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Am J Physiol Heart Circ Physiol 308: H1510–H1516, 2015.
First published April 17, 2015; doi:10.1152/ajpheart.00722.2014.
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Cardiovascular Consequences of Obesity and Type 2 Diabetes
Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the
human heart
Linda R. Peterson,1 Pilar Herrero,2 Andrew R. Coggan,2 Zulia Kisrieva-Ware,2 Ibrahim Saeed,1
Carmen Dence,1 Deborah Koudelis,2 Janet B. McGill,3 Matthew R. Lyons,1 Eric Novak,1
Víctor G. Dávila-Román,1 Alan D. Waggoner,1 and Robert J. Gropler2
1
Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; 2Division
of Radiological Sciences, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri;
and 3Endocrinology Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
Peterson LR, Herrero P, Coggan AR, Kisrieva-Ware Z, Saeed
I, Dence C, Koudelis D, McGill JB, Lyons MR, Novak E, DávilaRomán VG, Waggoner AD, Gropler RJ. Type 2 diabetes, obesity,
and sex difference affect the fate of glucose in the human heart. Am
J Physiol Heart Circ Physiol 308: H1510 –H1516, 2015. First published April 17, 2015; doi:10.1152/ajpheart.00722.2014.—Type 2
diabetes, obesity, and sex difference affect myocardial glucose uptake
and utilization. However, their effect on the intramyocellular fate of
glucose in humans has been unknown. How the heart uses glucose is
important, because it affects energy production and oxygen efficiency,
which in turn affect heart function and adaptability. We hypothesized
that type 2 diabetes, sex difference, and obesity affect myocardial
glucose oxidation, glycolysis, and glycogen production. In a first-inhuman study, we measured intramyocardiocellular glucose metabolism from time-activity curves generated from previously obtained
positron emission tomography scans of 110 subjects in 3 groups:
nonobese, obese, and diabetes. Group and sex difference interacted in
the prediction of all glucose uptake, utilization, and metabolism rates.
Group independently predicted fractional glucose uptake and its
components: glycolysis, glycogen deposition, and glucose oxidation
rates. Sex difference predicted glycolysis rates. However, there were
fewer differences in glucose metabolism between diabetic patients
and others when plasma glucose levels were included in the modeling.
The potentially detrimental effects of obesity and diabetes on myocardial glucose metabolism are more pronounced in men than women.
This sex difference dimorphism needs to be taken into account in the
design, trials, and application of metabolic modulator therapy.
Slightly higher plasma glucose levels improve depressed glucose
oxidation and glycogen deposition rates in diabetic patients.
type 2 diabetes; obesity; sex difference; glucose metabolism; myocardium; glucose oxidation
[type 2 diabetes mellitus (T2DM)] and obesity
are major risk factors for cardiac dysfunction and heart failure
(12, 14). Myocardial function is inextricably linked to substrate
metabolism. Under normal aerobic conditions, 50 –70% of
total energy is obtained from oxidation of fatty acids; the rest
is primarily derived from carbohydrates (glucose and lactate).
The proportional contribution of these various substrates to
myocardial energy metabolism is exquisitely sensitive to the
TYPE 2 DIABETES
Address for reprint requests and other correspondence: R. J. Gropler,
Cardiovascular Imaging Laboratory, Mallinckrodt Institute of Radiology, 510
S. Kingshighway Blvd., St. Louis, MO 63110 (e-mail: [email protected].
edu).
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substrate environment, hormonal milieu, level of myocardial
work, and level of myocardial blood flow (MBF). For example,
under fasting conditions, myocardial fatty acid metabolism is
the predominant energy source. However, glucose is a more
oxygen-efficient fuel per carbon than fatty acids, but only if
fully oxidized.
In the diabetic human heart, glucose uptake is decreased (18)
and glucose utilization/plasma insulin is lower than in nondiabetic controls (19). Animal models of diabetes and obesity
demonstrate impaired glucose uptake from reduced insulinmediated translocation of the GLUT4 transporter (3). In murine models of diabetes and obesity, glycolysis and glucose
oxidation rates are also decreased (3). However, the effects of
diabetes and obesity on glycolysis, glucose oxidation, and
glycogen deposition are unknown in humans.
Sex difference also plays a major role in determination of
glucose uptake and utilization by the heart in nonobese (21),
obese (20), and diabetic subjects (17). The effect of sex
difference on intramyocardial glucose metabolism in the human heart is not known. Thus we hypothesized that group
(diabetes, obese, and nonobese) and sex difference would
affect intracellular glucose metabolism. To test our hypothesis,
we quantified glycolysis, glucose oxidation, and glycogen
deposition rates in the human heart. We utilized time-activity
curves generated from previously performed positron emission
tomography (PET) scans in nonobese, obese, and diabetic
subjects, but we applied new, well-validated, compartmental
modeling for quantification of intramyocardiocellular glucose
metabolism (9).
MATERIALS AND METHODS
Subjects
Patients (n ⫽ 108) were divided into three groups: nonobese [n ⫽
10, body mass index (BMI) ⬍30 kg/m2], obese (n ⫽ 26, BMI ⬎30.0
kg/m2), and T2DM (n ⫽ 72). A medical history was obtained from
each patient, and clinical assessment, physical examination, and
routine blood chemistries were performed. Excluded from the study
were women with a lack of adequate birth control and patients with
Hb A1c ⬎7.0, serum triglycerides ⬎400 mg/dl, hypertension beyond
stage 1, or a history of coronary artery disease or any other cardiac
disease (except mild valvular disease), including left ventricular (LV)
wall motion abnormalities. All patients were nonsmokers and had no
other systemic illnesses.
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Submitted 8 October 2014; accepted in final form 30 March 2015
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DIABETES, SEX DIFFERENCE: INTRACARDIAC GLUCOSE EFFECT
The T2DM group also underwent rest/stress echocardiography to
rule out coronary artery disease. No patient was taking niacin, fibrate,
thiazolidinedione, or insulin; 40% were taking statins, and 43% were
taking antihypertensive medication. The Human Studies Committee
and the Radioactive Drug Research Committee at the Washington
University School of Medicine approved the study. All patients signed
informed consent prior to enrollment in the study.
predetermined end points, myocardial glucose fractional uptake, utilization, and their component parts, i.e., glycogen deposition and
glycolysis, as well as the portion of glycolysis accounted for by
glucose oxidation. Post hoc testing to analyze paired comparisons was
done using Fisher’s least significant difference test.
Positron Emission Tomography
Table 1 shows the baseline characteristics of the patients,
their plasma lipid and insulin levels, and MBF rates at the time
of the PET study. There was no difference in the percentage of
women in the groups. The T2DM patients were well controlled
on the basis of average Hb A1c. Age and BMI differed across
the three groups: patients in the T2DM group were the oldest,
and those in the obese group had the highest BMI. Plasma
insulin levels were highest in the obese and T2DM groups
(Table 1). MBF was also different among the groups: MBF
was highest in the obese group (Table 1). Plasma glucose
levels were different among the groups: glucose levels were
highest in the T2DM group (Fig. 1). There was also no
significant interaction between sex difference and group in the
determination of plasma FFA concentration, which was higher
(P ⬍ 0.05) in the obese and T2DM groups than in the nonobese
group and higher (P ⬍ 0.001) in women than in men (Fig. 1).
All PET studies were performed using a Siemens tomograph
(ECAT 962 HR⫹, Siemens Medical Systems, Iselin, NJ). Patients
were fasted for 12 h prior to the study. Two intravenous catheters, one
for infusion and one for blood sampling, were placed. All studies were
carried out at 0800 to avoid circadian variations in metabolism. Blood
pressure and heart rate were monitored throughout the study.
Myocardial H215O and [1-11C]glucose images were obtained for
measurements to determine MBF and glucose metabolism, respectively. Well-established kinetic models were used in conjunction
with PET-generated time-activity curves to quantify MBF (10) and
glucose metabolism (9). Calculations were based on models described previously using rate constants to determine glucose uptake by the cells and, ultimately, the mitochondria. The following
equations are used to describe calculation of the glucose metabolism measurements: fractional myocardial glucose uptake per gram
of heart muscle (ml·g⫺1·min⫺1) ⫽ glucose extraction fraction ⫻
MBF (ml·g⫺1·min⫺1); fractional myocardial glucose uptake ⫽ glucose for glycolysis ⫹ glucose for glycogen storage; portion of fractional glucose uptake undergoing glycolysis ⫽ portion undergoing
full glucose oxidation ⫹ lactate production; myocardial glucose
utilization (nmol·g⫺1·min⫺1) ⫽ fractional glucose uptake ⫻ plasma
glucose concentration at the time of the PET scan. Glucose utilization
was also subdivided on the basis of the kinetic modeling into glycolysis ⫹ glycogen storage rates. The portion of glycolysis that was
attributable to full glucose oxidation was also determined using the
modeling referenced above.
Echocardiography
All patients underwent a complete resting echocardiogram (Sequoia-C256, Acuson-Siemens, Mountain View, CA) during their PET
study, following their scan for MBF, and before their scan for
myocardial glucose metabolism. Two-dimensional echocardiograms
were performed and analyzed according to American Society of
Echocardiography guidelines (15). The area-length method was used
for measurement of LV mass. LV end-diastolic and end-systolic
volumes were measured in the four-chamber view, and the modified
Simpson’s equation was used to calculate ejection fraction.
Measurement of Plasma Insulin and Substrates
Plasma insulin was measured by radioimmunoassay (Linco Research, St. Charles, MO). Plasma glucose and lactate levels were
measured using a glucose-lactate analyzer (Yellow Springs Instruments, Yellow Springs, OH). Plasma free fatty acid (FFA) levels were
measured using an enzymatic kit (NEFA C kit, WAKO Chemicals
USA, Richmond, VA).
Statistical Methods
GraphPad Prism 6.05 (GraphPad Software, San Diego, CA) was
used to perform all statistical analyses. Data are presented as means ⫾
SD. Analysis of variance was used to determine differences in
continuous variables across the three groups: nonobese, obese, and
T2DM. ␹2 analysis was used for categorical variables. Two-way
analysis of variance was used to determine the independent effects of
group and sex difference and their interaction in determination of our
Hemodynamics and Cardiac Structure and Function
Hemodynamic and cardiac structure and function data are
shown in Table 2. Resting heart rate differed among the three
groups: rates were higher in the obese and T2DM groups than
in the nonobese group. Consistent with this heart rate difference, ejection fraction was highest in the T2DM group. Systolic blood pressure and ejection fraction were higher in the
T2DM than nonobese group. Diastolic blood pressure and LV
mass were not different among the groups. Rate-pressure
product, a surrogate of cardiac work, was highest in the T2DM
group. However, despite this evidence of higher work (and
higher ejection fraction), fractional glucose uptake was not
higher in the T2DM group (see below and Fig. 2).
Table 1. Baseline characteristics, plasma levels, and blood
flow
Group
Nonobese (n ⫽ 10) Obese (n ⫽ 26)
Age, yr
Sex, %women
BMI, kg/m2
Plasma insulin, ␮U/ml
Hb A1c
Total cholesterol, mg/dl
Low-density
lipoprotein, mg/dl
High-density
lipoprotein, mg/dl
Triglycerides, mg/dl
MBF, ml·g⫺1·min⫺1
T2DM (n ⫽ 72)
31 ⫾ 9
60
23 ⫾ 1
4.9 ⫾ 3.0
35 ⫾ 6
65
38 ⫾ 5***
13.3 ⫾ 6.1*
155 ⫾ 16
169 ⫾ 29
56 ⫾ 9†††,‡‡‡
55
34 ⫾ 7†††,‡‡‡
14.5 ⫾ 10.4††
6.6 ⫾ 0.7
149 ⫾ 30‡‡
82 ⫾ 20
95 ⫾ 26
75 ⫾ 23‡‡‡
57 ⫾ 13
78 ⫾ 26
0.97 ⫾ 0.12
46 ⫾ 11**
45 ⫾ 11††
141 ⫾ 76** 140 ⫾ 63††
1.18 ⫾ 0.38* 1.04 ⫾ 0.24‡
Values are means ⫾ SD. BMI, body mass index; MBF, myocardial blood
flow. Post hoc comparisons of groups: *P ⬍ 0.05, obese vs. nonobese; **P ⬍
0.01, obese vs. nonobese; ***P ⬍ 0.001, obese vs. nonobese; †P ⬍ 0.05,
T2DM vs. nonobese; ††P ⬍ 0.01, T2DM vs. nonobese; †††P ⬍ 0.001, T2DM
vs. nonobese; ‡P ⬍ 0.05, T2DM vs. obese; ‡‡P ⬍ 0.01, T2DM vs. obese;
‡‡‡P ⬍ 0.001, T2DM vs. obese.
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PET Image Analysis
RESULTS
DIABETES, SEX DIFFERENCE: INTRACARDIAC GLUCOSE EFFECT
1000
0.12
800
0.10
p<0.0001
p<0.0001
Nonobese
Obese
0.08
600
mL·min-1·g-1
Plasma [FFA] (µmol/mL)
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400
T2DM
p<0.001
p<0.01
0.06
p<0.0001
p<0.0001
p<0.0001
p<0.0001
0.04
200
0.02
0
Men
Women
Glucose uptake
Glycogen deposition
Glycolysis
Glucose Oxidation
Nonobese
Obese
T2DM
0.12
6
0.10
Nonobese
4
0.08
mL·min-1·g-1
Plasma [glucose] (µmol/mL)
8
2
Obese
T2DM
p<0.01
0.06
p<0.01
0.04
0
p<0.05
Men
Women
p<0.05
0.02
Fig. 1. Plasma free fatty acid (FFA) and glucose concentrations in men and
women. T2DM, type 2 diabetes mellitus. Plasma glucose concentration was
significantly higher (P ⬍ 0.001) in diabetic than nondiabetic subjects, but there
was no difference between men and women and there were no significant
interaction effects. Plasma FFA concentration was significantly higher (P ⬍ 0.05)
in obese and T2DM groups than nonobese group and also significantly higher (P
⬍ 0.001) in women than men, but there was no significant interaction effect.
Fractional Glucose Uptake and Intramyocardial Glucose Kinetics
Men. Fractional glucose uptake was markedly higher in
nonobese men than obese or T2DM men (Fig. 2, top). Similar
patterns were observed for the portion of fractional glucose
uptake that underwent glycolysis, glycogen deposition, and
glucose oxidation.
Women. The pattern of fractional glucose uptake and metabolism among the groups differed between women and men.
0.00
Glucose uptake
Glycogen deposition
Glycolysis
Glucose Oxidation
Fig. 2. Fractional myocardial glucose uptake and its components in men (top)
and women (bottom).
The difference in fractional glucose uptake among the groups
was due to higher glucose uptake in obese than T2DM women.
Similarly, glycogen deposition, glycolysis, and glucose oxidation rates were higher in obese than T2DM women.
Glucose Utilization and Intramyocardial Glucose Kinetics
Men. Among the three groups of men, glucose utilization
patterns were similar to glucose uptake patterns (Fig. 3, top).
Glucose utilization was higher in nonobese than obese or T2DM
Table 2. Hemodynamics and cardiac structure and function
Group
Heart rate, beats/min
SBP, mmHg
DBP, mmHg
Rate-pressure product, (beats·min⫺1)·mmHg
LV mass, g
Ejection fraction, %
Nonobese
Obese
T2DM
56 ⫾ 8
116 ⫾ 16
65 ⫾ 8
6,581 ⫾ 1,526
150 ⫾ 50
58 ⫾ 5
68 ⫾ 11**
126 ⫾ 12
69 ⫾ 8
8,591 ⫾ 1,724**
181 ⫾ 35
61 ⫾ 5
67 ⫾ 10††
131 ⫾ 17††
68 ⫾ 7
8,698 ⫾ 1,863†††
173 ⫾ 45
64 ⫾ 6†
Values are means ⫾ SD. SBP and DBP, systolic and diastolic blood pressure; LV, left ventricular. Post hoc comparisons of groups: **P ⬍ 0.01, obese vs.
nonobese; †P ⬍ 0.05, T2DM vs. nonobese; ††P ⬍ 0.01, T2DM vs. nonobese; †††P ⬍ 0.001, T2DM vs. nonobese.
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0.00
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DIABETES, SEX DIFFERENCE: INTRACARDIAC GLUCOSE EFFECT
600
500
p<0.01
p<0.01
Nonobese
nmol·min-1·g-1
Obese
400
T2DM
p<0.05
300
p<0.05
p<0.01
p<0.001
p<0.001
p<0.0001
Coupling of Glycolysis With Glucose Oxidation
200
100
Glucose utilization Glycogen deposition
Glycolysis
Glucose Oxidation
600
500
Nonobese
400
Obese
T2DM
300
200
100
0
Glucose utilization Glycogen deposition
Glycolysis
Glucose Oxidation
Fig. 3. Myocardial glucose utilization and its components in men (top) and
women (bottom).
men. The portion of glucose utilization accounted for by glycogen
deposition, glycolysis, and glucose oxidation was also higher in
nonobese than obese or T2DM men. The significance of the
difference (P value) in glucose utilization between nonobese and
T2DM men is less than the difference in fractional glucose uptake
between these same two groups (Figs. 2 and 3). This is likely due
to the higher plasma glucose levels in T2DM men (Fig. 1),
because glucose utilization is the product of fractional glucose
uptake and plasma glucose concentration.
Women. Glucose utilization did not differ among the three
groups of women (Fig. 3, bottom), nor did glycolysis, glycogen
deposition, or glucose oxidation rates differ among these
groups. The overall blunting of the significance of differences
(P values) in glucose utilization compared with fractional
glucose uptake among the groups of women was due to higher
plasma glucose levels in the T2DM group (Fig. 1).
Multivariate Analyses and Interactions Between Group and
Sex Difference in Determining Glucose Uptake and
Metabolism
Sex difference and group interacted significantly in the determination of glucose uptake and all its components (Table 3). Group and
In the fasted state, the percentage of glucose utilized for
glycolysis was relatively low and not statistically different
among the groups (Table 4). However, in men and women and
in all groups, glycolysis was closely coupled with glucose
oxidation (Fig. 4). For example, the portion of glucose that
underwent oxidation was ⬃83– 86% of the glycolytic rate in all
groups and both sexes. This would suggest that any differences
in the plasma FFA levels are not having a large effect on the
glucose metabolism measures (via the Randle cycle), because
FFA inhibits glucose oxidation more than glycolysis and glycolysis more than glucose uptake.
DISCUSSION
This study is the first to our knowledge to show that T2DM,
obesity, and sex difference affect myocardial intracellular glucose metabolism in humans. Knowledge of the intracellular
fate of glucose is important, because it determines ATP production (e.g., 1 ATP used for glycogen deposition vs. ⬃36
ATP made by full glucose oxidation) for the high-energy
demands of the human heart. Determination of the factors that
affect the heart’s glucose oxidation rate and coupling of glycolysis to glucose oxidation is also vital, because these rates
affect the heart’s efficiency and adaptability (16). Finally,
determination of the point in the chain of human cardiac
glucose metabolism at which defects may occur helps identify
potential therapeutic targets.
Effects of Diabetes and Obesity on Myocardial Glucose
Metabolism
We found that group (T2DM, obese, and nonobese) affected fractional glucose uptake and that the effect on
glucose utilization was less pronounced. Results from animal studies suggest that decreased glucose uptake in diabeTable 3. Effects of group, sex difference, and their
interaction on myocardial metabolism: results of two-way
ANOVA
Myocardial glucose uptake
Glycogen deposition
Glycolysis
Glucose oxidation
Myocardial glucose utilization
Glycogen deposition
Glycolysis
Glucose oxidation
Group
Sex
Difference
Interaction
(Group ⫻
Sex Difference)
0.0008
0.0024
0.0008
0.0002
0.0450
0.1941§
0.0127
0.0057
0.0091
0.0303
0.0069
0.0040
0.0094
0.0225
0.0096
0.0050
0.0016
0.0099
0.0017
0.0005
0.0173
0.0586§
0.0122
0.0050
§Not statistically significant (P ⬎ 0.05).
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0
nmol·min-1·g-1
sex difference were each determinants of fractional myocardial
glucose uptake, as well as glycolysis, glycogen, and glucose
oxidation deposition (Table 3).
In the case of glucose utilization, group and sex difference
interacted significantly in the determination of glucose utilization and on the metabolic fate of glucose within the cell (Table
3). Group was a determinant of glucose utilization, glycolysis,
and glucose oxidation. Sex difference was a determinant of
glucose utilization and all its components.
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DIABETES, SEX DIFFERENCE: INTRACARDIAC GLUCOSE EFFECT
Table 4. Myocardial glycogen deposition vs. glycolysis
Men
Glycogen deposition
Glycolysis
Women
Nonobese
Obese
T2DM
Nonobese
Obese
T2DM
55 ⫾ 16
45 ⫾ 16
72 ⫾ 11
28 ⫾ 11
67 ⫾ 14
33 ⫾ 14
69 ⫾ 12
31 ⫾ 12
70 ⫾ 10
30 ⫾ 10
71 ⫾ 14
29 ⫾ 14
Values (means ⫾ SD) are expressed as a percentage of glucose utilization.
potential clinical implications. First, it is thought that glycogen
may help with cardiac preservation should ischemia supervene
(5). The higher plasma glucose levels in patients with diabetes
may also enable more glucose utilization by the cell and
ameliorate their low glycolysis and glucose oxidation rates. In
the ACCORD trial, intensive lowering of blood glucose levels
was associated with a worse mortality rate than in patients
whose blood glucose was less aggressively managed (7).
Whether this outcome difference was due in part to dependence
of organs, such as the heart, on higher ambient glucose plasma
levels to help maintain intracellular glucose metabolism is an
interesting hypothesis requiring further study.
We recognize that many of the adult human’s waking
hours are not in the fasted state (similar to our testing
conditions); however, it is important to evaluate intramyocellular glucose use in the fasting state for several reasons.
1) It is a physiological condition (unlike studies performed
during hyperinsulinemic/euglycemic clamp). 2) It is a relatively stable state compared with postprandial conditions. 3)
Many important pathophysiological events occur during
fasting (e.g., there is a propensity for myocardial infarctions
in the early morning, and preoperative patients are usually
fasting). However, future study of glucose metabolism under conditions mimicking the postprandial state would
likely add additional insights.
Effect of Sex Difference on Intramyocardial Glucose
Metabolism
Part of the complexity of evaluating myocardial metabolism
in different groups is that sex difference has a profound effect
on myocardial metabolism (11, 19 –21). In animal models, sex
Percent of glycolysis oxidized
10
Nonobese
Obese
T2DM
80
60
40
20
0
Men
Women
Fig. 4. Extracted glucose that undergoes full glucose oxidation shown as
percentage of glucose that undergoes glycolysis in men and women. There
were no differences among the groups or between men and women.
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tes may be in part due to decreased GLUT4 and GLUT1
expression or GLUT4 translocation in response to insulin
(3). Previous human studies demonstrate that T2DM decreases myocardial glucose uptake in patients (following an
oral glucose load) (18) and that obesity and diabetes are
associated with decreased fasting cardiac glucose utilization/level of plasma insulin (19, 20). Results of our present
study are in agreement with these previous findings, because
we found that subject group (T2DM, obese, and nonobese)
was related to fractional glucose uptake. Group also was a
determinant of glucose utilization.
We also found that diabetes and obesity affected myocardial
glycolysis, glucose oxidation, and glycogen deposition rates.
Results from animal studies on glycolysis are mixed. Cardiac
glycolysis rates are low in ob/ob, but not db/db, mice (4).
Another model had higher glycolysis rates (2). We found that
group independently predicted the portion of glucose uptake
used for glycolysis and that group tended to affect the portion
of glucose utilization devoted to glycolysis. Murine studies
consistently show that obesity and diabetes decrease oxidation
rates (2, 4). These studies further suggest that the decrease in
oxidation is not solely due to a decrease in myocardial glucose
utilization, but may also be due to a decrease in pyruvate
dehydrogenase and/or mitochondrial oxidative capacity (3).
We found that group affected the fraction of glucose uptake
devoted to glycolysis, glycogen deposition, and glucose oxidation in humans. Group also affected the component parts of
glucose utilization: glycolysis, glycogen deposition, and glucose oxidation. However, there was no difference among the
groups in terms of the percentage of glycolysis that was needed
for glucose oxidation (Fig. 4). In fact, the patterns of glucose
oxidation differences among the three groups and in the two
sexes mirror the differences in fractional uptake and utilization
(Figs. 2 and 3). This suggests that in humans the primary defect
in glucose metabolism from diabetes and obesity is in glucose
uptake. This decrease in glucose uptake appears to be intrinsic
to the myocardium’s ability to extract glucose, because blood
flow rates are not lower in the obese or the T2DM group. In
addition, it suggests that the higher fatty acid levels in the
T2DM group did not have a marked effect on glucose metabolism, because fatty acid metabolism typically inhibits glucose
oxidation more than glycolysis or glucose uptake (22). Finally,
all groups demonstrated robust coupling of glycolysis to glucose oxidation. This also suggests that the amount of potentially damaging protons from uncoupled glycolysis/glucose
oxidation in all groups should be low (16).
It is also noteworthy that the significance of the differences
between glucose utilization (and its components) in the T2DM
group and either of the other two groups is generally less
pronounced than the differences in glucose uptake (and its
components). In fact, there were no group differences in the
portion of glucose utilized for glycogen deposition. This has
DIABETES, SEX DIFFERENCE: INTRACARDIAC GLUCOSE EFFECT
Limitations
This study’s findings cannot be extrapolated to subjects that
do not fit our entry criteria. The subjects were not age-matched
across the groups. The T2DM group was older than the other
groups. However, aging does not cause a change in resting
myocardial glucose utilization (13). Current PET modeling
cannot be used to measure endogenous glycogenolysis rates in
humans; however, in the resting state, these rates should be
exceedingly low (8). The amount of glycogen deposited (as
opposed to the rate of deposition) cannot be measured using
PET.
Summary
Our current study’s results extend our understanding of
glucose metabolism in the human heart by demonstrating that
group affects the intracellular fate of glucose. Group affected
all the components of glucose uptake (glycolysis, glycogen
deposition, and glucose oxidation), with the T2DM subjects
(both men and women) having low rates. Moreover, the primary defect leading to the decreased intramyocellular glucose
metabolism rates appears to be in the myocardium, specifically
glucose uptake in humans with T2DM. Sex difference affects
myocardial glucose metabolism and interacts with group in its
prediction.
Conclusions
T2DM diabetes, obesity, and sex difference have major
effects on intracellular glucose handling by the human heart.
They often interact in the determination of specific glucose
metabolism rates. These factors need to be taken into account
in the design and study of metabolic modulator therapy for the
heart. Decreased glucose uptake by the human heart appears to
be the primary factor limiting glucose oxidation and, hence, a
primary target for treatment. Moreover, it appears that a mildly
increased plasma glucose level in T2DM patients may help
ameliorate the low rates of myocardial glucose metabolism.
Thus aggressive lowering of plasma glucose levels (particularly during ischemia, when glucose metabolism is preferred)
may be detrimental in patients with diabetes.
ACKNOWLEDGMENTS
The authors thank Margaret Morton (Washington University School of
Medicine) for assistance with manuscript preparation and submission. The
authors also thank the subjects who volunteered to participate in the study.
GRANTS
This study was funded by National Institutes of Health Grants PO1-HL013851-43, MO1-RR-000036-461599, P30-DK-056341-08, UL1-RR-024992
(Clinical and Translational Science Award), RO1-HL-073120, and P60-DK020579-30 and a grant from the Barnes-Jewish Hospital Foundation (St. Louis,
MO).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
L.R.P. and R.J.G. developed the concept and designed the research; L.R.P.,
I.S., C.D., D.K., J.B.M., M.R.L., and R.J.G. performed the experiments;
L.R.P., P.H., Z.K.-W., E.N., V.G.D.-R., A.D.W., and R.J.G. analyzed the data;
L.R.P., E.N., and R.J.G. interpreted the results of the experiments; L.R.P. and
R.J.G. prepared the figures; L.R.P. and R.J.G. drafted the manuscript; L.R.P.,
A.R.C., V.G.D.-R., and R.J.G. edited and revised the manuscript; L.R.P. and
R.J.G. approved the final version of the manuscript.
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