Grant: Operating Grant

As first described nearly one century ago, the brain is targeted by diabetes, which leads to brain shrinkage, loss of brain white matter and slowed thinking and memory. Thus, diabetes can initiate or accelerate dementia, a major problem in our aging population. Diabetes-related brain changes are related to long duration and severity of diabetes, but there is additional evidence that the brain is starving for insulin in diabetes. We have developed the only experimental model of the diabetic brain which demonstrates changes analogous to the human condition. This diabetic brain also has disrupted insulin levels. Our work demonstrated that insulin replacement prevents changes in the DM brain, but giving insulin systemically is complicated by low blood sugars. In response, we have developed an alternative method of delivery, intranasal insulin which gives insulin through the nose, targeting the brain - this slowed the onset of brain changes found with magnetic resonance imaging and imrpoved memory performance, when compared to similar dosing of systemic insulin. Now, I would like to target the molecules modified by insulin called CREB and GSK3B with small molecules that can also be delivered through the nose without effects upon blood sugars. I also plan to use specialized mice genetically modified to have more or less of CREB and GSK3B. Then, I will use a new form of magnetic resonance imaging called diffusion tensor imaging to specifically examine brain white matter tracts injured by diabetes. If beneficial, these concepts could easily be translated to studies in human populations, and may also extend their value to brains affected by Alzheimer's Disease as well.