1636
Relation of Fasting Plasma Insulin
Concentration to High Density Lipoprotein
Cholesterol and Triglyceride
Concentrations in Men
Ami Laws, Abby C. King, William L. Haskell, and Gerald M. Reaven
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Low plasma high density lipoprotein (HDL) cholesterol concentration is a risk factor for
coronary heart disease (CHD) and is frequently associated with high triglyceride concentration.
Both of these abnormalities have been related to insulin resistance as estimated by plasma
insulin concentrations and to measures of obesity, regional adiposity, and physical fitness. To
determine which of these variables (fasting plasma insulin, obesity as measured by body mass
index [BMI], or regional adiposity as measured by waist to hip ratio [WHR]) best identifies
men with low HDL cholesterol and high triglyceride concentrations, we divided 83 men, aged
50-65 years, who were free of CHD or diabetes, into tertiles based on BMI, WHR, or fasting
plasma insulin concentration. Only for plasma insulin tertiles were there statistically significant differences in HDL cholesterol (tertile 1, mean±SEM, 134±0.08 mmol/1; 2, 1.16±0.05
mmol/1; 3, 1.10±0.06 mmol/l; p<0.03) and triglyceride (tertile 1, 1.05±0.08 mmol/1; 2,
1.48±0.12 mmol/1; 3, 1.82±0.17 mmol/1;p<0.005) concentrations. In forward stepwise regressions with HDL cholesterol and triglyceride as dependent variables, fasting insulin concentration but not BMI, WHR, or maximal oxygen uptake (Vo^max), a measure of physical fitness,
predicted HDL cholesterol {R2=0.07, p< 0.02) and triglyceride (R2=020, p< 0.001) concentrations. The data suggest that plasma insulin concentration is an important predictor of HDL
cholesterol and triglyceride concentrations independent of BMI, WHR, or Vo^max. (Arteriosclerosis and Thrombosis 1991;11:1636-1642)
L
ow plasma high density lipoprotein (HDL)
cholesterol concentration has been shown in
prospective studies to be a risk factor for
coronary heart disease (CHD) in men and women,
independent of total cholesterol and other risk factors.1"7 Although the role of hypertriglyceridemia as
an independent cardiovascular risk factor remains
controversial, a majority of studies examining the
relation of plasma triglyceride concentration to CHD
have found a positive relation in univariate analysis.8
In addition, a high plasma triglyceride concentration
may have increased importance as a CHD risk factor
From the Center for Research in Disease Prevention (A.C.K.,
W.L.H.), Stanford University, and the Geriatric Research, Education, and Clinical Center (A.L., G.M.R.), Department of Veterans Affairs Medical Center, Palo Alto, Calif.
Presented at the 31st Annual Conference of the American
Heart Association Council on Epidemiology, Orlando, Fla., March
1991.
Supported in part by National Institutes of Health research
grants HL-08506, HL-36272, and AG-00440.
Address for reprints: Dr. Ami Laws, GRECC 182B, VA Medical
Center, 3801 Miranda Avenue, Palo Alto, CA 94304.
Received June 19, 1991; revision accepted Jury 2, 1991.
in certain subgroups, namely those with normal or
low total cholesterol, 9 or those with impaired glucose
tolerance or diabetes. 10 Plasma HDL cholesterol and
triglyceride concentrations are strongly negatively
correlated, 8 and data from Framingham suggest that
those with low HDL cholesterol and high triglycerides are at particularly increased risk for CHD. 11
The basis for the association of high plasma triglyceride with low HDL cholesterol concentrations has not
been well defined. A previous study has shown that
both a low HDL cholesterol and a high triglyceride
concentration are associated with hyperinsulinemia,12
and it has been suggested that all three of these
abnormalities are secondary to a defect in the ability of
insulin to stimulate glucose uptake.13 On the other
hand, there is evidence that plasma triglyceride and
HDL cholesterol concentrations are modulated by a
number of other factors: variations in general degree of
obesity, regional fat distribution, and level of physical
activity.1415 Because insulin-stimulated glucose uptake
and plasma insulin concentrations are also associated
with these latter three variables,16"18 it could be argued
that the relation between plasma insulin concentration
Laws et al Insulin, HDL Cholesterol, and Triglyceride
and plasma triglyceride and HDL cholesterol concentrations is explained by obesity, regional fat distribution, and/or physical activity. This study was undertaken
to attempt to determine whether fasting plasma insulin
or measures of obesity, fat distribution, or physical
activity best predict individuals with low HDL cholesterol and high triglyceride concentrations. Our hypothesis was that plasma insulin concentration would be
associated with HDL cholesterol and triglyceride concentrations independently of these other factors.
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
Methods
Subjects
Subjects were recruited for participation in a physical activity trial through a random-digit dial telephone survey of the community of Sunnyvale, Calif.,
and by city-wide promotion. Eligibility criteria for
participation included age between 50 and 65 years;
absence of CHD, peripheral vascular disease, or
stroke (determined by medical history, physical examination, and resting and exercise electrocardiograms); absence of musculoskeletal problems that
would prevent participation in moderate levels of
physical activity; not currently engaged in a regular
exercise program; not currently taking medication for
the treatment of hypertension or hyperlipidemia;
cholesterol level below 300 mg/dl; triglyceride level
below 500 mg/dl; and blood pressure below 160/95.
One hundred sixty men were recruited for participation in the exercise study and were randomly assigned to one of four treatment groups. Subjects in
two of these groups (n=83) underwent oral glucose
tolerance tests (see below) and are included in this
analysis. No subject had fasting plasma glucose
greater than 140 mg/dl. Two subjects were excluded
who had 2-hour values in the diabetic range per
World Health Organization criteria.19 More than
90% of the subjects were Caucasian and of middle
socioeconomic status; most held professional jobs. In
summary, subjects included in this report were relatively healthy, generally sedentary older men without
clinical or laboratory evidence of CHD or diabetes.
Measurements
Subjects reported to the Stanford Outpatient Clinical Research facility in the morning after an overnight fast. Examinations took place on two mornings
at least 72 hours apart. At the first visit all subjects
underwent a medical history and physical examination. Body weight (in kilograms) and height (in
centimeters) were determined with the participant in
a hospital gown and shoes. Body mass index (BMI),
weight in kilograms divided by height in meters
squared, was calculated. Waist girth was measured in
centimeters at the level of the umbilicus and hip girth
at the widest circumference of the buttocks, with the
patient standing. Waist to hip ratio (WHR) was
calculated. Resting blood pressure was measured
three times with a Hawksley random-zero mercury
sphygmomanometer on the right arm after the pa-
1637
tient was seated for at least 5 minutes. Fifth-phase
Korotkoff sounds were taken as diastolic pressure.
The mean of the second two measures was used.
Body density was determined by hydrostatic weighing, and relative body fat (%BF) was computed
according to the equation of Siri.20 Each subject
performed a graded symptom-limited treadmill exercise test, during which the electrocardiogram and
indirect arterial blood pressure were recorded at the
end of each workload and at peak exercise. During
the treadmill test the subject's oxygen uptake was
determined each minute by a semiautomated metabolic analysis system, as described previously.21 Maximal oxygen uptake (Vc^max), a measure of physical
fitness, was defined as the highest value determined
during the last 2 minutes of exercise.
On the second visit, 72 or more hours later, subjects
had fasting (>12 hours) blood drawn for measurement
of lipoproteins, glucose, and insulin. Subjects were then
given a 75-g oral glucose load, and blood was drawn 2
hours later for measurement of glucose and insulin.
Venous blood samples were drawn into Vacutainer
tubes containing 1.5 mg/ml Na2EDTA while the subject
was seated. Plasma was prepared from blood within 2
hours, and blood and plasma were stored at 4°C.
Plasma total cholesterol and triglyceride concentrations
were determined by enzymatic procedures with an
Abbott ABA 200 instrument22-23 (Abbott Laboratories,
North Chicago, 111.). Plasma HDL and HDL subtractions 2 and 3 (HDL2 and HDL3 cholesterol) were
determined by a dextran sulfate-magnesium precipitation procedure.24 Glucose was determined by the glucose oxidase method25 and insulin by double-antibody
radioimmunoassay.26
Smoking and alcohol use information were obtained with a survey adapted from the National
Health Interview Survey.27
The study was approved by the Stanford Human
Subjects Committee, and each subject gave written
informed consent at the time of entry into the study.
Data Analysis
Spearman correlation coefficients were used to
determine simple correlations among the clinical and
metabolic variables. Analysis of variance, performed
by the general linear models procedure of the Statistical Analysis System (Carey, N.C.), was used to
determine differences among groups divided into
tertiles of BMI, WHR, and fasting plasma insulin. A
probability value less than 0.05 was considered significant. A series of forward stepwise multiple regression analyses were calculated to determine relations
among fasting insulin, HDL cholesterol, Vc^max, and
measures of body weight and body composition. In
the forward stepwise regression analysis, only variables that significantly (p<0.05) contributed to the
R2 were considered independent determinants of
each dependent variable.
1638
Arteriosclerosis and Thrombosis
TABLE 1.
Vol 11, No 6 November/December 1991
Mean, Standard Deviation, and Range of Clinical and Metabolic Characteristics of the Study Population
(71 = 81)
Variable
Age (yr)
BMI (kg/m2)
%BF
WHR
SBP (mm Hg)
DBP (mm Hg)
Vchmax (ml/kg/min)
Total cholesterol (mmol/1)
LDL cholesterol (mmol/1)
HDL cholesterol (mmol/1)
Triglyceride (mmol/1)
Fasting plasma glucose (mmol/1)
2-Hour plasma glucose (mmol/1)
Fasting plasma insulin (pmol/1)
2-Hour plasma insulin (pmol/1)
Mean
57
27.5
25
0.978
118
75
30
5.74
3.85
1.19
1.46
5.38
5.50
115
5%
SD
Range
4
4.2
7
0.048
13
8
5
0.93
0.83
034
0.75
0.56
1.61
50
459
50-64
18.4-44.0
9-41
0.832-1.082
88-154
59-94
21-47
3.78-7.76
2.02-5.66
0.67-2.43
0.32-3.70
4.11-6.83
2.78-12.16
43-258
93-2,475
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BMI, body mass index; %BF, percent body fat; WHR, waist to hip ratio; SBP, systolic blood pressure; DBP, diastolic
blood pressure; Vchmax, maximal oxygen uptake; LDL, low density lipoprotein; HDL, high density lipoprotein.
Results
Clinical and metabolic characteristics of the 81
men are listed in Table 1. There was a broad range of
BMI, WHR, and %BF in the study population. Mean
systolic and diastolic blood pressures were relatively
low for this age group,28 and the mean Vc^max was
consistent with that of a relatively sedentary population. Total and low density lipoprotein cholesterol
and triglyceride concentrations were slightly above
the mean for white American males of this age by use
of the Lipid Research Ginics value as a reference,
whereas HDL cholesterol level was approximately at
the mean.28 Glucose levels were clearly in the nondiabetic range.
Spearman correlation coefficients between plasma
HDL cholesterol and triglyceride concentrations and
other variables are shown in Table 2. These data
show that statistically significant (/?<0.05) negative
correlations were seen between HDL cholesterol and
TABLE 2. Spearman Correlation Coefficients Between Clinical
and Metabolic Variables
Variable
BMI (kg/m2)
WHR
%BF
Vc^max (ml/kg/min)
Fasting glucose
(mmol/1)
2-Hour glucose
(mmol/1)
Fasting insulin (pmol/1)
2-Hour insulin (pmol/1)
HDL cholesterol
-0.23*
-0.24*
-0.14
0.11
Triglyceride
0.25*
0.20
0.21
-0.21
-0.25*
0.48t
-0.03
-0.28t
-0.16
0.34f
0.40*
0.24*
HDL, high density lipoprotein; BMI, body mass index; WHR,
waist to hip ratio; %BF, percent body fat; Vc^max, maximal
oxygen uptake.
•p<0-5, tp<0.01,
BMI (r=-0.23,/><0.05), WHR (r=-0.24, /?<0.05),
fasting glucose (r=— 0.25,p<0.05), and fasting insulin (r=-0.28,/><0.01). Significant direct correlations
were present between plasma triglyceride concentration and many of the same variables: BMI (r=0.25,
p<0.05), fasting glucose (r=0.48, /><0.001), 2-hour
glucose (r=0.34, p<0.01), fasting insulin (r=0.40,
/7<0.001), and 2-hour insulin (r=0.24,/?<0.05). HDL
cholesterol was negatively correlated with triglyceride concentration (r=-0.51,/?<0.001). Of note, the
correlation of HDL cholesterol with fasting insulin
was accounted for by the HDL 2 subfraction
(r= -0.29,/><0.01); there was no correlation between
HDL3 cholesterol and fasting insulin (r=-0.07,
p=NS). Age (not shown) did not correlate significantly with any of the variables, most likely due to the
narrow age range of the participants. It is important
to note that BMI, %BF, and WHR were all highly
correlated with each other, that is, BMI was correlated with WHR (r=0.57, /><0.01) and with %BF
(r=0.75,/j<0.01). Additionally, the measures of obesity and fat distribution were highly negatively correlated (/?<0.01) with VOjmax (BMI, r=-0.70; WHR,
r=-0.65; and %BF, r=-0.42).
To determine if measures of obesity, regional fat
distribution, or plasma insulin concentration best identified subjects with low HDL cholesterol and high
triglyceride levels, subjects were divided into groups on
the basis of these variables. Table 3 displays results
where subjects were divided into tertiles on the basis of
BMI. As expected, the higher the BMI, the greater the
WHR and %BF. In addition, the higher the BMI, the
lower the Vc^max. The only other variable that significantly increased with the degree ofygeneral obesity, as
estimated by BMI, was fasting insulin concentration.
However, the expected gradient of decreasing HDL
cholesterol and increasing triglyceride concentrations
Laws et al
TABLE 3.
Insulin, HDL Cholesterol, and Triglyceride
1639
Clinical and Metabolic Variables by Tertile of Body Mass Index
Tertile
Variable
BMI (kg/m2)
WHR
%BF
VOjmax (ml/kg/min)
Total cholesterol (mmol/1)
HDL cholesterol (mmol/1)
Triglyceride (mmol/1)
Fasting glucose (mmol/1)
2-Hour glucose (mmol/1)
Fasting insulin (pmol/1)
2-Hour insulin (pmol/1)
1
(<25.6)
2
(25.6-28.5)
3
(=>28.5)
23.4
0.948
27.1
32.0
0.977
24
1.008
31
26
19
34
5.59
1.29
1.22
5.2
5.2
93
481
30
6.05
1.22
1.5
5.56
1.11
1.65
5.4
5.6
122
5.6
5.8
144
610
703
P
0.001
0.001
0.001
0.001
NS
NS
NS
NS
NS
0.001
NS
BMI, body mass index; WHR, waist to hip ratio; %BF, percent body fat; Vo^max, maximal oxygen uptake; HDL, high
density lipoprotein.
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with increasing BMI was seen, although it was not
statistically significant.
Table 4 shows similar data for subjects who were
separated into tertiles based on WHR. As before, the
greater the degree of abdominal obesity (as estimated by WHR), the higher the BMI and %BF and
the lower the Vc^max. Again, the only other variable
that significantly increased with increasing abdominal
obesity was fasting insulin concentration. As with
BMI, HDL cholesterol concentration decreased and
triglyceride concentration increased with increasing
WHR, but this was not statistically significant.
In contrast to the results in Tables 3 and 4 are the
data shown in Table 5. It is apparent that when
patients were divided into tertiles based on fasting
plasma insulin concentration, significant relations
were seen between insulin level and both plasma
triglyceride and HDL cholesterol concentrations.
The difference in HDL cholesterol by insulin tertile
was due to differences in the HDL2 subfraction
(tertile 1, 0.36 mmol/1; tertile 2, 0.23 mmol/1; and
tertile 3, 0.18 mmol/1; /><0.02), while there were no
differences between tertiles in HDL3 cholesterol. As
would be expected, fasting glucose and 2-hour insulin
values were also higher in those with the highest
fasting insulin concentration. BMI, WHR, and
VOjmax also varied as a function of fasting plasma
insulin concentration. Of note, there were no significant differences among the groups in alcohol consumption per week or in percent smokers (data not
shown), which might explain the differences in HDL
cholesterol and triglycerides.
To determine the relative contributions of fasting
insulin, obesity, and physical fitness to HDL cholesterol concentrations, we entered fasting insulin, BMI,
and Vc^max into a forward stepwise multiple regression program, with HDL cholesterol as the dependent variable. The program selected fasting insulin
and no other variables (#2=0.07, p<0.02). We ran
this program again, with WHR replacing BMI, and
obtained the same results. We repeated the analysis
with fasting plasma triglyceride as the dependent
TABLE 4. CUnlcal and Metabolic Variables by Tertile of Waist to Hip Ratio
Tertile
Variable
BMI (kg/m2)
WHR
%BF
Vojmax (ml/kg/min)
Total cholesterol (mmol/1)
HDL cholesterol (mmol/1)
Triglyceride (mmol/1)
Fasting glucose (mmol/1)
2-Hour glucose (mmol/1)
Fasting insulin (pmol/1)
2-Hour insulin (pmol/1)
1
(<0.963)
2
(0.963-0.998)
3
( a 0.998)
25.2
0.924
26.7
30.7
0.984
24
1.026
30
28
5.53
1.11
1.6
21
32
5.59
1.29
1.25
5.3
5.2
100
509
31
6.08
1.19
IS
5.4
5.7
108
552
5.4
5.7
P
0.001
0.001
0.001
0.002
NS
NS
NS
NS
NS
144
0.004
725
NS
BMI, body mass index; WHR, waist to hip ratio; %BF, percent body fat; Vcynax, maximal oxygen uptake; HDL, high
density lipoprotein.
1640
Arteriosclerosis and Thrombosis
TABLE 5.
Vol 11, No 6 November/December 1991
Clinical and Metabolic Variables by Tertiie of Fasting Plasma Insulin Concentration
Tertiie
Variable
BMI (kg/m2)
WHR
%BF
1(<93)
25.4
0.962
2(93-136)
3 (£136)
P
26.9
30.2
1.000
0.001
0.006
0.002
22
0.971
24
32
5.64
31
5.79
134
1.16
Triglyceride (mmol/1)
1.05
Fasting glucose (mmol/1)
2-Hour glucose (mmol/1)
5.0
5.4
1.48
5.5
5.7
Vo^max (ml/kg/min)
Total cholesterol (mmol/1)
HDL cholesterol (mmol/1)
Fasting insulin (pmol/1)
2-Hour insulin (pmol/l)
72
344
108
574
28
28
5.77
1.11
1.82
5.6
5.4
172
890
0.003
NS
0.03
0.005
0.001
NS
0.001
0.001
BMI, body mass index; WHR, waist to hip ratio; %BF, percent body fat; Vc^max, maximal oxygen uptake; HDL, high
density lipoprotein.
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variable with the same sets of regressions. In each
case the program entered fasting insulin and no
further variables (i?2=0.20,/?<0.001).
Because fasting plasma glucose was also shown to
be correlated with plasma HDL cholesterol concentration (see Table 2), we determined the relative
contributions of fasting glucose, obesity, and physical
fitness to HDL cholesterol concentration. Thus, we
entered fasting glucose, BMI or WHR, and VOjmax
into forward stepwise multiple regression programs,
with HDL cholesterol as the dependent variable. In
both cases fasting plasma glucose was the only variable that approached statistical significance, and this
was borderline (i?2=0.05,/><0.06).
Discussion
We determined metabolic and behavioral covariates
of plasma HDL cholesterol and triglyceride concentrations in a group of 50-65-year-old sedentary men free
of CHD or diabetes and found statistically significant
correlations between fasting plasma insulin and both
HDL cholesterol and triglyceride concentrations that
were not explained by obesity, abdominal obesity, or
physical fitness level. When subjects were divided into
tertiles on the basis of BMI, WHR, or insulin, fasting
insulin best delineated those with low HDL cholesterol
and high triglyceride concentrations. Division of subjects into tertiles of BMI or WHR did show the
expected gradients of decreasing HDL cholesterol and
increasing triglyceride concentrations, but they were
not statistically significant. The lesser strength of these
associations may be a true effect, or it may be due to the
small sample size or the variability of these measurements. However, in forward stepwise multivariate regressions, only plasma insulin was significantly related
to plasma HDL cholesterol and triglyceride levels. No
additional amount of the variance in either was explained by the addition of BMI, WHR, or Vc^max to
the model. This suggests that insulin may have a more
central role than BMI or WHR in the determination of
HDL cholesterol and triglyceride concentrations; however, assessing the relative strengths of these associa-
tions is limited by intraindividual variability and laboratory repeatability of the measurements.
The cross-sectional nature of this study precludes
causal inferences; however, the results are consistent
with an important role for plasma insulin in the
regulation of HDL cholesterol and triglyceride concentration. It is most likely that plasma insulin concentration is only serving as a marker for insulin
resistance. Plasma insulin levels, both fasting and in
response to an oral glucose challenge, have been
shown in normals to correlate negatively with insulinstimulated glucose uptake, a measure of insulin
resistance29; that is, the higher the insulin levels, the
greater the resistance. Therefore, the associations of
plasma insulin with plasma HDL cholesterol and
triglyceride concentrations are most likely due to
variations in the degree of insulin resistance. Of note,
plasma insulin concentration was more strongly related to triglyceride than to HDL cholesterol concentration. It has been shown that hepatic very low
density lipoprotein triglyceride secretion rate and
plasma triglyceride concentration are significantly
correlated with insulin resistance and hyperinsulinemia30 and that very low density lipoprotein catabolism plays a major role in the rate at which HDL
particles are formed in vivo.31 This suggests that the
relation between insulin and triglycerides may be the
more direct one.
On a broader level, the results of this and other
studies showing an independent relation between fasting plasma insulin and HDL cholesterol and triglyceride concentrations32-36 add some perspective to the
assessment of CHD risk factors in epidemiological
studies. Three of the metabolic variables examined in
this study, that is, plasma insulin, HDL cholesterol, and
triglyceride concentration, have been identified as risk
factors for CHD. 1-837-39 p^ ^ apparent from this and
other studies,32"36 however, significant correlations exist among these variables. Despite this, most published
studies of CHD risk factors do not take these interactions into consideration.
Laws et al Insulin, HDL Cholesterol, and Triglyceride
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For example, prospective epidemiological studies
have shown that plasma insulin levels are an independent risk factor for CHD in nondiabetic subjects.37"39 However, in these studies HDL cholesterol
concentrations were not measured. It seems likely
that the CHD risk attributed to increased plasma
insulin is related, at least in part, to associated
decreases in HDL cholesterol concentration.
Similarly, a number of prospective studies have
shown low HDL cholesterol to be an independent
risk factor for CHD,1-7 but in these studies plasma
insulin was not measured. Because plasma insulin
has been shown to correlate negatively with HDL
cholesterol and positively with triglyceride concentrations in our study as in others,32-36 it would be of
interest to know whether plasma insulin levels are
elevated in most subjects with low HDL cholesterol,
particularly those with high triglycerides.
One hypothesis linking insulin, triglyceride, and
HDL cholesterol as risk factors for CHD is that these
abnormalities exist as a cluster, with the underlying
defect being insulin resistance. This clustering has
been demonstrated to occur in at least one population with a high prevalence of CHD despite levels of
total cholesterol that are not elevated. Specifically,
Asian Indians in London have been shown to have
higher plasma insulin and triglyceride concentrations
and lower HDL cholesterol concentrations than do
British men and women,40 and this former population
has been shown to have a CHD risk that is about 50%
higher than that of the British population.41
Finally, it is notable that two recent reviews of the
relation of HDL cholesterol to atherosclerosis make no
mention of diabetes or hyperinsulinemia in the lists of
factors contributing to low serum HDL cholesterol.42"43
Given the demonstrated relations of the states of
insulin resistance, namely non-insulin-dependent diabetes mellitus, abnormal glucose tolerance, and hyperinsulinemia to low HDL cholesterol and elevated triglyceride concentrations, it would seem fruitful for
future studies investigating the contributions of these
risk factors to CHD to examine their possible clustering
rather than their independence.
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KEY WORDS • plasma insulin • high density lipoprotein
cholesterol • triglycerides • coronary heart disease risk
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Relation of fasting plasma insulin concentration to high density lipoprotein cholesterol and
triglyceride concentrations in men.
A Laws, A C King, W L Haskell and G M Reaven
Arterioscler Thromb Vasc Biol. 1991;11:1636-1642
doi: 10.1161/01.ATV.11.6.1636
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