This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance is now well accepted as a contributor to cardiovascular risk, and is felt to be causally associated with development of the metabolic syndrome, a clustering of cardiovascular risk factors. It is therefore of interest how pharmacologic agents which target hypertension affect insulin resistance. Deleterious effects of thiazides diuretics and beta-adrenergic antagonists on insulin resistance have been long recognized. Calcium channel blockers have been found to be neutral overall and angiotensin-converting enzyme inhibitors (ACEI) likely improve insulin resistance. ACEI and angiotensin receptor blockers (ARBs) have both been recently found to reduce the incidence of type 2 diabetes mellitus in cardiovascular epidemiologic studies, suggesting that beneficial effects on insulin sensitivity of ACEI may be relevant at the population level, and also suggesting that this benefit may extend to ARBs. ARBs are the newest class of antihypertensive agents, and the effects of ARBs on insulin sensitivity are largely undetermined. This is an open-label, stratified, randomized, 3-arm parallel-group, multi-center study. Following a 4-week, placebo run-in period to assess subjects for study compliance, 60 overweight or obese (BMI 25-39 kg/m2), hypertensive (JNC VI criteria) subjects will be randomized to one of the following three treatment groups: ' Omesartan medoxomil (a new ARB, recently FDA approved) ' Losartan potassium (an established ARB with known effects on insulin sensitivity, positive control) ' Atenolol (a beta-adrenergic antagonist, negative control) Insulin sensitivity will be assessed using the gold standard hyperinsulinemic euglycemic clamp procedures at the end of the placebo run-in period and following 12 weeks' therapy. The change in glucose disposal rate at steady state before and after therapy will be the primary endpoint for statistical analysis. Blood pressure and blood lipid parameters will also be assessed and analyzed as secondary endpoints. We plan to recruit 6 subjects locally for this study.
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