Effects of Obesity and Type 2 Diabetes on Mouse Platelet and PMN Leukocyte Markers of Activation

Abstract

The prevalence of obesity and type 2 diabetes continues to rise. People with obesity and diabetes are at risk of developing ischemic vascular disease due to chronic activation of thrombotic (platelet) and inflammatory (polymorphonuclear [PMN] leukocyte) blood cells. However, little research has examined these blood cell changes in mouse models. Therefore, the purpose of this dissertation was to examine the changes in thrombotic and inflammatory blood markers in response to obesity and diabetes in mice and to explore the impact of these blood changes on ischemic stroke and reperfusion. We studied db/db, ob/ob, high fat fed, and high fat+streptozotocin (HF+STZ) mouse models of obesity and type 2 diabetes. Using flow cytometry and several measures of platelet aggregation, we did not find significant evidence of platelet or PMN activation in the db/db, ob/ob, or high fat fed models. However, we found that the HF+STZ mouse expressed increased levels of PMN CD11b and may develop platelet activation with prolonged disease. We found that mice fed a high fat diet develop lower PMN counts in response to hyperglycemia. To our knowledge, this is the first study that examined platelet and PMN activation after middle cerebral artery occlusion (MCAO) in obese, diabetic mice. MCAO in mice is associated with a high mortality. No diabetic mice survived MCAO. However, of the nondiabetic mice that survived MCAO, there was an increase in platelet and PMN activation at 24 hours of reperfusion. Our results indicate that platelet and leukocyte activation in the mouse models we examined do not reflect the blood activation observed in humans with obesity and type 2 diabetes. The HF+STZ model does demonstrate some aspects of platelet and PMN activation and may be the most suitable for studying these disease processes. Technical difficulties in performing experimental stroke in mice suggest that it may be necessary to examine these blood processes in other animal models or in human studies of stroke and reperfusion. The results of this research may lead to the development of novel biomarkers and treatments for obese, diabetic patients who are at risk for ischemic vascular disease.