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Am J Physiol Heart Circ Physiol 291: H1489 –H1506, 2006.
First published June 2, 2006; doi:10.1152/ajpheart.00278.2006.
Invited Review
Role of changes in cardiac metabolism in development
of diabetic cardiomyopathy
Ding An and Brian Rodrigues
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences,
The University of British Columbia, Vancouver, British Columbia, Canada
heart disease; diabetes; insulin resistance; lipoprotein lipase; fatty acid transporters;
PPARs; lipotoxicity; mitochondria dysfunction
HEART DISEASE is a leading cause of death in diabetic patients
(226, 253), with coronary vessel disease and atherosclerosis
being primary reasons for the increased incidence of cardiovascular dysfunction (151, 225, 253). However, a predisposition to heart failure might also reflect the effects of underlying
abnormalities in diastolic function that can be detected in
asymptomatic patients with diabetes alone (24, 61, 74). These
observations suggest a specific impairment of heart muscle
(termed diabetic cardiomyopathy). Rodent models of chronic
diabetes demonstrate abnormalities in diastolic left ventricular
function, with or without systolic left ventricular dysfunction
(73, 205, 219). Because diastolic dysfunction is also seen in
patients with both Type 1 and Type 2 diabetes, it can be
proposed that the diabetic state can directly induce abnormalities in cardiac tissue independent of vascular defects. Several
etiological factors have been put forward to explain the development of diabetic cardiomyopathy, including an increased
stiffness of the left ventricular wall associated with accumulation of connective tissue and insoluble collagen (9, 204, 212)
and abnormalities of various proteins that regulate ion flux,
specifically intracellular calcium (90, 235). More recently, the
view that diabetic cardiomyopathy could also occur as a
consequence of metabolic alterations has been put forward
(146, 147, 149).
Address for reprint requests and other correspondence: B. Rodrigues, Div. of
Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The Univ.
of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3
(e-mail: [email protected]).
http://www.ajpheart.org
Because uninterrupted contraction is a unique feature of the
heart, cardiac muscle has a high demand for provision of
energy. Under normal physiological conditions, hearts can
utilize multiple substrates, including fatty acids (FA), carbohydrate, amino acids, and ketones (15). Among these substrates, carbohydrates and FA are the major sources from
which the heart derives most of its energy. In a normal heart,
70% of ATP generation is through FA oxidation, whereas
glucose and lactate account for ⬃30% of energy provided to
the cardiac muscle (86, 173, 210). It should be noted that the
heart can rapidly switch its substrate selection to accommodate
different physiological and pathphysiological conditions involving altered extracellular hormones, substrate availability, and
workload (energy demand) (11, 130, 204, 217, 227). Acutely or
chronically, this regulation occurs through various mechanisms.
Although substrate switching is essential to ensure continuous
ATP generation to maintain heart function, it has also been
associated with deleterious consequences (17, 267).
In Type 1 and Type 2 diabetes mellitus, glucose uptake,
glycolysis, and pyruvate oxidation are impaired. Additionally,
lack of insulin function augments lipolysis and release of FA
from adipose tissue. Under these conditions, the heart rapidly
adapts to using FA exclusively for ATP generation. Chronically, this maladaptation is believed to play a key role in the
development of cardiomyopathy. Hence, it is essential to identify
and understand the mechanisms that control substrate utilization
in the diabetic heart. This review discusses the acute and chronic
cellular changes that modify cardiac metabolism and elucidate
their roles in the development of cardiomyopathy.
0363-6135/06 $8.00 Copyright © 2006 the American Physiological Society
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An, Ding, and Brian Rodrigues. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 291: H1489 –
H1506, 2006. First published June 2, 2006; doi:10.1152/ajpheart.00278.2006.—In
patients with diabetes, an increased risk of symptomatic heart failure usually develops
in the presence of hypertension or ischemic heart disease. However, a predisposition to
heart failure might also reflect the effects of underlying abnormalities in diastolic
function that can occur in asymptomatic patients with diabetes alone (termed diabetic
cardiomyopathy). Evidence of cardiomyopathy has also been demonstrated in animal
models of both Type 1 (streptozotocin-induced diabetes) and Type 2 diabetes (Zucker
diabetic fatty rats and ob/ob or db/db mice). During insulin resistance or diabetes, the
heart rapidly modifies its energy metabolism, resulting in augmented fatty acid and
decreased glucose consumption. Accumulating evidence suggests that this alteration of
cardiac metabolism plays an important role in the development of cardiomyopathy.
Hence, a better understanding of this dysregulation in cardiac substrate utilization
during insulin resistance and diabetes could provide information as to potential targets
for the treatment of cardiomyopathy. This review is focused on evaluating the acute and
chronic regulation and dysregulation of cardiac metabolism in normal and insulinresistant/diabetic hearts and how these changes could contribute toward the development of cardiomyopathy.
Invited Review
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DIABETIC CARDIOMYOPATHY
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CARDIAC METABOLISM
Glucose Uptake and Oxidation
Under normal physiological conditions, glucose is one of the
major carbohydrates utilized by the heart. Glucose metabolism
is regulated through multiple steps, including uptake, glycolysis, and pyruvate decarboxylation (Fig. 1). Cardiac glucose
uptake is dependent on the transmembrane glucose gradient
and the content of sarcolemmal glucose transporters (GLUT1
and GLUT4) (132, 154, 189). GLUT1 has a more pronounced
sarcolemmal localization and represents basal cardiac uptake.
When compared with GLUT1, GLUT4 is the dominant transporter in the adult heart, and under basal conditions, a majority
of this transporter is located in an intracellular pool (154). Its
translocation from an intracellular compartment to the sarcolemmal membrane requires insulin (154). Other than recruiting GLUT to the sarcolemmal membrane, insulin also influences glucose transport through its regulation of GLUT gene
expression (137, 183). It should be noted that GLUT-mediated
glucose uptake could also be stimulated through insulin-independent mechanisms. For example, recent studies have demonstrated that AMP-activated protein kinase (AMPK) also
promotes GLUT4 redistribution to the sarcolemmal membrane
(143, 261).
Once inside the cardiomyocyte, glucose is broken down
through glycolysis, a sequence of reactions that convert glucose into pyruvate. Phosphofructokinase-1 (PFK1), the enzyme
that catalyzes the generation of fructose 1,6-bisphosphate from
fructose 6-phosphate, is a rate-limiting enzyme controlling
glycolysis (57, 202). PFK-1 is inhibited by low pH, high
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The central basis for diabetic heart failure is coronary
disease associated with atherosclerosis (151, 225, 253). Because diabetes is often accompanied by hypertension and/or
ischemic heart disease, which often causes diastolic dysfunction, it is difficult to attribute heart failure in these patients to
diabetes alone (23). On the other hand, Type 1 or Type 2
diabetic patients have also been diagnosed with reduced or
low-normal diastolic function and left ventricular hypertrophy
in the absence of coronary heart disease or hypertension,
identified as cardiomyopathy (24, 81, 192, 195, 200, 231).
These abnormalities in asymptomatic diabetic patients potentially might predispose them to symptomatic heart failure when
they develop hypertension or ischemic heart disease, particularly after myocardial infarction.
In animal models of Type 1 diabetes, either streptozotocin
(STZ)-induced rats or genetic nonobese diabetic mice, systolic
and diastolic dysfunction have been demonstrated using in vivo
or in vitro measurements (177, 185, 232, 239). For example,
systolic and diastolic dysfunction have been detected by using
echocardiography in STZ diabetic animals (123, 177). With the
use of in vivo catheterization of these animals, elevated left
ventricular end-diastolic pressure and reduced left ventricular
systolic pressure with diminished increase or decrease pressure
over time (⫾dP/dt) were observed (124). Reduced peak left
ventricular pressure and ⫾dP/dt were confirmed in ex vivo
perfused STZ hearts (239). Recently, evidence of cardiomyopathy has also been reported in animal models of insulin
resistance and Type 2 diabetes (ZDF rats and ob/ob or db/db
mice) (5, 21, 30, 266). In db/db mice, systolic and diastolic
dysfunction were detected by echocardiography (218). With
the use of ex vivo perfused hearts from db/db mice, augmented
left ventricular end-diastolic pressure and reduced cardiac
output and cardiac power have also been observed (21). Given
that rodents are resistant to atherosclerosis, these models provided strong evidence for the occurrence of diabetic cardiomyopathy. However, in another study, no evidence of impairment
in cardiac function was detected using in ex vivo Langendorff
perfusions of hearts from insulin resistant and obese Zucker
rats (224) and Type 2 diabetic Zucker diabetic fatty (ZDF) rats
(250). It is likely that such inconsistencies arose due to the
rodent models used and the methods employed for evaluating
heart function in the different studies.
It should be acknowledged that the features of cardiomyopathy between human diabetic patients and rodent diabetic
models might be different. The development of diabetic cardiomyopathy is influenced by the severity and duration of
alterations in plasma parameters such as insulin, leptin, glucose, and lipids. Given the discrepancy in changes in these
hormones and substrates between human diabetic patients and
rodent models of Type 1 and Type 2 diabetes, the etiology and
severity of diabetic cardiomyopathy may vary (196). For example, STZ-induced diabetes exhibit severe hypoinsulinemia,
whereas ob/ob mice show leptin deficiency, which are rare in
human diabetes. Additionally, it has been suggested that STZ
can directly impair the cardiac contractile function of isolated
ventricular myocytes (256). Finally, although db/db mice and
Zucker and ZDF rats exhibit hyperinsulinemia, hyperleptinemia, and hyperglycemia, the severity of these alterations vary
between animal models and patients with diabetes (196).
Taken together, experimental data obtained using animals
models of diabetes should be used with caution when extrapolating to the human condition.
Cardiomyopathy is a complicated disorder, and several factors have been associated with its development. These include
increased stiffness of the left ventricular wall associated with
accumulation of connective tissue and insoluble collagen (204,
212), depressed autonomic function (73), impaired endothelium function and sensitivity to various ligands (e.g., ␤-agonists) (23), and abnormalities of various proteins that regulate
ion flux, specifically intracellular calcium (90, 235). More
recently, there is a generalized view that diabetic cardiomyopathy also occurs as a consequence of altered fuel metabolism.
During insulin resistance or diabetes, glucose utilization is
compromised. This alteration, together with increased FA supply, switches cardiac energy generation to utilization of FA.
High FA uptake and metabolism not only augment accumulation of FA intermediates and triglycerides but also increase
oxygen demand and generation of reactive oxygen species
(ROS), leading to cardiac damage. Interestingly, increasing FA
uptake through overexpression of cardiac human lipoprotein
lipase (LPL) (260) or FA transport protein (47), or augmenting
FA oxidation through overexpression of cardiac peroxisome
proliferator-activated receptor (PPAR)-␣ (79) or long-chain
acyl CoA synthase (48), results in a cardiac phenotype resembling diabetic cardiomyopathy. Conversely, normalizing cardiac metabolism in diabetic animals reverses the development
of cardiomyopathy (21, 272). Taken together, these studies
strongly support the role of altered metabolism in the development of diabetic cardiomyopathy.
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ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
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(107, 258), which is inhibited by pyruvate and stimulated by
high mitochondrial acetyl-CoA-to-CoA and NADH-toNAD(⫹) ratios (29, 104). Acetyl-CoA then enters the tricarboxylic acid cycle and is eventually broken down to H2O and
CO2 for ATP generation. Oxidation of one glucose provides 30
ATP with 6 oxygen consumed, which combined with 2 glycolytic ATPs produces a phosphate-to-oxygen ratio of 2.58 ATP/
oxygen atom. Although glucose is the focus in this review,
other carbohydrates like lactate also make an important
contribution toward cardiac energy generation (39). In fact,
as greater lactate compared with glucose utilization is observed in the isolated working heart (119, 127, 148), the
inclusion of lactate in the perfusion buffer is recommended
in future studies.
Fig. 1. Glucose utilization in the cardiomyocyte. Glucose uptake into cardiomyocyte occurs through GLUT1 and GLUT4 transporters. Once inside, glucose is broken down through glycolysis, a sequence of reactions that convert
glucose into pyruvate. Phosphofructokinase-1 (PFK1), the enzyme that catalyze the generation of fructose 1,6-bisphosphate from fructose 6-phosphate, is
a rate-limiting enzyme controlling glycolysis. PFK1 is activated by 2,6bisphosphate, which is formed from fructose 6-phosphate catalyzed by PFK-2.
After glycolysis, the pyruvate generated is transported into mitochondria and
decarboxylated to acetyl-CoA through pyruvate dehydrogenase (PDH), a
multienzyme complex. PDH is phosphorylated and inactivated by pyruvate
dehydrogenase kinase (PDK). Acetyl-CoA then enters tricarboxylic acid cycle
(citric acid cycle) and is eventually broken down to H2O and CO2 for ATP
generation.
intracellular citrate, or ATP and is activated by ADP, AMP,
phosphate, and fructose 2,6-bisphosphate (57, 202, 228). Fructose 2,6-bisphosphate is formed from fructose 6-phosphate
catalyzed by PFK-2 (110). Given that PFK-2 is phosphorylated
and activated by hormones, such as insulin (25, 58) and
glucagon (228) or kinases such as AMPK (109, 161), stimulation of PFK-2 through these mechanism increases fructose
2,6-bisphosphate generation, activates PFK-1, and subsequently promotes glycolysis. In an aerobic heart, glycolysis
contributes ⬍10% of total ATP generated, with no oxygen
consumption.
After glycolysis, the pyruvate generated has three destinations: carboxylation to oxaloacetate or malate, reduction to
lactate, and most importantly, decarboxylation to acetyl-CoA.
To be oxidized, pyruvate is transported into the mitochondria
and decarboxylated to acetyl-CoA through pyruvate dehydrogenase (PDH), a multienzyme complex. PDH is phosphorylated and inactivated by pyruvate dehydrogenase kinase (PDK)
AJP-Heart Circ Physiol • VOL
When compared with glucose, FA is the preferred substrate
and accounts for ⬃70% of ATP generated in an aerobic heart.
FA metabolism includes multiple steps and can be regulated by
both acute and chronic mechanisms, with or without modulation of gene expression (Fig. 2).
Lipoprotein lipase. Because the heart has limited capacity to
synthesize and store FA, it relies on continuous exogenous
supply. FA supplied to the heart from the circulation is from
two sources: albumin-bound FA and triglyceride (TG)-rich
lipoproteins. It should be noted that the molar concentration of
FA in lipoprotein-TG is ⬃10-fold larger than FA bound to
albumin (165). Lipoprotein lipase (LPL) is the key enzyme that
hydrolyzes lipoproteins to release FA. Thus, when lipoproteins
are hydrolyzed by LPL, a large amount of FA are released and
are believed to be the principle source of FA supplied to the
heart (14, 237). LPL is produced in cardiomyocytes and subsequently secreted onto heparan sulfate proteoglycan binding
sites on the myocyte cell surface (33, 68, 70). From here, LPL
is transported onto comparable binding sites on the luminal
surface of coronary endothelial cells (193). At these sites, LPL
hydrolyzes TG-rich lipoproteins, such as very-low-density lipoprotein (VLDL) and chylomicrons, to release FA. Perfusion
of working hearts with VLDL or chylomicrons, in the absence
or presence of FA, has revealed that, compared with chylomicrons, VLDL is a poor substrate for LPL (100). In addition,
utilization of chylomicrons was inhibited by free FA, which
failed to affect cardiac VLDL utilization (100). Given the
important role that LPL plays in regulating FA delivery,
alteration in its level is able to change FA delivery and
subsequent oxidation. Indeed, overexpression of LPL in the
heart or skeletal muscle accelerates FA uptake (141, 260).
Conversely, tissue-specific knockout of LPL in the heart
switches the cardiac substrate selection preference to glucose
(12, 13). Other than hydrolysis by LPL, lipoproteins can also
be transported into the cardiac tissue with help of the lipoprotein receptor, with VLDL uptake through this mechanism
being more substantial compared with chylomicrons (178). In
perfused working hearts, inhibition of the lipoprotein receptor
significantly reduced FA oxidation without altering FA uptake,
suggesting that lipoprotein receptor mediated FA uptake channels FA toward oxidation, whereas LPL mediated FA uptake
channels FA toward both oxidation and TG storage (178).
FA transporters. Although FA can translocate into the cell
through passive diffusion across the plasma membrane, FA
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FA Uptake and Utilization
Invited Review
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ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
uptake shows saturation kinetics and is inhibited by proteases
(7, 158, 159, 230). Thus FA transporters are also likely required to support this process. In the heart, three FA transporters have been identified and these include CD36, FA transport
protein (FATP), and FA binding protein plasma membrane
(FABPpm) (157). Given that 55– 80% of FA transport was
blocked using general transporter inhibitors (131, 158) and that
overexpression of CD36 or FATP has been found to dramatically increase FA metabolism (47, 113), these FA transporters
are believed to play a key role in FA delivery to the cardiac
tissue.
Regulation of FA transport proteins occurs through different
mechanisms. In severe STZ-induced diabetes, expression of
cardiac CD36 and FABPpm were augmented (152), suggesting
transcriptional modification of these transporters. At present,
the mechanisms that induce this change have yet to be elucidated. Additionally, because muscle contraction or acute insulin treatment does not change protein but simply relocates
CD36 from an intracellular pool to the sarcolemmal membrane
(155, 156), posttranslational regulation of this transporter has
also been suggested.
Acyl-CoA synthase. Acyl-CoA synthase (ACS) catalyzes the
esterification of FA to fatty acyl-CoA, the initial step of FA
metabolism. Fatty acyl-CoA can be transported into the mitochondria for oxidation or used for intracellular TG synthesis.
The fate of fatty acyl-CoA is influenced by the location of
different ACS isoforms, energy demand, and the availability of
FA (37). Moreover, ACS not only functions as an enzymecatalyzing esterification but is also actively involved in controlling FA homeostasis (48). Recent studies have demonstrated that ACS is associated with CD36 or FATP on the
cytosolic side of the sarcolemmal membrane (84, 201, 214),
suggesting that ACS also influences FA uptake. Several studies
also suggest that FATP1 is a very long chain ACS (53).
Overexpression of ACS in the heart or fibroblast causes dramatically augmented FA uptake and intracellular TG accumulation (48).
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Under normal conditions, 70 –90% of the esterified FA that
enters cardiomyocytes is oxidized for ATP generation, whereas
10 –30% is converted to TG (228). The TG pool is not static,
with lipolysis and esterification taking place continuously
(240). In a normal heart, intracellular TG level is constant,
indicating a balance of lipogenesis and lipolysis (210). In
situations where FA supply supercedes the cellular oxidative
capacity, such as obesity or diabetes, intracellular TG accumulates and is associated with lipotoxicity (240). Although TG is
unlikely to be a direct mediator of cell apoptosis, its augmented
lipolysis expands fatty acyl-CoA levels, which may be a key
factor mediating cell apoptosis (117, 240). Thus TG is often
used as a marker of lipotoxicity.
PPARs. PPARs are a group of ligand-activated transcriptional factors belonging to the superfamily of nuclear receptors. They are activated by either natural ligands like FA or
numerous pharmacological ligands (80). Once activated,
PPARs form complexes with retinoid X receptors and bind to
the promoter regions of a number of target genes that encode
the proteins involved in controlling FA metabolism (76, 78).
Through regulation of expression of these genes, PPARs modulate FA utilization at the transcriptional level. PPARs have
three isoforms: PPAR-␣, PPAR-␤ (or -␦), and PPAR-␥.
PPAR-␣ is extensively expressed in tissues with high FA
metabolism like the heart (17). Activated by elevated intracellular FA levels, PPAR-␣ promotes expression of genes that
regulate FA oxidation at various steps, such as FA uptake and
binding (LPL, CD36, and FA binding protein), FA esterification (ACS), and FA oxidation (carnitine palmitoyltransferase-1, acyl-CoA oxidase, long-chain acyl-CoA dehydrogenase, and very-long-chain acyl-CoA dehydrogenase) (76, 78,
111). Knocking out cardiac PPAR-␣ abolishes fasting-induced
overexpression of FA metabolic genes and switches substrate
selection from FA to glucose (140, 172). Overexpression of
cardiac PPAR-␣ augments FA uptake and oxidation (77, 79).
Taken together, PPAR-␣ is believed to be the primary regulator of FA metabolism in the heart. Similar to PPAR-␣, PPAR-␤
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Fig. 2. Control of fatty acid (FA) delivery and
utilization in the cardiomyocyte. FA, either from
adipose tissue or released from triglyceride
(TG)-rich lipoproteins through hydrolysis by lipoprotein lipase (LPL), is taken up into the
cardiomyocyte by three FA transporters: CD36,
FA transport protein (FATP), and FA binding
protein plasma membrane (FABPpm). FA is converted to fatty acyl-CoA, which is transported
into the mitochondria through CPT1/CPT2. Inside the mitochondria, fatty acyl-CoA undergoes
␤-oxidation to generate acetyl-CoA, which is
further oxidized in the tricarboxylic acid cycle.
Utilization of FA is regulated through different
mechanisms. FA, through activation of peroxisome prolferator-activated receptor-␣ (PPAR␣), increases the expression of a number of
enzymes involved in FA oxidation. MalonylCoA, which is generated through carboxylation
of acetyl-CoA catalyzed by acetyl-CoA carboxylase (ACC), inhibits CPT-1 and FA oxidation.
AMP-activated kinase (AMPK) inhibits ACC,
relieves its inhibition on CPT-1, and promotes
FA oxidation. Similarly, malonyl-CoA decarboxylase (MCD), through decreasing malonylCoA by decarboxylating it to acetyl-CoA, enhances CPT-1 and FA oxidation.
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ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
lumen LPL activity (8). Interestingly, recent studies using
transgenic mice with a dominant negative form of AMPK has
demonstrated that the lack of AMPK does not affect cardiac
metabolism under physiological conditions (209, 259). At
present, it is unclear as to what compensatory mechanisms are
activated following knockout of AMPK. Additionally, it is
unknown whether overexpression of AMPK could affect cardiac lipid homeostasis and metabolism.
Malonyl-CoA decarboxylase. In addition to AMPK, malonyl-CoA decarboxylase (MCD) is also known to promote FA
oxidation through its lowering of malonyl-CoA. MCD catalyzes the degradation of malonyl-CoA to acetyl-CoA, leading
to reduction of malonyl-CoA (65). This action relieves the
inhibition of CPT-1 by malonyl-CoA and favors FA oxidation.
Recent studies have suggested that inhibition of cardiac MCD
leads to accumulation of malonyl-CoA and reduced FA oxidation (66).
Interaction Between Glucose and FA Metabolism
Regulation of glucose and FA metabolism does not occur
independently, and numerous studies have reported a “crosstalk” between the utilization of these substrates (Fig. 3) (199,
211, 233). Randle et al. (199) demonstrated that FA impairs
basal and insulin-stimulated glucose uptake and oxidation, an
event that is known as the “Randle cycle” (199). FA influences
glucose utilization at multiple levels. Accumulation of FA
impairs insulin-mediated glucose uptake through inhibition of
insulin receptor substrate and protein kinase B (94, 115, 187).
Accumulation of FA leads to augmented intracellular FA
derivatives, such as fatty acyl CoA, diacylglycerol, and ceramide. These FA metabolites activate a serine kinase cascade,
which involves protein kinase C-␪ and I␬B kinase-␤ (inhibitor
of NF-␬B kinase-␤), leading to serine phosphorylation of IRS
(129, 269). Serine phosphorylation of IRS-1 reduces tyrosine
Fig. 3. Inhibition of glucose oxidation by FA
utilization. Accumulation of FA impairs insulin-mediated glucose uptake through inhibition of insulin receptor substrate (IRS) and
protein kinase-B (PKB). Increased intracellular FA also activates PPAR-␣. As a consequence, PPAR-␣ promotes the expression of
genes involved in FA oxidation, as well as
PDK4, known to inhibit PDH and pyruvate
flux. Increased acetyl-CoA and NADH
caused by the high rate of FA oxidation
activate PDK4, leading to further inactivation
of PDH. Augmented acetyl-CoA also causes
accumulation of citrate in the cytosol, which
subsequently inhibits PFK1 and glycolysis.
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(or -␦) is expressed abundantly in the cardiac tissue (17).
Activated by elevated intracellular FA (45), PPAR-␤ (or -␦)
augments expression of a group of genes that promote FA
utilization (63, 169). Cardiac-specific knockout of PPAR-␤
also decreases FA oxidative gene expression and FA oxidation
(46). Although the targets of PPAR-␣ and PPAR-␤ are partially overlapping (169), their unique roles and interaction
remains unclear in the heart. PPAR-␥, the third number of the
PPAR family, is highly expressed in adipose tissue. Through
promoting lipogenic gene expression, PPAR-␥ controls lipogenesis. Loss and gain of function experiments have demonstrated that PPAR-␥ is necessary for adipose tissue proliferation and differentiation (16, 238). In isolated cardiomyocytes,
the expression of PPAR-␥ is barely detectable (89), suggesting
a limited direct role for this nuclear receptor in regulating
cardiac metabolism. However, the ability of PPAR-␥ agonists
to normalize elevated plasma concentrations of glucose and FA
in diabetic animals will have a profound indirect effect on
cardiac metabolism.
AMP-activated protein kinase. As an energy sensor, AMPactivated protein kinase (AMPK) is activated following a rise
in the intracellular AMP-to-ATP ratio (97). Once stimulated,
AMPK switches off energy-consuming processes like protein
synthesis, whereas ATP-generating mechanisms, such as FA
oxidation and glycolysis, are turned on (96, 105). In heart and
skeletal muscle, AMPK facilitates FA utilization through its
control of acetyl-CoA carboxylase (ACC) (133, 134). As ACC
catalyzes the conversion of acetyl-CoA to malonyl-CoA,
AMPK by inhibiting ACC is able to decrease malonyl-CoA
and minimize its inhibition of CPT-1, the rate-limiting enzyme-controlling FA oxidation. AMPK has also been implicated in FA delivery to cardiomyocytes through its regulation
of the FA transporter CD36 (155). Additionally, results from
our laboratory have demonstrated a strong correlation between
activation of whole heart AMPK and increases in coronary
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ALTERATION OF CARDIAC METABOLISM DURING DIABETES
Changes in Plasma Substrates
Glucose and lipids are the major substrates affected by
diabetes. Hyperglycemia is a consequence of decreased glucose clearance and augmented hepatic glucose production,
whereas enhanced lipolysis in adipose tissue and higher lipoprotein synthesis in the liver dramatically increases circulating free FA and TG. Because glucose entry into the cell is
largely dependent on insulin, whereas FA transport across
plasma membrane does not require any hormone, the augmented circulating lipids increase FA delivery to the cardiomyocyte. With the increase of intracellular FA, cardiac tissue
rapidly adapts to promote FA utilization. In addition to diabetes, augmentation of plasma lipids by fasting or intralipidheparin infusion also increases cardiac FA oxidation (52, 266).
Under conditions where FA supply supercedes the oxidative
capacity of the heart, the FA is converted to lipids like TG or
ceramide, with an end result being lipotoxicity (272). In obese
ZDF rats, lowering of plasma lipids with a PPAR-␥ agonist
reduced cardiac TG and ceramide and improved heart function
(272). Overall, these studies suggest that alterations in plasma
lipids may drive changes in cardiac metabolism. It should be
noted that a recent study using 4-wk-old ob/ob and db/db mice
demonstrated altered cardiac metabolism without any change
in plasma substrates (30). Hence, in these genetic mice models,
intrinsic changes in the cardiomyocyte, rather than changes in
circulating substrates, initiate alterations in cardiac metabolism
at this early time point.
Defects in Cardiac Carbohydrate Utilization
In the obese or diabetic heart, myocardial glucose utilization
is compromised at several points. In noninsulin-controlled
Type 1 diabetic animals, reduced GLUT gene and protein
expression compromises cardiac glucose uptake and oxidation
(34). In obese or Type 2 diabetic animals, although there is
hyperglycemia and hyperinsulinemia, cardiac glucose uptake is
reduced as a consequence of reduced GLUT4 protein and
impaired insulin signaling (38, 266). With the use of ob/ob and
db/db mice, a recent study (30) reported that cardiac glucose
oxidation is reduced at 4 wk of age and was associated with
increased FA oxidation. Interestingly, this lower glucose oxidation occurred before the onset of impaired insulin signaling
in the heart and development of hyperglycemia. Thus this early
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reduction in glucose utilization is likely due to suppression by
high FA oxidation rather than impaired cardiac-specific insulin
signaling. In another study that used db/db mice at different
ages, increased cardiac FA oxidation preceded the reduction in
glucose oxidation (5). Higher FA oxidation increases citrate,
which is known to inhibit PFK, the rate-limiting enzyme in
glycolysis. Elevated intracellular FA is also known to increase
PDK-4 expression, which phosphorylates and inhibits PDH.
Finally, high rates of FA oxidation augment acetyl-CoA that
inhibits PDH either allosterically or through activation of PDK.
When compared with animal models, the use of carbohydrates in the human diabetic hearts is more controversial. In
Type 1 diabetic patients, decreased myocardial carbohydrate
uptake is reported (15, 62). With the use of an euglycemic
insulin clamp, another study (179) has shown that cardiac
glucose uptake is normal in these patients, suggesting that
insulin is the major limiting factor that influences cardiac
glucose uptake and no cardiac-specific insulin resistance is
evident, as observed in skeletal muscle. In Type 2 diabetes,
cardiac expression of GLUT4 is compromised likely due to
elevated FA (10). However, a number of studies have also
reported that cardiac tissue from Type 2 diabetic patients
respond normally to insulin and show regular glucose uptake,
suggesting that myocardial insulin resistance is not a common
feature of Type 2 diabetes (118, 160, 242). Interestingly, a
recent study has suggested that impaired myocardial glucose
uptake is only observed in Type 2 diabetic patients with
hypertriglyceridemia, suggesting that myocardial insulin resistance in these patients is associated with hypertriglyceridemia
and augmented plasma FA levels (168).
Cardiac lactate utilization is also compromised following
diabetes. In STZ-induced Type 1 diabetes, cardiac utilization
of lactate is reduced to a greater extent when compared with
glucose oxidation (41, 42). Moreover, hearts from 12-wk-old
ZDF rats also showed lower carbohydrate oxidation, and this
was almost entirely due to a reduction in lactate rather than
glucose oxidation (43, 250). The mechanisms that mediate the
inhibition of lactate utilization are unclear but is likely independent of any alterations in lactate dehyrogenase or lactate
transporter (41).
The shift of cardiac energy substrate utilization from carbohydrate to lipids increases the intracellular glycogen pool,
probably through augmented glycogen synthesis, or impaired
glycogenolysis, or a combination of both processes (103, 136,
167, 223). Emerging evidence indicates that glycogen, in
addition to its role as energy storage, is also able to regulate
metabolism. At least in skeletal muscle, accumulation of glycogen acutely alters glycogen synthesis and glucose metabolism (59, 120 –122). Chronically, glycogen accumulation may
also impair insulin signaling in skeletal muscle (121). Whether
cardiac glycogen accumulation also influences insulin signaling and metabolism is unknown. In addition, recent studies
have identified a glycogen-binding domain in the ␤-subunit of
AMPK and suggests that this domain links AMPK and glycogen (108). Although an association between high glycogen
levels and repressed AMPK activity in human and rat skeletal
muscle have been documented (254, 255), it is still unclear
whether glycogen is able to regulate metabolism through
AMPK.
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phosphorylation and interferes with its ability to phosphorylate
and activate phosphatidylinositol 3-kinase and protein kinase B
(206). Increased intracellular FA also activates PPAR-␣. As a
consequence, PPAR-␣ promotes the expression of genes involved in FA oxidation, as well as pyruvate dehydrogenase
kinase-4 (PDK4), which is known to inhibit PDH and pyruvate
flux (257). Moreover, increased acetyl-CoA-to-free CoA and
NADH-to-NAD⫹ ratios caused by the high rate of FA oxidation are also known to activate PDK4, leading to inactivation
of PDH (29, 104). Augmented acetyl-CoA-to-free CoA ratio
also causes accumulation of citrate in the cytosol, which
subsequently inhibits PFK and glycolysis (85, 175). Conversely, inhibition of FA oxidation through elevation of malonyl-CoA levels, or using pharmacological inhibitors, favors
glucose oxidation.
Invited Review
ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
Alterations in FA Utilization
AJP-Heart Circ Physiol • VOL
expression of VLDL receptor decreases following STZ-induced diabetes (116).
FA transporters. During obesity and diabetes, the high rate
of FA uptake is facilitated by FA transporters, leading to
augmented FA oxidation and TG storage. In STZ-induced
diabetes, the increase in plasmalemmal CD36 and FABPpm
amplifies FA uptake, an effect resulting from increased CD36
and FABPpm protein expression (152). In Zucker fatty rats,
without a change in total protein, permanent relocation of
CD36 and FABPpm to the cardiomyocyte plasmalemmal membrane augments FA uptake (55, 56, 153). The mechanism for
this permanent repositioning of FA transporters at the plasma
membrane is still unknown. Interestingly, in young (4 wk)
ob/ob or db/db mice, cardiac FA oxidation increases without
any change in circulating substrates (30). Given that the high
rate of FA oxidation requires coordinated FA uptake, augmentation of CD36-mediated FA supply is suggested to be involved in facilitating FA oxidation at this early stage of insulin
resistance.
PPAR-␣. As the principle regulator of cardiac FA metabolism, PPAR-␣ plays an important role in controlling FA oxidation during obesity and diabetes. Activation of this nuclear
receptor in the heart has been reported in almost all obese or
diabetic animal models, including STZ-induced diabetic rats,
ZDF rats, and ob/ob and db/db mice (30, 79, 220). Given that
FA and its derivatives activate PPAR-␣, higher cardiac
PPAR-␣ activity is always observed when circulating lipids are
augmented (30, 171). Hence, in ob/ob and db/db mice, activation of PPAR-␣, evidenced by elevated expression of its
downstream targets, is only observed at 12 wk and is associated with augmented plasma lipid (30). A similar association
between plasma lipids and PPAR-␣ is also seen in hearts from
STZ-induced diabetic rats, with only chronic (6 wk) but not
acute (4 days) diabetes demonstrating activation of PPAR-␣
(unpublished data). Interestingly, in acute STZ diabetes or
4-wk ob/ob or db/db mice, increased FA oxidation is observed
even in the absence of any change in cardiac PPAR-␣ and its
downstream targets, suggesting PPAR-␣ independent control
of FA oxidation. Identification of these mechanisms requires
further studies.
After activation, cardiac PPAR-␣ promotes the expression
of a group of genes involved in various steps of FA oxidation.
Simultaneously, activation of PPAR-␣ also reduces expression
of genes involved in glucose uptake, glycolysis, and oxidation
through direct or indirect mechanisms (77, 79). With the use of
transgenic mice, a recent study (186) demonstrated that knocking out cardiac PPAR-␣ prevented suppression of GLUT4
expression and glucose uptake by elevated plasma FA and
improved myocardial recovery from ischemia following STZ
diabetes induction, high-fat feeding, or fasting. Taken together,
activation of cardiac PPAR-␣ not only favors FA oxidation but
also inhibits glucose uptake and utilization, leading to augmented susceptibility to ischemic damage.
MCD. In STZ-induced diabetes, overexpression of cardiac
MCD protein was observed and could contribute to the high
rate of FA oxidation (213). It is unknown whether MCD also
plays a role in augmenting cardiac FA oxidation in obese and
Type 2 diabetes. Nevertheless, given that PPAR-␣ increases
MCD expression (138, 265), higher MCD protein levels are
expected following PPAR-␣ activation during obesity and
Type 2 diabetes.
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Utilization of FA by cardiac tissue increases following
obesity and diabetes. This change occurs not only as a consequence of increased FA supply but also through an intrinsic
adaptation/maladaptation to elevated FA (234, 267). It must be
acknowledged that some studies have also observed a reduced,
rather than augmented, FA oxidation in Zucker fatty or ZDF
rats (266, 272). In human diabetic patients, obese women
demonstrate increased FA utilization, associated with augmented cardiac oxygen consumption, and reduced cardiac
efficiency (190). Moreover, elevated cardiac TG and increased
expression of PPAR-␣ target genes have been observed in
patients without ischemic heart disease, very similar to lipotoxic ZDF rat hearts (220).
Lipoprotein lipase. The amount of FA supplied to the heart
through LPL is influenced by multiple factors, including LPL
activity and plasma lipoprotein concentration and composition.
The relative contribution of cardiac LPL activity to the delivery
of free FA to the diabetic heart is inconclusive. Thus LPL
immunoreactive protein or activity has been reported to be
unchanged, increased, or decreased in the diabetic rat heart. In
part, this variability between different studies could be due to
the diversity in the rat strains used, the dosage of STZ used to
induce diabetes, and the duration of the diabetic state (203). In
addition, many of the above investigations utilized procedures
that did not distinguish between functional (i.e., heparin-releasable component localized on capillary endothelial cells that is
implicated in the hydrolysis of circulating TG) and cellular
(i.e., non-heparin-releasable pool that represents a storage form
of the functional enzyme) pools of cardiac LPL because cellular LPL activity or protein levels have largely been obtained
using whole heart homogenates. Rodrigues et al. (203) have
previously reported that in STZ (55 mg/kg)-induced moderate
diabetic Wistar rat hearts, HR-LPL activity is significantly
increased. Induction of more severe diabetes using 100 mg/kg
STZ did not influence HR-LPL (203). In another study using
hearts from 65 mg/kg STZ-induced diabetic rats, HR-LPL
decreased and was associated with reduced VLDL-TG lipolysis (182). Acute treatment of these diabetic rats with insulin
enhanced both HR-LPL and VLDL-TG lipolysis (182). In
mouse models of diabetes, although there is no change of
cardiac HR-LPL activity in either STZ or db/db hearts, utilization of chylomicron-TG increases (174). Hence, the mechanisms that control cardiac LPL during diabetes are complex
and have yet to be completely resolved.
It should be noted that even though LPL may not change
following obesity or diabetes, increased circulating lipoproteins through LPL cleavage could still elevate FA supply to the
cardiac tissue. However, increased concentration could be
offset by changes in lipoprotein composition or lipoprotein
receptor number. Binding of lipoproteins containing apolipoprotein (apo) CII to LPL enhances lipolysis (181), whereas
binding of lipoproteins containing apoCIII or apoE suppresses
LPL activity (1, 2). A recent study has shown that overexpression of HDL-associated apo AV accelerates hydrolysis of
TG-rich lipoproteins, indicating the importance of this apo
lipoprotein in stimulating LPL (166, 188). O’Looney et al.
(181) have shown that induction of diabetes by STZ changes
lipoprotein composition, with reduced apoCII levels, leading to
impaired VLDL-TG lipolysis. A recent study has reported that
H1495
Invited Review
H1496
ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
Limitations of Metabolic Measurements Using
Radiolabeled Substrate
CONSEQUENCES OF ALTERED METABOLISM IN
DIABETIC HEARTS
Impaired Cardiac Function
Emerging evidence supports the concept that alterations in
metabolism contribute toward cardiac contractile dysfunction.
In STZ-induced diabetes, a larger number of studies have
implicated metabolic abnormalities (FA oxidation provides
almost 100% of ATP, with a dramatic decrease of glucose
utilization) in cardiac contractile dysfunction (219, 227, 234,
267). In these animals, contractile failure begins as diastolic
dysfunction, followed by severe systolic dysfunction (196,
219). Normalizing energy metabolism in these hearts reverses
the impaired contractility (40, 176, 248). Animal models of
obesity and Type 2 diabetes also exhibit cardiac dysfunction
associated with altered cardiac metabolism (5, 21, 218). Some
studies have observed both impaired diastolic and systolic
function (3, 218), whereas other studies argue that no change in
systolic function is present (6, 18, 164, 197). This discrepancy
could be due to the severity of diabetes or the methods used to
evaluate cardiac function. In diabetic patients, left ventricular
hypertrophy and impaired isovolumic relaxation and ventricular filling are the most common abnormalities diagnosed (196).
During diabetes, changes in cardiac metabolism occur early
and precede the development of cardiomyopathy. For example,
in STZ-induced diabetes, altered cardiac metabolism is observed as early as 4 days following diabetes induction (88),
whereas evidence of cardiomyopathy is only apparent after
4 – 6 wk. Similarly, in ob/ob and db/db mice, changes in
cardiac metabolism are evident much before confirmation of
cardiac dysfunction (5, 30). To validate the role of altered
metabolism in provoking cardiac dysfunction, several studies
have treated 6- or 9-wk-old db/db mice with either PPAR-␣ or
AJP-Heart Circ Physiol • VOL
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The majority of metabolic data in the above studies were
obtained by using radiolabeled substrate perfusion of isolated
hearts. In these methods, [3H]glucose and [14C]glucose were
used to evaluate glycolysis and glucose oxidation, whereas
[3H]FA or [14C]FA was used to estimate FA oxidation by
measuring the generation of 3H2O and 14CO2. Although this
measurement allows for the manipulation of substrate concentration, there are limitations. First, the substrates used in
perfused hearts do not truly reflect what the heart receives in
vivo. For example, lipoproteins, lactate, and ketone bodies that
are important substrates for the heart in vivo (39, 98, 165) are
rarely used to examine metabolism in perfused hearts. In
addition, most metabolic data of diabetic hearts are obtained by
using normal concentrations of glucose and/or palmitate,
which differ from the elevated concentrations seen in the
diabetic conditions in vivo. Another drawback is that diabetic
hearts always have an elevated intracellular TG pool. Augmented intracellular TG turnover in diabetic hearts could dilute
utilization of exogenous radiolabeled palmitate oxidation, resulting in an underestimation of FA oxidation (180). Finally,
hormonal effects on energy metabolism are usually not considered (20), and lack of hormones in the in vitro perfusate may
contribute to functional abnormalities that are not recapitulated
in intact models.
PPAR-␥ agonists for 3– 6 wk (3, 4, 36). Even though these
treatments normalized cardiac metabolism, they failed to improve cardiac function in these mice, suggesting that metabolism may be unrelated to heart failure or that the treatment was
not initiated in time. Interestingly, when ZDF rats were treated
with a PPAR-␥ agonist at 6 wk of age [when insulin resistance
compared with 6-wk-old db/db mice is milder (37)], improvements of cardiac metabolism and heart function were observed
(272). In a different study, changing cardiac metabolic profile
by treating ZDF rats with PPAR-␥ agonist also improved
contractile function (91). Additionally, overexpression of
GLUT4 in db/db mice not only normalized cardiac metabolism
but also improved heart function (21, 218). These studies
suggest that acute changes in metabolism likely induce early
and reversible damage to cardiac tissue. Even though these
early alterations are inadequate to produce cardiac functional
changes, early interventions would be favored to provide
protection against development of cardiomyopathy in the later
stages of the disease.
The role of abnormal cardiac metabolism in cardiac dysfunction is also supported by studies using transgenic mice.
Overexpression of cardiac PPAR-␣ increased FA uptake and
oxidation (79). The hearts from these transgenic mice exhibit a
metabolic phenotype similar to diabetic hearts (79). Measurement of heart function revealed systolic dysfunction and ventricular hypertrophy in these hearts, indicating that, in the
absence of systemic metabolic disturbances, alteration of cardiac metabolism is sufficient to induce cardiac contractile
dysfunction (79). This concept is further substantiated by
transgenic mice overexpressing cardiac ACS, FATP1, or LPL
(47, 48, 260). These transgenic mice have shown increased FA
uptake, utilization, or lipid accumulation, and these changes
correlated well with contractile dysfunction.
In contrast, several studies have reported that altered metabolism has no impact on contractile function (224, 250). It
should be noted that, in these studies, heart function was
evaluated using a Langendorff heart perfusion. Given that
diabetic hearts exhibit reduced mitochondrial oxidative capacity and cardiac efficiency (28, 106), it is possible that with
increased workload and energy requirement, cardiac function
would be compromised.
In addition to heart dysfunction per se, diabetic patients also
have a greater incidence and severity of angina and acute
myocardial infarction (147). After a myocardial infarction,
diabetic patients have almost twice the rate of mortality compared with nondiabetics (229). Alterations in myocardial energy metabolism during diabetes are probably an important
contributing factor in explaining this increased susceptibility to
ischemic damage. In obese or diabetic animals, increased
ischemic damage is also observed (5, 60, 93, 147), and normalization of cardiac metabolism in hearts from these animals
has been shown to improve functional recovery following
ischemia-reperfusion (147, 224, 270). Interestingly, a number
of studies have also reported contradictory results, with decreased susceptibility to ischemia-reperfusion damage being
reported in STZ or ZDF hearts (145, 150, 236, 249). Although
the mechanisms for this observation are still unclear, decreased
glycolysis and glycolytic products, a lower Na⫹-Ca2⫹ activity,
and a decreased clearance of protons via the Na⫹/H⫹ exchanger have been proposed to explain this inconsistency (75).
Invited Review
ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
H1497
Although changes in metabolism have been implicated in
diabetic cardiac dysfunction, the mechanisms responsible are
still unclear. Several factors have been proposed, and these
include changes in Ca2⫹ homeostasis, decreased cardiac efficiency, lipotoxicity, and myocardial mitochondrial damage
(Fig. 4).
been documented (215, 271). Irrespective of the mechanism,
suppression of SERCA2a and the Na⫹/Ca2⫹ exchanger results
in poor calcium handling associated with impaired heart function (6, 22, 49). Interestingly, overexpression of SERCA2a in
the diabetic heart improved Ca2⫹ handling (243) and cardiac
function (239).
Effects on Ca2⫹ Homeostasis
Decreased Cardiac Efficiency
When compared with glucose, oxidation of FA consumes
more oxygen (2.58 vs. 2.33 ATP/oxygen atom). Cardiac efficiency, the ratio of cardiac work to myocardial oxygen consumption, changes with the type of substrate. Thus, in perfused
hearts, provision of FA decreases cardiac efficiency compared
with when glucose is the sole substrate (31, 162, 245). Additionally, decreased cardiac efficiency is also observed in human or experimental animals with obesity or diabetes (106,
162, 191). This reduction in cardiac efficiency and increased
oxygen demand makes the heart especially vulnerable to damage following increased workload or ischemia. Interestingly,
even though oxidation of FA requires 10% more oxygen
compared with glucose, cardiac oxygen consumption is over
30% higher in ob/ob or db/db mice compared with control
hearts, suggesting that other mechanisms also contribute to
higher oxygen consumption and lower cardiac efficiency (37).
A recent study reported oxygen wasting for noncontractile
purposes in the diabetic heart (106). The mechanisms for this
oxygen wasting are unknown, and uncoupled proteins (UCPs)
are suggested as a potential target. In hearts from STZ-induced
diabetic rats and ob/ob and db/db mice, augmented gene
expression or protein levels of UCP2 or UCP3 have been
reported (30, 102, 170, 171, 268). Other studies demonstrate no
association between change in cardiac UCP protein levels and
the onset of cardiac inefficiency (28, 30). Hence, additional
studies are required to identify the targets that cause oxygen
wasting observed in hearts from obese and diabetic animals.
Lipotoxicity
Fig. 4. Consequences of changes in cardiac metabolism during diabetes. After
insulin resistance or diabetes, augmented cardiac FA uptake promotes FA
utilization and storage, which contributes toward a reduction in glycolysis and
glucose oxidation. As ATP generated through glycolysis is preferentially used
by ion transporters (like Ca2⫹-ATPase), inhibition of cardiac glycolysis impairs intracellular Ca2⫹ homeostasis. High rate of FA oxidation increases
reactive oxygen species (ROS) generation, along with augmented lipid storage,
leading to lipotoxicity and mitochondrial dysfunction. High rate of FA oxidation also increases oxygen demand and reduces cardiac efficiency. All of these
changes can eventually contribute to the development of diabetic cardiomyopathy.
AJP-Heart Circ Physiol • VOL
A number of studies have suggested that excessive FA
overload induces lipotoxicity and contributes to the initiation
and development of cardiomyopathy (194, 272). With the use
of transgenic mice, studies have shown that elevation of FA
uptake or utilization induces lipotoxicity in the absence of any
systemic metabolic disturbance. Cardiac-specific overexpression of LPL or FATP1 significantly increased FA delivery with
ensuing lipid storage, lipotoxic cardiomyopathy, and contractile dysfunction (47, 260). Moreover, elevating FA utilization
by cardiac-specific overexpression of PPAR-␣ or ACS also
causes cardiomyopathy and cardiac dysfunction, similar to that
seen during diabetes (48, 79). Conversely, reducing FA supply
or utilization prevented the development of cardiomyopathy in
obese or diabetic animals. In ZDF or transgenic mice with
cardiac overexpression of LPL, a PPAR-␥ agonist decreased
plasma and cardiac intracellular lipids and ameliorated cardiomyopathy (244, 272). A recent study also demonstrated that
increasing lipoprotein excretion by overexpressing human
apoB reduced cardiac lipids and improved cardiomyopathy
(264). Taken together, these studies provide convincing evidence that augmented FA supply during obesity or diabetes
impairs cardiac lipid homeostasis and leads to lipotoxicity
cardiomyopathy.
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Within the cell, enzymes that catalyze glycolysis are located
close to the sarcoplasmic reticulum and sarcolemma (71, 251),
and ATP generated through glycolysis is preferentially used by
ion transporters [like Ca2⫹-ATPase (SERCA2a) and Na⫹-K⫹ATPase] in these membrane fractions (71, 228, 252). Thus
inhibition of cardiac glycolysis by high rates of FA oxidation
during obesity and diabetes may impair intracellular Ca2⫹
homeostasis, a defect that has been proposed to contribute
toward the development of cardiomyopathy. Altered Ca2⫹
homeostasis can also result from glycolysis-independent mechanisms. For example, decreased cardiac expression of
SERCA2a or Na⫹/Ca2⫹ exchanger have been observed in
Type 1 (99, 126) and Type 2 diabetic animals (22). Although
the mechanisms for this reduction in gene expression are
unclear, several studies have suggested that accumulation of
glucose metabolites due to dissociation of glucose influx and
pyruvate oxidation plays a role (51). Conversely, decreasing
glucose metabolites has been shown to prevent the decrease in
SERCA2a following diabetes (207). In other studies, a decrease in the activity of SERCA2a and Na⫹/Ca2⫹ exchanger,
without any change in expression or protein levels, have also
Invited Review
H1498
ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
Hyperglycemia
In addition to hyperlipidemia-induced lipotoxicity, hyperglycemia also provokes glucotoxicity, which could contribute
to cardiac tissue injury. Hyperglycemia promotes the producAJP-Heart Circ Physiol • VOL
tion of reactive oxygen and nitrogen species, leading to cytochrome c-mediated caspase 3 activation and myocardial apoptosis (32). Hyperglycemia-induced oxidative stress also activates poly(ADP-ribose) polymerase-1 (PARP) (64). Mild
activation of PARP regulates multiple cellular reactions such
as DNA repair, gene expression, and cell survival (246).
However, overactivation of PARP could initiate a series of
cellular processes, leading to cellular damage. Through depletion of NAD⫹, an ATP-consuming process, PARP may cause
energy deficit and cell death (69). PARP, through inhibition of
glyceraldehyde phosphate dehydrogenase (GAPDH), diverts
glucose from glycolytic pathways into alternative fates, including advanced glycation end product (AGE) formation, hexosamine, polyol pathway flux, and protein kinase C (PKC)
activation, which are believed to mediate hyperglycemia-induced cardiac tissue damage (64, 196). In this regard, increased
formation of AGE forms irreversible cross-links with many
macromolecules such as collagen, leading to tissue fibrosis,
inactivation of SERCA2a, and ryanodine receptor calciumrelease channel, impaired cardiac relaxation, contractility, and
ventricular stiffness (26, 27, 35, 54). Increased hexosamine
influx reduces SERCA2a protein levels, resulting in prolonged
calcium transients and delayed myocardial relaxation (51).
Increased hexosamine influx also impairs insulin signal transduction and contributes to insulin resistance (163). Increased
polyol flux is associated with a decrease in intracellular glutathione levels and an augmentation in cell apoptosis (83).
Conversely, inhibition of polyol flux protects hearts from
ischemic injury (125, 198). Finally, activation of PKC-␤2 leads
to left ventricular hypertrophy, cardiac myocyte necrosis, multifocal fibrosis, and decreased left ventricular performance,
resulting in cardiomyopathy (247). Taken together, hyperglycemia, through multiple pathways, causes cardiac cellular and
functional changes, possibly contributing to the development
of cardiomyopathy.
Mitochondrial Dysfunction
Mitochondria are the primary source of energy generation
within cells. Acetyl-CoA generated from FA ␤-oxidation or
glycolysis is used by the tricarboxylic acid cycle for production
of NADH and FADH2. These electron carriers transfer electrons to the mitochondria electron transport chain, where ATP
is ultimately generated. Thus cardiac mitochondrial dysfunction is expected to induce deleterious cellular effects, ultimately leading to heart disease. Indeed, humans with inherited
or acquired mitochondrial defects develop cardiomyopathy
(112, 208). With the use of transgenic mice models, mitochondrial dysfunction is also associated with heart disease. For
instance, knock out of Ant1 (which controls exchange of
mitochondrial ATP with cytosolic ADP) or Tfam (a mitochondrial transcription factor that regulates mitochondrial biosynthesis and gene expression) results in a cardiac energy deficit
and cardiomyopathy (92, 142). Mice with cardiac-specific
deletion of mitochondrial genes involved in FA oxidation also
display a cardiomyopathic phenotype (72, 135). Interestingly,
the opposite is also true with overexpression of PPAR-␣
(which regulates the expression of mitochondrial enzymes
involved in FA oxidation) (79) or PGC1 (which controls
mitochondrial biosynthesis) (139) resulting in mitochondrial
dysfunction and cardiomyopathy. In Type 1 or Type 2 diabetic
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Although limited evidence is available of the existence of
lipotoxicity in human diabetic patients, some studies have
documented similarities between rodent lipotoxicity and the
human metabolic syndrome (240). In a subgroup of patients
with heart failure, Sharma et al. (220) have identified severe
metabolic dysregulation characterized by intracellular TG accumulation and alterations in gene expression, similar to the
lipotoxic rat heart. Increased apoptosis was also detected in
ventricular biopsies from Type 2 diabetic patients (82). Additionally, cardiac PCr-to-ATP ratio was decreased in Type 2
diabetic patients and correlated well with plasma FA concentrations (216).
The mechanisms that mediate cardiac lipotoxicity are still
not completely understood. One potential target is over production of ROS (79). High rate of FA oxidation increases
mitochondrial action potential, leading to augmented ROS
generation. Under normal physiological conditions, ROS is
removed by cellular antioxidants. In the event of excessive
generation of ROS, as observed in STZ-induced diabetic rats,
ZDF rats, and db/db mice (19, 32, 272), it causes cardiomyocyte cell damage and augmented apoptosis. Another potential
mechanism for lipotoxicity is accumulation of lipids, when FA
uptake supercedes its oxidation. Regarding accumulation of
TG, the role of this neutral lipid in inducing contractile dysfunction is still unknown, although a strong association between TG storage and lipotoxicity has been established in both
animal models and human studies (50, 220, 272). Interestingly,
a recent study suggested that TG formation actually provides
protection against the deleterious effects of fatty acyl-CoA
(144). Besides TG, excessive FA also leads to ceramide generation, an intracellular messenger known to trigger apoptosis
(272). Accumulation of ceramide has been found in ZDF rats
(272) or in isolated cardiomyocytes incubated with high fat
(67, 101). Ceramide upregulates inducible nitric oxide synthase
through activation of NF-␬B, leading to increased generation
of nitric oxide and peroxynitrite (241, 272). As a highly
reactive molecule, peroxynitrite causes opening of the mitochondrial permeability transition pore and release of cytochrome c. Additionally, ceramide directly interacts with cytochrome c, leading to its release from the mitochondria (87). As
a consequence, caspase is activated, which initiates the apoptotic pathway in cells. Additionally, with the use of isolated
cardiomyocytes, high FA impairs cardiolipin and leads to
ceramide-independent cell apoptosis (184). Finally, accumulation of FA metabolites has also been associated with insulin
resistance. FA derivatives, such as fatty acyl CoA, diacylglycerol, or ceramide may activate a serine kinase cascade, which
involves protein kinase C-␪ and I␬B kinase-␤ (inhibitor of
NF-␬B kinase-␤), leading to serine phosphorylation of IRS
(44, 114, 128, 129, 269). Following this, tyrosine phosphorylation of IRS and its ability to activate phosphatidylinositol
3-kinase and protein kinase B are compromised (206). Future
studies are required to substantiate the roles of these FA
derivatives in the development of insulin resistance, especially
in the heart.
Invited Review
ABNORMAL REGULATION OF CARDIAC SUBSTRATE METABOLISM IN DIABETES
Summary
In this review, we document that both insulin resistance and
Type 1 and Type 2 diabetes exhibit similar alterations in
cardiac metabolism through extrinsic and intrinsic mechanisms. The predominant change is a suppression of cardiac
glucose utilization and a switch to excessive FA utilization
associated with lipid storage. It should be noted that, in the
majority of these studies, metabolic outcomes were obtained
using ex vivo perfused working hearts. Additionally, only two
substrates (glucose and fatty acid) were present in the perfusion
buffer, and lactate, lipoproteins, ketone bodies, and relevant
hormones were excluded. Hence, cardiac metabolism measured through this method may not reflect the in vivo situation.
Despite these drawbacks, many studies have documented a
strong correlation between altered cardiac metabolism and
cardiac dysfunction observed during insulin resistance or diabetes. This correlation was further substantiated using transgenic mice with lipid oversupply in the absence of systemic
interference. Regarding heart function, both diastolic and systolic dysfunction are observed in Type 1 diabetic animals. This
is likely a consequence of prolonged hypoinsulinemia and
hyperglycemia. With Type 2 diabetic models, there are conflicting reports, with some studies documenting both impaired
systolic and diastolic function, whereas other studies argue
against a change in systolic function. It is possible with Type
2 diabetic models, this discrepancy could be due to the severity
or duration of hyperinsulinemia, and eventual hyperglycemia,
or the techniques used to measure cardiac function. Finally,
during diabetes, changes in cardiac metabolism occur early and
precede the development of cardiomyopathy. Even though
altered metabolism is inadequate to produce cardiac functional
changes at this early time, it is likely that early metabolic
damage is occurring at the cellular or subcellular levels. Overtime, these cumulative defects could be contributing to diabetic
cardiomyopathy. Identification of this early damage could
AJP-Heart Circ Physiol • VOL
facilitate proper interventions and provide protection against
development of diabetic cardiomyopathy in the later stages of
the disease.
GRANTS
This work was supported by operating grants from Heart and Stroke
Foundation of BC and Yukon and Canadian Diabetes Association.
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rats, impaired mitochondrial function has been demonstrated
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