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Each of the bars in Figure 1 represents the mean SSPG concentration for 49 individuals. It is apparent that there is an enormous spread of SSPG concentrations in the 490 volunteers (i.e., the degree of insulin resistance varies dramatically in the population at large). Indeed, there is an approximate tenfold difference between the most insulin-sensitive and insulin-resistant individuals. It should also be noted from Figure 1 that the fasting (F) insulin concentrations increase in parallel with the SSPG concentrations.

Based upon the results of prospective studies, it has been estimated that the upper 25 to 33% of the nondiabetic population (i.e., the upper three deciles in terms of SSPG concentration) are at greatly increased risk of presenting with one or more of the manifestations of syndrome X.

If 25 to 33% of the population at large is sufficiently insulin resistant to be at increased risk of syndrome X and/or type 2 diabetes, it is of obvious interest to know what determines the ability of insulin to stimulate muscle glucose disposal. At one level, this question is easy to answer. Differences in degree of obesity and physical activity are the two most important lifestyle variables that modulate insulin action, and they explain approximately 25% each of the variations in insulin action from person to person. By inference, it can then be argued that differences in genetic background account for the remaining 50% of the variability in insulin resistance. Although the actual numerical values may not be entirely accurate, they represent reasonable approximations. The crucial thing to remember is that variations in body weight and level of physical activity are modulators of insulin action; they are not the primary cause of insulin resistance.

A second point that must be appreciated is that although the ability of insulin to mediate glucose disposal by muscle is the conventional way of assessing insulin resistance, adipose tissue appears to be as resistant to regulation by insulin as muscle. The belated recognition of adipose tissue insulin resistance is easily understood if both the techniques usually used to assess resistance to insulinmediated glucose disposal and the differences in the dose-response characteristics of insulin action on adipose tissue versus muscle are taken into account. For example, a plasma insulin concentration of ~20 |U/mL will suppress by approximately 50% the release of free fatty acids (FFA) by adipose tissue; a circulating insulin concentration that has relatively little effect on stimulating glucose disposal by muscle. The infusion techniques conventionally used to quantify insulin resistance (i.e., the ability of insulin to stimulate glucose disposal by muscle) are -o almost uniformly performed by maintaining steady-state plasma insulin concentrations at least fourfold greater than the level needed to half-maximally suppress adipose tissue lipolysis. As a result, plasma FFA levels are maximally suppressed in all subjects, and differences in adipose tissue resistance to insulin cannot be discerned. It is now clear that the degree of insulin resistance in muscle and in adipose tissue is highly correlated, and that both defects contribute to the manifestations of syndrome X.

If not for this difference in tissue dose-response curve, the increase in plasma FFA concentrations would be proportionate to the degree of hyperinsuli-nemia in subjects with syndrome X. However, because of the enhanced sensitivity of the adipose tissue to insulin, plasma FFA concentrations are only marginally increased as long as hyperinsulinemia is maintained. On the other hand, the fact that there is a less dramatic increase in plasma FFA concentration should not obscure the fact that adipose tissue insulin resistance contributes substantially to the development of syndrome X.

Although attention has been focused on the parallel abnormalities that exist in muscle and adipose tissue to their regulation by insulin, it is important to understand that many of the manifestations of syndrome X are due to the effects of the compensatory hyperinsulinemia on tissues that remain insulin sensitive, despite the presence of muscle and adipose tissue insulin resistance in the same individual. There are several examples of this phenomenon. For example, there is evidence that the sympathetic nervous system (SNS) remains normally responsive to insulin stimulation in individuals with muscle insulin resistance. Thus, the compensatory hyperinsulinemia present in insulin-resistant individuals leads to enhanced SNS activity and a series of changes that helps explain why insulin-resistant/hyperinsulinemic individuals are at increased risk to develop hypertension.

There is also substantial evidence that the liver does not share in the insulin resistance present in muscle and adipose tissue. For example, muscle insulin resistance leads to higher insulin levels (to prevent the development of type 2 diabetes), and higher FFA concentrations occur because of adipose tissue insulin resistance. In contrast, the liver is functionally normal, and its response to the higher insulin and FFA levels is to enhance its synthesis and secretion of triglyceride (TG)-rich lipoproteins, leading to hypertriglyceridemia.

Another major organ that retains normal insulin sensitivity, despite muscle and adipose tissue insulin resistance, is the kidney, and there are two features of syndrome X that are likely to be dependent on the retention of normal insulin action on the kidney—hyperuricemia and salt-sensitive hypertension—both of which will be discussed in greater detail subsequently.

III. WHY IS INSULIN RESISTANCE IMPORTANT? -g s u

As shown in Figure 2, insulin-resistant individuals are at increased risk of developing either type 2 diabetes or one or more of the cluster of abnormalities subsumed under the general heading of syndrome X. Although these two syndromes have been separated for pedagogic purposes, it should be emphasized that they share many attributes not the least of which is increased risk of CHD, and that a J

finite proportion of individuals initially designated as syndrome X will eventually a develop type 2 diabetes.

"Inadequate" Compensatory

Insulin Secretion Hyperinsulinemia

Type 2 Diabetes Syndrome X

Coronary Heart Disease

Figure 2 A schematic description of the relationship between insulin resistance, insulin secretory response, type 2 diabetes, and syndrome X and coronary heart disease (CHD).

The relationship between insulin resistance and type 2 diabetes has been defined as the consequence of multiple prospective, population-based studies published over the past 30 years. There seems to be little doubt that insulin resistance and/or hyperinsulinemia (a surrogate measure of insulin resistance in non-diabetic individuals) are the most powerful predictors of the development of type 2 diabetes. The role of an impairment of insulin secretory function is less well understood, and the phrase ''inadequate insulin secretion,'' as seen in Figure 2, is a euphemism that should not obscure the fact that absolute plasma insulin concentrations throughout the day are, on the average, higher in absolute terms in the majority of patients with type 2 diabetes as compared to normoglycemic individuals.

As emphasized earlier, most insulin-resistant individuals remain in the right limb of Figure 2; they secrete enough insulin to avoid becoming sufficiently hyperglycemic to merit the diagnosis of type 2 diabetes. However, this victory is a hollow one, and in 1988 a relationship between insulin resistance, compensatory hyperinsulinemia, and a cluster of related abnormalities, all of which increase risk of CHD, was identified and designated as syndrome X. In the remainder of this section, the evidence linking insulin resistance and compensatory hyperinsul-inemia to all the abnormalities now presumed to comprise syndrome X will be reviewed (Table 1).

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