Insulin-mediated glucose disposal varies widely in the population at large, with approximately 50% of the variability in insulin action resulting from differences in lifestyle variables; with degree of adiposity and physical fitness each accounting for approximately (25%). The remaining 50% is familial, likely to be of genetic origin, with powerful ethnic differences. Type 2 diabetes develops when insulin-resistant individuals cannot secrete the increased amounts of insulin needed to overcome the insulin resistance. However, the majority of insulin-resistant individuals are able to maintain the degree of hyperinsulinemia required to prevent manifest decompensation of glucose homeostasis. Although compensatory hyperinsulinemia prevents the development of frank hyperglycemia in insulin-resistant persons, insulin-resistant/hyperinsuline-mic individuals are at greatly increased risk of being somewhat glucose intolerant, with a dyslipi-demia characterized by a high plasma TG and low HDL-C concentration, and an increase in blood pressure. These changes increase CVD risk, and because the importance as CVD risk factors of insulin resistance/compensatory hyperinsulinemia and its associated cluster of abnormalities was not widely appreciated at the time, the term Syndrome X was introduced in 1988 to focus attention on these relationships.
An enormous amount of new information relevant to the role of insulin resistance in human disease had appeared since the introduction of the concept of Syndrome X, and the abnormalities related to insulin resistance have broadened considerably. At the same time, it has become clear that the adverse clinical outcomes associated with insulin resistance extend far beyond type 2 diabetes and CVD. For example, in addition to type 2 diabetes and CVD, insulin-resistant individuals are at increased risk to develop essential hypertension, PCOS, nonalcoholic fatty liver disease, congestive heart failure, sleep disordered breathing, cognitive dysfunction, and certain forms of cancer. In addition, insulin resistance and its consequences have been shown to complicate protease inhibitor treatment of HIV/AIDS, as well as the use of atypical antipsy-chotic drugs in patients with schizophrenia. Consequently, it is suggested that the various abnormalities and clinical syndromes more likely to occur in insulin-resistant individuals be subsumed under the rubric of the IRS.
To discuss the treatment of all of the manifestations of the IRS is beyond the competence of this individual, and would seem to require the creation of a multiauthored monograph. It did seem possible that some clinical utility might result from a consideration of lifestyle and pharmacological approaches to enhancing insulin sensitivity in apparently healthy, nondiabetic, insulin-resistant individuals, and this has been the main focus of the chapter. In the case of the dyslipidemia and essential hypertension associated with the IRS, an additional attempt was made to consider potential interventions, above and beyond improving insulin sensitivity, which might be useful in an effort to reduce risk of CVD. It is clear that we have learned a great deal since the original observation of Himsworth that a defect in insulin action could lead to a disease: type 2 diabetes. The clinical problems associated with insulin resistance will only increase as the world grows more obese and less physically active, and the need to develop therapeutic approaches much more effective than the relatively primitive ones discussed in this chapter will become paramount.
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