Causes Of Insulin Resistance

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Insulin resistance may be caused by rare genetic defects that alter insulin binding to its cellular receptors or cause defects in receptor or postreceptor signal trans-duction (1). Recently, defects in the nuclear receptor, PPARy, have also been linked to syndromes of severe insulin resistance (2). In addition, some endocrine-metabolic syndromes, such as Cushing's syndrome, acromegaly, and polycystic ovary syndrome, are associated with insulin resistance because of the hormonal imbalances associated with these conditions. However, in the most common forms of insulin resistance, single gene defects have not been identified and the development of insulin resistance represents a complex interaction among a poorly understood array of predisposing genetic factors and acquired environmental factors that modify insulin sensitivity. Among the latter, the most prominent are obesity (particularly intra-abdominal obesity), physical inactivity, and increasing age. It is also now well documented that metabolic abnormalities such as chronic elevations of plasma glucose or free fatty acids (FFA), as well as increases in tissue triglycerides, can lead to insulin resistance (3,4). This has led to the concepts of glucotoxicity and lipotoxicity, both of which are reversible with improved metabolic status. Although the mechanism by which chronic elevation of glucose results in insulin resistance is not fully understood, it is most likely related to changes in glucose transporter number and function as well as to changes in the activity of the PI-3'-K signaling pathway in insulin-sensitive tissues. Chronic elevation of FFAs, on the other hand, has multiple metabolic effects that both inhibit glucose utilization in peripheral tissues and increase hepatic glucose production through enhanced gluconeogenesis. In addition, intra-cellular triglyceride accumulation is associated with decreased insulin action in insulin-sensitive tissues. Yet another mechanism by which increased body fat accumulation may cause insulin resistance is through increased production of adipose tissue hormones such as TNF-a (5), which has an inhibitory effect on insulin action. Finally, various medications may cause insulin resistance. These include treatment with hormones such as glucocorticoids, growth hormone, pro-gestational agents, high doses of androgens and anabolic steroids, or commonly used agents such as beta-adrenergic agonists or nicotinic acid.

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