Diabetic Cardiomyopathy : The Search for a Unifying Hypothesis

Indu G. Poornima, Pratik Parikh and Richard P. Shannon

Circ Res. 2006;98:596-605
doi: 10.1161/01.RES.0000207406.94146.c2
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2006 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circres.ahajournals.org/content/98/5/596

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation Research is online at:
http://circres.ahajournals.org//subscriptions/

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

Reviews
This Review is part of a thematic series on Adipocyte Signaling in the Cardiovascular System, which includes the
following articles:
Adipose Tissue, Inflammation, and Cardiovascular Disease
Adipocyte Signaling and Lipid Homeostasis: Sequelae of Insulin Resistant Adipose Tissue
Diabetic Cardiomyopathy: The Search for a Unifying Hypothesis
Adipocyte Signaling and the Vasculature
PPAR Activation and Effects on the Vasculature

Phillip Scherer, Guest Editor

Diabetic Cardiomyopathy
The Search for a Unifying Hypothesis
Indu G. Poornima, Pratik Parikh, Richard P. Shannon
AbstractAlthough diabetes is recognized as a potent and prevalent risk factor for ischemic heart disease, less is known
as to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Left ventricular
systolic and diastolic dysfunction, left ventricular hypertrophy, and alterations in the coronary microcirculation have all
been observed, although not consistently, in diabetic cardiomyopathy and are not fully explained by the cellular effects
of hyperglycemia alone. The recent recognition that diabetes involves more than abnormal glucose homeostasis provides
important new opportunities to examine and understand the impact of complex metabolic disturbances on cardiac
structure and function. (Circ Res. 2006;98:596-605.)
Key Words: insulin resistance diabetic cardiomyopathy diastolic function cardiac hypertrophy

he conventional wisdom holds that diabetes causes myocardial contractile dysfunction through accelerated atherosclerosis and hypertension. Much less appreciated and
more controversial is the notion that diabetes mellitus affects
cardiac structure and function, independent of blood pressure
or coronary artery disease. Diabetic cardiomyopathy is a
clinical condition, diagnosed when ventricular dysfunction
develops in patients with diabetes in the absence of coronary
atherosclerosis and hypertension.1 4 Despite the potential
importance of this disease entity, the complex and multifactorial nature of the cellular and molecular perturbations that
predispose to altered myocardial structure and function remain incompletely understood.
The epidemiological link between diabetes mellitus and the
development of heart failure, independent of atherosclerotic
cardiovascular disease, has been evident for the better part of
three decades. The increased risk of heart failure persists in

the diabetic patients after considering age, blood pressure,

weight, cholesterol, as well as history of coronary artery
disease.5,6 Notably, there is a significant association between
diabetes and diastolic dysfunction leading to congestive heart
failure in the absence of impaired systolic function.7,8 More
recently, patients with unexplained idiopathic dilated cardiomyopathy were found to be 75% more likely to have diabetes
than age matched controls.9 The association between diabetes
and cardiomyopathy was strongest among individuals with
microvascular complications of diabetes that parallels the
duration and the severity of hyperglycemia. However, it has
been difficult to ascertain from these epidemiological correlations the causal relationship between the commonly observed metabolic abnormalities and the specific cardiac phenotype. In this review, we provide an update of our current
understanding of the complexities of diabetic cardiomyopathy with a special emphasis on the relationship between the

Original received May 11, 2005; resubmission received October 27, 2005; revised resubmission received December 27, 2005; accepted January 18,
2006.
From the Department of Medicine, Allegheny General Hospital, Pittsburgh; and the Drexel University College of Medicine, Philadelphia, Pa.
Correspondence to Richard P. Shannon, MD, Department of Medicine, Allegheny General Hospital, 320 East North Ave, Pittsburgh, PA 15212. E-mail
rshannon@wpahs.org
2006 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org

DOI: 10.1161/01.RES.0000207406.94146.c2

596
Downloaded from http://circres.ahajournals.org/
by guest on December 20, 2012

Poornima et al

Diabetic Cardiomyopathy

597

Figure 1. The relationship between diabetic metabolic disturbances (triggers)

and the mediators, effectors, and intracellular targets that lead to a diabetic
cardiomyopathic phenotype.

metabolic perturbations that accompany diabetes and the

cellular consequences leading to altered myocardial structure
and function.

Cellular Mechanisms Predisposing to

Diabetic Cardiomyopathy
The 3 characteristic metabolic disturbances evident in diabetic
states are hyperlipidemia (usually in the form of increased
triglycerides and nonesterified fatty acids [NEFAs]) and early
hyperinsulinemia followed by pancreatic -cell failure, leading
eventually to hyperglycemia. Type 1 diabetes differs principally
from type 2 diabetes in that it is unaccompanied by a period of
hyperinsulinemia and is characterized by early- as opposed to
late-onset hyperglycemia. Alterations in body mass (obesity)
and adipocytokines (leptin, adiponectin) have also been implicated in the cardiovascular pathophysiology observed in diabetes. As such, the effects of increased NEFAs, altered insulin
action, and hyperglycemia can be considered triggers to the
cardiac phenotype in diabetes. An understanding of the cellular
effects of these metabolic disturbances on cardiomyocytes
should be useful in predicting the structural and functional
cardiac consequences.
Extensive cellular and molecular studies have identified
putative mediators, effectors, and targets of these metabolic
triggers in the pathogenesis of cardiac dysfunction in diabetes
(Figure 1). We review the cellular signaling pathways associated with these metabolic triggers that lead to altered
myocardial structure and function.

Increased NEFAs
NEFAs play a critical role in triggering the development of
cellular insulin resistance but also have been implicated in the
development of myocardial contractile dysfunction. NEFAs
play a central role in altering cellular insulin signaling

through several mechanisms leading to insulin resistance and

compensatory hyperinsulinemia10 12 (Figure 2). In turn, hyperinsulinemia is an important trigger to the development of
cardiac hypertrophy in diabetic cardiomyopathy (see below).
NEFAs induce the activation of atypical protein kinase C
(PKC) , a serine/threonine kinase that phosphorylates and
subsequently activates IB kinase. IB kinase phosphorylates
serine residues on insulin receptor substrate-1 (IRS-1), inhibiting its ability to bind SH2 domains of the p85 regulatory
subunit of phosphatidylinositol 3-kinase (PI3K), impairing
insulin signal transduction.12 Although this mechanism is
active in skeletal muscle and adipose tissue, it has been less
clear whether similar mechanisms are apparent in cardiac
muscle.
Increases in intracellular NEFAs can also alter insulin
signaling without affecting IRS-1/PI3K activation (Figure 2).
Akt-1 activation is critically dependent on the generation of
phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) to
bind the N-terminal pleckstrin domain and activate membrane bound kinases responsible for the phosphorylation of
serine and threonine residues on Akt-1 that confer catalytic
and regulatory properties.1316 NEFAs are natural ligands for
the nuclear receptor, peroxisome proliferator-activated receptor (PPAR) , and can induce the upregulation of the
phosphatase and tensin homolog deleted on chromosome 10
(PTEN) which dephosphorylates PtdIns(3,4,5)P3, preventing
the activation of Akt-1.16
NEFAs can directly alter myocardial contractility independent of altered insulin action by increasing NEFA flux into
the myocardium.17 Recent evidence18 suggests that increases
in fatty acyl coenzyme A (CoA) esters within cardiac myocytes may modulate the contractile state of the myocardium
by opening of the KATP channel. Activation of the KATP
channel leads to shortening of the action potential and

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

598

Circulation Research

March 17, 2006

Figure 2. Role of increased NEFAs in the

pathogenesis of cellular insulin resistance. There are several putative mechanisms including the induction of atypical
PKC, phosphorylation, and activation of
IB kinase which serine phosphorylates
and deactivates IRS-1. NEFAs may also
activate the phosphatase PTEN,
decreasing the tris-inositol phosphates
to which the pleckstrin domain of Akt-1
binds. Finally, NEFAs can contribute to
ceramide production, triggering cellular
apoptosis.

reduces transsarcolemmal calcium flux and subsequently

myocardial contractility.
Finally, the increased intracellular accumulation of NEFAs
may directly contribute to cell death under circumstances in
which accumulating intracellular NEFAs do not undergo
oxidation. The reaction between palmityol-CoA, an intracellular intermediate of NEFAs, and serine leads to the generation of the sphingolipid ceramide, and this reaction may be
facilitated by the cytokine, tumor necrosis factor (TNF) .19
Ceramide can induce cellular apoptosis through the induction
of nuclear factor B, caspase 3 activation, and cytochrome c
release and can inhibit DNA repair by blocking poly (ADP
ribose) polymerase.20 Under these circumstances, increased
NEFAs are said to cause lipotoxicity.17 Although lipotoxicity
has been implicated in the reduction in pancreatic -cell
reserves, the relevance of these findings in the myocardium
remain controversial.
Thus, NEFAs play a central role not only in inducing
cellular insulin resistance but also in directly affecting myocardial contractility and, under specific circumstances, in the
promotion of cardiomyocyte cell death.

manifest cellular insulin resistance. In this regard, the mitogenic actions of insulin on myocardium during chronic
systemic hyperinsulinemia bear directly the commonly observed finding of cardiac hypertrophy in diabetic
cardiomyopathy.2123
There are at least 3 cellular mechanisms whereby hyperinsulinemia mediates cardiomyocyte hypertrophy (Figure 3).
Acutely, insulin stimulates growth through the same PI3K/
Akt-1 pathway by which it mediates glucose uptake. Akt-1
phosphorylates and inactivates glycogen synthases kinase-3
(GSK-3), a well-recognized inhibitor of nuclear transcription governing the hypertrophic process via the nuclear factor
in activated lymphocytes (NFAT-3).25,26 In addition, Akt-1

Hyperinsulinemia
Cellular insulin resistance may presage frank diabetes by a
decade or more and requires compensatory increases in
plasma insulin levels to maintain glucose homeostasis in the
face of impaired cellular insulin action, principally in skeletal
muscle and liver.10 The nature and extent of the cellular
insulin resistance may be selective to certain organ systems
and may vary in terms of the metabolic, mitogenic, prosurvival, and vascular actions of insulin.
How then can hyperinsulinemia cause cardiac hypertrophy2124 if the cellular actions of insulin are attenuated? The
paradox is reconciled by the recognition that systemic hyperinsulinemia may accentuate cellular insulin action in insulin
responsive tissues, such as the myocardium, that do not

Figure 3. Alternative pathways whereby compensatory hyperinsulinemia contributes to myocyte hypertrophy through the sympathetic nervous system activation and MAP kinase/ERK pathways at a time when insulin receptor mediated Akt-1 activation
is impaired.

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

Poornima et al
TABLE 1.

Diabetic Cardiomyopathy

599

Alternative Metabolic Fates of Glucose Leading to Cardiac Structural and Functional Abnormalities in Hyperglycemia

Mediators

Mechanisms of Action

Consequences

Increased AGE41 44

Crosslink RyRs41; crosslink type III collagen42,44

Decreased SR calcium release and myocyte contractility;

increased ventricular stiffness; impaired ventricular filling

Increased hexosamine flux45,46

Sp1-O-GluN acylation of transcription factors decreasing Prolonged calcium transients; impaired relaxation
SERCA2a expression45

Increased polyol flux47,48

Decreased regeneration of reduced glutathione leading

to oxidative stress; increased DNA fragmentation47;
sorbitol-induced AGEs48

Increased myocyte apoptosis; increased ventricular

stiffness

Increased protein kinase C activation4951

Increased cardiac hypertrophy; increased extra cellular

matrix; decreased SERCA 2a function51

Impaired relaxation; increased ventricular stiffness

AGE indicates advanced glycation end products; SR, sarcoplasmic reticulum.

activates the mammalian target of rapamycin (mTOR) that

activates the p70 ribosomal subunit S6kinase-1, leading to
increased protein synthesis.2730 However, these mitogenic
actions mediated through the insulin receptor may be mitigated when insulin signaling through the PI3K/Akt-1 pathway is impaired during chronic hyperinsulinemia
However, chronic hyperinsulinemia may augment myocardial Akt-1 activation indirectly through increased sympathetic nervous system activation.26,3133 Recent evidence suggests that chronic Akt-1 activation in cardiac myocytes is
mediated through 2-adrenergic receptors via protein kinase
A and Ca2-calmodulin dependent kinase (CaMK),26 and
these mechanisms may predominate when insulin signaling is
attenuated through the PI3K pathway.
In addition, there are other insulin-mediated, but Akt-1
independent, pathways that may be operative, most notably
the extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinase pathways.34,35 Significant cellular evidence exists for an insulin-induced activation of the
p38 MAP kinase pathway,34 as well as prenylation of both
Rho and Ras in the setting of hyperinsulinemia, leading to
myocyte hypertrophy and expansion of the extracellular
matrix (Figure 3). These redundant pathways provide a strong
mechanistic basis for the development of cardiac hypertrophy
associated with chronic hyperinsulinemia as an early accompaniment of type 2 diabetes, even though the glucoregulatory
effects of insulin are attenuated.

summarizes the effects of these alternative biochemical fates

of glucose on cardiac structure and function in states of
hyperglycemia.4151 Taken together, these data provide mechanistic evidence linking hyperglycemia to altered expression
and function of both the ryanodine receptor (RyR) and
sarco(endo)plasmic reticulum Ca2-ATPase (SERCA2) that
may contribute to decreased systolic and diastolic function. In
addition, hyperglycemia contributes to altered cardiac structure through posttranslational modification of the extracellular matrix.

Cardiac Phenotypes in Experimental Models

of Type 1 and Type 2 Diabetes Mellitus
The altered cardiac phenotypes associated with diabetic
cardiomyopathy have been investigated in a wide array of
experimental animal models.52,53 From a mechanistic perspective, the manifestations of diabetic cardiomyopathy
should be predictable based on the duration and the severity
of the abnormalities in NEFAs, insulin, and glucose homeostasis. However, the experimental conditions under
which the models are studied add significant complexity to
our understanding. In particular, the nature of the available
substrates and hormonal milieu may be limited in isolated
myocytes or isolated heart preparations and contribute to
functional abnormalities that are not recapitulated in intact
models. Table 2 summarizes the biochemical, structural, and
functional abnormalities reported in these models.

Hyperglycemia
The mechanism whereby hyperglycemia mediates tissue injury through the generation of reactive oxygen species has
been elucidated largely through the work of the Brownlee and
colleagues.36 38 Hyperglycemia leads to increased glucose
oxidation and mitochondrial generation of superoxide.37,39,40
In turn, excess superoxide leads to DNA damage and activation of poly (ADP ribose) polymerase (PARP) as a reparative
enzyme.36 However, PARP also mediates the ribosylation and
inhibition of glyceraldehyde phosphate dehydrogenase
(GAPDH), diverting glucose from its glycolytic pathway and
into alternative biochemical pathways that are considered the
mediators of hyperglycemia induced cellular injury. These
include increases in advanced glycation end products
(AGEs), increased hexosamine and polyol flux, and activation of classical isoforms of protein kinase C. Table 1

Models of Hyperglycemia
Without Hyperinsulinemia
Streptozotocin (STZ) and alloxan are the 2 of the most
common islet cell toxins that are used to induce type I
diabetes in experimental animal models. The metabolic features52,53 include the prompt development of profound hyperglycemia (25 to 30 mmol/L), modest hypertriglyceridemia
(200 to 400 mol/L), ketosis, and markedly reduced plasma
insulin levels (20 pmol/L). As such, the model is particularly useful in examining the effects of hyperglycemia in the
absence hyperinsulinemia.
STZ- and alloxan-induced diabetes have been associated
with myocardial atrophy as opposed to hypertrophy.54,55 This
is associated with loss of contractile proteins, myocyte
dropout without reparative fibrosis,56 consistent with the

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

600

Circulation Research
TABLE 2.

March 17, 2006

Metabolic and Cardiac Phenotypes in Experimental Models of Diabetic Cardiomyopathy

Biochemical

Morphological

Functional

Hyperlipidemia

Hyperinsulinemia

Hyperglycemia

Cardiac
Mass

Fibrosis

Intramyocardial
Lipids

Systolic

Diastolic

Coronary
Flow

11

111

11

22

22

ob/ob

11

db/db

11

11

ZF

11

11

11

ZDF

11

11

111

OLETF

11

11

11

Model
Type 1 diabetes
STZ/Alloxan
Type 2 diabetes

Humans

%, 2*

%, 2*

11

11

2, %*

11

2, %

22

222

22

*Only cardiac power was reduced. 1 indicates increase; 2 decrease; 1 arrow, mild; 2 arrows, moderate; 3 arrows, severe; %, no difference.

absence of the mitogenic and prosurvival effects of insulin.

Decreases in cardiac mass have also been noted with cardiac
specific knockout of the insulin receptor57 associated with
ventricular dilatation and impaired left ventricular (LV)
systolic performance. There has been consistent evidence of
intramyocardial lipid accumulation reflecting a compensatory
shift in myocardial preference for fatty acids in the absence of
insulin mediated glucose uptake.54,56
Alterations in SERCA2 have been reported in association
with the hyperglycemia in STZ induced diabetes leading to
decreased SR calcium sequestration and intracellular calcium
overload.54,55 Decreases in contractile proteins such as
-actin and myosin ATPase activity54,55 have also been noted
in association with shifts in myosin heavy chain isoforms
from to ,53,54,58,59 contributing to decreased systolic
tension development.
The functional consequences of these cellular effects have
been studied in cardiomyocytes, isolated perfused hearts and
in vivo in rats with STZ induced diabetes. Abnormalities in
diastolic function (increased LV end-diastolic pressure and
operating chamber stiffness) can be observed in isolated heart
preparations within 7 days, with significant decreases in LV
systolic pressure, LV developed pressure, and LV dP/dt max
evident within 3 weeks56 and progressing to profound systolic
function over 1 year.60 62 Notably, these impairments in
diastolic and systolic dysfunction occur in the absence of
significant changes in myocardial perfusion.56,60 These important observations indicate that diastolic abnormalities,
both impaired relaxation and increased stiffness, occur in the
absence of hypertrophy and precede by weeks the onset of
systolic dysfunction.60 Equally important is the observation
that administration of insulin in type 1 diabetic rats partially
corrects the systolic abnormalities in association with restoration of contractile proteins, even though modest hyperglycemia persists.61,62
These studies suggest that experimental type 1 diabetes,
characterized principally by hyperglycemia is associated with
altered calcium handling, impaired diastolic function, altered
contractile proteins, and progressive systolic dysfunction as
the magnitude and duration of the hyperglycemia progresses.54,55,58,59 These abnormalities occur in the absence of

myocyte hypertrophy or fibrosis. The findings are consistent

with a dominant influence of hyperglycemia and the absence
of the influence of insulin. Thus, hyperglycemia alone is
sufficient to account for the functional, but not necessarily the
structural, changes observed in diabetic cardiomyopathy.

Models of Hyperinsulinemia With or

Without Hyperglycemia
Models of type 2 diabetes are metabolically distinct from type
1 diabetes largely related to increased plasma insulin levels
associated with altered cellular insulin action. Increased
NEFAs and marked hyperinsulinemia are early accompaniments, whereas hyperglycemia is a later development attributable to exhaustion of pancreatic -cell reserves. However,
the cardiac manifestations in experimental models of type 2
diabetes vary considerably based on the onset and severity of
these metabolic perturbations, as well as the complex interactions of intramyocardial lipids, insulin, and glucose on the
cardiomyocyte structure and function.
Many of the commonly used experimental models of type
2 diabetes are associated with obesity caused by genetic
perturbations in the Ob gene and its product, leptin.63 67
Leptin is a 16-kDa peptide produced by adipocytes that acts
via specific receptors on the hypothalamus to inhibit food
intake and increase energy expenditure. Notably, leptin receptors have been identified in the rat myocardium63,64 and
regulate fatty acid oxidation independent of effects on the
acetyl CoA-malonyl CoA axis.65 Leptin has also been shown
to stimulate myocyte hyperplasia in rats66 and humans67
through both PI3-K and ERK1/2-dependent mechanisms,
similar to insulin. The metabolic phenotype associated with
both leptin-deficient (ob/ob) and the leptin receptor deficient (db/db) mice include obesity, insulin resistance,
compensatory hyperinsulinemia, hypertriglyceridemia, and
various degrees of hyperglycemia.
The cardiac phenotype of the ob/ob (leptin-deficient)
mice has been studied both early and later in its development
with varying results. There is evidence of LV hypertrophy
and intramyocardial lipid accumulation both early68 and
late,69 suggesting that hyperleptinemia is not necessary for the

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

Poornima et al
development of LV hypertrophy. At 3 months with normal
fasting glucose but impaired glucose tolerance, LV systolic,
diastolic, and developed pressures are normal, but there is
evidence of decreased cardiac power in isolated, working
heart preparations.68 Notably, the degree of functional impairment varies depending on the concentrations of palmitate and
insulin in the perfusate.69 In contrast, LV systolic function is
preserved at both 3 months70 and 6 months71 when intact
ob/ob mice are studied in vivo by echocardiography,
whereas impaired diastolic function has been noted in some
studies.
The hyperleptinemic db/db (leptin receptor deficient)
mice have a similar metabolic phenotype, but more profound
hyperglycemia (30 to 50 mmol/L) manifest earlier in development. The hyperglycemic db/db mice have no cardiac
hypertrophy at 3 months,72 despite combined hyperinsulinemia and hyperleptinemia, but develop LV hypertrophy
later.69 In isolated working hearts, db/db mice have normal
LV systolic and developed pressures but increased ventricular
stiffness and impaired cardiac power.72 However, systolic
function is preserved in db/db mice at 6 months when
studied in vivo.69 The conflicting data as to the nature and
extent of cardiac functional abnormalities between working
heart and intact preparations can be reconciled by considering
differences in substrate availability between the preparations.
Hormone and substrate concentrations are limited in the
isolated, crystalloid perfused hearts,68,72 whereas alternative
substrates (lactate and pyruvate) and metabolic hormones are
available in physiological concentrations in the intact models.69 Under circumstances in which a full array of substrates
is available, LV systolic function is preserved. Notably, both
models are associated with the development of cardiac
hypertrophy independent of plasma leptin levels or action,
suggesting that hyperleptinemia is not necessary for the
development of cardiac hypertrophy in type 2 diabetes.
Finally, in contrast to the cardiac phenotype in models of type
1 diabetes, systolic performance is largely preserved even in
the presence of profound hyperglycemia, provided that insulin is present. Instead, myocardial hypertrophy is the most
commonly observed abnormality with increased chamber
stiffness seen in some cases.
A similar evolution in cardiac phenotype is evident in
genetically engineered rat models involving the absence of a
functional leptin receptor. The Zucker fatty (ZF) rat is
characterized metabolically by hyperleptinemia and consequent obesity, hyperlipidemia, and marked hyperinsulinemia
with the late onset of hyperglycemia. As such, the model is
characteristic of obesity and insulin resistance early (3 to 6
months). In contrast, the Zucker diabetic fatty (ZDF) rat has
a similar genetic background but demonstrates earlier hyperglycemia, consistent with metabolic features of type 2
diabetes.
The morphological features of the ZF rat include increased
intramyocardial lipid and increased myocardial mass.7375
Hypertrophy is evident in individual myocytes75 and whole
hearts83 where there is an associated expansion in the extracellular matrix.76 However, cardiac functional abnormalities
have been observed inconsistently in isolated heart preparations with decreased cardiac power73 and systolic wall stress74

Diabetic Cardiomyopathy

601

in some studies, whereas LV pressures and LV dP/dt77 and

the rate-pressure product78 are maintained in others. Diastolic
abnormalities have been noted early with prolonged isovolumic relaxation,76 whereas chamber stiffness was reported to
be normal at 12 months.74
In contrast to the ZF rats, the ZDF rats do not demonstrate
consistent increases in cardiac mass.79 81 At 2 months, there
is increased mass in the presence of marked hyperinsulinemia
at a time when glucose levels are normal.82 However, by 3
months, there is no increase in mass when plasma glucose
levels are high (27 mmol/L) and plasma insulin levels are
reduced.80 Fredersdorf et al83 established the importance of
the balance between hyperglycemia and hyperinsulinemia in
5-month old ZDF rats by controlling hyperglycemia with
exogenous insulin and demonstrating increased cardiac mass,
whereas ZDF rats that remained persistent hyperglycemic had
no increase in mass. In isolated heart preparations, the
magnitude of systolic dysfunction in ZDF rats tends to be
greater when accompanied by severe hyperglycemia.79,82
These effects are dependent on the substrate availability in
the perfusate.79 In contrast, studies in intact ZDF reveal intact
systolic function83 85 myocardial hypertrophy,83 impaired
flow reserve,84 and diastolic relaxation.85
Thus, hyperinsulinemic ZF rats have myocardial hypertrophy and variable degrees of diastolic abnormalities, whereas
the diabetic ZDF rats have smaller increases in cardiac mass
and impairments in LV systolic function in isolated hearts but
not intact models. These findings are consistent with the
cellular effects of hyperinsulinemia to induce cardiac hypertrophy in contrast to the effects of hyperglycemia that
mitigate hypertrophy and affect systolic dysfunction to a
greater extent. Whether the observed abnormalities in diastolic function are a consequence of hypertrophy or hyperglycemia remains unresolved.

Models of Increased Intramyocardial Lipid

Without Hyperinsulinemia or Hyperglycemia

The model of cardiac specific overexpression of PPAR in

mice is associated with cardiac contractile dysfunction that is
mediated by increased NEFA uptake and intracellular accumulation.86,87 Although the cardiac phenotype is dramatic
both at baseline and in response to a superimposed cardiac
insult, the model does not possess characteristic features of
diabetes. However, this model is particularly useful in studying the contribution of excess intracellular lipid accumulation
to cardiac contractile dysfunction, in the absence of hyperglycemia and hyperinsulinemia.86 Recent data using transgenic murine models of cardiac specific overexpression of
fatty acid transport protein (FATP) demonstrated a cardiac
phenotype that features diastolic dysfunction.88 Taken together,
it is abundantly clear that increased circulating NEFAs, a
ubiquitous feature of both type 1 and 2 diabetes, contribute
fundamentally not only to the development of both insulin
resistance and compensatory hyperinsulinemia but also can
directly affect cardiac function.

Cardiovascular Manifestations in Humans

With Type 1 and Type 2 Diabetes
The most commonly observed cardiac abnormalities in clinical studies of asymptomatic diabetics included LV hypertro-

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

602

Circulation Research

March 17, 2006

Figure 4. Schematic illustration of a unifying hypothesis that links NEFAs, hyperinsulinemia, and hyperglycemia to the
structural and functional phenotypes in
diabetic cardiomyopathy.

phy and impairment in both isovolumic relaxation and ventricular filling, particularly among diabetic women.9,89,90
Recently, there is evidence to suggest that this gender
preference may relate to estrogen-induced activation of Akt-1
and its transcriptional effects in cardiomyocytes.91,92 In addition, clinical studies have demonstrated consistent abnormalities in coronary flow reserve in patients with diabetes in the
absence of epicardial coronary artery disease.70,9396 Both
findings correlate closely with microvascular complications,
particularly autonomic dysfunction.95,96 What is surprising is
the fact that the clinical manifestations are similar in both
type 171,97,98 and type 293 diabetics. How do we reconcile
these clinical findings with the phenotypic distinction noted
in experimental animal models? The principal explanation
involves the fact that type 1 diabetic patients are treated with
insulin and are therefore not truly hypoinsulinemic as in the
STZ models. Insulin has been shown to mitigate systolic
dysfunction in STZ-induced diabetes in rats.61 Notably,
systolic dysfunction at rest and during exercise in type 1
diabetes is observed most commonly in patients with microvascular complications, a reflection of poor glycemic
control.98

Unifying Hypothesis
There is an extensive body of epidemiological, clinical, and
experimental evidence that supports the existence of a distinct
form of cardiomyopathy related to pathogenic cellular and
molecular changes that accompany diabetes mellitus. Figure
4 provides a unifying hypothesis as to the relationship
between the common metabolic perturbations in diabetes and
altered cardiac phenotypes. Specifically, the magnitude of
ventricular hypertrophy may depend on the magnitude and
duration of hyperinsulinemia that, in turn, may depend on
magnitude and distribution of increasing NEFAs. In contrast,

the extent of systolic dysfunction may depend more on the

magnitude and duration of hyperglycemia and the presence or
absence of insulin. Diastolic abnormalities may occur as a
consequence of either hypertrophy or hyperglycemia. As
such, hypertrophy and diastolic abnormalities are observed
most commonly and earlier than systolic abnormalities and
thus dominate the clinical findings. The paradigm reconciles
the distinctive cardiovascular features attributable to type 1
(hypoinsulinemic/hyperglycemia3systolic dysfunction) and
type 2 (hyperinsulinemic/hyperglycemic3hypertrophy and
diastolic dysfunction) diabetes in experimental models studied in vivo. In humans with type 1 diabetes, systolic dysfunction is less evident than in STZ-induced models because these
patients receive exogenous insulin, making them metabolically akin to a type 2 diabetic from this mechanistic
perspective. These findings are generally consistent with the
established cellular consequences of increased NEFAs, hyperinsulinemia, and hyperglycemia on cardiac structure and
function. These insights afford the opportunity to design
therapeutic approaches targeted at specific pathogenic mechanisms including suppression of lipolysis, maturation of
adipocytes, and restoration of cellular insulin action, in
addition to the traditional target of maintaining euglycemia.

Acknowledgments
This work has been supported in part by US Public Health Service
grants NIH R01-HL75836 and R01-AG 023125. I.G.P. is the
recipient of a Beginning Grant in Aid from the Pennsylvania
Delaware Affiliate of the American Heart Association (AHA0465484U), and P.P. is the recipient of a Post-Doctoral Fellowship
Grant from the Pennsylvania Delaware Affiliate of the American
Heart Association (AHA-0525596U).

References
1. Francis GS. Diabetic cardiomyopathy: fact or fiction? Heart. 2001;85:
247248.

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

Poornima et al
2. Picano E. Diabetic cardiomyopathy. The importance of being earliest.
J Am Coll Cardiol. 2003;42:454 457.
3. Avogaro A, Vigili dKS, Negut C, Tiengo A, Scognamiglio R. Diabetic
cardiomyopathy: a metabolic perspective. Am J Cardiol. 2004;93:
13A16A.
4. Adeghate E. Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell
Biochem. 2004;261:187191.
5. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart
failure: the Framingham Study. J Am Coll Cardiol. 1993;22:6A13A.
6. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive
heart failure: the Framingham study. Am J Cardiol. 1974;34:29 34.
7. Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R,
Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL;
Cardiovascular Health Study Research Group. Importance of heart
failure with preserved systolic function in patients or 65 years of
age. CHS Research Group. Cardiovascular Health Study. Am J
Cardiol. 2001;87:413 419.
8. McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of
heart failure. Heart. 2000;83:596 602.
9. Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic
cardiomyopathy: a nationwide case-control study. Diabetes Care.
2003;26:27912795.
10. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest.
2000;106:171176.
11. Birnbaum MJ. Turning down insulin signaling. J Clin Invest. 2001;
108:655 659.
12. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li
ZW, Karin M, Perret P, Shoelson SE, Shulman GI. Prevention of
fat-induced insulin resistance by salicylate. J Clin Invest. 2001;108:
437 446.
13. Brazil DP, Hemmings BA. Ten years of protein kinase B signalling:
a hard Akt to follow. Trends Biochem Sci. 2001;26:657 664.
14. Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation,
survival and insulin responses? J Cell Sci. 2001;114:29032910.
15. Morisco C, Zebrowski D, Condorelli G, Tsichlis P, Vatner SF,
Sadoshima J. The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by betaadrenergic receptor stimulation in cardiac myocytes. J Biol Chem.
2000;275:14466 14475.
16. Schwartzbauer G, Robbins J. The tumor suppressor gene PTEN can
regulate cardiac hypertrophy and survival. J Biol Chem. 2001;276:
35786 35793.
17. Unger RH, Orci L. Lipotoxic diseases of nonadipose tissues in
obesity. Int J Obes Relat Metab Disord. 2000;24(suppl 4):S28 S32.
18. Liu GX, Hanley PJ, Ray J, Daut J. Long-chain acyl-coenzyme A esters
and fatty acids directly link metabolism to K(ATP) channels in the
heart. Circ Res. 2001;88:918 924.
19. Halse R, Pearson SL, McCormack JG, Yeaman SJ, Taylor R. Effects
of tumor necrosis factor-alpha on insulin action in cultured human
muscle cells. Diabetes. 2001;50:11021109.
20. Zhang DX, Fryer RM, Hsu AK, Zou AP, Gross GJ, Campbell WB, Li
PL. Production and metabolism of ceramide in normal and ischemicreperfused myocardium of rats. Basic Res Cardiol. 2001;96:267274.
21. Ilercil A, Devereux RB, Roman MJ, Paranicas M, OGrady MJ, Lee
ET, Welty TK, Fabsitz RR, Howard BV. Associations of insulin levels
with left ventricular structure and function in Am Indians: the strong
heart study. Diabetes. 2002;51:15431547.
22. Iacobellis G, Ribaudo MC, Zappaterreno A, Vecci E, Tiberti C, Di
Mario U, Leonetti F. Relationship of insulin sensitivity and left
ventricular mass in uncomplicated obesity. Obes Res. 2003;11:
518 524.
23. McNulty PH. Insulin resistance and cardiac mass: the end of the
beginning? Obes Res. 2003;11:507508.
24. Ueno M, Carvalheira JB, Tambascia RC, Bezerra RM, Amaral ME,
Carneiro EM, Folli F, Franchini KG, Saad MJ. Regulation of insulin
signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia. 2005;4:
506 518.
25. ONeill BT, Abel ED. Akt1 in the cardiovascular system: friend or
foe? J Clin Invest. 2005;115:2059 2064.
26. Morisco C, Condorelli G, Trimarco V, Bellis A, Marrone C,
Condorelli G, Sadoshima J, Trimarco B. Akt mediates the cross-talk
between beta-adrenergic and insulin receptors in neonatal cardiomyocytes. Circ Res. 2005;96:180 188.

Diabetic Cardiomyopathy

603

27. Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation

of the mammalian target of rapamycin pathway in liver and skeletal
muscle of obese rats: possible involvement in obesity-linked insulin
resistance. Endocrinology. 2005;146:14731481.
28. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol. 2004;167:399 403.
29. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/
Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin
resistance, and cell survival deficiencies. Curr Biol. 2004;14:
1650 1656.
30. Tremblay F, Marette A. Amino acid and insulin signaling via the
mTOR/p70 S6 kinase pathway. A negative feedback mechanism
leading to insulin resistance in skeletal muscle cells. J Biol Chem.
2001;276:3805238060.
31. Kern W, Peters A, Born J, Fehm HL, Schultes B. Changes in blood
pressure and plasma catecholamine levels during prolonged hyperinsulinemia. Metabolism. 2005;54:391396.
32. Grassi G. Counteracting the sympathetic nervous system in essential
hypertension. Curr Opin Nephrol Hypertens. 2004;13:513519.
33. Yosefy C, Magen E, Kiselevich A, Priluk R, London D, Volchek L,
Viskoper RJ Jr. Rosiglitazone improves, while Glibenclamide worsens
blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic
activity. J Cardiovasc Pharmacol. 2004;44:215222.
34. Wang CC, Goalstone ML, Draznin B. Molecular mechanisms of
insulin resistance that impact cardiovascular biology. Diabetes. 2004;
53:27352740.
35. Naito Z, Takashi E, Xu G, Ishiwata T, Teduka K, Yokoyama M,
Yamada N, Sugisaki Y, Asano G. Different influences of hyperglycemic duration on phosphorylated extracellular signal-regulated
kinase 1/2 in rat heart. Exp Mol Pathol. 2003;74:2332.
36. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C,
Brownlee M. Inhibition of GAPDH activity by poly(ADP-ribose)
polymerase activates three major pathways of hyperglycemic damage
in endothelial cells. J Clin Invest. 2003;112:1049 1057.
37. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T,
Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I,
Brownlee M. Normalizing mitochondrial superoxide production
blocks three pathways of hyperglycaemic damage. Nature. 2000;404:
787790.
38. Nishikawa T, Edelstein D, Brownlee M. The missing link: a single
unifying mechanism for diabetic complications. Kidney Int Suppl.
2000;77:S26 S30.
39. Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy: a brief
review. Cardiovasc Toxicol. 2001;1:181193.
40. Farhangkhoee H, Khan ZA, Mukherjee S, Cukiernik M, Barbin YP,
Karmazyn M Chakrabarti S. Heme oxygenase in diabetes-induced
oxidative stress in the heart. J Mol Cell Cardiol. 2003;35:1439 1448.
41. Bidasee KR, Nallani K, Yu Y, Cocklin RR, Zhang Y, Wang M, Dincer
UD, Besch HR Jr. Chronic diabetes increases advanced glycation end
products on cardiac ryanodine receptors/calcium-release channels.
Diabetes. 2003;52:18251836.
42. Candido R, Forbes JM, Thomas MC, Thallas V, Dean RG, Burns WC,
Tikellis C, Ritchie RH, Twigg SM, Cooper ME, Burrell LM. A
breaker of advanced glycation end products attenuates diabetesinduced myocardial structural changes. Circ Res. 2003;92:785792.
43. Cooper ME Importance of advanced glycation end products in
diabetes-associated cardiovascular and renal disease. Am J Hypertens.
2004;17:31S38S.
44. Herrmann KL, McCulloch AD, Omens JH. Glycated collagen crosslinking alters cardiac mechanics in volume-overload hypertrophy.
Am J Physiol Heart Circ Physiol. 2003;284:H1277H1284.
45. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda
M, Dillmann WH. Diabetes and the accompanying hyperglycemia
impairs cardiomyocyte calcium cycling through increased nuclear
O-GlcNAcylation. J Biol Chem. 2003;278:44230 44237.
46. Wu-Wong JR, Berg CE, Dayton BD. Endothelin-stimulated glucose
uptake: effects of intracellular Ca (2), cAMP and glucosamine. Clin
Sci (Lond). 2002;103(suppl 48):418S 423S.
47. Galvez AS, Ulloa JA, Chiong M, Criollo A, Eisner V, Barros LF,
Lavandero S. Aldose reductase induced by hyperosmotic stress
mediates cardiomyocyte apoptosis: differential effects of sorbitol and
mannitol. J Biol Chem. 2003;278:38484 38494.
48. Ramasamy R. Aldose reductase: a novel target for cardioprotective
interventions. Curr Drug Targets. 2003;4:625 632.

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

604

Circulation Research

March 17, 2006

49. Guo M, Wu MH, Korompai F, Yuan SY. Upregulation of PKC genes

and isozymes in cardiovascular tissues during early stages of experimental diabetes. Physiol Genomics. 2003;12:139 146.
50. Koya D, King GL. Protein kinase C activation and the development of
diabetic complications. Diabetes. 1998;47:859 866.
51. Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD,
Walsh RA, King GL. Targeted overexpression of protein kinase C
beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad
Sci U S A. 1997;94:9320 9325.
52. Tahiliani AG, McNeill JH. Diabetes-induced abnormalities in the
myocardium. Life Sci. 1986;38:959 974.
53. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence,
mechanisms, and therapeutic implications. Endocr Rev. 2004;25:
543567.
54. Depre C, Young ME, Ying J, Ahuja HS, Han Q, Garza N, Davies PJ,
Taegtmeyer H. Streptozotocin-induced changes in cardiac gene
expression in the absence of severe contractile dysfunction. J Mol Cell
Cardiol. 2000;32:985996.
55. Dhalla NS, Pierce GN, Innes IR, Beamish RE. Pathogenesis of cardiac
dysfunction in diabetes mellitus. Can J Cardiol. 1985;1:263281.
56. Jackson CV, McGrath GM, Tahiliani AG, Vadlamudi RV, McNeill
JH. A functional and ultrastructural analysis of experimental diabetic
rat myocardium. Manifestation of a cardiomyopathy. Diabetes. 1985;
34:876 883.
57. Hu P, Zhang D, Swenson L, Chakrabarti G, Abel ED, Litwin SE.
Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload. Am J Physiol
Heart Circ Physiol. 2003;285:H1261H1269.
58. Scognamiglio R, Avogaro A, Negut C, Piccolotto R, Vigili dK, Tiengo
A. Early myocardial dysfunction in the diabetic heart: current research
and clinical applications. Am J Cardiol. 2004;93:17A20A.
59. Rodrigues B, Cam MC, McNeill JH. Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J Mol Cell Cardiol.
1995;27:169 179.
60. Vadlamudi RV, Rodgers RL, McNeill JH. The effect of chronic
alloxan- and streptozotocin-induced diabetes on isolated rat heart
performance. Can J Physiol Pharmacol. 1982;60:902911.
61. Fein FS, Strobeck JE, Malhotra A, Scheuer J, Sonnenblick EH.
Reversibility of diabetic cardiomyopathy with insulin in rats. Circ
Res. 1981;49:12511261.
62. Malhotra A, Penpargkul S, Fein FS, Sonnenblick EH, Scheuer J. The
effect of streptozotocin-induced diabetes in rats on cardiac contractile
proteins. Circ Res. 1981;49:12431250.
63. Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M. The
obesity-associated peptide leptin induces hypertrophy in neonatal rat
ventricular myocytes. Circ Res. 2003;93:277279.
64. Purdham DM, Zou MX, Rajapurohitam V, Karmazyn M. Rat heart is
a site of leptin production and action. Am J Physiol Heart Circ
Physiol. 2004;287:H2877H2884.
65. Atkinson LL, Fischer MA, Lopaschuk GD. Leptin activates cardiac
fatty acid oxidation independent of changes in the AMP-activated
protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis. J Biol
Chem. 2002;277:29424 29430.
66. Tajmir P, Ceddia RB, Li RK, Coe IR, Sweeney G. Leptin increases
cardiomyocyte hyperplasia via extracellular signal-regulated kinaseand phosphatidylinositol 3-kinase-dependent signaling pathways.
Endocrinology. 2004;145:1550 1555.
67. Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A,
Carella C, de Divitiis O, Varricchio M. Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant
men. Hypertension. 1999;34:10471052.
68. Mazumder PK, ONeill BT, Roberts MW, Buchanan J, Yun UJ,
Cooksey RC, Boudina S, Abel ED. Impaired cardiac efficiency and
increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts.
Diabetes. 2004;53:2366 2374.
69. Barouch LA, Berkowitz DE, Harrison RW, ODonnell CP, Hare JM.
Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003;108:754 759.
70. McDonagh PF, Hokama JY. Microvascular perfusion and transport in
the diabetic heart. Microcirculation. 2000;7:163181.
71. Raev DC. Left ventricular function and specific diabetic complications in other target organs in young insulin-dependent diabetics: an
echocardiographic study. Heart Vessels. 1994;9:121128.

72. Belke DD, Larsen TS, Gibbs EM, Severson DL. Altered metabolism
causes cardiac dysfunction in perfused hearts from diabetic (db/db)
mice. Am J Physiol Endocrinol Metab. 2000;279:E1104 E1113.
73. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S,
Youker KA, Taegtmeyer H. Impaired long-chain fatty acid oxidation
and contractile dysfunction in the obese Zucker rat heart. Diabetes.
2002;51:25872595.
74. Paradise NF, Pilati CF, Payne WR, Finkelstein JA. Left ventricular
function of the isolated, genetically obese rats heart. Am J Physiol.
1985;248:H438 H444.
75. Ren J, Sowers JR, Walsh MF, Brown RA. Reduced contractile
response to insulin and IGF-I in ventricular myocytes from genetically
obese Zucker rats. Am J Physiol Heart Circ Physiol. 2000;279:
H1708 H1714.
76. Conti M, Renaud IM, Poirier B, Michel O, Belair MF, Mandet C,
Bruneval P, Myara I, Chevalier J. High levels of myocardial antioxidant defense in aging nondiabetic normotensive Zucker obese rats.
Am J Physiol Regul Integr Comp Physiol. 2004;286:R793R800.
77. Rosen P, Herberg L, Reinauer H. Different types of postinsulin
receptor defects contribute to insulin resistance in hearts of obese
Zucker rats. Endocrinology. 1986;119:12851291.
78. Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke
K. Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. Diabetes. 2002;51:
1110 1117.
79. Wang P, Lloyd SG, Zeng H, Bonen A, Chatham JC. Impact of altered
substrate utilization on cardiac function in isolated hearts from Zucker
diabetic fatty rats. Am J Physiol Heart Circ Physiol. 2005;288:
H2102H2110.
80. Chatham JC, Seymour AM. Cardiac carbohydrate metabolism in
Zucker diabetic fatty rats. Cardiovasc Res. 2002;55:104 112.
81. Huisamen B, van Zyl M, Keyser A, Lochner A. The effects of insulin
and beta-adrenergic stimulation on glucose transport, glut 4 and PKB
activation in the myocardium of lean and obese noninsulin dependent
diabetes mellitus rats. Mol Cell Biochem. 2001;223:1525.
82. Golfman LS, Wilson CR, Sharma S, Burgmaier M, Young ME,
Guthrie PH, Van Arsdall M, Adrogue JV, Brown KK, Taegtmeyer H.
Activation of PPAR{gamma} enhances myocardial glucose oxidation
and improves contractile function in isolated working hearts of ZDF
rats. Am J Physiol Endocrinol Metab. 2005;289:E328 E336.
83. Fredersdorf S, Thumann C, Ulucan C, Griese DP, Luchner A, Riegger
GA, Kromer EP, Weil J. Myocardial hypertrophy and enhanced left
ventricular contractility in Zucker diabetic fatty rats. Cardiovasc
Pathol. 2004;13:1119.
84. Yu Y, Ohmori K, Kondo I, Yao L, Noma T, Tsuji T, Mizushige K,
Kohno M. Correlation of functional and structural alterations of the
coronary arterioles during development of type II diabetes mellitus in
rats. Cardiovasc Res. 2002;56:303311.
85. Abe T, Ohga Y, Tabayashi N, Kobayashi S, Sakata S, Misawa H, Tsuji
T, Kohzuki H, Suga H, Taniguchi S, Takaki M. Left ventricular
diastolic dysfunction in type 2 diabetes mellitus model rats. Am J
Physiol Heart Circ Physiol. 2002;282:H138 H148.
86. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A,
Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP. The cardiac
phenotype induced by PPARalpha overexpression mimics that caused
by diabetes mellitus. J Clin Invest. 2002;109:121130.
87. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure:
a question of balance. J Clin Invest. 2005;115:547555.
88. Chiu HC, Kovacs A, Blanton RM, Han X, Courtois M, Weinheimer
CJ, Yamada KA, Brunet S, Xu H, Nerbonne JM, Welch MJ, Fettig
NM, Sharp TL, Sambandam N, Olson KM, Ory DS, Schaffer JE.
Transgenic expression of fatty acid transport protein 1 in the heart
causes lipotoxic cardiomyopathy. Circ Res. 2005;96:225233.
89. Rutter MK, Parise H, Benjamin EJ, Levy D, Larson MG, Meigs JB,
Nesto RW, Wilson PW, Vasan RS. Impact of glucose intolerance and
insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study. Circulation. 2003;107:
448 454.
90. Tenenbaum A, Fisman EZ, Schwammenthal E, Adler Y, Benderly M,
Motro M, Shemesh J. Increased prevalence of left ventricular hypertrophy in hypertensive women with type 2 diabetes mellitus. Cardiovasc Diabetol. 2003;2:14.
91. Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KDR,
Schaefer E, Kajstura J, Anversa P, Sussman MA. Myocardial Akt

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012

Poornima et al

92.
93.

94.

95.

activation and gender. Increased nuclear activity in females versus

males. Circ Res. 2001;88:1020 1027.
Sugden PH, Clerk A. Akt like a women. Gender differences in susceptibility to cardiovascular disease. Circ Res. 2001;88:975977.
Dagres N, Saller B, Haude M, Husing J, von Birgelen C, Schmermund
A, Sack S, Baumgart D, Mann K, Erbel R. Insulin sensitivity and
coronary vasoreactivity: insulin sensitivity relates to adenosinestimulated coronary flow response in human subjects. Clin Endocrinol
(Oxf). 2004;61:724 731.
Dietz U, Tries HP, Merkle W, Jaursch-Hancke C, Lambertz H.
Coronary artery flow reserve in diabetics with erectile dysfunction
using sildenafil. Cardiovasc Diabetol. 2003;2:8.
Pop-Busui R, Kirkwood I, Schmid H, Marinescu V, Schroeder J,
Larkin D, Yamada E, Raffel DM, Stevens MJ. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial

Diabetic Cardiomyopathy

605

blood flow reserve and diastolic dysfunction. J Am Coll Cardiol.

2004;44:2368 2374.
96. Yokoyama I, Yonekura K, Ohtake T, Yang W, Shin WS, Yamada N,
Ohtomo K, Nagai R. Coronary microangiopathy in type 2 diabetic
patients: relation to glycemic control, sex, and microvascular angina
rather than to coronary artery disease. J Nucl Med. 2000;41:978 985.
97. Sasso FC, Carbonara O, Cozzolino D, Rambaldi P, Mansi L, Torella
D, Gentile S, Turco S, Torella R, Salvatore T. Effects of insulinglucose infusion on left ventricular function at rest and during
dynamic exercise in healthy subjects and noninsulin dependent
diabetic patients: a radionuclide ventriculographic study. J Am Coll
Cardiol. 2000;36:219 226.
98. Huikuri HV, Airaksinen JK, Lilja M, Takkunen JT. Echocardiographic evaluation of left ventricular response to isometric exercise in
young insulin-dependent diabetics. Acta Diabetol Lat. 1986;23:
193200.

Downloaded from http://circres.ahajournals.org/ by guest on December 20, 2012