Treating the Endothelium to Restore Insulin Sensitivity

A study of 12 weeks' treatment with losartan or placebo, to test the hypothesis that RAS inhibition will improve insulin' vascular actions and therefore improve insulin sensitivity in skeletal muscle.

Recent studies suggesting an effect of cardiovascular therapies to prevent diabetes remain unexplained. We hypothesize that these therapies improve vascular endothelial function allowing improved actions of insulin in the vasculature, which comprise a significant portion of insulin's metabolic action. We therefore propose to measure insulin-mediated glucose disposal and insulin-mediated vasodilation before and after 12 weeks' therapy with Losartan (an angiotensin receptor blocker) or placebo, in a randomized design. Subjects will include 28 subjects with impaired glucose tolerance, which is generally accompanied by both insulin resistance and impaired vascular function. With this number of participants we have a 90% chance of showing a statistically significant and clinically meaningful effect of insulin on leg vascular resistance, and an even higher chance of showing a difference in insulin's metabolic effects. Exclusion criteria will include frank hypertension, diabetes, or hypercholesterolemia, and biochemical or other contraindications to losartan therapy. The primary endpoint for statistical analysis will be the invasive measure of insulin-stimulated endothelial function. We anticipate an improvement in both vascular and metabolic measures of insulin action following Losartan therapy but no change from untreated baseline following placebo.

Inclusion Criteria: Healthy Age 20-55 Male and female Obese, defined as Males: BMI >28 or > 30% fat by DEXA scan or Bod Pod; Females: BMI >30 or > 33% fat by DEXA scan or Bod Pod Weight stable over at least 4 months Exclusion Criteria: Diabetes mellitus (ADA criteria) Age <20 or > 55 yrs Blood pressure >160/90 or < 90/65 mmHg Total cholesterol >240 or LDL cholesterol >160 mg/dL Baseline elevations in AST or ALT > 3X ULN Baseline elevation in creatinine >1.6 ng/mL Unexplained baseline elevation in creatine kinase > 3X ULN Concurrent significant chronic medical illness including, but not limited to, human immunodeficiency virus infection, Syphilis, hepatitis B infection, or hepatitis C infection Pregnancy Known hypersensitivity or intolerance to the study agents