apoe-/- strains that are resistant to atherosclerosis have significantly lower non-fasting glucose levels and display greater glucose tolerance than those that are susceptible to atherosclerosis. In an intercross derived from C57BL/6 (B6) and BALB/c (BALB) Apoe-/- mice, we identified a significant QTL for atherosclerosis, named Ath42, which coincides precisely with Bglu13, a major QTL for blood glucose. A congenic strain with a BALB donor segment harboring Bglu13 and Ath42 in the B6-Apoe-/- background showed significant reductions in atherosclerotic lesion size and plasma glucose level. Thus, the hypothesis to be tested is that accelerated atherosclerosis in diabetes is due, in part, to genetic variants that influence both disorders. To test this hypothesis, specific aim 1 will dissect the congenic region harboring Bglu13 and Ath42 through fine mapping to determine whether atherosclerosis and blood glucose are controlled by the same or different causal gene(s). Postprandial glucose levels, rather than fasting glucose, are related to incident myocardial infarction in type 2 diabetic patients. Elevated postprandial glucose levels are frequently accompanied by elevated postprandial levels of LDL cholesterol and triglyceride, which accelerate atherosclerosis. In aim 2, we will characterize a segregating F2 population from phenotypically divergent Apoe-/- strains to partition individual contribution of postprandial glucose versus postprandial lipids to atherosclerotic lesion sizes and identify genetic factors that connect them. Elevated postprandial glucose levels are also accompanied by elevated postprandial inflammation. We have observed significant macrophage infiltration in the islets of Apoe-/- mice fed a Western diet. In aim 3, we will use the F2 population to identify genetic factors affecting macrophage infiltration into the islets as well as postprandial inflammation. The proposed research will lead to identification of genetic factors that connect two important diseases and reveal new targets for prevention and treatment of cardiovascular complications in diabetic patients.

Project narrative Atherosclerosis is the primary cause of heart attack, stroke, and peripheral arterial disease, which account for 35% of all death in the United States, and type 2 diabetes is the most common metabolic disease, affecting over 20 million people in the country. The objective of this proposal is to search for genes and pathways that connect the two disorders. This work will discover new disease mechanisms and suggest novel strategies for preventing or treating cardiovascular complications of diabetes.