Stroke outcome in a new mouse model of type II diabetes: therapeutic intervention
There are an estimated 25 million Americans with Type II diabetes and they have a 2 to 4 times higher risk of experiencing an ischemic stroke and a 2.8 times greater risk of mortality. Stroke is the third leading cause of death and the major cause of long-term disability in the USA. The confluence of increasing numbers of diabetic patients coupled with aging baby boomers predicts a dramatic escalation in strokes frequency. The specific objective of this proposal is to compare the relative efficacy of the three major classes of drugs used to treat hyperglycemia associated with Type II diabetes: sulphonylureas, thiazolidediones (TZDs) and metformin to insulin therapy in restoring euglycemia and promoting stroke recovery in the RCS10 mice. The RCS10 mice express several characteristics distinct from the widely used ob/ob and db/db mice that make them a potentially superior diabetic mouse model to study stroke outcomes that more closely parallels the human situation. The onset of diabetes in the RCS10 mice is induced by feeding male mice a 10-11% fat diet after weaning and the characteristic hyperglycemia, hyperinsulinemia and dyslipidemia become fully apparent by 12-14 weeks. Importantly, unlike the other mouse models, the RCS10 mice are readily responsive to therapeutic intervention and thus provide the first opportunity to directly compare the actions of these diabetic medications to modulate outcome following a hypoxic /ischemic (H/I) insult. Each reagent is able to restore euglycemia, however, we hypothesize that the additional anti-inflammatory properties associated with the TZDs will promote a more beneficial outcome. Specifically, we will compare the responses of the male diabetic RCS10 mouse to H/I when treated with the respective agents with vehicle-treated mice. The temporal evolution of the insult and the subsequent recovery following H/I will be monitored by a combination of immunohistochemistry, mRNA analysis, flow cytometry and metabolic analysis to provide a comprehensive assessment of the metabolic inflammatory and angiogenic responses, that will include microglial and astrocytic activation, cytokine expression, leukocyte recruitment, and BBB breakdown.

Curation Flag Information