ACE IRS Conference

Insulin Resistance Syndrome and Dyslipidemia

BACKGROUND

Cardiovascular disease is a major public health concern. The insulin resistance syndrome has been shown to be a key initiator of cardiovascular disease. In this communiqué, the role of dyslipidemia in the insulin resistance syndrome and in subsequent cardiovascular disease will be assessed with use of a statistical tool called factor analysis.

Factor analysis is a technique that uses statistical, graphical, and phenotypic tools to describe a complex set of variables, such as those found in the

TRIGLYCERIDES AND CARDIOVASCULAR RISK

In an assessment of a fairly homogeneous population of healthy, mainly white men, my colleagues and I developed an approach that defines the syndrome of high levels of triglycerides in the context of insulin resistance. Because of our homogeneous study population, this approach is not necessarily applicable to ethnic populations with insulin resistance. Nevertheless, this approach could possibly function as a laboratory model for analyzing triglyceride metabolism in terms of its other

A GENETIC LINK?

Does something in the log TG/HDL ratio have some important pathophysiologic significance? Are genetic components involved? Although no formal segregation studies have been published, genetic linkage analyses have been conducted. One analysis from the Framingham Study showed that the TG/HDL ratio is linked to a locus on chro- mosome 7q. An analysis by Rotter et al showed that a locus in the same region linked to the TG/HDL ratio was also strongly linked to insulin resistance. Although these

TG/HDL RATIO AND LOW-DENSITY LIPOPROTEIN PARTICLE SIZE

A bimodal distribution that is related to triglycerides and HDL is the LDL particle size distribution. Data that we obtained in collaboration with other investigators several years ago show that those subjects with small LDL particles (pattern B) have greater insulin resistance (as determined by glucose challenge and by using the steadystate insulin glucose measurements) in comparison with subjects who have larger LDL particles (pattern A). When the LDL particle diameter is analyzed as a

LIPOPROTEIN METABOLISM

Under conditions of normal VLDL metabolism with low plasma triglyceride levels, VLDL triglycerides are lipolyzed by lipoprotein lipase, a process that yields the cholesterol-rich LDL product (Fig. 3). Under normal circumstances, this product is rapidly cleared by the LDL receptor. In the presence of the abnormalities typically associated with insulin resistance and hyperinsulinemia, an increased drive for VLDL secretion accentuates plasma triglyceride levels. Investigators have shown that

INSULIN CONNECTION

Factor analysis of data from a subset of our study population revealed the same three key components of the insulin resistance syndrome as found in the Framingham Study: (1) the lipid component, including LDL peak particle diameter; (2) the adiposity component, which shows some modest correlations with HDL but a stronger correlation with insulin; and (3) blood pressure, which is a separate component that has a modest association with insulin (Table 1).

Within this small cohort, these three

CONCLUSION

One reason for developing a clear definition of insulin resistance syndrome stems from its relationship to coronary disease risk. Although the ATP III guidelines are not based on the kind of rigorous analyses needed for more refined criteria, they do provide clear and practical criteria for cardiovascular risk assessment with use of values that are available in clinical practice. From a biologic standpoint, any clinical definition of the insulin resistance syndrome will not adequately represent