1442
Editorial Comment
Insulin
A Sex Hormone
for Cardiovascular Risk?
Annick Fontbonne, MD
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T here is a well-established fact in cardiovascular epidemiology: women are somehow protected from the clinical complications of
atherosclerosis, which are a major cause of morbidity
and premature mortality in men in industrialized
countries.12 The reasons for this sex differential in
risk are as yet largely unknown. It is a logical
assumption that sex steroid hormones are at the root
of this differential. However, such an assumption may
seem of little utility in the search for a means of
reducing cardiovascular risk in men. Therefore, the
results of Modan and colleagues3 in this issue of
See p 1165
Circulation come as comforting news. If the hormonal
status of men should be changed, there should be no
harmful consequences to their maleness, because the
hormone that appears to "explain" the sex differential in cardiovascular risk is insulin.
What Modan clearly shows in her paper is that
men share the same cardiovascular risk as women,
provided they are normoinsulinemic. Their risk is
equal to that of women, that is, low, except in
hypertension in which case it is higher but still equal
to that of hypertensive women. But, when men are
hyperinsulinemic, the prevalence of cardiovascular
diseases greatly increases as compared to women and
in particular to hyperinsulinemic women. In other
words, high insulin levels appear to be linked to
cardiovascular diseases in men only. Additionally,
the high levels of insulin seem to be the discriminating anomaly that accounts for all of the sex differentials in cardiovascular diseases.
The fact that high insulin levels are related to cardiovascular risk in men has already been demonstrated
prospectively, at least for coronary heart disease, in
three different cohort studies.4-6 As found in crosssectional studies by Modan, the relation was independent of the levels of other cardiovascular risk factors.
However, the only one of these three cohort studies4
that included both genders also reported that insulin
level was not a significant independent predictor of
From INSERM U21, Villejuif, France.
Address for correspondence: Annick Fontbonne, MD, INSERM U21, 16 avenue Paul Vaillant-Couturier, F94807 Villejuif
Cedex, France.
cardiovascular diseases in women. This finding has
generally been mentioned in most of the papers dealing
with the issue of insulin and cardiovascular risk78 for
the sake of honesty, but for lack of an explanation it was
often regarded as a possible random finding. Although
based on cross-sectional studies, Modan's work provides us with a confirmation. Indeed, contrary to what is
found in men, insulin does not appear to be related to
cardiovascular risk in women.
Other results from Modan's paper are worth mentioning in order to attempt an explanation of its original
finding. First, there is one exception to the fact that
hyperinsulinemia is "dangerous" for men; it is when the
anomaly is isolated, that is existing in nonobese, normoglycemic, normotensive men. This finding is probably not fortuitous because it has already been shown
prospectively in the Paris Prospective Study9 and reported in an article largely quoted by Modan. Second,
a case where hyperinsulinemic women are at equal risk
with men is mentioned; that of hypertensive women
who also have high triglyceride and low high density
lipoprotein cholesterol levels. This result is perhaps
more questionable in the context of Modan's paper
because it was obtained on a subsample of approximately 700 individuals, in which only 14 hypertensive
dyslipidemic hyperinsulinemic women had prevalent
cardiovascular diseases. However, one cannot but think
of how characteristic of "syndrome X" these women
are. Syndrome X, as described by Reaven,8 who made
a masterly synthesis of several studies, is a combination
of hyperinsulinemia, glucose intolerance, high very low
density lipoprotein, low high density lipoprotein lipid
profile, and hypertension. Reaven and others10 maintain that this syndrome could explain much of the
cardiovascular morbidity in affluent societies as well as
being a risk factor for diabetes. This, however, is
another story.
Let us stay focused on syndrome X in relation to
Modan's paper, that is, cardiovascular risk. This
would provide a nice explanation to the two exceptions mentioned above. Hyperinsulinemic men are
not at high risk for cardiovascular diseases when
hyperinsulinemia is isolated, which may mean that
these men do not have syndrome X. By contrast,
hyperinsulinemic women with many of the features of
syndrome X, and essentially the abnormal lipid pro-
Fontbonne Insulin and CV Risk
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
file associated with this syndrome, are indeed at high
risk for cardiovascular diseases. To integrate this
explanation with the overall findings of Modan's
paper, there seems to be only one straightforward
answer: insulin is not the culprit, but syndrome X, of
which hyperinsulinemia is a marker and a possible
"innocent bystander," may well be the real culprit.
We are then left with another crucial question. If
insulin levels so neatly discriminate cardiovascular
risk between men and women, we have to suppose
that, with some exceptions, they indicate syndrome X
only in men. If we assume that hyperinsulinemia is
usually associated with excess fat mass,'1 then the
above supposition takes us back some 30 years when
the distinction was made between "android" and
"gynoid" obesity.12 Since then it has been repeatedly
demonstrated, and even reported in a recent issue of
Circulation,13 that the pattern of fat distribution,
abdominal versus gluteofemoral, is a sexual trait. It
becomes more and more apparent that android,
abdominal, or central fat deposition is related with
excess cardiovascular complications, whereas gynoid
curves, however exaggerated, convey no such
risk.14-16 Because abdominal fat distribution has
been found associated with many of the metabolic
abnormalities that have been named syndrome X,'17
this distributional pattern has even been proposed as
an actual feature of the syndrome.18
Even if Modan could not evaluate in her study the
influence of fat patterning on cardiovascular risk, it
seems reasonable to suppose that most of the men
with high body mass indexes stored excess fat in their
upper bodies to a much greater extent than do most
of the women with high body mass indexes. However,
in men with predominantly android obesity, hyperinsulinemia is found related to a high cardiovascular
risk. On the other hand, women with a more gynoid
obesity are not high risks for cardiovascular diseases.
This, then, is the reason why insulin appears as a sex
hormone for cardiovascular risk.
The possibility that Modan's results can be explained by a sex difference in fat distribution is
supported by other epidemiological findings. For
example there is cardiovascular risk in diabetics.
Diabetes is one well-known instance in which women
are said to lose their protection from cardiovascular
complications.19 Every physician can readily agree
with Jean Vague's observation that noninsulin-dependent diabetic women do indeed tend to have
android rather than gynoid obesity.'2 Welborn has
shown that in women diabetes, not hyperinsulinemia,
predicts cardiovascular diseases, whereas in men,
hyperinsulinemia, not diabetes, is the predictor.4-6
Again, fat patterning can provide a simple explanation to reconcile these apparently contradictory findings. In women, diabetes, not hyperinsulinemia, is
associated with an android shape and a high cardiovascular risk. In men, hyperinsulinemia, with or
without diabetes, is bound to be associated with
excess abdominal fat and a high cardiovascular risk.
At least one prospective study has reported that
1443
android fat distribution is a risk factor for cardiovascular diseases in women, whether or not they are
diabetics.20
All these findings converge to the hypothesis that as
far as cardiovascular risk is concerned, it is more
dangerous to be a man, simply because a man is more
likely than a woman to store excess fat in his abdomen.
A number of questions remain unanswered. One
question concerns the mechanism by which excess fat
is preferentially deposited. Although genetic or environmental factors, such as stress or excessive alcohol consumption,17 deserve to be explored, sex steroid hormones must play a role in this process,
particularly androgens. Central obesity in women has
been shown to be largely dependent on the androgenic activity of their serum (cf Reference 19);
therefore, the natural androgenicity in men would
explain why, while they gain fat, they store it in their
abdomens. However, it is interesting to remember at
this point that obese men tend to have a relative
hyperestrogenemia as a consequence of the metabolism of androgens in fat cells (Reference 21). Therefore, it is difficult to ascribe excess cardiovascular risk
in men directly to a particular sex hormone. The
main issue for most of them may well be either
getting fat or staying thin.
Another question concerns why abdominal as opposed to gluteofemoral fat deposits are linked to a
greater cardiovascular risk. Excess abdominal fat
appears to be metabolically more active,17 leading in
various ways to insulin resistance (or is it the other
way around?) and generating a chain of possibly
"deadly" events.'022 Indeed, some of the disturbances associated with insulin resistance are plausible
candidates for a causal relationship to vascular damage, for example high very low density lipoproteins,23
low high density lipoprotein cholesterol,24 or blood
hypercoagulability.25 These disturbances are generally moderate in magnitude; therefore it is probably
their clustering together that may be an important
determinant of risk. This remains to be evaluated.
Modan has brought us one step forward in understanding the issue of the sex differential in cardiovascular risk by identifying insulin as a harmless glucoregulatory hormone in most women and the marker
of a dangerous "at-risk" situation in most men. There
is no reason why this at-risk situation should not be
accessible to prevention and treatment without requiring a change of sex.
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KEY WORDS * insulin * atherosclerosis * hyperinsulinemic a
syndrome X * Editorial Comments
Insulin. A sex hormone for cardiovascular risk?
A Fontbonne
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Circulation. 1991;84:1442-1444
doi: 10.1161/01.CIR.84.3.1442
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1991 American Heart Association, Inc. All rights reserved.
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