TRAINING CORE

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Specific Aims The American Indian population is differentially affected by inflammatory connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus. In addition, obesity, insulin resistance, and type 2 diabetes mellitus as well as hypertension are much more common in American Indians than in Americans of European ancestry. Inflammatory connective tissue diseases are frequently treated with glucocorticoids, but these drugs have a high rate of serious complications that mirror the diseases listed above that are found in excess among American Indians; namely, obesity, insulin resistance, type 2 diabetes and hypertension. There are very little data concerning risk factors that predispose individuals to these complications. We hypothesize that a major predisposing factor is insulin resistance. Thus, a corollary hypothesis is that American Indians will be at increased risk of complications from glucocorticoids. Meanwhile, osteoporosis is also a common complication of glucocorticoid therapy; however, the pathogenesis of altered bone mineral density with glucocorticoids likely does not involve insulin resistance. Thus, we hypothesize that this complication will not be increased in American Indians. Agents that increase insulin sensitivity such as metformin are known to reduce future diabetes onset in persons with insulin resistance. We hypothesize that metformin will lower the incidence of obesity, diabetes and hypertension among American Indians treated with glucocorticoids. These hypotheses will be tested by studying American Indians with inflammatory connective tissue diseases who are being treated with glucocorticoids in the following specific aims - 1. Pre-existing insulin resistance will be assessed as a risk factor for development of obesity, hypertension, glucose intolerance and type 2 diabetes among American Indian and Caucasian rheumatic disease patients receiving glucocorticoid therapy. Hypothesis: American Indians are at high risk of these complications from glucocorticoid therapy because of a high rate of insulin resistance. 2. Pre-existing insulin resistance will be assessed as a risk factor for development of osteoporosis among American Indians and Caucasian rheumatic disease patients receiving glucocorticoid therapy. Hypothesis: Osteoporosis as a complication of glucocorticoid therapy is not related to insulin resistance and will not be found more commonly among American Indians than Caucasians. 3. Determine whether metformin reduces obesity, hypertension, glucose intolerance and/or type 2 diabetes in American Indians receiving glucocorticoid therapy for inflammatory rheumatic diseases in randomized, double blinded trial. Hypothesis: By virtue of improving insulin resistance metformin will reduce complications of glucocorticoid therapy that are known to be associated with insulin resistance.