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Numerous studies have shown that overweight people are at increased risk for
several diseases. A 12-year follow-up of 336,000 men and 419,000 women by the
American Cancer Society, for example,106 shows that persons who are greater than
40 per cent overweight suffer increased mortality from diabetes, coronary heart
disease, and cancer. The importance of less severe obesity, however, has remained
controversial, with several studies reporting that moderate obesity is not associated
with increased mortality.5. 64. 82 This article critically reviews the body of evidence
implicating obesity as a risk-factor disease and possible reasons for the many
conflicting findings. A classification of obesity based upon the site of body fat
distribution and the possible biologic mechanisms associating regional adiposity with
morbidity are addressed.
From the Divisions of Endocrinology and Metabolism, and Biostatistics and Clinical Epide-
miology, Medical College of Wisconsin, Milwaukee, Wisconsin
*Professor of Medicine; and Program Director, Clinical Research Center, Froedtert Memorial
Lutheran Hospital
tAssistant Professor of Biostatistics and Clinical Epidemiology
tAssistant Professor of Medicine; and Attending PhYSician, Froedtert Memorial Lutheran
Hospital
Supported in part by grants Nos. HL34989 and RR00058 from the National Institutes of
Health
high degree of site and observer variability exists in their measurements. Because
height and weight measurements are obtained easily and are reproducible, various
height-for-weight indices typically have been related to disease. Body mass index
generally shows the largest correlation with other measures of adiposity, and is
weakly correlated with height. Body mass index therefore often is considered to be
the "best" weight-for-height index. &4 Although there are conflicting opinions,,04 the
various weight-for-height indices are highly intercorrelated and order persons almost
identically.
Diabetes Mellitus
Obesity is the most powelful risk factor for noninsulin-dependent diabetes
mellitus (NIDDM), with both its magnitude and duration being important consid-
erations. H" Ecologic studies show a strong correlation between relative weight and
the prevalence of diabetes across populations,16fi and cross-sectional studies show
that diabetic patients have an increased relative weight. 140 Prospective studies in
the United States,92, 106 Sweden, 100 Israel, H5 and Norway 167 also show that overweight
increases the risk of diabetes. A 12-year study, for example, 106 showed that, compared
with persons of "ideal" weight, those with relative weights equal to or greater than
140 per cent have mortality ratios of 5. 2 (men) and 7.9 (women) because of diabetes
(Table 1). These mortality ratios are greater than for any other disease.
Although negative findings have been reported, they likely are attributable to
weight loss among diagnosed diabetics, obesity of short duration, or the nonrepre-
sentativeness of undiagnosed diabetics. l65 Knowler and coworkers,92 for example,
have shown that BMI is related more strongly to the incidence, rather than the
prevalence, of NIDDy[ among Pima Indians.
Cardiovascular Disease
Data collected by insurance companies first showed overweight to be associated
with increased morbidity and mortality from heart disease, with overweight men
having a 49 per cent higher death rate from cardiovascular disease than men of
"optimal" weight. 111 These insurance studies have been criticized on methodologic
HEALTH RISKS OF OBESITY 113
grounds, 15, 82 however: (1) obese persons were greatly under-represented among
policyholders, with those enrolled likely having a high prevalence of undisclosed
diabetes and hypertension, and (2) both the anthropometric and follow-up data
often were of poor quality . .\1ore recently, the American Cancer Society studi 06
showed a linear relation between self-reported relative weight and subsequent
coronary heart disease death in volunteers (see Table 1).
Numerous cross-sectional studies have found obesity to be related to adverse
levels of several cardiovascular disease (CVD) risk factors, including blood pressures,
lipids, and glucose. Several prospective studies also indicate that the increased
CVD risk in overweight persons primarily is related to an adverse risk-factor
profile. 22, 135 Recent results,73 however, suggest that additional factors, in part, are
responsible.
Although extremely obese persons (BMI greater than 30 kg per m 2) are at high
risk for CVD,82 the relation of moderate obesity to CVD remains controversial.
Geographic studies" indicate that differences in CVD rates among countries is not
attributable to differences in relative weight or skinfold thicknesses. Analyses of
secular trends do not support an association between overweight and CVD: The
proportion of overweight adults in the United States has increased over the past
two decades, 160 but CVD mortality has shown a concomitant decrease. Furthermore,
no consistent relation of weight, weight/height", or subcutaneous fat to coronary
atherosclerosis has been observed in autopsy studies,116 and weight gain is not
associated with the progression of atherosclerosis in arteriographically examined
individuals. 94
Prospective studies also have yielded conflicting results. In a review of 13
studies, Keys82 concluded that only one showed a definite association between
overweight and coronary heart disease. Reviews by Larrson and associates, 100
Hubert,72 and Barrett-Connor lO also illustrate substantially different results among
the prospective studies, with the relation of moderate obesity to CVD considered
to be small or nonexistent 5 , 82, 112 to "consistent and substantial. "159 Interestingly, a
U -shaped relationship between relative weight and CVD has been observed in
several studies,74, 82, 134, 161, 167 often with a minimum at 15 to 25 per cent overweight.
Differences in statistical methods cannot account for these disparate findings:
Each of eight populations included in the Pooling Projece 34 shows a different
relationship of relative weight-to-CVD incidence, even though similar analyses were
used in each cohort. Results from the separate studies included: (1) no association,
(2) a U-shaped pattern, (3) a threshold effect, and (4) a stepwise association. 10
Endocrine Disorders
It has long been recognized that obesity is associated with impotence and
oligospermia in men, and with amenorrhea and decreased fertility in women. 143
Subsequently, other disorders in women, including early menarche, 51 delayed
menopause,148 and anovulatory cycles 66 148 have been associated with obesity.
Obese postmenopausal women show an increased conversion of androstenedi-
one to estrone. Among these women, adipose tissue serves as the major source of
estrogen formation, with the conversion of androstenedione increasing from 1 to 2
per cent in normal weight subjects to 12 to 15 per cent in women who weigh over
300 lb. 149 This extraovarian estrogen (which is physiologically active) in conjunction
with observations that exogenous estrogens increase the risk of cancer,33 in part,
may explain the increased cancer incidence in obese females. 71 Estrogens likely act
as promoters, maintaining the growth of the tumor after neoplastic changes have
occurred.
The production of androstenedione is increased in obese women'6 and, although
conflicting findings have been reported, levels of sex hormone binding globulin are
decreased. 29 Obesity also is known to influence the production and/or circulating
114 A!l\IED H. KISSEBAH ET AL.
Although it is possible that a primary factor causes both obesity and other
disease, there are scveral explanations that possibly could reconcile the contrasting
findings concern cd with an etiologic relationship between obesity and these other
diseases.
The size of the sample was not large enough to detect the hazards of moderate
obesity. It has been observed 160 that, of the frequently cited studies reporting no
association between obesity and mortality, only three followed more than 4000
subjects and, of these, two failed to exclude subjects with health problems at
baseline. However, KeysR2 has emphasized the distinction between a statistically
significant association between overweight and mortality (which can be achieved
with very small differences in large studies) and the clinical importance of these
findings.
Moreover, the lack of an association between obesity and mortality is not
limited to small studies. In a Norwegian study of 1.8 million people, 161 overall
mortality was related inversely to baseline BMI even after excluding deaths within
116 AII~IED H. KISSEB.A.I1 ET AL.
the first 5 years of follow-up. Furthermore, a e -shaped relation was seen in a study
of 18,000 men after deaths that occurred in the first 2 years of follow-up were
excluded. "
The distribution of other risk factors, particularly cigarette smoking, may
differ between ohese and nonohese persons. In the Framingham study, more than
80 per cent of men who were underweight were smokers whereas only 55 per cent
of men whose relative weights were 140 per cent or higher reported smoking, and
it was shown that the effect of underweight on CVD risk was almost entirely due
to smoking. 53 The possible confounding effects of high socioeconomic status also
may explain the negative results of some case-control studies examining obesity and
breast cancer. 144
Barrett-Connor,lo however, has suggested that smoking is unlikely to explain
all the conflicting results concerning obesity and CVD. For example, no consistent
association was seen between overweight and CVD mortality in nonsmoking men
followed for 10 years. l' Although it is possible that cigarette smoking also may
account for the increased incidence of lung, stomach, and bladder cancers that have
been observed in underweight persons, Nomura and colleagues 120 found that, even
after controlling for cigarette smoking, increases in weight remained inversely
associated with these cancers.
Obesity may exert its deleterious effects only after a long follow-up period.
Harrison~' has emphasized that all prospective studies with 15 or more years of
follow-up have shown an association between high relative weight and mortality.
The effect of the length of follow-up on CVD risk has been documented particularly
well in two prospective studies: :vIanitoba and Framingham. In each study,
associations between body mass indices and CVD became apparent only after 16 135
or 8 to 1447 73 years of follow-up. West lfi5 also has stressed the importance of the
duration of obesity in diabetes.
But, although a long follow-up would result in more events and, therefore,
more statistical power, the long-term importance of overweight still has been
questioned. In a 30-year follow-up of 284 men, for example, the mean BMI of those
dying from coronary heart disease was only 3 per cent greater than those who
remained alive. '2
Low-weight persons are thin because they already have the disease in question.
Results of the Whitehall Study'· show the effect of not excluding persons with
cancer: A strong inverse relation between baseline BMI and total cancer mortality
was observed during the first 2 years of follow-up. This "force of mortality," which
should be greatest in studies with short follow-up, also may explain the inverse
relationship of baseline BMI to stomach and lung cancer incidence,'20 and why all-
cause mortality in the second 12 years in Framingham showed a stronger association
with relative weight than in the first 12 years. 79
Although this effect also should exist in studies that have used self~reports
(rather than physical examinations) to exclude baseline cases, at least some have
found a linear, stepwise relation of overweight to both CVD lO6 and cancer. IOu. 151 In
addition, although the effects of (sub)clinical disease would weaken with longer
periods of study, a low B:vII has remained associated with increased mortality after
274 or 5 161 years of follow-up. The U -shaped association seen in some studies
therefore is unlikely to be caused entirely by the inclusion of diseased persons.
The relationship of obesity to CVD and cancer may differ according to the
end-point studied. Although 24-year follow-up data from the Framingham study2'
indicate that increased relative weight is related to sudden death, angina pectoris,
and myocardial infarction, the latter association is weaker and was not apparent
after 12 years of follow-up. Differences in the relationship of overweight to cancers
at various body sites also may dilute its association with overall cancer incidence
(or mortality). Among men in the American Cancer Society study, relative weight
HEALTH RISKS OF OBESITY 117
was related negatively to cancers of the lung and urinary bladder, and B.\11 has
been shown to be associated inversely with both lung and stomach cancer incidence
in another prospective study. 120 Furthermore, the classification of cancers according
to morphology (rather than sitc) may reveal unsuspectcd associations, and it is
possible that the relationship of overweight to the incidencc of cancer (or CVD)
differs from its relationship to mortality.
Although these findings suggest that the relationship of overweight to a specific
manifestation of CVD or cancer at a specific site may be hidden by thc inappropriate
grouping of cases, they also may be a result of chance fluctuations, given the small
numbers involved. In contrast to the Framingham findings,28 other prospective data
indicate that, compared with angina pectoris, overweight is related more strongly
to myocardial infarction. 22
The crude methods used to define obesity in most epidemiologic and clinical
studies have little relation to adiposity. A possible misclassification of obese persons
could result in only the extremely obese (or extremely thin) classified correctly,
which could explain the lack of association between modest overweight and disease.
Body mass index is correlated highly with skinfold thicknesses and body density
but it fails to "explain" one-third to one-half of the variability in these more accurate
measures,82 and does not distinguish between adiposity, muscularity, and edema.
In addition, the association between B.\11 and obesity may not be the same for all
ages B": Excess weight results from muscularity most often in young male subjects.
The possibility of misclassifying obese persons has been demonstrated in several
studies. After adjusting for relative weight, for example, diabetic subjects have less
muscle mass than do nondiabetics l "7 and, independently of relative weight, skinfold
thicknesses are predictive of subsequent diabetes."2 Compared with relative weight,
baseline measurements of skinfolds are more predictive of subsequent CVD.
Furthermore, the possibility that the various weight/height indices may not be
interchangeable lO4 has been suggested as an explanation for the inconsistent reports
between obesity and breast cancer. 170
More direct measures of body fat do not improve the prediction of CVD,
however. Among 1483 consecutive referrals, the use of tritium dilution showed only
a small difference in body fat between patients with and without coronary disease. Hi:l
Although these results used prevalence (rather than incidence) data, Larrson and
coworkers lOo found no association between obesity (as assessed by total body
potassium) and the incidence of angina or myocardial infarction over a 10 to 12.5
year follow-up period.
The association between obesity and various complications may differ among
various age groups, with the favorable health margin associated with leanness
diminishing among older persons. Insurance data and results from several prospec-
tive studies indicate that the relationship of overweight to both total mortality" lOB, III
and CVD incidence 22. 47 • 104, 135 is strongest in young (that is, less than 50 or less than
40 years of age) persons. Similar findings also have been reported in a clinical study
of 200 morbidly obese men, initially between the ages of 23 and 70 years."
Compared with the expected mortality, after 7.5 years, the 25- to 34-year-olds
showed a 12-fold increase, but men who were 65 years or older showed only a two-
fold excess.
This decreasing effect of overweight may be caused by the increased mortality
of overweight persons at younger ages, resulting in the selective survival of
"resistant" persons at older ages. Alternatively, obesity may be a risk factor only
for premature CVD, or weights at older ages may be less typical of a person's
lifetime exposure to obesity.
Weight increases during adulthood may be more important than the actual
degree of overweight. Many events in prospective studies occur long after the
baseline examination, but relatively few studies have examined the importance of
118 AH~IED H. KISSEBAH ET AL
weight changes during follow-up. Evcn after adjusting for relative weight in early
adulthood, however, subsequent changes in weight were related significantly to the
26-hour incidence of CVD7J and to the incidence of angina pectoris in women. 121
Weight gain during adulthood also has been related to adverse changes in several
CVD risk factors 6 . 121 and may increase the risk of breast 108 124 and endometriaP71
cancer.
The timing of obesity also may be important. Abraham's team ' found that the
prevalence of cardiovascular renal disease and hypertension in middle-aged, over-
weight adults was greatest in those who were thin as children. Furthermore, Albrink
and Meigs 3 found that moderate obesity attained after maturity was related more
strongly to hypertriglyeeridemia than was lifelong obesity; they also noted that
"acquired" obesity in males tended to be localized in the trunk.
Obesity may be a surrogate risk factor, reflecting physical inactidty,'" 122
dietary intake,85. 144. 169. 170 or the effects of other body components. Tannenbaum 156
suggested that factors controlling weight may be more important in the etiology of
cancer than the resultant increases in weight. It is possible that the relationship of
obesity to CVD also is indirect: The observation that obesity in Africa is not
associated with increased mortality has been attributed to dietary differences. 162 The
results of several recent studies, however, suggest that the relationship of diet to
cancer l33. 151 and CVD 85 exists independently of obesity.
Obese persons usually have an increased lean body mass, and it has been
suggested that the amount of muscle,'52 rather than adipose tissue, shows the
strongest association with CVD. Results indicate that blood pressure may be
correlated more strongly with body build l41 than with adipose tissue and, after
accounting for lean body mass, fat mass shows no residual association with blood
pressure. H\4 In addition, although the prevalence of hypertension and hypercholes-
terolemia is greatest in adults who arc overweight (based on kg per m 2) and obese
(based on the sum of skinfold thicknesses), these complications frequently arc seen
among adults who are overweight but not obese. 160 These observations may reflect
an association between body build (frame size and muscularity) and the pattern of
body fat distribution (see next section).
It is possible that a moderate excess of body fat may confer some protective
advantages. The obese may have different dietary patterns, stress adaptation, or
differences in protective endogenous hormone levels. But, although there is
disagreement between studies, overweight persons do not necessarily consume
more alcohoF5 or fiber. [3 Obese men may have higher levels of endogenous estrogen
than do lean men, but endogenous estrogen levels are not elevated in male survivors
of myocardial infarction compared with controls.2.3
Studies have been pursued to define the major morphologic and metabolic
features that distinguish upper from lower body obesity and to evaluate their
relationship to health risks. These studies focused on three main questions:
1. Does body fat distribution detect abnormalities in the metabolic profile that are
predictive of morbidity?
2. What metabolic sequences are involved and how do they relate to obesity?
3. What factors determine body fat distribution and how does the regional fat depot
initiate deleterious metabolic events?
Relationship of Body Fat Distribution to the Metabolic Profile
To determine whether the site of body fat predominance predicts aberrations
in the metabolic profile, cohorts of premenopausal Caucasian women were evalu-
HEALTH RISKS OF OBESITY 121
ated. 45, 46. 56. 78, 90, 91 The distribution of fat between the upper and lower body initially
was assessed using WHR. Table 2 shows that increasing WHR is accompanied by
progressively increasing fasting plasma glucose and insulin levels, and higher insulin
and glucose responses to oral glucose challenge. Fasting plasma levels of triglyceride
are increased and HDL-cholesterol decreased with increasing WHR, Partial and
multiple regression analysis revealed that the effects of body fat topography are
independent of and additive to those of obesity. Although WHR also correlates
with the plasma cholesterol level, this association depends on its correlation with
increasing relative body weight, Body fat distribution and the degree of obesity
independently and additively also are associated with increasing systolic and diastolic
blood pressure, Similar correlations have been reported in men,96
The waist-to-hip girth ratio has been found to be as effective in predicting the
metabolic profile as more complicated procedures, including multiple skinfold
thickness measurements, Vague's diabetogenic fat mass index, and Ashwell's fat
distribution score, Indeed, almost all anthropometric measures assessing the relative
distribution of fat between the trunk and the thigh, including the waist-to-thigh
circumference ratio and the subscapular-to-medial thigh skinfold ratio, predict the
metabolic profile equally well. l28 More important, however, is the significantly
higher association of the metabolic profile with the abdominal visceral fat mass
(determined by computed tomography scanning at the fourth lumbar vertebra) than
with total body fat (determined by underwater weighing method) (Table 3), This is
not entirely surprising because WHR correlates highly with the intra-abdominal
visceral fat mass.
The conclusions from these studies can be summarized as follows:
1. The WHR is a strong predictor of abnormalities in the metabolic profile
that predispose to health complications such as NIDDM and CVD.
2, The association of WHR with the metabolic abnormalities is independent of
and additive to effects of the degree of overweight.
3. The correlative power of WHR is the result of its prediction of the abdominal
visceral fat mass.
122 AHMED H. KISSEBAH ET AL.
Table 3. Relationship of Total Body and Visceral Fat to the Metabolic Profile
in Premenopausal Women
PER eEl'T
PER CENT VARIANCE (r')
VARIAl'CE (r') EXPLAI:\ED BY
EXPLAINED BY VISCERAL FAT
TOTAL FAT MASS VIASS
• •••
-
300 3 • (0.78, 4.72)
• •
l
r.O.80 r • .o.56
p eO.Ol peO.OS
.::- • •• •• •
~
g
200
•• • 2
• • •
••• ••
~ 100
~
• • ~
0 0
0.8 0.7 0.8 0.9 1.0 0.7 0.8 0.9 1.0
WHR w-R
Figure 1. Relationship of body fat distribution to in vivo insulin sensitivity. (SSPG =
steady-state plasma glucose attained during the insulin impedance test; M/I = glucose
metabolized relative to plasma insulin levels during the euglycemic clamp; WHR = waist-to-
hip girth ratio.)
HEALTH RISKS OF OBESITY 123
diminished glucose disposal. As an index of insulin action in this organ, basal and
insulin-stimulated activities of glycogcn synthase I (CSI) were determined in
quadriceps muscle biopsies. 46 Insulin promotes glycogen deposition by increasing
per cent-CS I in skeletal muscle. Obese women, separated into three age- and
weight-matched subgroups by WHR, demonstrate that as WHR increases, the per
cent-CSI response to submaximal insulin levels declines significantly. This decline
is correlated highly with the impairment in overall glucose disposal. Insulin-specific
binding to circulating monocytes also is decreased as WHR increased. The decrease
in insulin binding is associated with the decline in skeletal muscle per cent-CSI
and the increase in SSPC.
Compared with the nonobese, obese women have greater prehepatic insulin
production basally and following intravenous or oral glucose stimulation. "9 In age-
and weight-matched upper and lower body segment obese subjects, however,
prehepatic insulin production is increased similarly (Table 4).
Figure 2 shows that, in the obese group, prehepatic production and portal
plasma levels of insulin are increased at all time-points during the oral glucose
stimulation. But no remarkable differences are observed between the upper and
the lower body obese subgroups. Insulin secretion thus appears to be influenced
markedly by total body fat but uninfluenced by the regional distribution of the
adipose mass.
Compared with nonobese, the upper body obese demonstrate a significant
decrease in hepatic insulin extraction both basally and during intravenous or oral
glucose stimulation (Table 5).'29 Increasing WHR also is correlated with a decreasing
hepatic insulin extraction fraction. Consequently, posthepatic insulin delivery is
increased, correlating well with thc increase in peripheral insulinemia. Further-
more, the diminished hepatic insulin extraction is proportionate to the decline in
insulin metabolic clearance rate and in the impairment of peripheral insulin
sensitivity accompanying upper body obesity. 129. 131
The insulin-stimulated glucose-utilization dose-response curve for the lower
body obese shows a rightward shift compared with that of the nonobese subject. 13'
The curve for the upper body obese exhibits a greater rightward shift and a marked
reduction of the maximal glucose utilization rate (Fig. 3). Compared with the
nonobese, the lower body obese dose-response curve for the insulin-mediated
suppression of hepatic glucose production also is shifted to the right, while the
curve for the upper body obese shows an even greater rightward shift. In both the
nonobese and the two obese subgroups, however, hepatic glucose production is
nearly completely suppressed at an insulin infusion rate of 40 mU per minute per
m' (Fig. 4). Obesity and body fat distribution thus influence glucose metabolism
via independent and additive mechanisms. An increase in relative body weight is
associated with a moderate decline in hepatic and peripheral insulin sensitivity.
124 AHMED H. KISSEBAH ET AL.
• OBESE SUBJECTS
• LEAN SUBJECTS
oo LOWER
UPPER BODY OBESE
BOOY OBESE
-i 300 300
Q::::~.~
~200 200
~
''0\.
100 100
"~·e;...e
030 10 110 240 300 030 10 180 240 300
.;....
••• • • • • • •
120
JI·4 120
c ~ .......... \····6
i 10 80 \
~ ...
"E
:I
40
,
' ~
"""
.•....-i
..........-....
40 \\~'-e
0 0
030 10 ,., MO 300 030 10 110 240 300
Figure 2. Relationship of obesity and body fat distribution to insulin secretion rate and
portal vein insulin levels basally and following oral glucose stimulation.
Nonobese 70 ± 3 49 ± 4 59 ± 6
Obese
WHR < 0.76 81 ± 4 50 ± 6 62 ± 4
WHR> 0.85 69 ± 3* 10 ± 2* 22 ± 5*
*p < 0.05 or less compared to lower body obese.
WHR < 0.76; IV = intravenous; WHR = waist-to-hip girth ratio.
HEALTH RISKS OF OBESITY 125
600
.......
N
C
E
500
.....
-D-
-0-
NonObese
Upper Body Obese
Lower Body Obese
'E 400
C,
§.
.. c
0 300
..
III
,~
::::>
Q)
200
UI
0
U
c:;
::J
100
0
10 100 1000 10000
80
.......
N
.....
-D-
-0-
NonObese
Upper Body Obese
Lower Body Obese
E
C
'E 60
c,
§.
.. c
0
u 40
..
::J
"C
0
a..
Q)
UI
0 20
u
.a
(!)
10 100 1000
Figure 5. Relationship of body fat distribution to insulin sensitivity and insulin dynamics.
Genetic Predisposition
U nsuppressed hepatic glucose production
(rate-limiting step)
-
Te8toa- Andro8- % Free
Eatradlol terone tenedlone DHEA-S SHBG T88t08-
(ng/dl) (ng/dl) (ng/dl) (Ilg/dl) (llQIdl) terone
N8 NS NS NS -*
3.0
storage of easily and rapidly mobilizable energy reserves. This anatomical and
functional specialization is governed by the sex hormone balance.
The growth potential of adipose tissue is contingent upon the number of cells
capable of accumulating fat (preadipocytes). If sex hormones are determinants of
body fat distribution, they also may influence regional recruitment and differentia-
tion of preadipocytes. Sexual maturation of the female rat is associated with
significant increases in the differentiated preadipocytes and fat cell number in all
regions. This increase is accompanied by a significant decrease in the undifferen-
tiated pool of preadipocytes in all depots except the femoral. In contrast to other
regions, the femoral depot possesses an infinite capacity to provide precursor cells
capable of rapid differentiation and transformation into mature adipocytes. This
characteristic appears to be maintained by ovarian factors. 93
In premenopausal women, the degree of androgenic activity correlates signifi-
cantly with the aberrations in plasma glucose and insulin levels. 56 Increasing
androgenic activity also correlated with decreasing peripheral insulin sensitivity
(Fig. 8) and the decline in hepatic insulin extraction (Fig. 9).130 These findings
suggest that the association between upper body fat localization, the aberrations in
hepatic insulin extraction and peripheral insulin sensitivity, and the resultant
changes in the metabolic profile, may be mediated by a common mechanism
involving the increase in androgenic activity. This contention is supported by the
finding of significantly impaired peripheral insulin sensitivity in nonobese hyper-
androgenized hirsute women. This impairment is overcome by administration of
the an tiandrogen, spironolactone. 43
Androgenic activity may influence glucose-insulin homeostasis via two additive
mechanisms. First, by influencing the deposition of adipocytes in areas around the
waist (visceral and subcutaneous) that are different morphologically and metabolically
from those deposited in the gluteofemoral region, androgens could result in
increased plasma free fatty acids (FFA) flux and overexposure of hepatic and
extrahepatic tissues to FF A. This mechanism is suggested by the following obser-
vations:
1. Upper body adipocytes are large and exhibit high rates of basal and
catecholamine-stimulated lipolysis, presumably caused by increased beta- to alpha-
adrenergic activities. 91
2. Upper body obese women demonstrate higher nocturnal levels of plasma
FFA, despite higher plasma insulin levels. 90
HEALTH RISKS OF OBESITY 129
(1.7. 4.1)-e . ,
"'" • , • •-<0.8. 4.1)
.......
(1.9. 5.5) (0.7. 5.5)
'E
.-
'"c i
i
E • E~
E ••• •••
·1·
••
2
- • • •
~ ~
• • •
......
po 0.54 ~ r- -0.49
pc 0.05 pc 0.05
3. Feeding a high-fat diet to rats increases portal vein plasma FF A level and
hepatic triglyceride content, which correlates with a decline in hepatic insulin
extraction. 155
4. Animal and human studies suggest that FF A could inhibit insulin stimulation
of peripheral glucose metabolism and insulin suppression of hepatic glucose pro-
duction. 12. 49. 137
The second mechanism assumes that the androgenic activity might be directly
responsible for the abnormalities in insulin dynamics and in hepatic and extrahepatic
insulin actions. The influence of increased androgen activity on carbohydrate
metabolism is supported by the following observations:
1. When expressed per kg of lean body weight, insulin-mediated glucose
disposal, measured during the euglycemic clamp, is 45 per cent lower in healthy
men relative to women of similar age and body weight. 174
.0
, .0
•
:,
11 11
•
•• I . • • • •
"" 50 "" 50
...
~ ~
X X
I
~3I
20
• I• po 0.57
~ 31
20
• •• r- -0. S4
pc 0.05
• •
0.' 1.0 1••
pc 0.01
1.1 2.2
•
0,7 0..
I.
1.1 1.3 1.5
• '.7
SHBG " FT
Figure 9. Relationship of sex hormone profile (SHBG and percent-FT) to the hepatic
insulin extraction fraction (percent- HEF) in obese women with varying body fat distribution
patterns.
130 AH'-'IED H. KISSEllAH ET AL.
,,
_ _ _I . tInsulin Secretion
+
+Hepatic Insulin Extraction
Hyperinsulinemia
l
~peripheral Insulin Sensitivity~--------________~
Abdominal Adipocytes } -
(Subcutaneous and Visceral) t
Enhanced Plasma
+Recruitment Lipolysis - FFA Flux
+Size
tS/a Adrenergic Activity
Gluteofemoral Adipocytes ]
[ + Recruitment
+S/a Adrenergic Activity
Figure 10. Mechanisms associating hody fat distrihution and obesity to abnormalities in
insulin and glucose homeostasis.
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