Ischemic Heart Disease
Insulin, Carbohydrate, and Lipid Interrelationships
By MENARD M. GERTLER, M.D., HILLAR E. LFETMA, M.D.,
ERICH SALusTE, PH.D., JAMES L. ROSENBERGER, B.A.,
AND ROBERT G. GUTHRIE, B.S.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
SUMMARY
This study evaluates interrelationships between carbohydrate and lipid metabolism
during oral glucose tolerance tests (GTT) in 65 ischemic heart disease (IHD) males
and 69 age-matched healthy controls (age range 45 to 69 years). The frequency of
abnormal GTT, usually accompanied by type IV hyperlipoproteinemia, was significantly
higher in IHD (37%) than in controls (19%). The mean immunoreactive insulin (IRI)
of IHD patients with abnormal GTT showed an elevated and delayed
peak at 2 hours. The mean free fatty acid response curve of IHD patients had a significantly lower rebound at 3 hours. IHD patients and controls with abnormal GTT
showed significantly higher and lagging lactate levels at 2 and 3 hours. Incidence of
abnormal GTT was neither related to relative weight nor to elapsed time from onset of
IHD to time of examination. Canonical correlations revealed that IRI is the common
denominator in both carbohydrate and lipid abnormalities in IHD.
response curve
Additional Indexing Words:
Immunoreactive insulin
Glucose tolerance test
Free fatty acids
Lactate
Diabetes mellitus
individuals and in the survivors of acute
myocardial infarction.
Extensive reviews concerning the frequency
of abnormal glucose tolerance tests in IHD
are available.4 5 Many factors, e.g. the selection of populations, age and sex distribution,
differences in laboratory technics, and classification criteria of impaired carbohydrate tolerance have contributed to the disparities in
these reports.A9
Our previous studies on carbohydrate and
lipid interrelationships demonstrated that
differences between IHD patients and controls do exist in glucose utilization and
immunoreactive insulin (IRI) response. These
differences were more striking in patients with
ischemic thrombotic cerebrovascular disease.'0
This paper will evaluate and compare
glucose utilization and IRI response of IHD
patients with age-matched healthy controls
during the oral GTT and establish some
IT IS GENERALLY accepted that serum
lipid abnormalities are closely associated
with the development of atherosclerosis and
ischemic heart disease (IHD) 1' 2 and that one
of the major complications of diabetes mellitus
is the acceleration of IHD.3 Thus, it would be
of interest to determine whether a relationship
exists between serum lipid abnormalities and
impaired carbohydrate metabolism in healthy
From the Department of Cardiovascular Research,
Department of Rehabilitation Medicine, New York
University Medical Center, New York, New York.
Supported by grants from the John A. Hartford
Foundation and RD-1715-M from the Social and
Rehabilitation Service of the Department of Health,
Education and Welfare.
Address for reprints: Dr. Menard M. Gertler,
Department of Cardiovascular Research, New York
University Medical Center, 400 East 34th Street, New
York, New York 10016.
Received December 7, 1971; revision accepted for
publication February 14, 1972.
Circulation, Volume XLVI, July 1972
Hyperlipoproteinemia
103
GERTLER ET AL.
104
interrelationships between carbohydrate and
lipid metabolism in these two populations.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Material and Methods
The study population consists of 75 male
ischemic heart disease (IHD) patients and 161
healthy male controls. The IHD group was
comprised of patients with myocardial infarction
or angina pectoris diagnosed by WHO criteria."
The healthy controls were comparable to the
IHD group in their physical activity and
socioeconomic status. All subjects were in good
nutritional status, on regular diets, consumed
between 150 and 200 g of their daily intake as
carbohydrates, and were screened to exclude
associated diseases, e.g. overt diabetes mellitus,
liver disease, and hypo- or hyperthyroidism. None
was receiving steroid or thiazide therapy.
A 3-hour oral glucose tolerance test (GTT)
was administered to each participant, and blood
glucose, plasma immunoreactive insulin (IRI),
free fatty acid (FFA), and lactate levels were
determined on fasting and following the ingestion
of the equivalent of 75 g of glucose in the form of
Glucola*12 at 3X, 1, 2, and 3 hours. The GTTs
were classified according to the cutoff levels of
glucose recommended by Fajans and Conn,13 and
for comparison by the University Group Diabetes
Program14 and the Wilkerson's point system.15 In
addition, fasting serum total cholesterol, triglyceride, lipid phosphorus, and uric acid levels were
determined. These methods have been described
in detail elsewhere.16 Cholesterol values were regularly compared with samples from the National
Communicable Disease Center. Lactate was
accomplished by the method of Hohorst.17
Lipoprotein electrophoresis was performed according to Lees and Hatch'8 and typed according
to Fredrickson.19 The sum of glucose, IRI, FFA,
and lactate was obtained by adding the respective
levels at fasting, and at Xi, 1, 2, and 3 hours
during the oral GTT.
Data analyses were accomplished by stratifying the study groups according to age, relative
weight, and time elapsed from onset of disease to
examination. Relationships were investigated by
use of the Student t-test, chi-square contingency
tables, and Pearson's product-moment correlation
coefficients.20 Multivariate relationships between
sets of variables were assessed by computing the
canonical correlations.21
Results
Population Description
The IHD group ranged in age from 36 to 72
years with a mean age of 53 years and the
*Ames Co., Inc., Elkart, Indiana.
control subjects from 21 to 82 years, with a
mean age of 46 years
(fig. 1).
In the 75 IHD patients, 42 (56%) had a
family history (i.e. mother, father, or siblings)
of myocardial infarction compared to 60
(37%) of the 161 controls (P<0.05). There
was no relationship between the frequency of
abnormal GTT and the elapsed time between
the disease onset and the examination.
Height and weight were significantly and
negatively correlated to age (r = -0.238 and
r =-0.213, respectively) in IHD and controls,
and because of the strong correlation between
height and weight (r = 0.552) relative weight
was used as a measure of obesity.22 Both the
IHD and control groups showed a tendency
toward relative overweight with mean percentages of 11.0 and 10.5, respectively. There
was no increase in the number of abnormal
GTT with increasing relative weight in either
group.
Incidence of Normal and Abnormal GTT
according to Various Criteria
The percentage of abnormal GTT in IHD is
significantly higher (P < 0.01) than in healthy
control subjects regardless of the GTT classification'13-5 (table 1). The classification of
Fajans and Conn yielded the highest percentage of abnormal GTT in IHD and control
subjects, and thus it was chosen to ensure a
better analysis of the data.
Metabolic Differences in Subjects with Angina
Pectoris, Myocardial Infaretion and those with
Both Angina Pectoris and Myocardial Infarction
The 75 IHD patients were subdivided as
follows: 21 had angina pectoris (AP), 36 had
myocardial infarction (MI), and 18 had both
MI and AP. The subgroup with both MI and
AP showed significantly higher sum IRI and 3and 2-hour IRI levels, with a delayed decay at
2 and 3 hours when compared with the
subgroup with AP only. There were no other
significant differences between the subgroups.
IHD and Age-Matched Control Subjects
between 45 and 64 Years
Since IHD is most prevalent in the age
range of 45 to 64 (fig. 1), the 65 IHD and 69
healthy control subjects from this age range
were selected. The mean ages were 54 (±+ 5.6)
Circulation, Volume XLVI, July 1972
ISCHEMIC HEART DISEASE
105
I HD
8
6
4
2
0 NORMAL GTT
IABNORMAL GTT
a
-
3
a
a
aiaaa
a,a,aaca a,
a
aXa,
35 37 39 41 43 45 47 49 51 53 55 5759 61 63 65 67 69 71
CONTROLS
; 14
| 12
4 10
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
8
6
4
2
aaa aaaaa
aaaaaa aa
a
21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 7779 81
AGE I YEARS
Figure 1
Age distribution of male IHD and control subjects with normal and abnormal GTT. Agematched groups from 45 to 64 years are indicated.
and 51 years (±+ 5.9), respectively. In the agematched groups the ratio of abnormal tests in
this age range remained consistent with the
total populations, and the frequency of
abnormal GTT in IHD remained significantly
higher than that of control subjects (P < 0.05).
Table 1
Prevalence of Normal and Abnormal GTT in
Male IHD and Control Subjects
GTT
Group
Normal
Fajans and Conn"3
46 (61%)
IHD
Control
135 (84%)
X2 = 13.3
University Group Diabetes
62 (83%)
IHD
Control
158 (98%)
2 = 17.0
Wilkerson Point System"
IHD
65 (87%)
Control
157 (98%)
X2 = 8.9
Abnormal
29 (39%)
26 (16%o)
P < 0.001
Total
75 (100%)
161 (100%)
Program'4
13 (17%)
3 ( 2%)
P < 0.001
75 (100%)
161 (100%)
10 (13%)
4 ( 2%)
P < 0.01
75 (100%)
161 (100%)
Circulatton, Volume XLVI, July 1972
The mean GTT curves of the healthy agematched controls peaked at S hour, and that
of IHD was shifted to 1 hour with a slightly
higher peak. The 2-hour glucose level in IHD
was significantly higher (P < 0.01) than in the
control subjects. The mean IRI response
curves of both groups peaked at 1 hour but
the 2- and 3-hour IRI levels were elevated in
IHD, though not to a statistically significant
degree.
Mean GTT and IRI Response Curves by
Normal and Abnormal Classification of GTT
The mean GTT and IRI response curves are
virtually identical in the subgroups of IHD
and age-matched control subjects with normal
GTT (fig. 2). In the IHD and control
subgroups, with abnormal GTT the peaks of
the mean GTT curves are shifted from X hour
to 1 hour. The 2- and 3-hour glucose levels
were 20 mg% higher in IHD than in control
subjects, and the difference at 3 hours was
statistically significant (P <0.05) indicating
slower glucose utilization in IHD despite
GERTLER ET AL.
106
ABNORMAL GTT
- IHD N=24
NORMAL GTT
-IHD N:4/
CONTROLS N:56
|sa CONTROLS NW/3
o P,.05
180 1-
160 h
0
L&j
140H
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
120 H
100 1-1
4
80 _
4K 60
40
2 lH
20 H
1
A
l
l
o
1"2
l
2
TIME IN HOURS
1
l
---
3
0
3
2
12 1
TIME IN HOURS
Figure 2
Mean GTT and IRI response curves in male IHD and control subjects (age range 45 to 64
years) according to normal and abnormal GTT.
higher IRI response. In both IHD and control
subgroups with abnormal GTT, the IRI
response rose sharply and identically to 90 ,u
units/ml at 1 hour and continued to rise in
IHD to a delayed 2-hour peak at 106 ,u
units/ml. The 3-hour IRI levels were nearly
identical at 45 and 41 g units/ml.
The IRI response curves peaked at 2 hours
in 63% of the 24 IHD patients and in 31% of
the 13 control subjects with abnormal GTT. In
IHD and control subjects with abnormal
GTT, IRI response levels of 50-150 gu units/ml
were found in 83% and 46%, respectively.
Maximum IRI response levels above 150 ,u
units/ml were found in 13% of IHD and 15%
of the control subjects. In IHD with abnormal
Circulation, Volume XLVI, July 1972
107
ISCHEMIC HEART DISEASE
lactate curve is similar to that of the mean
GTT curve in this subgroup (fig. 2). The
mean lactate curves of the control subjects
with abnormal GTT and IHD patients with
normal and abnormal GTT exhibit lagging
maximum lactate levels at 1 and 2 hours. The
IHD patients with abnormal GTT have the
highest lactate levels at all time intervals and
the fasting, the 3-hour lactate, and the
sum lactate levels are significantly higher when
compared to the control subjects with abnormal GTT.
GTT, only one in 24 (4%) had a IRI response
level less than 50 g units/ml versus 5 of 13
(39%) in control subjects.
Free Fatty Acid (FFA) Response
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
All groups had nearly identical slopes
between fasting and the 2-hour nadir (fig. 3).
However, the IHD subgroup with abnormal
GTT had an elevated fasting FFA level when
compared with the subgroup with normal
GTT. In the control group, the FFA response
showed a marked rebound between 2 and 3
hours, regardless of whether the GTTs were
normal or abnormal, whereas the rebound in
IHD patients was considerably less (P < 0.05)
at 3 hours, when the total IHD group was compared with the control group.
Lipoprotein Electrophoretic Patterns,
Lipid, and Uric Acid Levels
Lipoprotein electrophoresis was accomplished on a subsample of 45 IHD subjects
and 91 healthy control subjects as shown in
table 2.
Chi-square analysis revealed a significantly
(P < 0.001) greater frequency of abnormal
lipoprotein patterns in IHD than in control
subjects. When type II are excluded from the
Lactate Levels
It is evident from figure 4 that in the agematched control subjects with normal GTT,
the lactate level reached a sharp peak at 1
hour, followed by a rapid decay to below
fasting level at 3 hours. This type of mean
AB NORMAL GTT
NORMAL GTT
-IHD
450
. ...
-
N:22
TOTAL GTT
_-IHD N=39
*IHD #N/7
CONTROLS N:33
.|--CONTROLS N-43
'CONTROLS N:/0
X
0 pc.05
~350O
300250-
K200150
l1
0
2 1
2
3
response curves in
3
0
1/21
2
3
TIME I HOURS
male IHD and control subjects (age range 45 to 64 years) ac-
cording to normal and abnormal GTT.
Circulation, Volume XLVI, July 1972
2
r/ME IN HOURS
Fiigure 3
TIME / HOURS
Mean FFA
0 1/;21
108
GERTLER ET AL.
ABNORMAL GTT
IHD N:/9
-
NORMAL GTT
-IHD #N26
m""
La4i
|Zm CONTROLS IV:!!
o pc'.05
CONTROLS N=37
I.5
1.4
1.3
I.2
I.1
1.0
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
.9
8
.7
.6
I1
O
^
1/2
1
3
2
°
TIME/N HOURS
s
.
.
1/2
.
1
2
a*|a
3
TIME IV #OURS
Figure 4
Mean lactate response curves in male IHD and control subjects (age
cording to normal and abnornal GTT.
chi-square analysis, the
same
significant
asso-
ciation of type IV with IHD is obtained.
In the 77 subjects with normal lipoprotein
patterns, 62 had normal and 15 abnormal
GTT. In the 59 subjects with lipoprotein
abnormalities, 37 had normal and 22 abnormal
GTT. The chi-square analysis of the lipopro-
range 45 to 64
years)
ac-
tein and GTT classifications yielded
a
signifi-
cant dependence (P <0.05), indicating that
lipoprotein abnormalities accompany abnormal GTT.
The lipid and uric acid interrelationships in
IHD and age-matched control subjects are
summarized in table 3.
Table 2
Lipoprotein Electropharetic Patterns in Male IHD and Control Subjects
Group
IHD
Control
GTT
Type II
Normal
Abnormal
Total
Normal
Abnormal
Total
1
1
2 (4%o)
2
0
2 (2%)
Type IV
14
15
29 (65%)
20
6
26 (29%)
Normal
9
5
14 (31%)
53
10
63 (69%)
Total
24 (53%)
21 (47%)
45 (100%)
75 (82%)
16 (18%)
91 (100%)
Circulation, Volume XLVI, July 1972
ISCHEMIC HEART DISEASE
109
Table 3
Mean Lipid and Uric Acid Levels in Male IHD and Control Subjects
Control
group
IHD
group
GTT
Variable
X
SD
Normal
Triglycerides
Lipid phosphorus
Cholesterol
Uric acid
135.0
10.1*
248.0
6.0*
.52.1
1.38
49.5
1.24
N
Abnormal
Triglycerides
Lipid phosphorus
Cholesterol
Uric acid
60.1
1.60
56.0
1.3
=
24
BD
5.5.6
1.34
39.8
0.99
N =56
41
153.0
11.0*
270.0
6.8*
N
X
120.0
9.6
223.Ot
5.4*t
157.0
10.1
94.2
1.11
30.0
1.05
228.0$
6.1*
N = 13
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Significant difference between subgroups with normal and abnormal GTT: *P < 0.03.
Significant differences between IHD and control subjects: tP < 0.01; JP < 0.05.
Glucose and Insulin Interrelationships
The correlation coefficients between glucose
and IRI levels during GTT provide further
evidence that the IRI response is delayed and
elevated in IHD. In IHD the 1-hour glucose
level is significantly correlated with the 2and 3-hour IRI levels, the 2-hour glucose with
the 2- and 3-hour IRI levels, and the 3-hour
glucose with the 3-hour IRI level in a forward
manner (i.e. early glucose to later insulin). In
the control group, the 1-hour glucose level is
correlated with the 1- and 2-hour IRI levels,
and the 2-hour glucose with the 2-hour IRI
level in a more immediate manner.
Canonical Correlations
Canonical correlations which maximize the
relationship between variables were calculated in pairs between glucose, IRI, FFA, and
lactate levels at all time intervals during the
oral GTT, in order (1) to determine the
independence of these metabolic variables
and (2) to assess the interdependence which
may exist between any two pairs. The
strongest canonical correlation was between
the glucose and IRI levels (r =0.68). The
remaining correlations in order of descending
strength were: IRI-FFA (0.50), IRI-lactate
(0.47), GTT-FFA (0.42), GTT-lactate (0.41),
and FFA-lactate (0.34).
Discussion
It is difficult to establish the absolute
Circulation, Volume XLVI, July 1972
frequency of the abnormal GTT in IHD and
control subjects because of the various interpretations in the literature of normal and
abnormal GTT. The glucose load employed in
this study was compared with that recommended by the Committee on Statistics of the
American Diabetes Association.23 The mean
(+ SD) of height and weight for our total
population is 69 in ( ± 3) and 170 lb ( + 22),
respectively. The recommended glucose load
for a 69-in. and 170-lb subject is 77 g,
calculated from 40 g/m2 of body surface. This
agrees with the 75 g of glucose equivalent
used in this study.
Despite the higher frequency of abnormal
GTT in the IHD group, comparison of the
mean GTT and IRI curves showed only slight
elevation in the IHD group. This is due to the
relatively small percentage of abnormal GTTs
which account for these differences between
the groups.
There is a marked delay in the peak time of
the IRI response in the IHD subgroup
with abnormal GTT when compared to the
age-matched healthy control subjects. The
IHD patients with abnormal GTT have a 2hour IRI response peak, versus a 1-hour peak
in the control subjects. Similar observations
have been made in mild diabetics24 and in
patients with premature coronary heart disease.9
110
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
In the IHD patients but not in the agematched control subjects, the serum total cholesterol and lipid phosphorus are significantly
and positively correlated with the M- and 1hour glucose levels, and cholesterol is further
correlated with the 1-hour IRI level. It is
reasonable to assume that the elevated i- and
1-hour glucose levels contribute in some
significant, as yet unknown, manner to the
elevated cholesterol and lipid phosphorus
levels in IHD patients only. These observations are somewhat similar to those reported
by Hatch et al.25 and by Heinle et al.26
In the control group, the triglycerides are
more strongly correlated with the glucose and
IRI levels than in the IHD group. This may
be related to the delayed and elevated IRI
response in IHD.
Levy and Fredrickson et al. state that
younger individuals with inborn type II or IV
lipoprotein abnormalities are more prone to
IHD.19 The data presented here show that 65%
of IHD patients have type IV lipoprotein
patterns and that 52% of these also have an
abnormal GTT. These results confirm the
findings of Salel et al.27 The ratios of type
IV/abnormal CTT are virtually identical in
both studies. This raises the possibility that
the abnormal GTT alone may not be as important a risk factor of IHD unless it coexists
with lipoprotein abnormalities.
The elevated uric acid levels in subjects
with abnormal GTT are significant since it has
been postulated by Galzigna et al. that uric
acid is a potent inhibitor of monoamine
oxidase,28 and by Cegrell et al. that the
inhibition of monoamine oxidase could affect
the biogenic amine levels in the pancreatic
beta-cells and thereby effect increased insulin
secretion.29
A possible explanation for the accumulation
of lactate in IHD patients with abnormal
GTT would be the excessive availability of
FFA and competition for the. availability of
coenzyme A for the decarboxylation of pyruvate (fig. 3), which supports the existence of
a glucose-FFA cycle as suggested by Randle,
Hales, et al.30
The three strongest canonical correlations,
GERTLER ET AL.
found between IRI and glucose, IRI and FFA,
and IRI and lactate levels, imply that insulin
is the controlling factor in both carbohydrate
and lipid metabolism. It is possible that
prolonged and excessive availability of insulin
will promote conversion of more glucose to
FFA and also the trapping of more FFA in
tissues as triglycerides, phospholipids, and
cholesterol.
References
MM, WmHTE PD: Coronary Heart
Disease in Young Adults: A Multidisciplinary
Study. Cambridge, Massachusetts, Harvard
University Press, 1954, p 112
ALBRINK MJ: Triglycerides, lipoproteins and
coronary artery disease. Arch Intern Med
(Chicago) 109: 145, 1962
GOLDENBERG S, ALEx M, BLUMENTHAL HT:
Sequelae of arteriosclerosis of the aorta and
coronary arteries: A statistical study in diabetes
mellitus. Diabetes 7: 98, 1958
EPSTEIN FH: Hyperglycemia: A risk factor in
coronary heart disease. Circulation 36: 609,
1967
WAHLBERG F, THOMASSON B: Glucose tolerance
in ischemic cardiovascular disease. In Carbohydrate Metabolism and its Disorders, edited
by Dickens F, Randle PJ, Whelan Wj. New
York, Academic Press, 1968, p 185
BROWN DF, AYERS WR, DOYLE JT: Glucose-lipid
interrelationships in ischemic heart disease.
Circulation 28: 696, 1963
RYAN WG, ECONOMOU PG, SCHWARTZ TB:
Intravenous glucose tolerance test in an
industrial population: Controls, subjects with
coronary heart disease and relatives of diabetics. Diabetes 16: 171, 1967
REAVEN G, CASCIANo A, CODY R, LUCAS C,
MILLER R: Carbohydrate intolerance and
hyperlipemia in patients with myocardial
infarction without known diabetes mellitus. J
Clin Endocr 23: 1013, 1963
TZAGOURNIS M, SEIDENSTICKER JF, HAMWI GJ:
Serum insulin, carbohydrate, and lipid abnormalities in patients with premature coronary
heart disease. Ann Intern Med 67: 42, 1967
GERTLER MM, LEETMA HE, SALUSTE E, WELSH
JJ, RusE HA, COVALT DA, ROSENBERGER J:
Carbohydrate, insulin and lipid interrelationship in ischemic vascular disease. Geriatrics 25:
134, 1970
WORLD HEALTH ORGANIZATION: Ischemic Heart
Disease Registers: Report of the Fourth
Working Group. Copenhagen, 1970
1. GERTLER
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Circulation, Volume XLVI, July 1972
ISCHEMIC HEART DISEASE
12. LEONARDS JR, MCCULLAGH EP, CHRISTOPHER
TC: A new carbohydrate solution for testing
glucose tolerance. Diabetes 14: 96, 1965
13. FAJANS SS, CONN JW: The early recognition of
iabetes mellitus. Ann NY Acad Sci 82: 208,
1959
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
14. KLIMT CR, MEINERT CL, MILLER M, KNOWLES
HC JR: University Group Diabetes Program
(UGDP): A study of the relationships of
therapy to vascular and other complications of
diabetes. In Tolbutamide . . . after Ten Years,
Brook Lodge Symposium, August 1967. New
York, Excerpta Medica International Congress
Series No. 149, 1967, p 261
15. WILKERSON HLC, HYMAN H, KAUFMAN M,
MCCUSTION AC, FRANCIS JO: Diagnostic
evaluation of oral glucose tolerance tests in
non-diabetic subjects after various levels of
carbohydrate intake. New Eng J Med 262:
1057, 1960
16. GERTLER MM, LEETMA HE, SALUSTE E, COVALT
DA, ROSENBERGER JL: Covert diabetes mellitus
in ischemic heart and cerebrovascular disease.
Geriatrics 27: 105, 1972
17. HOHORST HS: L-( + )-lactate: Determination with
lactic dehydrogenase and DPN. In Methods of
Enzymatic Analysis, ed 2, edited by Bergmeyer
HU. New York, Academic Press, 1965, p 266
18. LEES RS, HATCH FT: Sharper separation of
lipoprotein species by paper electrophoresis in
albumin-containing buffer. J Lab Clin Med
61: 518, 1963
19. LEVY RI, FREDRICKSON DS: Diagnosis and
management of hyperlipoproteinemia. Amer J
Cardiol 22: 576, 1968
20. OSTLE B: Statistics in Research, ed 2. Ames,
Iowa, Iowa State University Press, 1963
21. ANDERSON TW: An Introduction to Multivariate
Statistical Analysis. New York, John Wiley and
Sons, Inc., 1958, p 288
22. Build and Blood Pressure Study. Chicago, Society
of Actuaries, 1959
Circulation, Volume XLVI, July 1972
ill
23. Report on Committee on Statistics of the
American Diabetes Association, 1968: Standardization of the oral glucose tolerance test.
Diabetes 18: 299, 1969
24. SELTZER HS, ALLEN EW, HERRON AL, BRENNAN
MT: Insulin secretion in response to glycemic
stimulus: Relation of delayed initial release to
carbohydrate intolerance in mild diabetes
mellitus. J Clin Invest 46: 323, 1967
25. HATCH FT, REISSELL PK, POON-KING TMW,
CANELLOS GP, LEES RS, HAGOPIAN LM: A
study of coronary heart disease in young men:
Characteristics and metabolic studies of the
patients and comparison with age-matched
healthy men. Circulation 33: 679, 1966
26. HEINLE RA, LEVY RI, FREDRICKSON DS: Lipid
and carbohydrate abnormalities in patients
with angiographically documented coronary
artery disease. Amer J Cardiol 24: 178,
1969
27. SALEL AF, AmSTERDAM EA, MASON DT, ZELIS
RF: The importance of type IV hyperlipoproteinemia as a major predispQsing metabolic
factor in coronary artery disease. Circulation 44
(suppl II): II-47, 1971
28. GALZIGNA L, MAINA G, RUMNEY G: Role of Lascorbic acid in the reversal of the monoamine
oxidase inhibition by caffeine. J Pharm
Pharmacol 23: 303, 1971
29. CEGRELL L, FALK B, HELLMAN B: Monoaminergic mechanisms in the endocrine pancreas. In
The Structure and Metabolism of the Pancreatic Islets, edited by Brolin SE, Hellman B,
Knutson H. New York, Macmillan Co., 1964, p
429
30. RANDLE PJ, HALES CN, GARLAND PB,
NEWSHOLME EA: The glucose fatty-acid cycle:
Its role in insulin-sensitivity and the metabolic
disturbances of diabetes mellitus. Lancet 1:
785, 1963
Ischemic Heart Disease: Insulin, Carbohydrate, and Lipid Interrelationships
MENARD M. GERTLER, HILLAR E. LEETMA, ERICH SALUSTE, JAMES L.
ROSENBERGER and ROBERT G. GUTHRIE
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation. 1972;46:103-111
doi: 10.1161/01.CIR.46.1.103
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
75231
Copyright © 1972 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://circ.ahajournals.org/content/46/1/103
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles
originally published in Circulation can be obtained via RightsLink, a service of the Copyright
Clearance Center, not the Editorial Office. Once the online version of the published article for
which permission is being requested is located, click Request Permissions in the middle column
of the Web page under Services. Further information about this process is available in the
Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/