Fellowship for Ly: Role of Diabetes-Associated Hyperamylinemia in Stroke

Type-2 diabetes increases the risk of stroke, but the mechanisms remain incompletely understood. Recent reports (including work from our laboratory) showed that the brain microvessels of patients with type-2 diabetes and vascular disease contain large deposits of amylin, an amyloidogenic hormone synthesized and co-secreted with insulin from pancreatic islets. Accumulation of amylin is associated with brain microhemorrhages, perivascular astrocyte recruitment, and white matter injury. Using a rat model of late-onset type-2 diabetes that overexpresses human amylin in the pancreas (the HIP rat), we found that the amylin deposition in the brain blood vessels is promoted by circulating aggregated amylin and causes brain hemorrhages and neurological deficits. In this research project, we will test the hypothesis that elevated blood amylin levels provoke alteration of endothelial cell tight junctions leading to microhemorrhages and neurologic deficits. To test this hypothesis, we will combine behavior testing with in vivo magnetic resonance imaging of the brain and biochemical assays of the brain blood vessel injury in HIP and control rats. To investigate amylin-mediated effects in the absence of diabetes, we will investigate amylin knockout rats intravenously infused with oligomerized human amylin versus rodent (non-amyloidogenic amylin). The successful completion of our studies will define mechanisms of amylin-induced vasculopathy and establish testable hypotheses for future translational studies aiming at prevention and improvement of post-stroke recovery in the setting of diabetes.