The announcement of the new section in Diabetes Care (Metabolic Syndrome/Insulin Resistance Syndrome/Pre-Diabetes) by Davidson (1) and the response by Vinicor and Bowman (2) point out that there is no consensus on the name, components, or treatment of the constellation of risk factors that is associated with cardiovascular disease. I would like to suggest that the constellation may be important primarily as an etiological concept—that the constellation implies the existence of a common underlying factor linking its components. Further, the presence of a common underlying factor, which could lead directly to myocardial infarction (MI), increases the possibility that any one or more of the components of the constellation could be incidental to the development of MI (3). An underlying factor, if identified, could define the components of the constellation and provide a focus for their treatment as well as for the prevention of MI. I suggest that the underlying factor may not be insulin resistance, as proposed by Reaven (4) and generally accepted as the prime suspect, but rather an increase in visceral adipose tissue (VAT) that may be secondary to an alteration in the sex hormone milieu.
In 1977, I reported correlations of glucose, insulin, cholesterol, and triglyceride with each other and with sex hormones in men with MI and control subjects (5). I hypothesized that the risk factors for MI were part of a “glucose-insulin-lipid defect” that was secondary to an increase in the estradiol-to-testosterone ratio (E/T). I also noted an association of this defect with hypertension.
The following year, I reported that glucose intolerance, hyperinsulinemia, hyperlipidemia, and hypertension concurred to form a constellation of factors that occurred not only with MI, but also with obesity, aging, and other clinical states (6). The observation that these risk factors concurred in other clinical states, as well as MI, provided further evidence that the risk factors were related to each other and linked by a common underlying factor. That the other clinical states were also associated with alterations in the levels of sex hormones supported the hypothesis that an increase in E/T or a closely related alteration might be the underlying factor for the constellation (6). I also suggested that obesity could induce the constellation and be both a cause and a result of the hormonal alteration (6). All of the major and most of the more recently identified risk factors for MI have since been reported to be associated with sex hormone levels (7–9). Moreover, a low testosterone level has been reported to be prospective for the “metabolic syndrome,” as well as for diabetes, in men (10).
In a recent study in men in which we had measurements of body composition, we compared the relationships of sex hormones, insulin, and adiposity variables with each other and with risk factors for MI and found that correlations of sex hormones and insulin with risk factors lost significance after controlling for VAT. We concluded that an increase in VAT is the most likely factor directly underlying the constellation, that a sex hormone alteration may underlie the increase in VAT, and that an increase in E/T may also directly contribute to the insulin defect (11). Of interest, a low testosterone level has been reported to be prospective for VAT accumulation in men (12).
If we are correct in attributing the constellation to an increase in VAT, then its components could also include any factor associated with VAT, such as plasminogen activator inhibitor-1, fibrinogen, factor VII, and C-reactive protein.
If interest in naming the constellation survives, and if our hypothesis is correct, I do not believe “metabolic syndrome” or “insulin resistance syndrome” would be appropriate names. Hypertension and hemostatic factors do not seem to be “metabolic,” and “insulin resistance” would be a secondary factor. A better name might be simply the “risk factor syndrome.” Should an alteration in the sex hormone milieu be confirmed as underlying the increase in VAT, and the VAT in turn underlie the constellation, perhaps an appropriate name would be the “Glucose-Insulin-Lipid-Hypertension-Testosterone–Estrogen” or “GILHT-E” syndrome.
