Role of Diabetes-Associated Hyperamylinemia in Stroke

Summary Title: Role of diabetes-associated hyperamylinemia in stroke Stroke is a major cause of death and long-term disability worldwide. Type-2 diabetes increases the risk of stroke, but the mechanisms remain incompletely understood. Epidemiologic studies have shown that diabetes is a well-established independent but modifiable risk factor for both ischemic and hemorrhagic stroke. People with diabetes have 1.5-2 times higher risk of stroke compared to people without diabetes. 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. Previous research has shown that amylin aggregate buildup in brain tissues is linked to white matter injury, microhemorrhages, and brain microvascular injury. These findings led us to hypothesize that amylin protein accumulation may also play a role in the development of stroke in diabetes individuals. 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). We will also give drug through the drinking water to check if we can reverse the effect of amylin in HIP rats. 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. By identifying the pre-diabetes associated elements that contribute to the development of stroke and focusing on them in order to limit the disease''s progression before it starts, this strategy helps prevent or stop stroke in people with diabetes.