Insulin resistance is not a disease, but a physiological abnormality that increases the likelihood that one or more of the abnormalities listed in Table 2 will be present. Furthermore, because the abnormalities seen in Table 2 occur more commonly in insulin-resistant individuals, they are at increased risk to develop one or more of the clinical syndromes listed in Table 3. However, the relationship between insulin resistance and the changes seen in Tables 2 and 3 is complicated, and the abnormalities and clinical syndromes listed in these tables can occur in the absence of insulin resistance. It must also be emphasized that insulin-resistant individuals do not necessarily develop any of the clinical syndromes listed in Table 3.
The focus of this chapter does not permit an extensive discussion of the complex relationship between insulin resistance, compensatory hyperin-sulinemia, and the abnormalities and clinical syndromes that makeup the IRS, and reviews of these issues are available [27,28]. However, it is important to briefly discuss the relationship between insulin resistance, compensatory hyperinsulinemia, and differential tissue insulin sensitivity in the pathogenesis of the abnormalities and clinical syndromes that make up the IRS. To begin with, type 2 diabetes is the only clinical syndrome listed in Table 3 that is not associated with a significant degree of hyperinsulinemia. Obviously, in this instance, it is the failure of the pancreatic P-cell to adequately compensate for the insulin resistance that is responsible for the development of the clinical syndrome . In the case of the other abnormalities and clinical syndromes listed in Tables 2 and 3, it is the relationship between insulin resistance, compensatory hyperinsulinemia, and the individual tissue response to the chronically elevated plasma insulin concentrations that is responsible for the observed pathophysiology. In this context, it is necessary to address the question of differential tissue insulin sensitivity, for if this phenomenon did not exist, there would be no IRS. For example, the ability of insulin to stimulate muscle glucose uptake and inhibit free fatty acid (FFA) release from the adipose tissue is highly correlated . In insulin-resistant individuals, daylong increases in plasma insulin (muscle insulin resistance) and FFA (adipose tissue insulin resistance) concentrations act upon a liver that is insulin sensitive to stimulate hepatic TG synthesis [17,18]. One consequence of these events will be an increase in hepatic very low-density lipoprotein (VLDL)-TG synthesis and secretion, leading to hypertriglyceridemia, while at the same time there will be a tendency for the fat content of the liver to increase and nonalcoholic fatty liver disease to develop. The kidney is another example of an organ that retains normal insulin sensitivity in the presence of muscle and adipose tissue insulin resistance, and the compensatory hyperinsulinemia increases renal sodium retention and decreases uric acid clearance, thus contributing to the increased prevalence of essential hypertension and higher plasma uric acid concentrations in individuals with the IRS . A third example is polycystic ovary syndrome (PCOS), where insulin increases testosterone secretion by ovaries that are likely to be hypersensitive to the stimulatory effects of insulin .
Thus, although insulin resistance at the level of the muscle and the adipose tissue may be the fundamental abnormality that underlies the IRS, it is the compensatory hyperinsulinemia, preventing the development of type 2 diabetes in insulin-resistant individuals, which is responsible for most, if not all, of the abnormalities and clinical syndromes that constitute the IRS. In other words, if differential tissue sensitivity to insulin did not exist, and if all tissues were equally resistant to the action of insulin, there would be no IRS.
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