Diabetes Publish Ahead of Print, published online October 3, 2007
FATTY ACIDS AND INSULIN MODULATE MYOCARDIAL SUBSTRATE
METABOLISM IN HUMANS WITH TYPE 1 DIABETES MELLITUS
Linda R. Peterson, MD1,2
Pilar Herrero, MS3
Janet McGill, MD4
Kenneth B. Schechtman, PhD5
Zulfia Kisrieva-Ware, MD, PhD3
Donna Lesniak, RN3
Robert J. Gropler, MD1,3
Cardiovascular Division1, the Division of Geriatrics and Nutritional Sciences2, and Division of
Endocrinology3 in the Department of Internal Medicine, Mallinckrodt Institute Department of
Radiology4 and the Division of Biostatistics5 at the
Washington University School of Medicine,
660 S. Euclid Ave,
St. Louis, Missouri, 63110, USA
Running title: Myocardial metabolism manipulation in DM
To whom correspondence should be addressed:
Linda R. Peterson, MD
Campus Box 8086
660 S. Euclid Ave.
St. Louis, MO 63110
E-mail [email protected]
Received for publication 24 August 2007 and accepted 1 October 2007.
1
Copyright American Diabetes Association, Inc., 2007
Myocardial metabolism manipulation in DM
ABSTRACT
Objective: Normal human myocardium switches substrate metabolism preference, adapting to
the prevailing plasma substrate levels and hormonal milieu, but in type 1 diabetes mellitus
(T1DM), the myocardium relies heavily on fatty acid (FA) metabolism for energy. Whether
conditions that affect myocardial glucose use and FA utilization, oxidation, and storage in
nondiabetic subjects alter them in T1DM is not well known.
Research Design and Methods: To test the hypotheses that in humans with T1DM myocardial
glucose and FA can be manipulated by altering plasma free fatty acid (FFA) and insulin levels,
we quantified myocardial MVO2, glucose and FA metabolism in nondiabetics and 3 groups of
T1DM subjects (euglycemic, hyperlipidemic, and hyperinsulinemic/euglycemic clamp) using
positron emission tomography.
Results: T1DM subjects had higher MVO2 and lower glucose utilization rate/insulin than
controls. In T1DM, glucose utilization increased with increasing plasma insulin and decreasing
FFA levels. Myocardial FA utilization, oxidation, and esterification rates and the percent of
utilization accounted for by esterification increased with increasing plasma FFA. Increasing
plasma insulin levels decreased myocardial FA esterification rates but increased the percentage of
FAs going into esterification.
Conclusion: T1DM myocardium has increased MVO2 and is insulin resistant during euglycemia.
However, its myocardial glucose and FA metabolism still responds to changes in plasma insulin
and plasma FFA levels.
Moreover, insulin and plasma FFA levels can regulate the
intramyocardial fate of FAs in humans with T1DM.
2
Myocardial metabolism manipulation in DM
INTRODUCTION
A growing literature suggests that
impaired cardiac metabolism in diabetes
contributes to cardiac dysfunction, leading
to overt heart failure, a so-called “diabetic
cardiomyopathy” (1-4).
Results from
studies in animal models of type 1
diabetes (T1DM) show that myocardial
substrate metabolic alterations may play a
key role in the development of diabetic
cardiomyopathy (5).
Specifically, in
diabetes, there is increased lipid delivery
to the myocardium, myocardial fatty acid
(FA) utilization and oxidation, and
decreased myocardial glucose uptake and
triglyceride hydrolysis (2,6,7).
This
excessive myocardial FA utilization may
be detrimental to cardiac function via
impairing glucose utilization (particularly
when glucose is required, e.g., ischemia),
decreasing transsarcolemmal calcium
flux-induced
contractility,
and/or
increasing free radical production (8-11).
Moreover, decreasing free fatty acid
(FFA) delivery to the myocardium in
animal models decreases its fat storage
and improves function (12). These results
suggest that metabolic modulation of
myocardial substrate metabolism may be a
new paradigm for treatment of diabetic
cardiomyopathy (12,13).
There is little data on the effects of
altering FFA or hormonal delivery to the
myocardium on myocardial FA utilization in
humans with T1DM.
Furthermore, these
alterations’ effect
on the fate of
intramyocellular FAs is unknown. Thus, we
hypothesized that although over-dependence
on myocardial FA metabolism was present in
humans with T1DM, the myocardium would
still be responsive metabolically to the
prevailing plasma hormonal and substrate
milieu. In order to prove or disprove this
hypothesis we quantified myocardial FA and
glucose metabolism using positron emission
tomography (PET) in nondiabetic controls and
3 groups of subjects with diabetes: those
3
studied during euglycemia, hyperlipidemia,
and during a hyperinsulinemic/euglycemic
(HIEG) clamp.
METHODS
Study population. We studied 34
T1DM subjects and 12 nondiabetic controls.
We chose to study patients with T1DM to
avoid the possible confounding effects of
obesity and hypertension that often
accompany type 2 diabetes (14,15). T1DM
classification was based on need for
supplemental insulin the first year, a history
of ketoacidosis, and a plasma C-peptide level
of <0.50µmol/mL. No subject had active
retinopathy, clinically significant autonomic
neuropathy, or a serum creatinine >1.5mg/dL.
Sedentary subjects were chosen to minimize
confounding effects of training-induced
adaptations on substrate metabolism (16). All
were nonsmokers and normotensive. Cardiac
disease was excluded by a normal physical
exam
and
normal
rest/exercise
echocardiograms. Subjects were not taking
any vasoactive medications at the time of the
study and did not have other systemic
illnesses. The T1DM subjects were randomly
assigned to one of 3 groups. Twelve were
studied under resting, euglycemic conditions,
10 were studied during an Intralipid infusion,
and 12 during a HIEG clamp.
The
nondiabetic controls were age-, sex-, and
BMI-matched with the euglycemic T1DM
subjects. The study was approved by the
Human Studies and the Radioactive Drug
Research Committees at the Washington
University School of Medicine. Written
informed consent was obtained from all
subjects before enrollment into the study.
Experimental procedure. All studies
were performed on a Siemens tomograph
(ECAT 962 HR+, Siemens Medical Systems,
Iselin, New Jersey).
All subjects were
admitted overnight to the General Clinical
Research Center and were fasted for 12 hours
before the study. Two i.v. catheters were
placed: 1 for infusion and one for blood
sampling. All were studied at 08:00 AM to
avoid circadian variations in metabolism (17).
In the “euglycemia” group the substrate
Myocardial metabolism manipulation in DM
environment was standardized using a low
dose insulin infusion ± D5W infusion in order
to maintain blood glucose level in the 80-120
mg/dL range. The Intralipid subjects were
given a heparin bolus (7.0 U heparin/kg i.v.)
followed by a continuous infusion of
heparin/Intralipid mixture (5000U of heparin
in 500cc of Intralipid) at 0.7mL/kg/hr. They
also received a regular insulin infusion ±
D5W infusion to maintain their blood glucose
in the 80-120mg/dL range. The subjects in
the HIEG clamp group were started on the
clamp 2 hours prior to the PET imaging
session (18). The nondiabetic controls were
studied after the same fasting period as the
T1DM subjects.
All subjects were on
telemetry and had blood pressures obtained
throughout the study. Rate-pressure product =
systolic blood pressure*heart rate.
Myocardial blood flow, oxygen
consumption (MVO2), FA and glucose
metabolism were measured after injections of
15
O-water, 11C-acetate; 1-11C-palmitate, and 111
C-glucose, respectively. During the study,
plasma substrates and insulin levels were
measured. 11CO2 and 11C-lactate activity was
also measured to correct the PET data as
required for the compartmental modeling of
the myocardial kinetics of the metabolic
tracers (19,20).
PET image analysis. Myocardial 15O11
water, C-acetate, 1-11C-palmitate , and 111
C-glucose images were generated. Blood
and myocardial time-activity curves were
generated as reported previously (19-22). The
curves were used in conjunction with wellestablished kinetic models to quantify
myocardial blood flow, MVO2, FA and
glucose
extraction
fractions
(20-22).
Myocardial FA/glucose utilization was
calculated as the product of myocardial
FA/glucose extraction fraction*myocardial
blood
flow*[plasma
FFA/glucose].
Myocardial FA extraction fraction was also
divided into the portion of extracted FAs that
were oxidized and the portion that entered
slow turnover pools or “esterification.”
Myocardial FA oxidation was calculated as
the fraction of the myocardial FAs that was
oxidized*myocardial blood flow*[plasma
FFAs].
Myocardial FA esterification was
4
calculated as the fraction of the myocardial
FAs
that
entered
slow
turnover
pools*myocardial blood flow*[plasma FFAs].
Measurement of plasma insulin and
substrates. Plasma insulin levels were
measured by radioimmunoassay.
Plasma
glucose and lactate levels were measured
using a glucose-lactate analyzer (YSI, Yellow
Springs, Ohio).
Plasma FFA level was
determined by capillary gas chromatography
and HPLC.
Echocardiography. During the PET
study, subjects had a complete 2-D and
Doppler echocardiographic examination using
a
Sequoia-C256®
(Acuson-Siemens,
Mountain View, CA). LV mass index and
ejection fraction were obtained as previously
described (23).
Statistical analysis. SAS software
(SAS Institute) was used for the statistical
analyses. Data are expressed as the mean
values ± the SD. Comparisons of continuous
and categorical variables between the
nondiabetic controls and the euglycemic
T1DM group were made using unpaired
students’ t-tests and Chi square tests,
respectively.
Comparisons among the 3
groups were made using ANOVA for the
continuous variables and the Chi-square test
for the categorical variables.
Pearson
correlations were performed to determine the
univariate
relationships
between
the
independent variables (age, body mass index,
diabetes duration, HbA1c, rate pressure
product, and plasma insulin level) and the
predetermined
dependent
variables:
myocardial glucose extraction fraction and
utilization, myocardial FA utilization,
oxidation, esterification, the percent of
myocardial FA utilization that is oxidized, and
the percent of myocardial FA utilization that
is esterified. A Pearson correlation was also
used to determine the relationship between
plasma insulin and plasma FFAs and the
relationship between plasma FFA level
(during the 1-C11-glucose imaging) and
myocardial glucose extraction fraction and
utilization. (The relationship between plasma
FFA and the dependent variables regarding
myocardial FA utilization and metabolism
was not analyzed because plasma FFA is used
Myocardial metabolism manipulation in DM
in their calculation). For entry into the
multivariate analyses, an independent variable
was required to have a significant relationship
with the dependent variables at the P <.10
level. Type III sum of squares multivariate
analyses were used to determine the
independent predictors of the dependent
variables.
RESULTS
The patients in the euglycemic T1DM group
and the nondiabetic controls were not
different in terms of age, sex, race, metabolic
profiles, LV structure, or function. Only
diastolic blood pressure was higher and ratepressure product trended towards being higher
in the T1DM subjects (Table 1). As shown in
Table 2 the three T1DM groups were also
well-matched
in
their
demographics,
metabolic characteristics, hemodynamics, LV
structure and function.
Myocardial blood flow and MVO2.
Myocardial blood flow between the
euglycemic T1DM group and the nondiabetic
controls did not differ. However, MVO2 was
higher in the T1DM group and their MVO2
per rate-pressure product was trending
towards being higher than in nondiabetic
controls (Table 3). There were no differences
in myocardial blood flow among the
euglycemia (1.16 ± 0.28 mL/g/min), Intralipid
1.10 ± 0.25 mL/g/min), and HIEG clamp
groups (1.06 ± 0.23 mL/g/min, P =.83).
There were no differences in MVO2 among
the same 3 groups (5.34 ± 1.27 [Intralipid],
6.09 ± 1.29 µmol/g/min [HIEG clamp], P
=.47).
Plasma
substrates,
insulin,
myocardial glucose metabolism. The T1DM
euglycemic group had higher plasma glucose
levels and higher insulin levels compared with
controls. However, plasma FFA levels did
not differ between the 2 groups. Myocardial
glucose extraction fraction and utilization
were not different between the 2 groups but
myocardial glucose/plasma insulin level was
lower in T1DM compared with controls
(Table 3). There were no differences in the
plasma glucose concentrations at the time of
the PET 1-11C-glucose imaging among the 3
groups (euglycemia = 5.75 ± 0.73; Intralipid
5
5.34 ± 1.27; HIEG clamp 6.09 ± 1.29mM/L,
P=.67). There were marked differences in
plasma insulin levels (Fig. 1, panel A) with
the HIEG clamp group having the higher
levels than the other 2 groups. Myocardial
glucose extraction fraction and utilization
paralleled the changes in insulin, with the
HIEG clamp group having the highest
myocardial glucose extraction fraction and
utilization levels (Fig. 1, panels B, C).
Furthermore, the higher the plasma insulin
level, the higher the myocardial glucose
extraction fraction (r =.53, P <.005) and
glucose utilization (r =.48, P <.005).
Conversely, the higher the plasma FFA levels,
the lower the myocardial glucose extraction
fraction and utilization (Fig. 2). Interestingly,
in the multivariate analyses only plasma FFA
level was an independent predictor of
myocardial glucose extraction fraction and
utilization (P <.05 and P <.01); (the
correlation between plasma FFAs and insulin
levels was r = -0.65, P<.0001).
Plasma substrates and insulin levels
and myocardial FA metabolism. Table 3
shows that neither plasma FFA nor any of the
measures of myocardial FA uptake or
metabolism were different between the
euglycemic T1DM subjects and fasting
nondiabetic controls. Plasma FFA levels,
were markedly different amongst the 3 T1DM
subject groups, with the HIEG clamp group
having the lowest levels (Fig. 3 panel A).
Plasma FFA levels were higher in the
Intralipid group than in the euglycemia group.
Of note, myocardial FA extraction fraction
was fairly constant among the 3 groups (Fig.
3, panel B). In contrast, myocardial FA
utilization was markedly lower in the HIEG
clamp group when compared with either the
euglycemia or Intralipid group (Fig. 3, panel
C), paralleling the differences in plasma FFA
levels.
Myocardial FA utilization was
strongly and negatively correlated with
plasma insulin level (r = -.60, P <.0005), and
it was the only independent predictor of
myocardial FA utilization (P <.0005).
The change in FA oxidation also
mirrored the differences in plasma FFA levels
and myocardial FA utilization with a
difference among the 3 groups and significant
Myocardial metabolism manipulation in DM
differences between the HIEG clamp group
and the other 2 (Fig. 4, panel A). Myocardial
FA oxidation, like FA utilization, inversely
correlated with insulin level (r = -.57,
P<.001), and it was the only independent
predictor of FA oxidation in a multivariate
model (P <.001).
In order to evaluate the differences in
fractional myocardial FA oxidation amongst
the groups apart from the influence of the
plasma FFA levels, we also evaluated the
differences in percent oxidation among the 3
groups.
The percentage of the total
myocardial FA utilization that was accounted
for by oxidation was highest in the
euglycemic group and lowest in the HIEG
clamp group (Fig. 4, panel B).
There
were
also
significant
differences in myocardial FA esterification
among the 3 groups. In this comparison, the
Intralipid group had the highest level
compared with the other 2 groups(Fig. 5,
panel A). As with myocardial FA utilization,
esterification was inversely related to plasma
insulin levels (Figure 6); myocardial FA
esterification also correlated significantly but
positively with age (r = .39, P <.05) and
duration of diabetes (r = .38, P <.05).
Multivariate analysis demonstrated that both
plasma insulin and age were independent
predictors of myocardial FA esterification (P
<.05, and P =.01, respectively).
Since the percent of myocardial FA
utilization that was accounted for by
myocardial FA esterification is by definition
the percentage of FA not oxidized, the HIEG
clamp group had the highest percentage of
myocardial FA utilization going to
esterification, and the euglycemic group had
lowest (Fig. 5, panel B). Since in the
calculation of the percentage of oxidation or
esterification the concentration of plasma
FFAs drops out, this suggests that the
differences in percent myocardial FA
oxidation and esterification cannot be
explained solely by differences in plasma
FFA levels.
Thus, although overall
myocardial esterification correlated inversely
with plasma insulin levels, the percent of
myocardial utilization accounted for by
esterification correlated directly with plasma
6
insulin level (r = .39, P <.05), and it was the
only independent predictor of the percent
myocardial esterification (P <.05).
DISCUSSION
Results of prior studies have shown
that the myocardium in humans with T1DM
relies more heavily on myocardial FA (as
opposed to glucose) metabolism than in
nondiabetics (7, 24, 25). The results of our
study further extend this concept. First, our
current results show that when T1DM
subjects are euglycemic and fasting, and have
similar plasma FFA levels, they have similar
myocardial FA metabolism to nondiabetic
fasting controls. This occurs despite T1DM
subjects exhibiting higher plasma insulin
levels. In our previous study of T1DM, we
sought to match insulin and glucose (rather
than FFA) levels between nondiabetic and
T1DM subjects, so the controls were fed. In
that study myocardial FA utilization was
increased in the T1DM subjects primarily
dues to the increase plasma FFA levels (7).
Taken together, these results further highlight
the importance of increased plasma FFA
delivery in determining the myocardial
metabolic pattern in T1DM. Furthermore, the
presence of similar rates of myocardial
glucose use and FA oxidation in the T1DM
compared with nondiabetics despite higher
plasma insulin levels suggests myocardial
insulin resistance is present in T1DM under
these conditions. Second, our results show
that although the myocardium in T1DM is
overly dependent on FA metabolism, both
myocardial glucose and FA uptake can be
manipulated by altering plasma hormonal and
substrate milieu. Lastly, we have shown that
alterations in plasma FFA and insulin levels
can change the fate of FFA extracted by the
heart in humans with T1DM.
Our finding that myocardial FA
utilization may
be manipulated
by
increasing/decreasing FFA delivery extends
the findings of R.J. Bing and others who
showed that substrate delivery to the heart is
an important determinant of myocardial
substrate utilization in humans without T1DM
to those with T1DM (26,27). Thus, although
the myocardium in T1DM relies on FA
Myocardial metabolism manipulation in DM
utilization for generation of ATP for
contractile function, it can still be
manipulated.
Our data also show that increasing
plasma free FFA levels increase the rates of
myocardial FA oxidation above the high
baseline levels seen in euglycemic T1DM
subjects. Thus, the euglycemic level of FA
oxidation in T1DM is not at its maximal
oxidative capacity and may be further
increased. This may have detrimental
consequences. Results of studies of animal
models show that high FA oxidation occurs
early in diabetes before marked changes are
seen in cardiac function (28). Increased
production of reactive oxygen species with
increased oxidation, may impair efficient
calcium handling (10,29,30). Our finding that
increased plasma FFA (and hence increased
myocardial FA oxidation) was associated with
a decrease in myocardial glucose utilization
would also be detrimental during ischemia
(when the myocardium prefers glucose use).
These observations also extend those of
Nuutila et al., who demonstrated Randle cycle
operation in nondiabetic human myocardium,
to T1DM myocardium (31).
Despite the increase in myocardial FA
oxidation with the increase in plasma FFA, it
appeared that the oxidative capacity of the
myocardium can be overwhelmed, as
evidenced by a trend toward a decrease in
percentage oxidized, and an increase in the
percentage esterified. Although an increase in
esterification rate does not necessarily
translate to an increase in chronic lipid
deposition, it agrees with findings of studies
in animal models of diabetes and human
autopsies, which demonstrated increased
cardiac triglyceride content in diabetics
compared with controls (13; 32-34). This
increase in esterification may be due to FA
uptake in excess of oxidation and/or an
increase in the amount or activity of
triglyceride synthesis enzymes in response to
increased FA availability (35). This FA
esterification increase in humans with T1DM
may be detrimental based on the results of
studies in animals and humans suggest that
excessive myocardial FA storage may result
in apoptosis, oxidative stress, abnormal
7
energy metabolism, fibrosis, and contractile
dysfunction (12, 36-40). Future imaging
and/or pathological sample studies of lipid
accumulation and function are necessary to
confirm this hypothesis in humans.
Effects of Plasma Insulin Levels.
Increasing plasma insulin in T1DM has a
more complicated effect on myocardial
glucose and FA utilization and on the
metabolic fate of FAs within the myocardium.
Our results are consistent with those of Monti
et al., who found that increased plasma insulin
resulted in increased myocardial glucose
extraction fraction and utilization in patients
with T1DM (41). We also demonstrated for
the first time in humans with T1DM that
increasing plasma insulin levels decreases
rates of myocardial FA utilization. This
decrease is likely due to insulin’s inhibition of
peripheral lipolysis and resultant decrease in
plasma FFA because myocardial FA
extraction fraction was not different in the
HIEG clamp group compared with the
euglycemic group. In addition, we showed in
humans with T1DM that the increase in
plasma insulin and myocardial glucose
utilization impaired myocardial FA oxidation
proportionately more than other FA processes,
such as myocardial FA extraction and
esterification (Figures 3B, 4B, 5B). This
decrease in myocardial FA oxidation with an
increase in glucose metabolism, previously
demonstrated in animal models, has not
heretofore been demonstrated in humans with
T1DM (42,43). The net result of the HIEG
clamp is that plasma FFA decreases to such a
degree that myocardial FA esterification rates
decrease, but insulin’s anabolic effect on the
FFAs that do enter the myocardium
encourages a high proportion to enter
esterification processes in lieu of oxidation.
Clinical implications. Because our
data demonstrate that it is possible to
manipulate myocardial glucose and FA
metabolism by manipulating plasma substrate
and hormone levels in humans with T1DM,
and because animal data demonstrate
deleterious effects of excessive FA oxidation
and/or storage on the myocardium, it may be
desirable to decrease excessive delivery of
FFAs to the myocardium in humans with
Myocardial metabolism manipulation in DM
T1DM, particularly desirable during ischemia,
when the myocardium needs to switch fuel
sources and utilize predominantly glucose.
Thus, our data, although not obtained in
patients with ischemia, indirectly support the
utility of glucose-insulin-potassium (GIK)
therapy or other treatments for decreasing FA
and increasing glucose utilization in patients
with T1DM and ischemia. Exogenous insulin
therapy, clearly necessary in subjects with
T1DM for myocardial glucose metabolism,
may also have a beneficial effect on
decreasing plasma FFA levels, thereby
ameliorating the tendency for excessive FA
utilization. The myocardium in T1DM may
be especially prone to excessive dependence
on FA metabolism and its potential
deleterious effects (particularly during
ischemia) because it appears to be somewhat
insulin resistant (although it still responds to
high doses of insulin during the HIEG clamp).
(12,44). It appears insulin resistant based on
our data showing subjects with T1DM in the
euglycemic group had a lower myocardial
glucose utilization/plasma insulin ratio than
the nondiabetic controls. Although requiring
further study, these findings may be very
applicable to patients with type 2 diabetes
mellitus
where
insulin
resistance
predominates.
Limitations. Our results may not be
extrapolated to subjects who do not fit our
inclusion/exclusion criteria. We did not study
nondiabetic controls under all the same
conditions as the T1DM although how the
nondiabetic myocardium’s substrate choice is
modified by substrates, insulin, and condition
is known (45, 46). Myocardial metabolism of
other substrates, (e.g., lactate), were not
measured although since subjects were not
ketotic, ischemic, or exercising at the time of
the study, these should be minor contributors
to metabolism. Myocardial glucose oxidation
and myocardial metabolism or deposition of
endogenous substrates were not be quantified.
Based on previous studies endogenous
triglycerides would be expected to contribute
less to FA oxidation when plasma FFA levels
are high, and glycogen should contribute more
during adrenergic stimulation (not an
intervention in our study) (47,48). Also,
8
Intralipid infusion and a HEIG clamp are not
physiological conditions; however, high levels
of FFAs (as evoked by Intralipid in our study)
may be seen in obese subjects or those with
poorly controlled T1DM, and very low levels
(e.g., ~ 100 nmol/mL) may be seen in normal
subjects after a high carbohydrate meal ( +
insulin) in T1DM subjects. Thus, our
interventions mimicked these physiologic
conditions without altering the fasting status
or glucose and ketone levels of our subjects.
Moreover, although a HIEG clamp is not a
physiologic state, it is being clinically tested
as a therapy for patients with ischemia,
including those with T1DM, and therefore is a
relevant intervention.
Conclusions. Humans with T1DM
have higher MVO2 than nondiabetics, which
is mostly but perhaps not all accounted for by
increased cardiac work. In humans with
T1DM myocardial utilization and the
metabolic fate of substrates can be
manipulated by altering plasma FFA and
insulin levels although some degree of
myocardial insulin resistance is present.
Alterations in myocardial glucose and FA
metabolism affected by increasing plasma
FFA levels conform to Randle’s hypothesis,
with increasing FA utilization and oxidation
decreasing myocardial glucose extraction
fraction and utilization. Furthermore, shortterm increases in plasma FFA can increase
myocardial FA oxidation rates, but also
overwhelm the already overtaxed myocardial
oxidative capacity and lead to increased
myocardial FA esterification rates. Insulin
therapy, increases myocardial glucose
extraction
and
utilization,
decreases
myocardial FA utilization, oxidation, and
esterification yet increases the percentage of
the myocardial FA extraction fraction that is
directed to esterification. These findings fine
tune our notions of myocardial metabolism in
humans with T1DM and support the theory
that metabolic manipulation of the
myocardium is feasible, and may have benefit
in humans with T1DM.
ACKNOWLEDGMENTS
Special thanks to the participants in this study
and to the staff of the GCRC and our
Myocardial metabolism manipulation in DM
laboratory for their help with data collection
and technical assistance. Thanks to Jean E.
Schaffer, MD for critical reading of the
manuscript and Ava Ysaguirre for secretarial
assistance. Part of this work was presented in
abstract form in J Nucl Cardiol
9
2003;10:S3.14. This work was supported by
National Institutes of Health grants PO1HL13581, MO1-RR00036, RO1-HL073120,
P60-DK020579, and a grant from the BarnesJewish Hospital Foundation.
Myocardial metabolism manipulation in DM
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12
Myocardial metabolism manipulation in DM
Table 1. Demographics, metabolic characteristics, hemodynamics, and
cardiac structure and function of nondiabetic vs. T1DM euglycemic
subjects
Nondiabetic
controls
T1DM
Euglycemia
12
12
33 ± 7
37 ± 10
0.18
Sex (% men)
75
75
1.0
Race (% white)
83
92
.54
Body mass index (kg/m2)
28 ± 5
26 ± 4
0.13
Total cholesterol (mg/dL)
172 ± 27
188 ± 44
0.73
LDL (mg/dL)
96 ± 18
105 ± 39
0.76
HDL (mg/dL)
49 ± 13
60 ± 21
0.15
132 ± 74
81 ± 52
0.06
64 ±14
70 ±13
0.33
119 ± 11
126 ± 17
0.20
N
Age (yrs)
Triglycerides (mg/dL)
P
value
Heart rate (bpm)
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
Average rate-pressure
product during MVO2
(mmHg*bpm)
67 ± 7
75 ± 8
0.02
7406 ± 1971
8743 ± 1835
0.09
LV mass index (g/m2)
91.3 ± 19.8
83.8 ± 24.5
0.43
Ejection fraction (%)
64 ± 6
64 ± 6
0.8
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Myocardial metabolism manipulation in DM
Table 2. Demographics, metabolic characteristics, hemodynamics, and
cardiac structure and function in the 3 groups of T1DM subjects
P
value
Euglycemia
Intralipid
HIEG clamp
12
10
12
37 ± 10
39 ± 12
35 ± 12
0.7
Sex (% men)
75
60
75
0.68
Race (% white)
92
100
80
0.39
26 ± 4
25 ± 3
26 ± 4
0.77
24 ± 10
22 ± 11
19 ± 11
0.63
Hemoglobin A1c
8.5 ± 1.8
7.8 ± 1.5
8.8 ± 2.5
0.48
Total cholesterol (mg/dL)
188 ± 44
167 ± 29
185 ± 41
0.43
LDL (mg/dL)
105 ± 39
99 ± 21
108 ± 32
0.8
HDL (mg/dL)
60 ± 21
59 ± 13
66 ± 15
0.6
Triglycerides (mg/dL)
81 ± 52
50 ± 29
61 ± 30
0.19
Heart rate (bpm)
Systolic blood pressure
(mmHg)
Diastolic blood pressure
(mmHg)
Average rate-pressure
product (mmHg*bpm)
71 ±11
70 ± 13
69 ± 10
0.32
121 ± 16
126 ± 17
123 ± 17
0.27
73 ± 7
75 ± 8
72 ± 5
0.36
8738 ± 1792
8620 ± 1573
8942 ± 1717
0.92
LV mass index (g/m2)
83.8 ± 24.5
77.1 ± 13.0
91.8 ± 26.8
0.34
Ejection fraction (%)
64 ± 6
65 ± 5
65 ± 6
0.8
N
Age (yrs)
Body mass index (kg/m2)
Duration of T1DM (yrs)
14
Myocardial metabolism manipulation in DM
Table 3. Measurements of plasma substrate and insulin levels and
myocardial perfusion and metabolism in nondiabetic controls vs. T1DM
euglycemic subjects
Nondiabetic
controls
T1DM
Euglycemia
12
12
1.03 ± 0.22
1.16 ± 0.28
.23
MVO2 (µmol/g/min)
(MVO2*1000)/rate-pressure
product
([µmol/g/min]/([bpm*mmHg])
4.41 ± 0.87
6.92 ± 2.33
<.005
0.62 ± 0.15
0.82 ± 0.33
.06
Plasma glucose (µmol/mL)
4.94 ± 0.55
5.75 ± 0.73
<.01
Plasma insulin (µmol/mL)
7±5
25 ± 30
.05
242 ± 152
207 ± 108
.54
59 ± 50
17 ± 15
<.05
604 ± 179
669 ± 479
.67
Myocardial FA utilization
(nmol/g/min)
132 ± 59
127 ± 81
.85
Myocardial FA oxidation
(nmol/g/min)
109 ± 41
119 ± 77
.71
Myocardial FA esterification
(nmol/g/min)
13.4 ± 12.4
8.1 ± 11.3
.31
Myocardial FA oxidation (%)
89 ± 10
94 ± 7
.19
N
Myocardial blood flow
(mL/g/min)
Myocardial glucose utilization
(nmol/g/min)
Myocardial glucose
utilization/Plasma insulin
([nmol/g/min]/[µmol/mL])
Plasma FFA (nmol/mL)
15
P value
Myocardial metabolism manipulation in DM
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21