Diabetes mellitus is a rapidly growing public health problem throughout the world. Approximately 140 million people worldwide currently have diabetes, with the number estimated to reach 300 million by 2053. Type 2 diabetes accounts for approximately 90% of all diabetes cases and is characterized by insulin resistance and hyperglycemia. It has been well established that the principal cause of diabetes morbidity and mortality is due to heart disease. One of the consequences of diabetes has been reported to be oxidative stress. This is a significant finding in that recent studies have implicated oxidative stress in the pathogenesis of cardiovascular disease in diabetic individuals. Mice with cardiac selective deletion of the glucose transporter 4 gene (G4H-/) have been recently used as a model to examine the effects of cardiac insulin resistance upon the heart itself without the influence of other secondary pathologies common to whole body models of diabetes. The G4H-/- mouse has been shown to have cardiac hypertrophy which is thought to develop as early as 3-4 weeks of age. We have recently found that G4H-/- mice have significant activation of protein kinase c (PKC) in the heart. This is a notable because signal transduction via PKC is an important regulator of cardiac hypertrophy. The presence of cardiac hypertrophy increases the risk for myocardial infarction and heart failure. Our preliminary data also suggests that G4H-/- mice have cardiac oxidative stress. Given that oxidative stress has previously been shown to activate PKC, we hypothesize that oxidative stress is activating PKC in G4H-/- mouse heart and resulting in cardiac hypertrophy. The general aim of this study is to determine if reducing oxidative stress can prevent PKC activation and cardiac hypertrophy. First, we will rigorously confirm the presence of oxidative stress in the G4H-/- heart. Next, we will determine if reducing cardiac oxidative stress using a pharmacological approach can attenuate PKC activation and cardiac hypertrophy. Finally we shall determine if a dietary approach using supplemented antioxidant minerals and Coenzyme Q10 can be equally successful in reducing cardiac oxidative stress, PKC activation, and hypertrophy. This study will provide important insight into the role of oxidative stress as a trigger for cardiac hypertrophy in the insulin resistant heart and is highly relevant to public health given the growing rate of diabetes worldwide and the associated mortality due to cardiovascular disease in this population. ? ? ?
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