Diabetic Cardiomyopathy
Heart disease is the leading cause of death in patients with diabetes.
1
Although advances in medical management and lifestyle interventions have reduced cardiovascular
mortality in diabetic patients by as much as 40% over the last decade, the actual
number of deaths is predicted to rise as a result of the obesity epidemic (which is
clinically linked to diabetes) and an aging population.
1
The underlying causes of cardiovascular dysfunction in diabetes are complex and include
increased susceptibility to atherosclerosis, vascular dysfunction, dyslipidemia, hypertension,
and the prothrombotic state.
2–7
Furthermore, the results of Framingham, Strong, and other large epidemiologic studies
showed that the incidence of cardiomyopathy is higher in diabetic patients even after
adjustment for hypertension, microvascular disease, hypercholesterolemia, body mass
index, and other risk factors.
8–12
The impairment of left ventricular function in a diabetic patient without underlying
coronary artery disease or hypertension is now recognized as a distinct clinical entity
termed “diabetic cardiomyopathy.”
13–14
Diabetic cardiomyopathy in humans is characterized by diastolic dysfunction, which
is often followed by the development of systolic dysfunction.
15
Echocardiographic analysis of patients with type 1 diabetes mellitus (T1DM) and no
microvascular or macrovascular disease revealed increased left ventricular thickness
and left ventricular end‐diastolic diameter, whereas the ejection fraction was reduced.
16
In a similar study of patients with type 2 diabetes mellitus (T2DM), the prevalence
of diastolic dysfunction was as high as 30%.
17–19
Various rodent models of diabetes have been developed, including streptozotocin‐induced
destruction of pancreatic β cells, genetic deletion of leptin (ob/ob) or leptin receptor
(db/db) in mice, Zucker fatty rat strain, and others. Moreover, wild‐type mice fed
a high‐fat diet (Western diet) develop obesity and insulin resistance reminiscent
of T2DM and metabolic syndrome in humans.
20–21
Notably, all these animal models develop various degrees of cardiac dysfunction that
starts, similar to in human patients, with ventricular thickening and diastolic defects
and may eventually progress to systolic dysfunction.
20
It is important to note that rodents are resistant to atherosclerosis and hypertension
even in the setting of disrupted insulin signaling or lipid homeostasis. Although
there is still considerable debate regarding human diabetic cardiomyopathy as a discrete
disorder or as a complication of diabetic comorbidities (eg, hypertension, elevated
triglycerides), the presence of cardiac dysfunction in these animal models strongly
argues for a direct pathophysiologic link between diabetes and heart disease and also
allows for the study of diabetic cardiomyopathy without the confounding factors commonly
present in human studies.
In the diabetic heart, there is significant disruption of molecular processes essential
for normal cardiac function. First, calcium signaling is impaired, leading to altered
relaxation‐contraction dynamics and the resultant diastolic and systolic dysfunction.
22–24
Second, the diabetic heart shows signs of increased oxidative stress, which damages
structural components of the heart and activates signaling pathways such as NF‐κB,
c‐Jun N‐terminal kinases, and p38 mitogen‐activated protein kinases through oxidative
modifications to select residues.
25–27
Third, endoplasmic reticulum stress and accumulation of unfolded proteins exert significant
toxicity and eventually lead to cardiomyocyte apoptosis.
28–29
Finally, disruption in cytokine signaling and low‐grade inflammation of the heart
further repress cardiac function in diabetes.
30
In addition to these pathways, diabetic cardiomyopathy is being exceedingly recognized
as a metabolic disease of the heart characterized by increased reliance on fatty acids
(FAs) compared with glucose as a source of energy, and the resulting maladaptive changes
of this metabolic switch will be highlighted in this review.
Diabetic Cardiomyopathy as a Metabolic Disease of the Heart
Derangements in cardiac lipid and glucose metabolism are becoming recognized as an
early event in the deterioration of heart function in diabetes. To sustain continuous
contractions, the human heart consumes the largest amount of energy per gram of tissue
in the body, about 6 kg of ATP, or ≈20 times its own weight, per day.
31
This energy can be generated from a variety of substrates, such as fat, carbohydrate,
protein, ketone bodies, or lactate, with 95% of total energy being derived from mitochondrial
oxidative phosphorylation of fatty acids and glucose.
32–34
Oxidation of fatty acids amounts to ≈70% of all ATP produced by the heart under resting
conditions, whereas increased work load such as exercise or adrenergic stimulation
increases the relative contribution of glucose to this process.
32,35
Moreover, the inherent flexibility of the heart to use different types of fuel is
critical for maintaining consistent ATP production with ever‐changing metabolic substrate
availability.
In diabetic hearts, there is a dramatic shift away from glucose utilization and almost
complete reliance on FAs as the energy source, resulting in loss of metabolic flexibility.
In human patients with T2DM and heart failure, a dramatic accumulation of lipids within
the myocardium and restructuring of the lipid metabolic gene expression profile were
observed.
36
In addition, McGavoc et al found intramyocardial lipid deposits in diabetic patients
with normal cardiac function, suggesting that metabolic disturbances may precede the
onset of left ventricular dysfunction.
37
Functionally, positron emission tomography studies of human patients with T1DM revealed
increased myocardial FA utilization, with a concurrent reduction in glucose oxidation,
38–39
and similar findings were obtained in patients with T2DM.
40
Similar to human patients, rodent models of T1DM and T2DM exhibit striking intramyocardial
lipid accumulation, as well as an approximately 2‐fold increase in fatty acid oxidation
and a decrease in glucose use.
41–43
To better understand the contribution of metabolic remodeling to the development of
diabetic cardiomyopathy, mouse models with disruption of select regulatory points
in FA and glucose metabolism were created and studied. It was shown that a decrease
in glucose utilization is detrimental to the heart, as mice with heterozygous deletion
of glucose transporter 4 (GLUT4+/−) and subsequent reduction in glucose delivery to
the cardiomyocytes increased their use of FAs as an energy source and developed a
cardiac phenotype resembling diabetic cardiomyopathy in humans.
44
On the other hand, overexpression of GLUT4 in diabetic db/db mice increased glucose
delivery to the heart and reduced its use of FAs and was protective against the development
of cardiac dysfunction.
42
An increase in FA utilization by the heart through targeted cardiac‐specific overexpression
of human lipoprotein lipase and increased uptake of FAs from circulating very‐low‐density
lipoproteins led to cardiac lipid accumulation and the development of dilated cardiomyopathy.
45
A similar phenotype of cardiac steatosis and reduced heart function was observed in
other mouse models of increased FA utilization either by cardiac‐restricted transgenic
expression of long‐chain acyl coenzyme A (CoA) synthetase 1 involved in FA transport
across membranes,
46
FA transport protein 1 (FATP),
47
or peroxisome proliferator‐activated receptor α (PPARα) transcription factor, which
upregulates the expression of genes involved in FA uptake and oxidation.
48
Thus, the switch from glucose to FA oxidation is an important determinant in the development
of diabetic cardiomyopathy.
Fatty Acid Metabolism in the Heart
The heart has a limited capacity for de novo synthesis of FAs; thus, it primarily
relies on the exogenous supply of FAs from circulation, including albumin‐bound free
FAs and triglyceride (TAG)–rich lipoproteins.
49–50
The rate of FA uptake by the heart is not primarily under hormonal control and instead
is largely determined by the arterial FA concentration, which can range from very
low levels in fetal circulation to >2 mmol/L in an adult with uncontrolled diabetes
and metabolic syndrome.
32,51
Although free FAs can translocate into the cardiomyocyte through passive diffusion
across the plasma membrane, this mechanism demonstrates slow kinetics and is inhibited
by proteases.
52
To facilitate FA uptake, the heart has a protein‐mediated carrier system consisting
of 3 FA transporters: CD36, FATP, and the plasma membrane form of FA‐binding protein.
53
Of these potential carriers, CD36 plays a major role in the translocation of FAs across
the sarcolemmal membrane of cardiac myocytes.
54
Indeed, studies in CD36‐knockout mice demonstrated that CD36‐mediated transport is
responsible for up to 70% of FA uptake into contracting cardiomyocytes.
55
Furthermore, patients with CD36 deficiency have low rates of myocardial FA tracer
uptake, consistent with a key role for CD36 in regulating cardiac FA metabolism in
vivo.
56
Approximately 50% of cellular CD36 is stored in intracellular vacuoles where it can
be recruited to the sarcolemmal membrane to facilitate FA uptake.
57
Muscle contraction, insulin, and several pharmacological agents, including caffeine
and phenylephrine, stimulate CD36 translocation to the sarcolemmal membrane, thereby
facilitating FA uptake.
58
After uptake by the cardiomyocyte, approximately 75% of cytosolic FAs is transferred
into the mitochondria and oxidized for ATP generation, whereas the remainder is converted
to TAG for storage that can be rapidly mobilized for energy purposes based on cellular
demand.
59
Long‐chain FAs cannot freely enter the mitochondria and must be first esterified into
fatty acyl CoA by cytosolic fatty acyl CoA synthetase (FACS). Studies have demonstrated
that FACS is associated with CD36 or FATP on the cytosolic side of the sarcolemmal
membrane, suggesting that FACS also influences FA uptake.
60
Consistent with this finding, overexpression of FACS in the heart or fibroblasts causes
increased FA uptake and intracellular TAG accumulation.
61
The fatty acyl CoAs are then converted to acylcarnitine by carnitine palmitoyltransferase–1
(CPT1) and transported across the inner mitochondrial membrane by a carnitine‐acylcarnitine
translocase that exchanges acylcarnitine for carnitine.
62
Finally, mitochondrial FAs undergo β‐oxidation to yield acetyl CoA, which is then
fed into the tricarboxylic acid cycle for ATP production (Figure 1). The generation
of acetyl CoA and 3 NADH from β‐oxidation also decreases glucose oxidation via the
activation of pyruvate dehydrogenase kinase (PDK) and the subsequent phosphorylation
and inhibition of the pyruvate dehydrogenase (PDH) enzyme complex, allowing the heart
to switch sources for energy production based on nutritional status. This relationship
between FA and glucose metabolism, first described by Philip Randle in 1963, is known
as the glucose–FA cycle or the Randle cycle.
63
Figure 1.
Overview of myocardial fatty acid (FA) metabolism. FAs are imported into the cell
by various FA transporters, including CD36, FA transport protein (FATP), and plasma
membrane FA‐binding protein (FABPpm). Imported FAs may be stored as triglyceride (TAG)
or converted to fatty acyl CoA by FA CoA synthase (FACS). The acyl group of fatty
acid CoA can be transferred to carnitine via carnitine palmitoyltransferase (CPT)
1. The acylcarnitine is then shuttled into the mitochondria by carnitine translocase
(CT), where it can undergo β‐oxidation, producing acetyl CoA, which can be used in
the tricarboxylic acid (TCA) cycle to produce adenosine triphosphate (ATP).
Enzymes involved in FA transport and oxidation are under a high degree of transcriptional
control, particularly by the nuclear receptor transcription factor superfamily known
as the PPARs, with PPARα the dominant isoform in the heart.
64
Activation of PPARα promotes the expression of genes that mediate nearly every step
of FA oxidation, including FA uptake (CD36, FATP), cytosolic FA binding, FA esterification
(FACS), malonyl‐CoA metabolism (malonyl‐CoA decarboxylase), mitochondrial FA uptake
(CPT1), FA β‐oxidation (very‐long‐chain acyl CoA dehydrogenase, long‐chain acyl CoA
dehydrogenase; medium‐chain acyl CoA dehydrogenase; 3‐ketoacyl‐CoA thiolase), mitochondrial
uncoupling (mitochondrial thioesterase 1), and glucose oxidation (pyruvate dehydrogenase
kinase 4 [PDK4]; for a review, see reference
65
). The end result of PPARα activation is increased breakdown of fats via increased
FA flux into the cell and upregulation of enzymes involved in FA β‐oxidation.
48
Another PPAR isoform, PPARγ, is expressed in the heart, and its activation is associated
with increased insulin‐stimulated glucose uptake by peripheral tissue and reduced
hepatic gluconeogenesis.
66–67
However, the use of certain forms of glitazones, which are PPARγ agonists, is associated
with edema, plasma volume expansion, and the development of congestive heart failure,
thus limiting their use.
68–69
Alterations in Lipid Homeostasis in the Diabetic Heart
That both T1DM and T2DM are associated with lipid accumulation and cardiac dysfunction
21,70
is suggestive of a common molecular mechanism for these diseases. In fact, the underlying
pathways for the 2 disorders appear to converge at the point of increased delivery
and utilization of FA for ATP production, although the primary reasons for the overreliance
on lipid as an energy source are distinct.
Early Steps of Metabolic Derangement in T1DM and T2DM
Studies of human patients with T1DM have shown that their hearts remain responsive
to some of the actions of insulin
71
; however, their cardiac glucose uptake is dramatically impaired because of the lack
of insulin production.
72–73
Insulin stimulates glucose uptake by inducing transcription of the GLUT4 glucose transporter
in metabolically active tissues such as liver, heart, skeletal muscle, and adipocytes.
In addition, activation of insulin signaling triggers translocation of GLUT4‐containing
cytoplasmic vesicles to the plasma membrane, thus bringing the transporter to its
site of action.
74–75
In streptozotocin‐induced T1DM animals, GLUT4 levels were significantly reduced in
cardiac and skeletal muscle,
76–77
accounting for the low rates of cardiac glucose uptake that force cardiomyocytes to
rely heavily on FAs as their energy source in the absence of insulin. Notably, ample
amounts of fat are available to the heart in T1DM because of enhanced lipolysis in
adipose tissue, which is normally inhibited by insulin.
78
Although GLUT4 expression was also shown to be reduced in the hearts of T2DM patients,
79
functional studies of their myocardium revealed preservation of insulin sensitivity
and no impairment in glucose uptake in response to insulin.
80–81
Moreover, in the db/db mouse model of T2DM, reduced cardiac glucose oxidation and
increased reliance on FAs preceded the development of insulin resistance and hyperglycemia,
82
suggesting that insulin resistance was not the primary mechanism for the metabolic
switch. It is well recognized that circulating FA and TAG levels are significantly
elevated in patients with T2DM and metabolic syndrome.
83–84
This is because of increased consumption of FAs as a part of the Western diet, which
exceeds adipose tissue capacity for fat storage, increased lipolysis of stored fat,
and enhanced very‐low‐density lipoprotein secretion by the liver. Unlike glucose,
whose entry into cardiomyocytes is tightly controlled by insulin action and the presence
of GLUT4 on the sarcolemmal membrane, FA uptake into the heart is not hormonally regulated
and is largely driven by the availability of lipids in the bloodstream.
53
As a result of high circulating lipid content, the type 2 diabetic heart takes in
disproportionately more FAs and suppresses glucose uptake,
85
as oxidation of FAs that are already present in the cell is sufficient to maintain
normal ATP levels. This results in almost 100% reliance on FAs as the energy source.
In summary, the type 1 diabetic heart is glucose‐starved and forced to oxidize FAs
as an alternative substrate to maintain normal ATP levels. On the other hand, the
heart in the T2DM patient is flooded with fat, leaving little room for glucose oxidation
by the mitochondria. This paradigm is also supported by animal model studies, although
it should be noted that differences in cardiac function exist among rodent models
of T1DM and T2DM (Table 1).
20,86–88
The end result, however, is the same: loss of metabolic flexibility through exclusive
use of fat as the energy substrate.
Table 1.
Differences in Cardiac Function in Diabetic Humans and Among Rodent Models of Types
I and II Diabetes
Obese/Diabetic Patient
ob/ob
db/db
ZDF
STZ
Cardiac size
↑
↑
↑
↑
=
Systolic function
↓
↑↓
↓
↓
↓
Diastolic function
↓
↓
↓
↓
↓
LV hypertrophy
↑
↑
↑
↑
↑
Lipid content
↑
↑
↑
↑
↑
FA oxidation
↑
↑
↑
↑
↑
db/db indicates leptin receptor in mice; FA, fatty acid; LV, left ventricle; ob/ob,
genetic deletion of leptin in mice; STZ, streptozotocin; ZFD, Zucker diabetic fatty.
See text for references.
Common Pathways for Cardiac Dysfunction in Diabetes
Once metabolic preference is given to FAs and the heart moves away from glucose oxidation,
the downstream changes are similar between T1DM and T2DM. This metabolic switch is
mediated by FAs, which activate several signaling cascades to match the rates of FA
and glucose oxidation to the availability of these substrates in the cell. The changes
induced by FAs in cardiomyocytes include inhibition of insulin receptor substrate
1 (IRS1), allosteric suppression of glycolytic enzymes, and transcriptional activation
of fatty acid metabolism genes through PPARα, which collectively lock the heart in
a metabolically inflexible FA‐dependent state.
IRS1 inhibition
Increased accumulation of FAs and their derivatives fatty acyl CoA, diacyglycerol
(DAG), and ceramide dampens insulin signaling through activation of serine kinases
such as protein kinase C, c‐Jun N‐terminal kinases, mammalian target of rapamycin,
and inhibitor κB kinase β.
89–92
Insulin signaling requires phosphorylation of IRS1 by tyrosine kinase phosphatidylinositol
3‐kinase (PI3K).
93
However, phosphorylation of residues adjacent to the PI3K binding sites by serine
kinases displaces PI3K and thus interferes with its ability to activate IRS1.
90,94
The inhibitory effect of free FAs on IRS1 and insulin signaling was demonstrated in
cell culture,
95–96
animal models,
97–99
and human volunteers
100
and may contribute to the development of diabetes in patients with elevated plasma
triglyceride levels.
Glycolysis inhibition
In addition to dampening insulin signaling, the products of mitochondrial FA oxidation
have been shown to repress cellular glucose utilization through allosteric inhibition
of key glycolytic enzymes. First, a high rate of FA oxidation increases the amount
of acetyl‐CoA and NADH relative to free CoA and NAD(+), respectively. Both these metabolites
activate PDK4, an inhibitor of the PDH complex, thus preventing pyruvate oxidation
by the mitochondria.
101–102
Consistently, increased PDK4 levels and activity were found in the hearts of diabetic
rats
103
and in the skeletal muscle of mice fed a high‐fat diet,
104
and cardiac glucose oxidation was also reduced in db/db and ob/ob mice.
82
Metabolic reprogramming by PPARα
Another target of free FAs in cardiomyocytes is the PPARα pathway. As discussed earlier,
PPARα is a transcription factor that increases cellular utilization of FAs by upregulating
a subset of genes that promote FA uptake and β‐oxidation, as well as suppressing glucose
use through the induction of inhibitory proteins.
105–106
Importantly, various saturated and unsaturated FAs were shown to bind to and activate
PPARα in ligand‐binding assays,
107
establishing a direct link between elevated FA levels in cardiomyocytes and the induction
of PPARα signaling. An increase in PPARα expression was reported in almost all rodent
models of diabetic cardiomyopathy, including streptozotocin‐induced T1DM,
108–109
Zucker diabetic fatty rats,
110
and ob/ob and db/db mice,
111
whereas deletion of the PPARα gene protected mice against high‐fat‐diet‐induced diabetes.
112–113
The key role of PPARα induction in the development of diabetic cardiomyopathy is exemplified
by the study by Finck et al,
48
in which cardiac PPARα overexpression in the mouse produced a phenotype that mimicked
diabetic cardiomyopathy in the absence of systemic insulin resistance, hyperglycemia,
or dyslipidemia. Importantly, the hearts from PPARα transgenic mice exhibited increased
rates of palmitate uptake and oxidation, reduction in glucose utilization, accumulation
of intramyocardial lipid droplets, and diastolic dysfunction.
48
The downstream targets of PPARα are significantly upregulated in diabetic hearts and
were shown to be responsible for the development of cardiac dysfunction. Thus, in
streptozotocin‐induced diabetes there was a significant increase in the levels of
CD36 and the plasma membrane form of FA‐binding protein transporters,
114–115
which are responsible for FA uptake into the cell across the plasma membrane. Moreover,
in Zucker diabetic fatty rats
116
and in diabetic mice induced by high‐fat feeding,
117
there was permanent relocalization of inactive CD36 and/or the plasma membrane form
of FA‐binding protein in cytoplasmic vacuoles to the plasma membrane, although the
precise mechanism for this finding is unknown. Consistent with membrane localization
of CD36, diabetic rats exhibited enhanced rates of FA uptake and lipid accumulation
in the heart,
115,118–120
whereas mice with genetic deletion of CD36 were protected against diet‐induced insulin
resistance.
121
Notably, CD36‐knockout hearts exhibited a reduction in FA oxidation and a compensatory
increase in glucose oxidation.
122
Although CD36‐sufficient animals experienced reduced insulin sensitivity and steady
decline in heart function with aging, CD36‐knockout mice had preserved rates of glucose
oxidation and exhibited no drop in cardiac function with age.
123
Finally, deletion of CD36 in the hearts of PPARα transgenic mice reduced myocardial
TAG content, increased glucose oxidation rates, and restored their cardiac function.
124
Another target of PPARα, CPT1, which functions in FA uptake into the mitochondria
for β‐oxidation, was shown to play a role in diabetic cardiomyopathy. In streptozotocin‐induced
diabetic rats, administration of the CPT1 inhibitor methyl palmoxirate in combination
with triiodothyronine, prevented the development of cardiomyopathy and normalized
the levels of long‐chain acylcarnitines in the myocardium.
125
Similar results were obtained with another inhibitor of CPT1, etomoxir, which also
increased cardiac glucose utilization.
126
Finally, in addition to facilitating FA uptake and β‐oxidation, PPARα also suppresses
cellular glucose utilization, thus locking the cell in a FA‐dependent, metabolically
inflexible state. PDK4, an inhibitor of the key glycolytic enzyme PDH, was shown to
be a direct target of PPARα. A study of T1DM and T2DM rats reported increased PDK4
protein level and PDK activity in the heart,
103,127
and similar upregulation of PDK4 was also shown in PPARα transgenic mice.
48
Finally, PDK4 protein was elevated in the skeletal muscle of insulin‐resistant human
subjects
128
and in healthy human volunteers consuming a high‐fat, low‐glucose diet.
129
Consistent with the function of PDK4 in the regulation of glucose oxidation, mice
with a targeted deletion of PDK4 in the heart had lower blood glucose levels and improved
glucose tolerance compared with wild‐type mice after a high‐fat diet.
130
However, PDK4‐overexpressing mice were also found to be resistant to high‐fat diet
through a novel mechanism involving the activation of AMPK and distinctive metabolic
reprogramming.
131
Although the exact contribution of PDK4 to diabetic cardiomyopathy remains to be determined,
its upregulation in diabetic hearts appears to block the ability of the heart to use
glucose as an energy substrate and thus further lock it into a metabolically inflexible
state. Therefore, insulin resistance, lipid accumulation, overreliance on FA metabolism,
and PPARα dysregulation may all contribute to metabolic derangements, resulting in
diabetic cardiomyopathy (Figure 2).
Figure 2.
Pathophysiology of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus on energy metabolism
in the heart. Both T1DM and T2DM lead to insulin receptor substrate 1 (IRS1) inhibition,
peroxisome proliferator‐activated receptor α (PPARα) activation, and suppression of
glycolysis, resulting in metabolic rigidity, reduced adenosine triphosphate (ATP)
generation efficiency, and generation of toxic fatty acid (FA) intermediates. PDK4
indicates pyruvate dehydrogenase kinase 4.
Molecular Pathology in the Diabetic Heart
The metabolic rigidity of the diabetic heart is a well‐recognized phenomenon, but
the exact mechanism by which overreliance on FAs for ATP production culminates in
cardiac pathology remains a subject of intense debate. Several hypotheses have been
proposed, including reduced efficiency of a fat‐burning heart and toxicity of FA metabolites
accumulating in the myocardium.
Metabolic Inefficiency of FA Oxidation
Hearts from diabetic animals, such as ob/ob mice, consume ≥30% more oxygen compared
with nondiabetic hearts, while generating the same or even reduced amounts of contractile
force.
132
The reasons for this metabolic inefficiency of the diabetic heart are multiple and
relate to the underlying disruption of energy balance. First, a substrate switch from
glucose to FAs, even in the absence of pathology, was shown to reduce the efficiency
of oxidative phosphorylation because of increased oxygen consumption.
133
The complete oxidation of 1 molecule of palmitate requires 46 atoms of oxygen and
generates 105 molecules of ATP. On the other hand, glucose oxidation consumes 12 atoms
of oxygen to produce 31 molecules of ATP. Thus, each molecule of ATP that came from
the oxidation of FA costs ≈0.3 oxygen molecules more than the ATP generated from glucose.
134–135
Several experimental studies in nondiabetic animals and humans supported the notion
of reduced metabolic efficiency of fat oxidation in the heart. Perfusion of isolated
mouse working hearts with high concentrations of free FAs resulted in increased myocardial
oxygen consumption. Moreover, acute elevation of FA oxidation in a canine model achieved
by intravenous infusion of a heparin‐TAG mixture also increased cardiac oxygen consumption
by ≈25% with no corresponding change in cardiac power output.
136–137
A reduction in mechanical efficiency of the heart was also observed in healthy human
volunteers with increased circulating free FAs achieved by infusion of a heparin‐TAG
mix.
138
Alternatively, boosting cardiac glucose oxidation was shown to reduce cardiac oxygen
consumption and to improve cardiac efficiency, as exemplified by studies in pigs receiving
intravenous infusions of a glucose‐insulin cocktail.
139
Disproportional reliance on FAs for ATP generation not only requires more oxygen,
but also alters other aspects of cardiac energetics, including cellular ATP shuttling,
noncontractile energy expenditure, and mitochondrial coupling. Long‐chain acyl CoA
derivatives were shown to inhibit the adenine nucleotide translocator required for
the transport of ATP from mitochondria to the cytosol,
140–142
resulting in inefficient energy delivery to myofibrils and potentially affecting cardiac
contractility. FA loading of the heart was also linked to the futile cycling of lipid
intermediates, such as conversion of TAG to fatty acyl derivatives and back to TAG,
presumably as a protective mechanism against free FA toxicity.
135
Although the relative contribution of this pathway to the overall energy expenditure
of the diabetic heart is unknown, in isolated noncontracting cardiomyocytes, futile
cycling of lipid derivatives was shown to consume up to 30% of total cellular energy.
143
Finally, the metabolic switch to FA utilization in diabetes was linked to mitochondrial
uncoupling and reduction in mitochondrial membrane potential by uncoupling proteins
(UCPs) 2 and 3. UCPs were originally identified in brown fat as proteins that dissipate
mitochondrial proton gradient to generate heat, bypassing the ATP synthesis step and
reducing mitochondrial energetic efficiency.
144
Upregulation and activation of UCP2 or UCP3 were reported in the hearts of db/db and
ob/ob mice
82
and streptozotocin‐treated rats,
145
as well as in humans with increased circulating plasma free FAs. UCP2 and UCP3 were
shown to be positively regulated by FAs, as intravenous infusion of lipid in nondiabetic
lean Zucker rats resulted in elevated mRNA levels of UCP2 and UCP3 in the heart.
146
Moreover, treatment of cultured L6 myotubes or neonatal rat cardiomyocytes with free
FAs significantly upregulated the expression of UCP3 and UCP2 proteins, respectively.
147–148
The effects of FAs on UCP expression may be mediated by PPARα, as pharmacologic activation
of this transcription factor was shown to increase the levels of UCP3, whereas PPARα
knockout dramatically decreased UCP3 content in the mouse heart.
149–150
Overall, overreliance on FAs as a metabolic substrate appears to increase oxygen consumption,
uncouple the mitochondria, and alter energy transfer within the myocyte, disrupting
the vital aspects of cardiac physiology.
Lipotoxicity
The dramatic accumulation of intramyocardial lipids in the diabetic heart led to the
hypothesis of “toxic lipids” as mediators of cardiac dysfunction in diabetic cardiomyopathy,
151
and the role of different lipid intermediates in the heart have since been examined.
The accumulation of neutral lipids such as TAG positively correlated with body mass
index and left ventricular hypertrophy in patients with obesity or impaired glucose
tolerance, suggesting that they may play a role in deterioration of cardiac function.
152
However, studies of mice transgenic for diacylglycerol acyltransferase 1 (DGAT1) in
the heart displayed normal cardiac function despite increased accumulation of neutral
TAG in the myocardium, suggesting that increased TAG content itself may not be toxic
to the heart.
153
In fact, when crossed with a mouse model of diabetic cardiomyopathy through cardiac‐restricted
overexpression of ACS, DGAT1 overexpression actually protected the heart from dysfunction.
153
Thus, more toxic lipid intermediates, such as ceramide and DAG, have been implicated.
Accumulation of ceramide and DAG has been demonstrated to alter intracellular signaling
pathways and promote apoptotic cell death.
154–155
In addition to its structural role as a key component of the cell membrane, ceramide
functions as an intracellular messenger that can trigger apoptosis by inducing the
release of cytochrome c from the mitochondria.
156
Moreover, as mentioned earlier, ceramide and DAG desensitize the heart to insulin
action by compromising tyrosine phosphorylation of the IRS and its ability to activate
the PI3K/protein kinase B pathway involved in insulin signaling.
157
Inhibition of ceramide synthesis in transgenic mouse models of lipotoxic cardiomyopathy
improves cardiac structure, function, and metabolism. For example, mice fed a high‐fat
diet and treated with fenretinide, an inhibitor of the rate‐limiting enzyme in ceramide
biosynthesis, had reduced tissue ceramide levels and increased insulin action.
158
In addition, the lipotoxic dilated cardiomyopathy of mice with cardiac‐specific overexpression
of glycosylphosphatidylinositol–anchored lipoprotein lipase was rescued by myriocin,
a serine palmitoyl transferase I inhibitor that blocks the first enzyme in de novo
ceramide synthesis.
159
In a clinical study conducted in Poland that assessed the apoptotic role of ceramides
in the human heart, apoptotic markers were higher in the myocardium of obese and diabetic
patients compared with lean patients. However, ceramide content remained stable among
the groups, and mRNA levels of enzymes involved in both the synthesis and degradation
of ceramides were increased in obese and diabetic patients compared with lean patients,
suggesting that ceramide may not be the main factor in cardiomyocyte apoptosis in
the setting of obesity or diabetes.
160
Therefore, further research is needed to elucidate the role of ceramides in the development
of lipotoxic cardiomyopathy.
In addition to ceramide, the toxic lipid intermediate DAG is known to accumulate in
obesity and diabetes.
161
DAG is a byproduct of lipolysis, derived from TAG hydrolysis via adipose TAG lipase.
DAG is hypothesized to interfere with the cardiac insulin‐signaling cascade by activating
protein kinase C, leading to decreased glucose uptake.
162
Cardiac overexpression of DGAT1, the enzyme that converts the toxic lipid intermediate
DAG to TAG, in a lipotoxic mouse model, prevented cardiac dysfunction, despite increasing
heart TAG levels.
153
In addition, mice fed a high‐fat diet showed a decrease in insulin‐stimulated glucose
oxidation that was positively associated with increased myocardial DAG accumulation
and decreased DGAT expression.
163
However, the effects of DAG on apoptosis remain to be elucidated.
Although the lipotoxic effects of FA accumulation in the heart have been demonstrated
in animal models, limited evidence is available regarding the role of cardiac lipotoxicity
in obese or diabetic humans. This issue is further complicated by the confounding
effects of genetic and dietary variability, as well as risk factors such as physical
inactivity, hypertension, and hyperlipidemia. Ventricular biopsies from type 2 diabetic
patients demonstrate increased apoptosis, consistent with the activation of lipotoxic
mechanisms, although the cause‐and‐effect relationship with toxic lipid species has
not been established.
164
To further elucidate the role of cardiac lipotoxicity in humans, noninvasive in vivo
imaging techniques to track TAG metabolism, such as [1H] magnetic resonance spectroscopy,
will become increasingly important.
Targeting FA Metabolism as a Therapeutic Intervention in Diabetic Cardiomyopathy
The strategy of targeting myocardial metabolism as a therapeutic intervention in the
maintenance of cardiovascular health in diabetes is promising. Diabetic hearts exhibit
increased FA oxidation, decreased glucose utilization, and decreased insulin sensitivity,
and recent data indicate that these changes may be detrimental to cardiac function.
70
In addition to commonly used treatments in T2DM, such as PPAR agonists and metformin,
myocardial substrate utilization can be modulated by indirect and direct approaches
to decrease FA oxidation and increase glucose utilization. Indirect approaches are
aimed at decreasing circulating FA levels, such as by the administration of glucose–insulin–potassium
(GIK) solutions, nicotinic acid, glucagon‐like peptide (GLP)–1 agonists, and β‐adrenergic‐blocking
drugs. Direct approaches include inhibition of FA mitochondrial uptake via suppression
of CPT1, the inhibition of enzymes involved in β‐oxidation, and activation of the
PDH complex through inhibition of PDK (Table 2).
Table 2.
Compounds Targeting Fatty Acid Metabolism as a Treatment for Diabetic Cardiomyopathy
Approach
Class
Examples
Mechanism of Action
References for Human Trials
Direct
Fatty acid (FA) uptake inhibitors
EtomoxirPerhexiline
Irreversible inhibition of CPT1Reversible inhibition of CPT1
165–166
167–170
Malonyl‐CoA decarboxylase (MCD) inhibitors
CBM‐301106
Allosteric inhibition of CPT1 by increasing malonyl‐CoA
None
Mitochondrial β‐oxidation partial inhibitors
TrimetazidineRanolazine
Inhibition of 3‐ketoacyl‐CoA thiolase (3‐KAT)Inhibition of late sodium current, partial
inhibition of FA oxidation
171–175
176–177
Pyruvate dehydrogenase kinase (PDK) inhibitors
Dichloroacetate
Inhibition of a negative regulator of glucose oxidation
178
Indirect
Glucose–insulin–potassium (GIK)
GIK therapy
Increase glucose uptake, decrease circulating plasma free FA (FFA) levels
179–183
Nicotinic acid
Acipimox
Decrease circulating plasma FFA levels through reduction in lipoprotein lipase (LPL)
184–185
Glucagon‐like peptide (GLP)–1 agonists
Liraglutide
Increase insulin secretion, decrease glucagon release, delay gastric emptying
186
β‐adrenoreceptor antagonists (β‐blocker)
Carvedilol
Decrease circulating plasma FFAs, inhibit mitochondrial FA uptake
187–190
It is important to note that, although the concept of decreasing myocardial FA oxidation
to increase glucose oxidation is appealing, the actual process of drug development
is likely to be much more complicated. Targeting different points in metabolic pathways
may result in unanticipated metabolic and nonmetabolic side effects, as energy homeostasis
is intimately linked to an array of other cellular networks. Therefore, extensive
experimentation in animal models and large, randomized, controlled multicenter clinical
trials are needed to properly investigate the effects of these agents in diabetic
patients.
Glucose–Insulin–Potassium
Insulin is a powerful inducer of GLUT1 and GLUT4 expression, which significantly enhance
myocardial glucose uptake and utilization.
191
Because insulin and ischemia increase GLUT4 translocation via independent but additive
mechanisms, it was originally proposed that exposure to insulin during episodes of
ischemia could further increase myocardial glucose uptake at the expense of FA metabolism,
resulting in a lower myocardial oxygen requirement.
192
However, acute administration of insulin alone (in hyperglycemic diabetics) or together
with glucose and potassium (GIK) in an attempt to stimulate glucose disposal and overcome
insulin resistance yielded conflicting results. The Diabetic Patients with Acute MI
study showed that intensive insulin and glucose infusion during acute myocardial infarction
followed by subcutaneous insulin therapy for 3 months after myocardial infarction
reduced mortality in diabetic patients.
179
However, the Polish GIK trial did not demonstrate any decrease in cardiovascular mortality
with GIK,
180–181
and a follow‐up study (Diabetic Patients with Acute MI 2) failed to show any advantage
with intensive insulin therapy.
182
The failure of certain GIK regimens may be because of differential effects on glycolysis
versus glucose oxidation, as GIK disproportionally stimulates glycolysis, leading
to intracellular acidosis.
183
In addition, infusion of glucose into diabetic patients may further exacerbate hyperglycemia,
resulting in cardiomyocyte apoptosis and oxidative stress.
193–194
Therefore, the differences in clinical outcomes with GIK therapy may be a result of
the dosage and timing of GIK administration, the patient population studied, and the
negative effects of hyperglycemia.
Nicotinic Acid
Another indirect therapeutic approach to modulate FA oxidation in the failing heart
is to reduce the circulating levels of FAs. Nicotinic acid and its derivatives such
as acipimox reduce the activity of lipoprotein lipase in adipose tissue, which progressively
decreases plasma levels of FAs, resulting in decreased myocardial FA oxidation.
195–196
Acipimox administration in Zucker diabetic rats decreased plasma free FA, glucose,
and insulin concentrations and improved glucose tolerance.
197
Although acute treatment with acipimox lowered plasma free FAs, reduced myocardial
free FA uptake, and enhanced glucose uptake in patients with dilated cardiomyopathy,
these results were also surprisingly associated with decreased left ventricular stroke
work and mechanical efficiency (work done/oxygen consumption).
184
This may be explained by insufficient increase in glucose uptake to compensate for
the loss of FAs as a substrate, suggesting that FAs are a critical source of energy
that can lead to functional disorders if inhibited by aggressive pharmacological treatment.
Unfortunately, this study did not include a control group or placebo. A more recent
study in patients with ischemic heart failure treated with either acipimox or placebo
for 28 days demonstrated no beneficial effect of acipimox on cardiac function, despite
a significant decrease in plasma FA levels.
185
Taken together, the available evidence suggests that FA lowering by suppression of
lipolysis in adipose tissue does not improve cardiac function in heart failure.
GLP‐1 Agonists
GLP‐1 is a major incretin hormone released from L cells in the gut in response to
food intake to stimulate insulin secretion and reduce glucagon release, leading to
a reduction in blood glucose levels.
198
GLP‐1 receptor agonists are currently used in T2DM patients who are refractory to
oral hypoglycemic agents and have been shown to increase insulin synthesis and secretion,
suppress glucagon secretion, and slow gastric emptying.
199–200
Recent reports have also demonstrated that GLP‐1 therapeutics have beneficial effects
on the cardiovascular system; for example, the GLP‐1 analogue liraglutide improves
cardiac function in db/db mice and streptozotocin‐induced diabetic rats via downregulation
of endoplasmic reticulum stress.
201–202
In addition, GLP‐1 reduced intestinal lymph flow, TG absorption, and the synthesis
of chylomicron‐related apolipoproteins in rats.
203
In the LEAD‐6 trial, liraglutide reduced plasma TG and free FAs in patients with T2DM.
186
In addition to their therapeutic effects on diabetic cardiomyopathy, GLP‐1 receptor
agonists have also been shown to reduce infarct size after coronary ligation in murine
models and improve the left ventricular ejection fraction in patients with heart failure.
204–207
β‐Adrenoreceptor Antagonists
β‐Adrenoceptor antagonists (β‐blockers) are an established, commonly prescribed treatment
for improving the symptoms of angina and as a therapy for patients with ischemic heart
disease. Despite concerns of masking hypoglycemic symptoms and aggravating peripheral
artery disease, β‐blockers are effective for the treatment of hypertension and angina
in diabetic patients.
208
Although their predominant mode of action is to reduce cardiac workload through both
negative inotropic and negative chronotropic effects, some of their beneficial effects
may also be through metabolic modulation.
209
Although short‐term stimulation of β‐adrenergic receptors increases glucose uptake,
glycolysis, and glucose oxidation, long‐term stimulation antagonizes the actions of
insulin, promotes lipolysis, and increases circulating free FA levels, all of which
can exacerbate insulin resistance.
210
By inhibiting catecholamine‐induced lipolysis, β‐blockers may reduce the mobilization
of free FAs from adipose tissue and therefore decrease circulating plasma free FA
concentrations.
211
Long‐term therapy with the β‐blockers metoprolol and carvedilol is known to improve
cardiac function and survival in patients with heart failure through several mechanisms,
including an energy‐sparing effect, consistent with the possibility of a switch in
myocardial substrate preference from FA to carbohydrate oxidation.
187–189
Using radioactive free FA and glucose tracers, heart failure patients with carvedilol
treatment were found to exhibit a 57% reduction in myocardial free FA uptake.
188
Although this study did not note an increase in myocardial uptake of labeled glucose
tracers or in the rate of glucose utilization, the decreased ratio of myocardial free
FA–to–glucose utilization does suggest a “metabolic shift” induced by carvedilol.
It is also important to note that there are differences in the pharmacological effects
and clinical efficacy of various β‐adrenergic receptor antagonists, as seen in clinical
studies demonstrating that administration of carvedilol increased insulin sensitivity
and improved glycemic control compared with metoprolol in patients with hypertension
and T2DM.
190
Inhibitors of Mitochondrial FA Uptake
Several studies have suggested that direct inhibition of mitochondrial fatty acyl
CoA uptake is an effective approach to shift myocardial energy metabolism from free
FA to glucose utilization.
212–214
Several CPT1 inhibitors have been studied for this purpose, including etoxomir and
perhexiline. Originally introduced as an antidiabetic agent because of its hypoglycemic
effects, etomoxir is an irreversible inhibitor of CPT1 that efficaciously inhibits
myocardial FA oxidation and causes reciprocal activation of the PDH complex and glucose
oxidation.
215–217
Furthermore, chronic treatment with etoxomir was shown to induce the expression of
the sarcoendoplasmic calcium ATPase (SERCA) in cardiomyocytes, which may lead to improved
calcium handling and improved cardiac function.
218
Streptozotocin‐induced diabetic rats treated with etomoxir demonstrated increased
myocardial glucose oxidation rates and restoration of cardiac function.
219
Consistent with these animal data, a small open‐label, uncontrolled study of etomoxir
appeared to improve myocardial function and clinical status in patients with heart
failure.
165
However, this study was not able to assess the long‐term effects of etomoxir treatment.
The more recent Etoxomir for the Recovery of Glucose Oxidation randomized placebo‐controlled
study had to be stopped prematurely because several patients with moderate heart failure
in the etomoxir group developed abnormalities in liver function tests.
166
Although the study did not detect significant improvement in the etomoxir group compared
with placebo, there was a trend toward an increase in exercise time.
Perhexiline shifts myocardial substrate utilization from FAs to carbohydrates through
reversible inhibition of CPT1 and, to a lesser extent, CPT2.
213
Perhexiline was originally designated as a calcium channel blocker and was introduced
as an anti‐ischemic agent for the treatment of angina in the 1970s; however, its use
declined rapidly in the 1980s amid reports of hepatic toxicity and peripheral neuropathy.
167
Subsequent studies demonstrated that the toxicity occurred because of chronic exposure
to high drug levels, leading to phospholipidosis in the liver and peripheral nerves.
168
These adverse effects were found to occur most commonly in patients who are “slow
hydroxylators,” bearers of a genetic variant in the P450 2D6 enzyme that is responsible
for perhexiline clearance by the liver.
169
In vitro studies have shown that perhexiline is more effective at inhibiting the cardiac
isoform of CPT1 than the liver isoform, which allows for the use of a lower dose to
minimize adverse effects.
220
Maintaining plasma perhexeline concentration within the therapeutic range of 150 to
600 μg/L prevents the development of long‐term toxicity without compromising drug
efficacy.
170
This has led to a resurgence of the use of perhexiline for the treatment of chronic
stable angina in Australia and some parts of Asia, although it is not yet clinically
available in the United States or Europe.
221
MCD Inhibitors
Malonyl‐CoA decarboxylase (MCD) enzyme promotes FA oxidation by catalyzing the degradation
of malonyl‐CoA to acetyl‐CoA and thus removing allosteric inhibition of CPT1 by malonyl‐CoA.
Cardiac overexpression of MCD protein has been observed in streptozotocin‐induced
diabetic rats, contributing to the high rate of FA oxidation in these animals.
222
Selective MCD inhibitors are effective at increasing myocardial levels of malonyl‐CoA,
leading to a decrease in cardiac FA oxidation with a parallel increase in cardiac
glucose oxidation secondary to inhibition of CPT1.
223
Animal studies using MCD inhibitors have shown that the drug is associated with reduced
FA β‐oxidation, increased glucose oxidation, and increased insulin sensitivity.
224–225
In addition, MCD‐deficient mice have enhanced cardiac function and efficiency, suggesting
that the inhibition of malonyl‐CoA may be an effective method to modulate myocardial
metabolism in diabetics with heart disease.
226
Partial Inhibition of Mitochondrial FA β‐Oxidation
Trimetazidine is a metabolic agent used for antianginal therapy throughout Europe
and Asia.
227
By acting as a competitive inhibitor of 3‐ketoacyl‐CoA thiolase, the terminal enzyme
of β‐oxidation, trimetazidine shifts the energy substrate preference from FA oxidation
to glucose oxidation.
228
The improved coupling of glycolysis and glucose oxidation limits the intracellular
acidosis attributed to glucose metabolism and also minimizes sodium and potassium
overload during ischemia and reperfusion.
229–230
This allows trimetazidine to increase cardiac efficiency during ischemic episodes
by sparing ATP hydrolysis from being used to correct myocardial ionic homeostasis.
The effects of trimetazidine in experimental studies make this drug an attractive
treatment for angina in diabetic patients.
171
This hypothesis was confirmed by the TRIMPOL‐1 trial, in which the addition of trimetazidine
to the treatment regimen improved exercise capacity and duration and reduced anginal
attacks in diabetic patients with chronic stable angina without influencing heart
rate or blood pressure.
172
Subsequent studies have also shown trimetazidine to improve heart function and overall
insulin sensitivity in patients with idiopathic dilated cardiomyopathy.
173–174
However, reports of side effects, such as parkinsonian symptoms and restless leg syndrome,
have recently prompted the European Medicines Agency to restrict use of trimetazidine‐containing
medicine in the treatment of patients with angina to second‐line, add‐on therapy and
to discontinue its use in patients who develop movement disorders.
175
Ranolazine is an antianginal drug used in the United States and some European countries
for the treatment of chronic stable angina, with the additional benefit of glycemic
control.
231–232
Similar to trimetazidine, ranolazine have been shown to suppress FA oxidation in rat
cardiac and skeletal muscle and result in a reciprocal increase in glucose oxidation.
233
Recent reports also implicate the ability of ranolazine to inhibit the late inward
sodium channel, which prevents adverse increases in sodium‐triggered calcium overload
that occur in failing cardiomyocytes.
234
The MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) and CARISA (Combination
Assessment of Ranolazine in Stable Angina) clinical trials demonstrated that ranolazine
is an effective antianginal therapy, alone or in combination with other antianginal
agents, by increasing the time to 1‐mm ST‐segment depression, reducing the number
of angina attacks, and reducing nitroglycerin consumption in both diabetic and nondiabetic
patients.
176–177
Subgroup analysis of the CARISA trial also showed significant reduction of hemoglobin
A1c in diabetic patients treated with ranolazine, consistent with increased systemic
glucose clearance. Ranolazine also decreased the incidence of ventricular tachycardia,
supraventricular tachycardia, and ventricular pauses, likely because of its ability
to inhibit the late sodium current.
235–236
Therefore, ranolazine may be particularly effective in treating heart disease in diabetic
patients.
Reduction in FA‐Induced Inhibition of Glucose Oxidation
Dichloroacetate (DCA) promotes myocardial glucose oxidation at the expense of FA oxidation
by inhibiting the major negative regulator of glucose oxidation, PDK.
237
The PDH complex is normally in its active dephosphorylated state to facilitate glucose
oxidation by directing pyruvate into the tricarboxylic acid cycle. The main mechanism
of long‐term PDH complex inactivation is its phosphorylation by PDK. Therefore, by
inhibiting PDK, DCA increases glucose oxidation. In perfused working rat hearts, DCA
enhanced postischemic recovery of cardiac function by improving the coupling between
glycolysis and glucose oxidation.
238
In addition, DCA restored contractile performance in cardiomyocytes isolated from
streptozotocin‐induced diabetic rats.
239
Another PDK inhibitor, SDZ048‐619, increased PDH complex activity in the liver, kidney,
and skeletal and cardiac muscle of Zucker diabetic rats; however, it did not lower
blood glucose.
240
Although clinical experience with DCA is limited, DCA increased left ventricular stroke
volume and myocardial efficiency in 9 patients with coronary artery disease.
178
Further animal and human studies are needed to better characterize the safety profile
of PDK inhibitors and their relevance in the treatment of cardiac dysfunction in diabetic
patients.
Conclusions
Despite considerable research efforts, we are yet to uncover the precise mechanism
by which molecular changes in cardiac metabolism are linked to the gross pathology
of the diabetic heart. However, the major contribution of metabolic inflexibility
to this process is becoming well recognized,
53
and the model for the development of diabetic cardiomyopathy is emerging. The inciting
event appears to be the increased reliance of the heart on lipid substrates. This
may be a result to reduced glucose availability, as found in T1DM, or increased availability
of FA in circulation in metabolic syndrome and T2DM. Elevated levels of free FAs inside
the cardiomyocyte, while providing ample substrate for ATP generation, also directly
and indirectly affect multiple signaling pathways, including inhibition of insulin
signaling, suppression of glycolysis, and activation of the PPARα transcription factor,
all of which lock the heart in a metabolically rigid state. The diabetic heart thus
can no longer sufficiently increase its glucose utilization in response to elevated
workload requirements, making it more vulnerable to external insults. Moreover, oxidation
of fat brings about myriad other maladaptive changes, including reduced efficiency
of ATP production and export, generation of toxic FA intermediates, and accumulation
of lipids inside the myocardium. As a consequence of these changes, cardiac function
gradually declines, finally manifesting itself as diabetic cardiomyopathy. The therapeutic
strategies to reverse diabetic cardiomyopathy thus must be aimed at restoring the
lipid–glucose balance and preventing metabolic lockdown of the diabetic heart.