Abstract W P252: Amylin Vasculopathy, a Novel Mechanism of Cerebrovascular Injury and Neurologic Deficits in Diabetes

Human amylin is an amyloidogenic hormone that forms toxic oligomers that kill the insulin-producing β-cells in the pancreas of patients with type-2 diabetes. We recently showed that the pancreatic amylin pathology is also linked with cerebrovascular dementia and diabetic heart disease by increased circulating levels of toxic oligomerized amylin. Here, we tested the hypothesis that the cerebrovascular accumulation of oligomerized amylin injures the brain, leading to neurologic deficits independently of hyperglycemia. A diabetic rat model overexpressing amyloidogenic human amylin in the pancreas (the HIP rat) and appropriate controls were used to investigate mechanistically cerebrovascular effects of amylin accumulation. As controls, we employed wild-type (WT) littermates and age- and glucose-matched diabetic rats expressing only non-amyloidogenic WT amylin, which does not accumulate in pancreas or other organs. Compared to controls, HIP rats showed reduced exploratory drive, vestibulomotor performance and ...