The influence of gender on the association between hyperinsulinemia/insulin resistance and hypertension

The primary objective of this study was to examine the relationship between hyperinsulinemia / insulin resistance and hypertension in female rats. A link between these two conditions has been well established in studies employing male animal models as well as in human studies, however, it has not been possible to discern what role gender plays in this relationship, if any, based on these previous reports. To investigate the effect of gender on the association between hyperinsulinemia / insulin resistance, two different hyperinsulinemic, hypertensive rat models were used; the fructose fed hypertensive rat (FHR) and a chronically insulin treated rat. In the first set of experiments using fructose fed animals, we found that fructose causes hyperinsulinemia, insulin resistance and hypertension in males, but does not affect metabolism or blood pressure at all in females. However in a separate experiment, female rats that had been ovariectomized did develop insulin resistance and hypertension, indicating that normal levels of ovarian sex hormones are involved in protecting female rats against the effects of a fructose diet. In a second set of blood pressure experiments, we employed a chronic exogenous insulin treatment to attempt to create a state of insulin resistance in females. In this study, we observed that exogenous hyperinsulinemia causes insulin resistance in both male and female rats, however, this occurs to a greater degree in males. Furthermore, hyperinsulinemia and insulin resistance were only associated with hypertension in male rats. Several mechanisms have been proposed to play a role in the development of hypertension associated with hyperinsulinemia and insulin resistance. A secondary objective of this thesis was to identify potential mechanisms that might explain any gender differences observed. To this aim, we focused on vascular function. We examined the vascular effects of insulin and found that it tends to act more as a vasoconstrictor in female rats rather than a vasodilator, as we had previously demonstrated in males. We also demonstrated that there is a significant gender difference in the effect of U46619, a synthetic thromboxane analogue, which may be related to gender differences in the development of hypertension associated with hyperinsulinemia and insulin resistance.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat