The overall objective of this proposal is to determine the mechanism(s) mediating the increased cellular damage and the impaired subsequent recovery in the diabetic brain following a stroke. The underlying hypothesis of this proposal is that the greater damage and impaired recovery in the diabetic patient/animal following a stroke results from a breakdown in the wound healing machinery of the brain. Impaired peripheral wound healing is a well-documented diabetic complication and is associated with impaired inflammatory responses however, nothing is known about the effects of diabetes on wound healing in the brain. We will determine the interrelationship between a compromised wound healing/inflammatory response and impaired stroke recovery in the ob/ob mouse, a well-established model of type II diabetes. Using a simple and reproducible model of experimental stroke we demonstrated greater ischemic damage in the ob/ob mouse compared to ob/+. This increased damage is associated delayed and diminished activation of microglial and astrocytes that mediate the brain's inflammatory response. The ob/ob mouse shares several pathological features with the human Type I and II diabetics including, hyperglycemia, hyperinsulinimea, elevated glucocorticoids, and impaired leptin signaling which may be implicated in the impaired stroke recovery. In the proposed specific aims we will determine the individual contributions of each of these components.
Aim 1 : To determine the role hyperglycemia plays in the impaired diabetic inflammatory response following a hypoxic/- ischemic (H/l) insult and to assess the therapeutic effects the reduction of hyperglycemia with diaglitazone has on recovery.
Aim 2 : To determine the role the absence of leptin plays in the impaired wound-healing response observed in the ob/ob mouse following a hypoxic/ischemic insult.
Aim 3 : To determine the role of elevated corticosterone in the increased cerebral infarct observed in the ob/ob mouse following H/l. We will monitor the temporal evolution of the stroke in the various aims by a combination of magnetic resonance imaging, cytokine microarray and RT-PCR analysis, ELISA and immunohisto-chemistry.The diabetic patient is 2-4 times more likely to experience a stroke and mortality is increased 3-4 fold. This study will investigate which components of the Type II diabetic pathology, such as hyperglycemia, insulin and leptin resistance, and elevated stress hormones are involved in mediating the detrimental recovery from stroke.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Jones, Teresa L Z
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Pennsylvania State University
Schools of Medicine
United States
Zip Code
Mangia, Silvia; DiNuzzo, Mauro; Giove, Federico et al. (2011) Response to 'comment on recent modeling studies of astrocyte-neuron metabolic interactions': much ado about nothing. J Cereb Blood Flow Metab 31:1346-53
Kumari, Rashmi; Willing, Lisa B; Patel, Shyama D et al. (2011) Increased cerebral matrix metalloprotease-9 activity is associated with compromised recovery in the diabetic db/db mouse following a stroke. J Neurochem 119:1029-40
Kumari, Rashmi; Willing, Lisa B; Jefferson, Leonard S et al. (2011) REDD1 (regulated in development and DNA damage response 1) expression in skeletal muscle as a surrogate biomarker of the efficiency of glucocorticoid receptor blockade. Biochem Biophys Res Commun 412:644-7
Leroy, Claire; Pierre, Karin; Simpson, Ian A et al. (2011) Temporal changes in mRNA expression of the brain nutrient transporters in the lithium-pilocarpine model of epilepsy in the immature and adult rat. Neurobiol Dis 43:588-97
Kumari, Rashmi; Willing, Lisa B; Patel, Shyama D et al. (2010) The PPAR-gamma agonist, darglitazone, restores acute inflammatory responses to cerebral hypoxia-ischemia in the diabetic ob/ob mouse. J Cereb Blood Flow Metab 30:352-60
Mangia, Silvia; Simpson, Ian A; Vannucci, Susan J et al. (2009) The in vivo neuron-to-astrocyte lactate shuttle in human brain: evidence from modeling of measured lactate levels during visual stimulation. J Neurochem 109 Suppl 1:55-62
Simpson, Ian A; Dwyer, Donard; Malide, Daniela et al. (2008) The facilitative glucose transporter GLUT3: 20 years of distinction. Am J Physiol Endocrinol Metab 295:E242-53
Simpson, Ian A; Carruthers, Anthony; Vannucci, Susan J (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27:1766-91