No abstract

Accelerated atherosclerosis is the critical manifestation of macrovascular disease in both type 1 and 2 diabetics and the major etiology of morbidity and mortality in these individuals ( 1, 2 ). In 2000, the global excess mortality attributable to diabetes mellitus was estimated at 2.9 million deaths ( 3 ), with 80% the result of major cardiovascular events ( 4 ). Clinical studies of diabetic cardiovascular disease have mainly focused on type 2 diabetes. However, despite its younger age of onset, type 1 diabetes is also associated with a signifi cantly increased risk of cardiovascular diseases, with an age-adjusted risk greater than 10 times the general population, which even exceeds that of type 2 diabetes ( 2, 5-8 ). The mechanism of type 1 diabetesaccelerated atherosclerosis is not well studied, and a major reason has been the lack of a good animal model ( 9 ). The most commonly used animal model of type 1 diabetes is the streptozotocin (STZ)-treated mouse. In this model, injection of STZ ablates pancreatic ␤ -cells. Deficiencies of this model include considerable mouse-tomouse variation; age dependency of pancreatic ␤ -cell destruction; toxicity to other cells and tissues, including DNA damage and induction of carcinogenesis; instability of the diabetes phenotype due to pancreatic islet ␤ -cell regeneration; and the diffi culty of inducing diabetes in females ( 10-12 ). The variability and instability of STZ-treated mouse model make it especially diffi cult to perform the long-term experiments required for atherosclerosis studies.Abstract Accelerated atherosclerosis is the leading cause of death in type 1 diabetes, but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well understood, in part due to the lack of a good animal model for the longterm studies required. In an attempt to create a model for studying diabetic macrovascular disease, we have generated type 1 diabetic Akita mice lacking the low density lipoprotein receptor (