The term 'insulin resistance', when applied to human disease, is often equated with impaired whole-body insulin-mediated glucose disposal as determined using techniques such as the hyperinsulinaemic glucose 'clamp' technique. Insulin resistance may be defined in more generic terms as 'a state in which normal concentrations of insulin produce an attenuated biological response'--a definition which does not restrict consideration of insulin action to a solitary aspect of metabolism and emphasizes the importance of examining the effects of insulin at concentrations which are relevant to normal physiology. While a number of useful investigative techniques have been developed for the assessment of insulin action in man, most focus narrowly on glucose metabolism; other key aspects of metabolism have received far less attention. Moreover, the pharmacological hyperinsulinaemia usually attained during euglycaemic clamp studies is unsuitable for assessing processes such as adipocyte lipolysis which are maximally inhibited by insulin concentrations within the low-physiological range. In this article we present a summary of our investigations of insulin action in vivo using a low-dose incremental insulin infusion technique. This technique permits examination of circulating insulin/metabolite dose-response relationships within the lower physiological range of plasma insulin concentrations. Using this approach, we have identified multiple abnormalities in the regulation of carbohydrate and lipid metabolism in subjects with a diverse array of insulin-resistant states characterized by variable degrees of glucose intolerance. Of note are the consistent observations of defective regulation of non-esterified fatty acid and glycerol metabolism, being apparent even in patients in whom glucose tolerance was either normal or only marginally impaired. Our studies indicate that defective insulin action is not confined to impaired glucose disposal in insulin-resistant disorders and is usually evident in other aspects of intermediary metabolism. We suggest that the concept of insulin resistance as a pathological entity would be usefully enhanced by greater recognition of the multiple defects in insulin action which may be encountered in insulin-resistant states.
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