Glycemic control has long been the cornerstone of treatment to reduce diabetic cardiovascular (CV) complications. However, other factors also contribute to these complications: the leading candidate being the genetic background. Likewise, in hypertension (HBP), control of blood pressure is important, but not sufficient to maximally reduce CV complications. Again genetic background has come to the fore as a major contributor. Data also support the concept that angiotensin II (ANGII) and aldosterone (ALDO) are major risk factors for inflammation associated, and fibrinolytic system driven CV damage. We have identified a specific intermediate phenotype comprising 25% of the hypertensive (HBPive) population whom we have termed non-modulators. Non-modulators are insulin resistant, have abnormalities in renal function, elevated levels of markers associated with CV damage and an increased risk of CV damage. The non-modulating phenotype is associated with specific polymorphisms in the genes of the renin-angiotensin aldosterone system (RAAS). The fundamental pathophysiology in non-modulators is dysregulation of tissue ANGII production leading to inappropriately increased tissue levels, particularly in the presence of an average or higher sodium intake. Our preliminary results in type II diabetics suggest that the non-modulating phenotype may be present in twice as many diabetics as in HBPives. Thus, the greater frequency of CV disease in diabetes may in part be accounted for by the higher frequency of an intermediate phenotype associated with increased renal and CV abnormalities. Thus, the overall goal of this proposal is to test the hypothesis that the genetic underpinnings of hormonal factors mediating CV risk in diabetes are similar to those previously identified in HBP and that non-modulation is a substantial contributor to that CV risk. Our approach will be similar to that used in HBP. We will define intermediate phenotypes in diabetic patients, determine whether genetic polymorphisms associated with them are similar to those previously identified in HBP subjects, determine the association of activity of the RAAS and markers of inflammation and the fibrinolytic system, and use a pharmacologic intervention to determine if interruption of the RAAS reverses abnormalities associated with a specific intermediate phenotype. In support of this proposal are data from more than 1000 normals and HBPives who have been studied on identical protocols. We anticipate the following results in type II diabetics: an increased frequency of the non-modulating phenotype and lower frequency of low renin compared to HBPives;similar polymorphisms in diabetic and HBPive non-modulators;increased levels of inflammatory markers that correlate with RAAS activity;and correction of the abnormalities in the non-modulating but not other diabetics with ACE inhibition.
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