Recent studies in our laboratory along with the work of others have suggested a link between insulin resistance, increased sympathetic nervous system activity and obesity hypertension. We hypothesize that central nervous system activation of the sympathetic nervous system may be responsible for both the insulin resistance and hypertension observed in our obese dog model. We should be able to determine what portions of the sympathetic nervous system are responsible for the insulin resistance and hypertension observed in obese dogs, by placing the dogs, before and during the development of obesity, on four different sympathetic agents (clonidine that works centrally as an alpha2 agonist, moxonidine I1-imidazoline agonist, prazosin a peripheral a alpha1-receptor blocker and atenolol a beta receptor blocker). To better clarify whether a direct and independent relation between blood pressure and insulin resistance exists, we will determine if a low sodium diet plus Lasix will also improve insulin resistance. If our hypothesis is correct, we should observe that since a low sodium diet plus Lasix lowers blood pressure but t the same time activates the sympathetic nervous system, the dogs make fat while on a low sodium diet will remain insulin resistant. Insulin mediated glucose uptake is determined both by insulin's ability to stimulate glucose extraction at the level of tissues/cells and by the rate of glucose and insulin delivery (blood flow). Therefore, the relative contributions of tissues and blood flow actions of insulin will determine the overall rate of glucose uptake (i.e., degree of insulin resistance). In the current proposal we will determine if the insulin resistance associated with obesity in the dog is due to an impairment in insulin's actions to increase blood flow and/or to an impairment of insulin to stimulate glucose extraction at the tissue level. We plan to accomplish this specific aim by evaluating in dogs made obese are treated with and without sympathetic agents, the effect of three different insulin infusion levels (euglycemic clamps) to alter regional (leg and cardiac muscular) blood flow (measured by Doppler flow probes) and tissue glucose extraction (arteriovenous difference in glucose). We will evaluate the ability of the central sympathetic agents to alter salt and water retention. Finally we will evaluate what role the sympathetic nervous system plays in the changes in vascular reactivity that occur with obesity. We believe that the results of these experiments will help us to understand why obesity is an important risk factor for the development of both diabetes and cardiovascular disease.
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