INSULIN RESISTANCE AND GLUCOCORTICOIDS

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American Indians are differentially affected by inflammatory connective tissue diseases (CTD) such as rheumatoid arthritis and systemic lupus erythematosus. In addition, obesity, insulin resistance, and type 2 diabetes mellitus are much more common in American Indians than in Americans of European ancestry. CTD 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, which is extremely commonin Indians. 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. These hypotheses will be tested in the first two Specific Aim. First, preexisting insulin resistance will be assessed as a risk factor for development of trunchal obesity, hypertension, glucose intolerance and type 2 diabetes among American Indian and Caucasian rheumatic disease patients receiving glucocorticoid therapy. In the second aim, pre-existing insulin resistance will be assessed as a risk factor for development of osteoporosis among American Indians and Caucasian rheumatic disease patients receiving glococorticoid therapy. 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 and diabetes among American Indians treated with glucocortioids. This hypotheses will be tested by a randomized placebo-controlled clinical trial of metformin in Indians with inflammatory connective tissue diseases who are being treated with glucocorticoids. American Indians very commonly have a condition in which the body does not respond well to insulin, this eads to type 2 diabetes, high blood pressure, obesity and elevated blood lipids. We think that this problem may give Indians worse complications from glucocorticoids, which are used to treat inflammatory illness.