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Department of Physiology, New York Medical College, Valhalla, New York 10595
Submitted 25 July 2002 ; accepted in final form 2 May 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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-hydroxybutyric acid (-HBA), and lactate
were measured, and myocardial uptake was calculated before and at week 1,
2, 3, and 4 of alloxan-induced diabetes. The heart of healthy
dogs consumed FFA (19.2 ± 2.6 µeq/min) and lactate (19.7 ±
3.4 µmol/min). Dogs in the late stage of diabetes (at week 4) had
elevated arterial -HBA concentrations (1.6 ± 0.7 µmol/l) that
were accompanied by an increased -HBA uptake (0.3 ± 0.2
µmol/min). In contrast, myocardial lactate (–4.8 ± 3.0
µmol/min) and FFA uptake (2.5 ± 1.9 µeq/min) were significantly
reduced in diabetic animals. Despite a marked hyperglycemia (449 ± 25
mg/dl), the heart did not take up glucose (–7.9 ± 4.1 mg/dl). Our
results indicate significant changes in the myocardial substrate utilization
in dogs only in the late stage of diabetes, at a time when myocardial NO
production is already decreased.
lactate; free fatty acids; glucose; keto acids; myocardium
Besides the changes in the myocardial substrate uptake and utilization,
patients with diabetes mellitus also have much higher circulating levels of
glucose, FFA, and ketone bodies
(1). The enhanced breakdown of
FFA and ketones by the diabetic heart has been shown to finally lead to an
intracellular accumulation of acetyl-CoA and of reducing equivalents from
fatty acid -oxidation
(14). The accumulation of both
products was found to account for the inhibition and inactivation of pyruvate
dehydrogenase, the rate-limiting enzyme in the oxidation of glucose and
lactate (5,
17). On the other hand, a
reduction in the mRNA and protein levels of the glucose transporter family
[GLUT], especially GLUT 1 and GLUT 4, was identified as one of the key factors
leading to an impaired glucose uptake
(14). This aggravates the
mismatch of substrate utilization with a further reduction in glucose
oxidation by the diabetic heart.
Over the last several years we have focused considerable attention on
nitric oxide (NO) as a modulator of myocardial substrate utilization. Recchia
and co-workers (11)
demonstrated that inhibition of NO synthesis by
NG-nitro-L-arginine (L-NNA) in
conscious dogs resulted in a reduced FFA uptake by the heart. In contrast,
glucose and lactate uptake increased significantly after blockade of NO
synthesis. This was paralleled by an elevation in the respiratory quotient,
indicating a switch from FFA to carbohydrate oxidation, and all of these
changes could be immediately reversed by a NO donor. However, the NO synthase
inhibitor NG-nitro-L-arginine methyl ester
(L-NAME) was shown to decrease FFA oxidation and increase glucose
oxidation without changing the activity of key enzymes of glycolysis or
-oxidation (12).
Inhibition of NO synthase in normal dogs and a reduction in NO bioavailability
due to a downregulation of endothelial NO synthase (eNOS) protein expression
in dogs with chronic heart failure were found to be associated with an
increased glucose uptake by the heart
(10–12).
Furthermore, we have demonstrated that coronary eNOS protein expression and
eNOS-derived NO are diminished in a canine model of chronic Type I diabetes
(19). However, FFA, lactate,
glucose, and -HBA uptake were not assessed as a function of NO
production in that study.
Numerous studies investigating substrate uptake and oxidation have been
conducted over the last several years comparing diabetic with healthy patients
or animals. To our knowledge, no data are available about the exact time
course of changes in the myocardial substrate uptake during the development of
Type I diabetes and also the late stage of the disease, when NO production is
reduced. We hypothesize that the increase in plasma glucose and the reduced NO
bioavailability in late-stage diabetes together would result in an enhanced
glucose uptake by the heart. Therefore, the aim of this study was 1)
to investigate arterial FFA, lactate, glucose, and -HBA concentration;
and 2) to determine the myocardial uptake of those substrates in
conscious dogs during the development of Type I diabetes.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Surgical procedure and instrumentation. Male mongrel dogs (n = 7), weighing 23–33 kg, were premedicated with acepromazine maleate (1 mg/kg body wt im), anesthetized with pentobarbital sodium (25 mg/kg body wt iv), intubated, and then ventilated with room air. A thoracotomy was performed in the fifth intercostal space by use of sterile surgery techniques. A catheter (Tygon, Cardiovascular Instruments; Wakefield, MA) was placed into the descending thoracic aorta for measurement of arterial pressure and collection of arterial blood samples. A second catheter was inserted into the coronary sinus with the tip leading away from the right atrium to collect coronary sinus blood samples. A solid-pressure gauge (model P6.5, Konigsberg Instruments, Pasadena, CA) was placed in the left ventricle through the apex for measurement of left ventricular (LV) systolic pressure (LVSP). The left circumflex coronary artery was isolated and cleared of fat and connective tissue, and a Doppler flow transducer was placed around the artery for measurement of blood flow. The wires and catheters were run subcutaneously to the intrascapular region, the chest was closed, and the pneumothorax was reduced. For 6 days after surgery, antibiotics were given, and the dogs were allowed to recover fully. Ten days after surgery, the dogs were trained to lie quietly on the laboratory table.
Hemodynamic recordings. The aortic catheter was connected to a strain-gauge transducer (P23 ID, Statham; Rahway, NJ) for measurement of aortic pressure. LV pressure was measured with the previously implanted pressure gauge. The first derivative of LV pressure (LV dP/dt) was calculated by using an operational amplifier (LM 324, National Semi-conductor; Newark, NJ), and triangular wave signals with known slope were substituted for the pressure signals to calibrate the differentiator directly. Left circumflex coronary blood flow (CBF) was measured with a pulsed Doppler flowmeter (model 100, Triton Instruments; San Diego, CA). Mean CBF and mean arterial pressure (MAP) were derived from a 2-Hz low-pass filter. Heart rate (HR) was monitored from the LV pressure-pulse interval using a cardiotachometer (model 9857B, Beckmann Instruments; Newark, NJ). All hemodynamics were recorded continuously on an eight-channel chart recorder (Gould RS 3800, National Instruments; Rahway, NJ). The triple product, an index of mechanically related cardiac oxygen consumption, was calculated as LVSP multiplied by dP/dtmax and HR.
Induction of diabetes. After the control experiment, the dogs were injected with alloxan monohydrate (40 mg/kg body wt iv) over 1 min, prepared as a 5% solution in citrate buffer (pH 4.0–4.5) (19). Plasma glucose levels were measured again 3 days after the first alloxan administration. Dogs with plasma glucose levels <200 mg/dl were reinjected with alloxan monohydrate (60 mg/kg body wt iv). Only dogs with fasting blood glucose levels above 200 mg/dl on day 7 after the first alloxan injection were studied.
Western blot analysis. Tissue from the LV free wall was harvested from dogs in end-stage diabetes and from dogs that had received alloxan but did not develop diabetes. The tissue was pulverized in liquid nitrogen and resuspended in lysis buffer containing protease inhibitors (4). After sonification for 60 s, samples were centrifuged at 5,000 rpm for 10 min, and protein concentration was determined as previously described (4). Briefly, 100 µg of protein were separated on a 7.5% SDS-polyacrylamide-gel (SDS-PAGE), followed by electronic transfer to a polyvinylidene fluoride membrane (PVDF, Amersham; Piscataway, NY). Human umbilical vein endothelial cells were loaded as a positive control for eNOS. The transferred proteins were incubated with a 1:500 dilution of a monoclonal anti-eNOS antibody (Affinity BioReagents; Golden, CO), at 4°C overnight. The bound primary antibody was detected by a peroxidase-coupled anti-mouse antibody (dilution 1:2,000, Amersham) followed by a chemiluminescent reaction using luminol (SuperSignal West Pico, Pierce; Rockford, IL). Afterward, the membrane was exposed to a film, and bands were analyzed by densitometry as previously published (4).
Blood analysis and cardiac metabolites. Blood samples were
collected from the aorta and the coronary sinus in syringes containing either
EDTA or heparin and immediately stored on ice. Blood was withdrawn slowly from
the coronary sinus to avoid contamination with right atrial blood. Blood gases
were measured using a blood-gas analyzer (model 1306, Instrumentation
Laboratory; Lexington MA), and hemoglobin was analyzed by a CO-Oximeter (model
482, Instrumentation Laboratory). PO2 was multiplied by
0.003 to obtain the concentration of oxygen dissolved in plasma and added to
the measured O2 content to calculate total oxygen content of the
blood (vol/vol). Hematocrits were obtained by centrifugation. Blood samples
were centrifuged 15 min at 6,000 rpm. Plasma glucose and -HBA
concentration were determined by a spectrophotometric enzymatic assays (Sigma;
St. Louis, MO) according to the instructions of the manufacturer. Total
lactate was measured in serum deproteinized with ice-cold 1 M perchloric acid
(1:2 vol/vol) using an enzymatic assay (Sigma). Total FFA concentration was
determined spectrophotometrically (Kontron Instruments) in plasma after
centrifugation of EDTA-treated blood samples with the use of a calorimetric
assay (NEFA C kit, Wako Pure Chemical Industries; Richmond, VA). The
arterial-coronary sinus concentration differences of oxygen, lactate, glucose,
-HBA, and FFA were multiplied by the mean CBF assumed as double of the
mean flow measured in the left circumflex coronary artery to calculated
cardiac uptake. Respiratory quotient and cardiac production of CO2
were calculated as previously described
(11).
The concentration of nitrite/nitrate in plasma was measured using the method established in our laboratory previously (19).
Data calculation and statistical analysis. All the data in the
tables, text, and figures are presented as mean values ± SE.
Statistical analysis was performed using commercially available software
(Sigma Stat 2.03, SPSS; San Rafael, CA). Body weight, hemodynamics, blood
gases, arterial substrate levels, substrate uptake at different time points,
and plasma NOx levels were compared using a one-way repeated
measures ANOVA followed by Tukey's test to evaluate statistical differences
between the time points. Furthermore, one-way ANOVA followed by Tukey's test
was applied to determine whether substrate uptakes at different time points
significantly differ from zero. eNOS protein expression in the myocardium of
dogs in end-stage diabetes and dogs that received alloxan but did not develop
diabetes was compared by a t-test. Linear regression analysis was
performed to determine the relationship among lactate, plasma NOx,
FFA uptake, and -HBA uptake, respectively. A P value of
<0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Myocardial eNOS expression and concentration of nitrate/nitrite in
plasma. We found a 33% reduction of eNOS protein in the myocardium of the
diabetic dogs at week 4 after alloxan injection (164,850 ±
22,495 arbitrary units) compared with the myocardium of dogs that received
alloxan but did not develop diabetes (245,000 ± 10,312 arbitrary units,
P 
0.05). This reduction in eNOS protein expression during the
development of diabetes was accompanied by a gradual decrease in plasma
NOx from 1.69 ± 0.29 µM before diabetes to 1.55 ±
0.33 µMat week 1, to 1.42 ± 0.28 µM at week 2,
to 1.18 ± 0.20 µM at week 3, and to 1.10 ± 0.13
µM at week 4 of diabetes (P 0.05 vs. before
diabetes).
Cardiac metabolism. Arterial blood glucose levels before and after alloxan injection are shown in Table 1. Induction of diabetes mellitus increased arterial glucose levels by 190% at week 1, by 235% at week 2, by 230% at week 3, and by 354% at week 4, respectively (P < 0.05 vs. control). Despite the marked elevation in arterial plasma glucose concentrations up to 450 mg/dl in some dogs, the heart did not consume significant amounts of glucose at any time (Fig. 1A). Furthermore, arterial concentrations of FFA were increased by 95% at week 1 of diabetes compared with control (Table 1, P < 0.05). This elevation was even more pronounced at week 2.At week 3 of diabetes, arterial FFA levels began to fall, and at 4 wk, levels were not significantly different from control (Table 1).
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The heart of a healthy dog primarily consumed FFA (Fig. 1B). After the onset of diabetes, FFA uptake declined by 33% at week 1, by 33% at week 2, by 55% at week 3, and by 87% at week 4 (Fig. 1B, P < 0.05), respectively, despite increased or unchanged arterial plasma FFA concentration compared with control (Table 1).
Arterial lactate levels (Table 1) were unaffected by the development of diabetes over the entire study period. Besides FFA, the normal dog heart took up lactate (Fig. 2A). However, the lactate uptake decreased significantly during the development of diabetes. At week 1 and 2 of diabetes, the heart consumed only 9.29 ± 7.52 and 3.60 ± 4.01 µmol/min lactate, respectively (Fig. 2A). At week 3 and 4 of diabetes, the heart did not take up lactate at all (week 3: –1.05 ± 2.87 µmol/min, week 4: –4.84 ± 3.02 µmol/min; P < 0.05 vs. control, Fig. 2A).
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Almost no -HBA was detectable in the plasma of healthy dogs
(Table 1), and the heart did
not utilize significant amounts of -HBA. One week after induction of
diabetes, arterial -HBA plasma concentrations were elevated by 330%, at
week 2 by 450%, at week 3 by 1,240% (P < 0.05
vs. control), and at week 4 by 1,280% (P < 0.05 vs.
control), respectively (Table
1). This increase in the arterial plasma concentrations of
-HBA during the development of diabetes was accompanied by a significant
myocardial -HBA uptake at week 4
(Fig. 2B). To
determine whether -HBA replaces FFA and lactate as a fuel of the heart,
linear regression analysis was performed. It revealed that an increased
-HBA uptake was closely associated with a decrease in myocardial lactate
uptake (r = –0.94, P < 0.05,
Fig. 3A) and a
reduction in FFA uptake (r = –0.98, P < 0.01,
Fig. 3B).
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To assess whether the change in NO bioavailability during the development
of diabetes impacts on myocardial substrate uptake, a regression analysis was
applied. We found a close inverse linear correlation between plasma
NOx levels and -HBA uptake (r = –0.91,
P 0.05, Fig.
4A), indicating that a decrease in the NO production is
associated with an increase in the myocardial -HBA uptake during the
development of diabetes. In contrast, the reduction in NO production was
associated with a decline in the myocardial uptake of FFA (r = 0.94,
P 0.05, Fig.
4B).
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Blood gases. Arterial pH, PO2, PCO2, and oxygen content did not change during the development of diabetes (Table 2). However, dogs were characterized by a significant reduction of the hematocrit at week 4 of diabetes compared with control (Table 2, P < 0.05).
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Myocardial O2 consumption and respiratory
quotient. Cardiac oxygen consumption and respiratory quotient are
presented in Table 3. Cardiac
oxygen consumption was decreased by 11% at week 1 of diabetes, by 33%
at week 2 (P < 0.05 vs. control), by 33% at week
3 (P < 0.05 vs. control), and by 37% at week 4
(P < 0.05 vs. control), respectively. However, myocardial
O2 consumption
(M
O2) per beat did not
change during the entire study period
(Table 3).
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To determine whether the shift in the uptake of cardiac substrates was related to their oxidation, the respiratory quotient (RQ) of the heart was calculated for the control and diabetic state. However, RQ did not significantly change during the development of diabetes.
Hemodynamics. The hemodynamic data are shown in
Table 4. LVSP and LV
dP/dt did not change from control during diabetes. MAP decreased
gradually, and this reduction reached statistical significance at week
4 of diabetes (Table 4).
Moreover, at week 2 of diabetes, heart rate and mean CBF were
significantly diminished by 37% and 50%, respectively, compared with control
(P < 0.05). However, neither MAP nor mean CBF dropped further
within the last 2 wk of the study. The triple product, an index of
mechanically related cardiac
MO2, tended to decrease,
but this did not reach statistical significance.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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-HBA increased shortly after the
onset of diabetes and reached the maximum at week 4. The elevation of
plasma -HBA was paralleled by a significant -HBA uptake of the
heart. Furthermore, -HBA uptake was inversely correlated with FFA and
lactate uptake, suggesting that -HBA replace FFA and lactate as
substrates of the myocardium in diabetes. This trade in substrates leads to no
change in calculated RQ.
Diabetes and substrate metabolism. To our knowledge, this is the
first study investigating the changes in arterial substrate concentration and
substrate uptake of the heart in conscious chronically instrumented dogs
during the development of diabetes over a period of 4 wk. Numerous studies in
the past have been focused on the acute effects of diabetes on myocardial
substrate metabolism in anesthetized dogs. In 1973 Wiener and Spitzer
(18) found that 3 days after
alloxan injection, dog hearts did not extract significant amounts of glucose,
despite a remarkable increase in the arterial glucose concentration. Arterial
lactate concentrations were also unchanged compared with normal dogs, and the
heart did not utilize lactate consistently at this early stage of diabetes. In
contrast, arterial FFA concentration and FFA turnover were elevated by 100%
compared with normal dogs. However, the rate of FFA oxidation did not
significantly differ between control and diabetic dogs
(18). Furthermore, a moderate
ketosis was detectable in the diabetic animals. The earliest time point of
measurement in our study was day 7 of diabetes. At this time, dogs
exhibited significantly elevated arterial glucose concentrations that were not
accompanied by a consistent glucose uptake of the heart. The unchanged lactate
concentration and the slight ketosis in our study are also in accord with the
previous results. However, we found a significant myocardial lactate uptake
before diabetes that was diminished at 3 wk of diabetes. The differences with
respect to lactate uptake might be explained by the use of pentobarbital to
anesthetize the animals in the previous study, because pentobarbital is known
to affect the cardiovascular system in dogs
(8). Wiener and Spiter
(18) infused ketone bodies
intravenously to mimic the effects of advanced diabetes. The resulting
increase in plasma ketones was accompanied by a further reduction in FFA
extraction by the heart. This effect was even more pronounced in our conscious
dogs when the arterial -HBA concentrations and uptake reached 
15
times the control values at week 4 of diabetes resulting in a marked
decline of FFA uptake by the heart.
To our knowledge, only one study in the past examined the metabolic
alterations at two different time points after alloxan injection in dogs
(6). Kraupp and co-workers
(6) showed that 17 days
after alloxan injection dogs had significantly increased arterial FFA
concentrations but FFA uptake by the heart remained unchanged compared with
control. The arterial levels as well as the uptake of hydroxybutyrate and
acetoacetate, the two main ketone bodies, were significantly elevated in the
diabetic animals. However, despite a threefold higher arterial glucose
concentration after alloxan, the heart of the diabetic animals did not utilize
significant amounts of glucose. Additionally, arterial lactate concentrations
were not different in diabetic and normal animals
(6). In our investigation, we
could confirm the increase in the arterial serum concentrations of glucose,
FFA, and -HBA in diabetic dogs. We also found an augmented utilization
of ketone bodies and a reduced lactate uptake by the diabetic heart. However,
in our study, diabetic dog hearts consumed significantly less FFA at day
21 of diabetes compared with the nondiabetic state. The disparate results
might be explained by the differences in the study design. Whereas Kraupp et
al. (6) summarized three
different animals that were investigated at days 5, 16, and
30 of diabetes in the anesthetized state in one group and compared
them with a group of normal dogs, our conscious dogs were studied every week.
Our longitudinal study design with a larger group size makes it easier to
detect differences between the prediabetic and the diabetic state, e.g., for
the FFA uptake. Furthermore, we were able to assess differences in the
arterial substrate concentrations and substrate uptake by the heart every week
during the development of diabetes, whereas the study of Kraupp and co-workers
(6) did not.
Possible causes for the metabolic alteration in the diabetic
heart. From our data, it appears that arterial FFA and -HBA
concentrations are increased in diabetes due to enhanced lipolysis over time.
In contrast to previous studies, we found a reduction in FFA uptake in the
diabetic state. This may be explained by the dramatic elevation of ketone
bodies normally not seen in human diabetes. Hydroxybutyric acids can be
directly converted into acetyl-CoA units without using the -oxidation.
Acetyl-CoA is further converted by the acetyl-CoA decarboxylase in malonyl-CoA
that represents an effective inhibitor of carnitine palmitoyl transferase I
(CPT-I), a part of an enzyme complex that is necessary to transfer the acyl
moiety from the fatty acyl-CoA into the mitochondrium. An increased uptake of
-HBA, the conversion into malonyl-CoA with the consequence of an CPT-I
inhibition, might reflect one cause of the reduced FFA uptake into the
mitochondrium. This provides one explanation why ketone bodies seem to replace
FFA as substrates of the heart and may account for the impaired FFA uptake in
our model of diabetes. In diabetic dogs, regardless of whether HBA or FFA is
metabolized by the heart, both pathways would result in increased cellular
citrate and acetyl-CoA concentrations that are known to inhibit lactate and
glucose utilization (5,
17).
Previously, we had shown that plasma NOx levels were
significantly reduced at week 3 of diabetes. The impaired NO
production was attributed to a decreased gene expression and protein formation
of eNOS and accompanied by an impaired endothelium-dependent vasodilatation
(12). We confirm these
previous results regarding the decrease in the plasma levels of NOx
in the present study. Moreover, we are showing that myocardial eNOS expression
is also decreased in endstage diabetes. Besides the impact of NO on myocardial
respiration, it exerts additional effects on substrate utilization of the
heart. Recchia et al. (10)
clearly demonstrated that attenuation of myocardial NO release during the
development of pacing-induced heart failure was accompanied by a shift in
myocardial substrate utilization from FFA to glucose. This effect could be
mimicked in normal dogs by the injection of a nonselective NOS inhibitor and
was fully reversible after administration of a NO donor
(11). The modulating effect of
eNOS-derived NO on myocardial glucose utilization was further confirmed by
Tada et al. (15). They showed
only a moderate glucose uptake by hearts in normal mice, whereas eNOS knockout
mice consumed much higher amounts of glucose. Treatment with L-NAME
to block eNOS activity significantly increased myocardial glucose utilization
in normal mice but did not change glucose utilization in eNOS knockout mice.
Therefore, it is conceivable that the heart of diabetic dogs also switches
from FFA to glucose utilization when cardiac NO production decreases. In fact,
at week 4 of diabetes when FFA uptake was severly impaired, not only
were plasma NOx concentrations significantly reduced but myocardial
eNOS protein expression was significantly diminished compared with a
nondiabetic state. Moreover, we found that the gradual decrease in plasma
NOx levels was accompanied by a decline in FFA uptake and an
increase in -HBA uptake during the development of diabetes. However, the
altered FFA uptake was not paralleled by an elevated glucose or lactate uptake
in diabetic animals as it was in heart failure
(10). Furthermore, the RQ of
the heart did not increase during the development of diabetes and makes it
therefore unlikely that carbohydrates were used as a fuel. Because the heart
favors ketones as an energy supply and ketones are available in excess in
untreated diabetes, the heart does not switch to glucose utilization despite
high plasma glucose levels and an impaired cardiac NO production. On the
contrary, ketones seem to partially replace FFA as well as lactate despite
increased arterial FFA (Fig.
3). However, in heart failure and eNOS knockout mice, arterial
ketone concentrations are negligible excluding the use of ketone bodies as a
myocardial energy supply.
Hemodynamics,
MO2,
and RQ. In our study the time course for changes in baseline hemodynamics
and coronary circulation was also observed. In accord with previously
published data (19), we found
a reduction in MAP and CBF over time. Furthermore, the heart rate was
significantly reduced in conscious diabetic dogs at week 4 of
diabetes. In contrast, LVSP and dP/dtmax, measures of
systolic function, were unchanged over the study period. The triple product,
an estimate of cardiac work, tended to decrease during the development of
diabetes; however, this did not reach statistical significance.
In contrast, the MO2,
a measure of mechanically related oxygen consumption, was significantly
diminished at week 3 and 4 compared with the nondiabetic
state. However, the MO2
normalized per beat remained constant over the entire study period, suggesting
that the reduction in MO2
was due to bradycardia. In summary, our data provide evidence that the
efficiency of the heart in terms of the ratio of mechanically related energy
to MO2 in diabetic dogs
is not altered.
Study limitations. In the present study we measured arterial
concentrations and myocardial substrate uptake of FFA, -HBA, lactate,
and glucose in conscious dogs before and during the development of
alloxan-induced diabetes mellitus. Our longitudinal study design and the used
methods do not allow a measurement of substrate oxidation at any time.
However, the absence of a marked glucose uptake despite increased arterial
plasma concentrations and the significant reduction in lactate uptake at
week 3 and 4 of diabetes together with the unchanged RQ
makes it unlikely that carbohydrates play an important role as myocardial fuel
in alloxan-induced diabetes. In our study we found an increase in myocardial
-HBA uptake during the development of diabetes, indicating that
-HBA replaces FFA as a fuel. This notion is further supported by the
inverse correlation between -HBA and FFA uptake. However, no matter
whether FFA or -HBA is oxidized by the heart, the RQ remains the same.
Furthermore, HBA uptake was inversely related to lactate uptake, suggesting
that lactate is only of minor importance as a substrate for the heart in
diabetes. Because only a small part of myocardial energy supply is derived
from glycolysis and lactate uptake, this might explain why the shift in
substrate utilization from lactate to -HBA is not accompanied by a
detectable change in RQ.
Finally, the relevance of these studies to our understanding of cardiac function and metabolism should be pointed out. In our study and those previously conducted in humans (1, 3), there is no evidence of glucose uptake by the diabetic heart. Rather the heart takes up ketone bodies. In vitro studies incubating cardiac and other parenchymal cells only with glucose as a model of diabetes are not reasonable. Coincubation with ketone bodies would better reflect the pathophysiological circumstances in vivo.
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DISCLOSURES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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P < 0.05 vs. 0; 
P < 0.001 vs. 0.
