Project Summary
The long-term goal of this project is to improve the neurological health of patients with diabetes by
decreasing the severity and incidence of cerebral ischemia. Stroke and heart disease are the most serious
complications of diabetes, accounting for more than 84% of the mortality. Epidemiological studies of cerebral
ischemia suggest that diabetes increases its incidence and exacerbates the consequences of cerebral ischemia,
with one of the main contributing factors being hyperglycemia. In clinical studies, intensive anti-diabetic therapy
was able to delay the onset and slow progression of secondary complications of diabetes. The major side-effect
of intensive anti-diabetic therapy is hypoglycemia. Recurrent hypoglycemia (RH) episodes are common among
type 1 and type 2 patients receiving intensive therapy. Thus, the goal of this project is to evaluate the impact of
prior exposure to hypoglycemia on the risk of stroke/thrombosis, delineate underlying mechanisms, and
understand the mechanism by which hypoglycemia exacerbates cerebral ischemic damage using insulin-treated
diabetic (ITD) rats. Using an in vivo model of thrombosis, we observed that ITD rats with prior exposure to RH
develop significantly larger thrombi compared to the controls. We also observed that platelets from RH-exposed
ITD rats are more sensitive to an aggregation stimulus. Unbiased RNA-seq analysis, subsequent real-time PCR,
and immunoblotting experiments demonstrate increased levels of phospholipase c ¿-1 (PLC¿1), a member of
phosphoinositide-specific PLCs that plays an important role in platelet activation via intracellular calcium
signaling, in platelets harvested from RH-exposed ITD rats. We also observed that exposure of ITD rats to RH
leads to pronounced post-cerebral ischemic hypoperfusion. Post-ischemic platelet activation may be responsible
for post-cerebral ischemic perfusion deficits. In view of these, we hypothesize that prior exposure to RH
increases the risk of cerebral ischemia and exacerbates post-cerebral ischemia hypoperfusion by
platelet dysfunction. To test this hypothesis, we propose the following specific aims: Aim 1: Determine the
minimum frequency of RH exposure required to increase the risk of thrombosis (a surrogate for stroke risk) in
ITD rats as well as the duration of this effect. Aim 2: Evaluate the mechanism by which prior exposure of ITD
rats to RH increases the risk of thrombosis. Aim 3: Evaluate the role of platelet dysfunction in exacerbated
ischemic brain damage in RH-exposed ITD rats. We expect these studies to provide insight into the mechanism
by which prior exposure to RH increases cerebral ischemia risk and post-cerebral ischemic damage in patients
with diabetes in order to help lower their risk of cerebral ischemia.