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Circ Res. Author manuscript; available in PMC 2017 April 01.
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Published in final edited form as:

Circ Res. 2016 April 1; 118(7): 1151–1169. doi:10.1161/CIRCRESAHA.116.306206.
Insulin Signaling and Heart Failure

Christian Riehle, MD, PhD1 and E. Dale Abel, MB.BS., D.Phil.
Fraternal Order of Eagles Diabetes Research Center, and Division of Endocrinology and
Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City,
52242 USA.
Abstract
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Heart failure is associated with generalized insulin resistance. Moreover, insulin resistant states
such as type 2 diabetes and obesity increases the risk of heart failure even after adjusting for
traditional risk factors. Insulin resistance or type 2 diabetes alters the systemic and neurohumoral
milieu leading to changes in metabolism and signaling pathways in the heart that may contribute
to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes
develop in the failing heart. The changes range from activation of proximal insulin signaling
pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction
to repression of distal elements of insulin signaling pathways such as forkhead (FOXO)
transcriptional signaling or glucose transport which may also impair cardiac metabolism, structure
and function. This article will review the complexities of insulin signaling within the myocardium
and ways in which these pathways are altered in heart failure or in conditions associated with
generalized insulin resistance. The implications of these changes for therapeutic approaches to
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treating or preventing heart failure will be discussed.
Subject Terms
Heart Failure; Hypertrophy; Remodeling; Metabolic Syndrome; Insulin action; insulin resistance;
insulin receptor; cardiac hypertrophy
Cardiovascular disease (CVD) remains the leading cause of death globally in developed and
developing economies 1. The morbidity from CVD is broad-based and includes
consequences of atherosclerosis, hypertension leading to ischemic heart disease, stroke and
heart failure. Heart failure is a major cause of death in industrialized nations and exceeds the
mortality of most types of cancers. It is estimated that about 5.1 million patients are affected
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by heart failure in the United States. The annual incidence is approximately 670,000 cases,
with about half of these patients dying within 5 years after the initial diagnosis 2. The
associated annual costs are about $34.4 billion, resulting in an enormous economic burden 3.
Thus, heart failure once it develops has a dismal prognosis that has not significantly
improved despite advances in pharmacological therapies. Much work has been done to
Corresponding author: E. Dale Abel, MB.BS., D.Phil., Fraternal Order of Eagles Diabetes Research Center, Division of
Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 4312 PBDB, 169 Newton
Road, Iowa City, IA 52242-1101, Telephone: 319-353-3050, Fax: 319-335-8327, DRCadmin@uiowa.edu.
1Current Address: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
Disclosures: None
Riehle and Abel Page 2
examine diverse signaling pathways that contribute to heart failure, pathological cardiac
hypertrophy and adverse left ventricular remodeling and have been reviewed extensively 4, 5.
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A relatively understudied signaling pathway that could represent an important contributor to

the pathophysiology of heart failure is insulin signaling, which will be the subject of this
review.
The connection between abnormal insulin signaling and heart failure arises in part from the
established epidemiological association between obesity, type 2 diabetes, insulin resistance
and heart failure. Diabetes increases the risk for ischemic heart disease as evidenced by a
two- to four-fold increase in myocardial infarction in diabetic patients compared to non-
diabetics and is associated with a poorer prognosis 6. In addition, coexistence of ischemic
cardiomyopathy and diabetes accelerate the progression to heart failure 7. Numerous
epidemiologic studies identified insulin resistance and diabetes as risk factors for the
development of heart failure independent of myocardial ischemia. The Framingham Heart
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Study revealed that diabetes independently increases the risk of heart failure by about 2-fold
in men and about 5-fold in women compared with age-matched control subjects,
independent of blood pressure and serum cholesterol levels 8, 9. Furthermore, a longitudinal
study in the same cohort identified obesity as a risk factor for the future incidence of heart
failure in both men and women 10. These data are supported by the United Kingdom
Prospective Diabetes Study (UKPDS), which reported that the risk for developing heart
failure increases by 16% for every 1% increase in serum HbA1c concentrations 11. Similar
results reporting an association between diabetes and the incidence of heart failure have been
provided by the Cardiovascular Health Study 12, the New Haven cohort of the Established
Populations for Epidemiological Studies in the Elderly 13, post hoc analyses of clinical
trials14 and have been reviewed comprehensively15.
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In contrast, a number of studies reported a significant increase in survival in obese subjects

in the context of heart failure 16, 17 and following myocardial infarction after adjusting for
age, severity of illness, and gender 18. This resulted in the term “obesity paradox” which has
been previously reviewed 19, 20. Although obesity and type 2 diabetes are well-described and
commonly accepted risk factors for the development of cardiovascular disease, these studies
suggest a protective role of obesity when cardiac decompensation occurs. Given that
cachexia is independently associated with a worse prognosis in heart failure, the possibility
exists that the obesity paradox could in part reflect the adverse consequences of cachexia,
which would lower body weight. These lower body weight subjects with heart failure were
reported for example to have higher circulating concentrations of tumor necrosis factor α
(TNFα) 21, implying an adverse consequence of systemic inflammation in these subjects. In
another cohort, the potential benefit of the obesity paradox in heart failure was seen in the
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elderly and those with acute heart failure and was not present in subject in diabetes 21. Thus
many of the interactions between insulin resistance obesity and heart failure might differ
between acute and chronic heart failure. The neurohumoral changes in obesity that might
confer a survival benefit in acute heart failure are currently poorly understood. Moreover, the
absence of a benefit in subjects with type 2 diabetes suggests that long-standing insulin
resistance, hyperinsulinemia or hyperglycemia might offset any survival advantages that can
be attributed to the “obesity paradox”. Thus, the pathophysiology of the increased risk of
heart failure in insulin resistant states is complex and multifactorial, and the potential impact

of generalized insulin resistance and hyperinsulinemia per se remains incompletely

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understood.
Moreover, studies in humans and animal models have revealed that heart failure is associated
with generalized insulin resistance 22. Metabolic abnormalities observed in patients with
advanced heart failure resulting in catabolism, cardiac cachexia and insulin resistance might
correlate with decreased survival23. Although it is has not been definitively shown that
insulin resistance in the context of heart failure directly contributes to a worse prognosis, a
recent report suggested that ventricular unloading leads to improvement in whole body
insulin sensitivity 24. This review will therefore explore the current state of knowledge
linking generalized insulin resistance with heart failure with a focus on the physiological and
pathophysiological roles of insulin signaling within the heart, the cardiac adaptations to
generalized insulin resistance and the interaction between systemic insulin resistance and
changes in myocardial insulin signaling, which may inform the pathophysiology of heart
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failure.
Insulin Signaling Pathways

Insulin mediates its signaling upon ligand binding to the insulin receptor, which is a member
of the tyrosine kinase family of receptors and is closely related to and partially homologous
with the receptor for insulin-like growth factor −1 (IGF-1). Upon ligand binding, insulin
receptors are autophosphorylated, which in turn increases its tyrosine kinase activity for
other substrates such as insulin receptor substrates (IRS) proteins (Figure 1). The activated
insulin receptor interacts with IRS proteins and other binding partners to activate a network
of intracellular signaling pathways including PI3K/Akt and MAP Kinases such as
ERK 25, 26. As summarized in Figure 1, an essential initial step in IR/IGF-1R receptor
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signaling is activation of IRS proteins. IRS1 and IRS2 are the two most abundant IRS
isoforms in the heart and are required for insulin-mediated activation of PI3K. PI3K consists
of a p110 catalytic subunit and a p85 regulatory subunit, which catalyzes the generation of
the lipid product phosphatidylinositol (3,4,5)-triphosphate (PIP3). This results in
phosphoinositide dependent kinase 1 (PDPK1) mediated activation of the kinase Akt
(protein kinase B). Three members of the Akt family have been identified. Akt1 and Akt2
represent the most abundant Akt isoforms in the heart. Akt mediates a variety of cellular
processes by phosphorylating proteins involved in autophagy and members of the forkhead
transcription factor (FOXO) family which inhibits nuclear translocation and transcriptional
activity27 of promoters that encode pro-apoptotic signaling molecules, such as members of
the BCL-2 family. The isoform-specific contribution of Akt on the regulation of these
processes is incompletely understood. However, Akt1 but not Akt2 signaling has been
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identified to mediate somatic growth28, 29. Furthermore, it has been shown that Akt2 is
required for insulin-stimulated glucose uptake and metabolism in isolated cardiomyocytes
and this effect is independent of Akt130. Together, this suggests a predominant role for Akt1
in the regulation of somatic growth and for Akt2 in the regulation of metabolism. Inhibition
of glycogen synthase kinase 3β (GSK-3β) by Akt-mediated phosphorylation promotes
cardiac hypertrophy 31 and glycogen synthesis. In addition, Akt mediates phosphorylation of
mechanistic target of Rapamycin (mTOR), a protein complex regulating somatic growth and
protein synthesis. mTOR consists of two distinct complexes, mTORC1 and mTORC232.

Among other components, mTOR Complex 1 (mTORC1) is composed of Raptor

(regulatory-associated protein of mTOR)33. Rictor (Rapamycin-insensitive companion of
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mTOR) is part of mTOR Complex 2 (mTORC2)34. mTOR mediated phosphorylation of 70

kDa ribosomal protein S6 kinase (p70S6K) and 4E-binding protein 1 (4E-BP1)35 results in
its dissociation from eukaryotic translation initiation factor 4E (eIF4E) and activation of cap-
dependent translation36, which is attenuated by the mTOR inhibitor Rapamycin.
In addition to activating the Akt / mTOR signaling cascade and mediating GLUT4
translocation, insulin activates the mitogen-activated protein kinase (MAPK) / extracellular
regulated kinase (ERK) pathway. This pathway involves activation of a cascade including
Raf, MEK and ERK kinases, resulting in nuclear translocation of ERK and phosphorylation
of transcription factors such as p62TCF, initiating a transcriptional program that mediates
cellular differentiation and proliferation37. A variety of genetically altered mouse models
with perturbed insulin / IGF-1 signaling has been utilized to investigate insulin signaling in
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the heart. Table 1 summarizes the characteristics of previously described transgenic models
under basal conditions and superimposed pathological stressors.
Insulin receptors are ubiquitously expressed and are highly abundant in tissues of the
cardiovascular system such as the heart and endothelial cells 38. Given its identification as a
hormone that is intimately involved in fuel metabolic homeostasis, much of the work on
insulin signaling has focused on its impact on tissues such as adipose, liver, skeletal muscle
and brain and the mechanisms by which insulin regulates glucose uptake, lipogenesis and
hepatic glucose utilization for example 39–41 . Subsequent studies have revealed that insulin
signaling by activating cell survival pathways may play an important role in the regulation of
apoptosis and autophagy and cellular growth 42, 43. Thus a brief review of the physiological
role of insulin signaling in the heart and vasculature is warranted to set the stage for a deeper
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discussion of the pathophysiological consequences of insulin signaling in heart failure.
Insulin Signaling in the Vasculature

The major cell types in the vasculature in which insulin signaling has been evaluated are
endothelial and vascular smooth muscle cells. In endothelial cells, insulin signaling via PI3K
and Akt leads to activation of endothelial nitric oxide synthase. Nitric oxide release not only
promotes vasorelaxation, but may also activate anti-inflammatory and anti-atherosclerotic
pathways. As such, impaired endothelial insulin signaling has been suggested to contribute
to obesity and diabetes-related vascular dysfunction that may contribute to hypertension and
accelerated atherosclerosis 44, 45. It is important to note that whereas there is broad
consensus that impaired nitric oxide availability will contribute to vascular pathology in
insulin resistant states, impairment of eNOS activity may occur independently of defects in
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insulin signaling per-se 46–48. Another important consideration in understanding impaired

endothelial insulin signaling in the context of insulin resistant states is the concept of
imbalanced insulin signaling, whereby peripheral hyperinsulinemia, leads to activation of
certain branches of the insulin signaling pathway, while others remain inhibited. For
example, in certain circumstances, whereas insulin signaling to PI3K-Akt and eNOS might
be impaired in endothelial cells, activation of MAPK signaling pathways leading to
induction of endothelin1 expression might remain active and indeed be activated by ambient

hyperinsulinemia, thereby leading to increased vasoconstriction 49–51. Similarly, in vascular

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smooth muscle cells, the hyperinsulinemia that accompanies insulin resistant states has been
suggested to be a contributor to vascular smooth muscle cell hyperplasia, which may
promote intimal injury and vascular stenosis 52. The role of impaired insulin signaling in the
coronary vasculature and the pathophysiology of heart failure in insulin resistant states is
incompletely understood. However, subjects with insulin resistance and type 2 diabetes were
shown to have significantly impaired endothelial-dependent coronary vasodilation 53. Thus
the possibility exists that impaired coronary vasodilation in insulin resistant states could
contribute to impaired myocardial contractile reserve in heart failure, particularly in subjects
with insulin resistance.
Insulin Signaling and the Regulation of Substrate Metabolism in

Cardiomyocytes
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Like skeletal muscle, activation of insulin signaling pathways in cardiomyocytes leads to an

increase in glucose uptake by promoting the translocation of GLUT4 containing vesicles to
the plasma membrane 54. These vesicles ultimately fuse with the plasma membrane and
expose GLUT4 proteins on the cellular surface. This process involves the modulation of
filamentous actin networks, SNARE proteins, and small GTPases of the Rab family55.
Insulin signaling mediates GLUT4 translocation at multiple checkpoints. Recently identified
mechanisms include Akt-mediated phosphorylation of Akt substrate of 160 kDa (AS160), a
GTPase-activating protein for the Rab family of small G proteins. Phosphorylation of AS160
in response to insulin regulates its interaction with 14-3-3 and inhibits AS160 GTPase
activity. This results in increased Rab activity and translocation of GLUT4 vesicles to the
plasma membrane 56, 57. It has also been shown that selective activation of Akt might be
sufficient to stimulate GLUT4 translocation to an extent which is similar to insulin58.
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However, Akt-independent mechanisms have also been identified 57. In perfused hearts or in
vivo, the increase in glucose utilization (uptake and oxidation) that is mediated by insulin
signaling is associated with reduced fatty acid oxidation on the basis of the Randle
phenomenon 42, 59.
Transmembrane uptake of fatty acids (FA) in cardiomyocytes is mediated in part by fatty

acyl translocases of the FA transporter family and CD36 60. FAs are then converted to FA-
CoA by the enzyme Acyl-CoA synthase (ACS) and may be stored in the form of
triglycerides. However, excess lipids may also be shunted into non-oxidative pathways
which results in the generation of toxic lipid intermediates. This eventually results in
mitochondrial dysfunction61, perturbed cellular signaling62, incomplete FA oxidation and
increased apoptosis63, a phenomenon called lipotoxicity (reviewed in 64). Lipotoxicity has
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been extensively studied in animal models of obesity and type 2 diabetes, including ob/ob,
db/db mice (models for obesity and insulin resistance based on leptin deficiency or
resistance, respectively) and Zucker fatty rats65. Importantly though, insulin also promotes
the translocation of the fatty acid translocase CD36, which may increase FA uptake that may
be partitioned towards lipid synthesis and storage 60. This insulin-mediated increase and
translocation of CD36 is transduced by PI3K/Akt signaling pathways66 and may contribute
to increased FA oxidation and increased myocardial oxygen consumption (mVO2) in

hyperinsulinemic states that is often associated with increased availability of triglycerides

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and FA to the heart. Increased FA utilization is associated with decreased cardiac efficiency
(cardiac work / mVO2). Studies in ob/ob and db/db mice suggest that mitochondrial
uncoupling and increased reactive oxygen species (ROS) parallel the increase in FA
oxidation67, 68. Mitochondria-derived ROS can activate uncoupling proteins (UCPs)69
allowing protons to bypass the ATP synthase of the electron transport chain and decrease
coupling of mitochondrial ATP production to O2 consumption. As a consequence, fatty acid
oxidation further increases, which subsequently decreases cardiac efficiency. Similar to these
studies performed in animal models, a recent study using human myocardial samples from
type 2 diabetics showed mitochondrial dysfunction and increased oxidative stress70.
Furthermore, increased mVO2 along with increased FA oxidation was reported for young
women with obesity, insulin resistance and increased body mass index71. Increased ROS
production and mitochondrial uncoupling was not observed in rodent models of type 1
diabetes72. This suggests that ROS mediated mitochondrial uncoupling might not be
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attributable to hyperglycemia per se, but is more likely a consequence of generalized insulin
resistance and type 2 diabetes. Interestingly, hearts from cardiomyocyte-specific insulin
receptor knockout mice show increased ROS generation and mitochondrial uncoupling, in
the absence of hyperglycemia73.
Insulin may also directly regulate mitochondrial metabolism by promoting mitochondrial

fusion via a mechanism that involves the induction of OPA1 74. Short-term Insulin-mediated
Akt activation may also activate pro-survival signaling pathways related to Akt inhibition of
apoptotic signaling 75. Studies in gene targeted mice with cardiomyocyte-restricted loss of
insulin receptors or IRS1 proteins have also suggested that insulin signaling may play an
important trophic role within the heart 42. Thus, loss of insulin receptors or IRS-1 is
associated with a reduction in cardiomyocyte size with little hemodynamic consequences in
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non-stressed animals 42, 76. In addition insulin/IGF-1 or IRS1 or IRS2 signaling pathways
appear to be required for physiological cardiac hypertrophy in response to exercise 76–78.
Insulin signaling also regulates mitochondrial oxidative capacity. Thus mice with genetic
deletion of the insulin receptor, or IRS proteins develop reduced mitochondrial oxidative
capacity via partially understood mechanisms that may involve repressed expression of
nuclear-encoded mitochondrial genes 43, 73, 76. We have also shown that activation of PI3K
signaling is responsible for increasing mitochondrial oxidative capacity in response to
physiological cardiac hypertrophy 76, 79, 80. However, this effect of PI3K appears to be
independent of changes in Akt signaling and as will be discussed later, constitutive
activation of Akt appears to repress mitochondrial oxidative capacity.
Insulin Resistance
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Insulin resistance has been classically defined as the inability of insulin to promote its
metabolic actions in organs such as adipose tissue, skeletal muscle and liver (Figure 2).
Insulin resistance is a hallmark of obesity and type 2 diabetes and also is a characteristic of
heart failure. Thus in insulin resistant states there is impaired insulin-mediated glucose
uptake in muscle and adipocytes, impaired suppression of hepatic glucose production and
impaired suppression of lipolysis 81. Paradoxically, triglyceride synthesis and hepatic
secretion of VLDL is increased on the basis of increased insulin mediated activation of

lipogenesis 82. This underscores the important concept of selective insulin resistance,
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indicating that whereas certain targets of insulin signaling might be repressed in insulin
resistant states other targets may retain their “sensitivity” 83. The metabolic milieu in insulin
resistant individuals is therefore characterized by increased circulating concentrations of
FFA, and triglycerides, and variable increases in glucose concentrations. Moreover, beta
cells adapt to the insulin resistant environment by increasing insulin release, leading to
hyperinsulinemia. In addition to these systemic metabolic abnormalities, insulin resistance is
associated with additional changes to the systemic metabolic milieu including low-grade
inflammation, increasing circulating concentrations of various cytokines and altered
secretion of adipokines such as leptin, resistin and adiponectin 84, 85. Mechanisms for insulin
resistance include ectopic accumulation of lipid intermediates in skeletal muscle and liver. In
the liver, a proposed mechanism for steatosis is hyperinsulinemia-driven de novo lipogenesis
in the face of excess caloric intake. The molecular mechanisms for hepatic insulin resistance
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are incompletely understood; however, increased endoplasmic reticulum stress, ROS

generation and mitochondrial dysfunction have been suggested to contribute to the
development of insulin resistance86. Ectopic lipid accumulation and oxidative stress have
been proposed to contribute to skeletal muscle insulin resistance 87. Additional mechanisms
contributing to insulin resistance include adipose tissue dysfunction that impairs the release
of “insulin sensitizing” adipokines such as adiponectin, mitochondrial dysfunction,
incomplete FA oxidation, and activation of inflammatory responses leading to increased
promulgation of inflammatory cytokines such as TNFα and interleukins. Mechanistically,
TNFα, IL-6 and free fatty acids (FFAs) activate intracellular kinases that induce serine
phosphorylation of IRS proteins, thereby attenuating insulin signaling and inducing insulin
resistance88. This complex pathophysiology of insulin resistance has been classically
associated with obesity and a sedentary lifestyle. However, in heart failure generalized
insulin resistance develops in patients with cardiac cachexia. Most studies seeking to explore
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the mechanisms for insulin resistance have been performed in subjects with obesity or type 2
diabetes. Fewer studies have been conducted in patients with heart failure.
Insulin resistance in heart failure also correlates with increased serum concentrations of
proinflammatory cytokines, catecholamines, catabolic steroids and growth hormone89–93. In
addition, decreased physical activity, loss of skeletal muscle mass and sympathetic over-
activity, increases lipolysis thereby increasing the circulating concentrations of free fatty
acids, which may further exacerbate insulin resistance in skeletal muscle and liver by
promoting the accumulation of bioactive lipids. FFAs may further increase the activity of the
sympathetic nervous system94, which may independently attenuate peripheral insulin
signaling and reduce glucose utilization in skeletal muscle95. Furthermore, increased
catecholamine concentrations stimulate hepatic glycogenolysis and gluconeogenesis leading
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to increased circulating glucose. Heart failure is also associated with hyperactivation of the
renin-angiotensin-aldosterone system (RAAS), system, which has been implicated in the
pathophysiology of insulin resistance 96. In addition to increasing circulating concentrations
of angiotensinogen (originating from adipose tissue)97, chronic hyperinsulinemia may also
increase the expression of angiotensin II receptors, which may further exacerbate adverse
left ventricular remodeling98. Recent studies have also indicated that heart failure patients
with insulin resistance also exhibit evidence of ectopic accumulation of bioactive lipids such

as ceramide in their skeletal muscles, adipose tissue inflammation and hypo-

adiponectinemia, all of which may contribute to generalized insulin resistance 99, 100.
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Moreover, skeletal muscle hypo-perfusion impairs skeletal muscle oxidative capacity. This
induces growth hormone resistance and a state of low-grade inflammation which might also
contribute to insulin resistance 101–103. Growth hormone resistance described in patients
with heart failure results in decreased hepatic IGF-1 production in response to growth
hormone, but circulating growth hormone concentrations increase 92. Increased growth
hormone receptor signaling has been shown to induce insulin resistance in multiple tissues
including the heart104–106, thereby exacerbating peripheral insulin resistance which might
further impair cardiac function (Figure 2).
The changes in the metabolic milieu summarized above may contribute to the myocardial
mal-adaptations that have been described in insulin resistant states, often referred to as
diabetic cardiomyopathy and which have been extensively reviewed 107, 108. In brief and as
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outlined above, multiple mechanisms have been proposed to contribute to the increased
vulnerability of the heart in insulin resistant states such as increased FA utilization, impaired
mitochondrial oxidative capacity, mitochondrial dysfunction, decreased cardiac efficiency,
oxidative stress, accumulation of bio-active lipids, inflammation, increased apoptosis,
altered calcium metabolism and signaling, increased apoptosis and myocardial fibrosis. In
addition, expansion of local adipose tissue depots might compromise cardiac function under
conditions of obesity and type 2 diabetes. Epicardial adipose tissue (EAT) is a visceral-like
adipose depot that is located on the surface of the ventricles, along the coronary arteries, and
at the apex of the heart. Perivascular adipose tissue (PVAT) surrounds the blood vessels.
EAT mass and diameter are increased in obesity 109, 110, and the volume of PVAT is
associated with visceral obesity 111. Neither, EAT nor PVAT, are separated by a fascial layer
from the surrounding tissue. Therefore, it has been suggested that adipokines and possibly
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fatty acids secreted from EAT and PVAT might directly contribute to the development of
cardiovascular dysfunction in type 2 diabetes112. The induction of generalized insulin
resistance and hyperinsulinemia in the context of pressure overload accelerates LV
remodeling 113, 114. Thus it is plausible that insulin resistance that accompanies heart failure
could further exacerbate myocardial dysfunction by similar mechanisms. There is a paucity
of studies that have directly addressed the possible beneficial effects of therapeutic
manipulations that might increase insulin sensitivity in patients with heart failure to
determine if such changes will meaningfully impact LV function or alter long-term
prognosis. In a cohort of patients with advanced heart failure the Schulze group recently
reported that mechanical unloading resulted in a significant reduction in indices of systemic
insulin resistance that occurred in concert with improvement in hemodynamic indices 24.
Their study design did not address the question of whether or not the improvement in insulin
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sensitivity directly contributed to improved LV function. However, the authors reported that
improvement in insulin sensitivity did correlate with reversal of certain metabolic and
signaling abnormalities in the heart. An important question that these observations raise is:
What are the contributions of altered insulin signaling and insulin resistance per se in
cardiomyocytes and the potential contribution of these changes to heart failure and LV
remodeling?

Cardiac Muscle Insulin Signaling in Insulin Resistant States or in Heart

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Failure
Prior to summarizing important studies in the field, it is important to discuss the various
ways in which myocardial insulin resistance has been defined in the literature. In most
instances, “insulin resistance” has been defined as a reduction in insulin-mediated
myocardial glucose uptake. This definition is advantageous in the sense that it enables the
inclusion of non-invasive studies that evaluate myocardial glucose utilization. The limitation
however, is that this definition of myocardial insulin resistance does not account for changes
in the activation of signaling intermediates that are downstream of the insulin receptor. For
example, a reduction in GLUT4 protein could account for decreased insulin mediated
glucose uptake in the face of an otherwise intact insulin signaling pathway, whereas
impaired intracellular signaling could also reduce insulin-mediated glucose uptake even
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when GLUT4 protein levels are normal. As will be discussed, intact versus impaired
intracellular signaling might influence LV remodeling in distinct ways.
Nearly all studies that have examined insulin-stimulated glucose uptake in humans or in
animals with generalized insulin resistance, usually induced by diet-induced obesity, have
demonstrated impaired insulin-mediated glucose uptake 115. Studies of myocardial glucose
uptake in subjects with heart failure need to be interpreted in light of whether or not
measurements of glucose uptake were performed under basal conditions or in response to
physiological or pharmacological hyperinsulinemia as would occur during a euglycemic
hyperinsulinemic glucose clamp. In many animal studies in which heart failure is induced by
aortic banding (thoracic or abdominal) or by coronary artery ligation, basal glucose uptake
has been reported to be increased, and this has been attributable to an increase in the GLUT1
transporter 116–119. However, when the augmentation of glucose uptake in response to
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insulin was evaluated, the fold increase in insulin-mediated glucose uptake was impaired
relative to non-failing control groups 120. Importantly, in contrast to GLUT1, GLUT4
protein levels in the hearts of experimental models of heart failure or pathological cardiac
hypertrophy are variable 117, 118, 121, 122 and the impact of GLUT4 expression and
translocation in the context of heart failure is incompletely understood. Studies in transgenic
mouse lines revealed that GLUT4 expression is dispensable for contractile function under
basal conditions123, while these mice exhibited increased fibrosis124 and a poor response to
ischemic injury125. In contrast, deletion of GLUT1 in the hearts of mice did not exacerbate
heart failure progression following TAC 117. Thus it is likely that GLUT1 and GLUT4
mediated glucose transport may play divergent as well as overlapping roles in the
modulation of myocardial glucose uptake in heart failure. It is important to note that whereas
myocardial glucose utilization might be increased in compensated stages of LV hypertrophy
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and early in the course of heart failure, glucose utilization may be reduced in the hearts of
patients and animals with advanced heart failure 126.
Insulin stimulation of the heart activates PI3K and Akt, which are requisite upstream
signaling steps that promote GLUT4 translocation and increased glucose uptake. Studies of
insulin-mediated activation of Akt in the heart in rodent models of generalized insulin
resistance have yielded variable and potentially divergent results, which might be explicable

by differences in the models used and differences in experimental conditions, such as dietary
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lipid composition. Studies based on 45% fat diets of varying durations have suggested that
the ability of insulin to stimulate Akt might be augmented or preserved at a time when
insulin-mediated glucose uptake is impaired 127. In contrast, studies in more severe models
of insulin resistance such as ob/ob mice or following a more aggressive high-fat protocol
with 60% fat leads to impaired insulin-mediated activation of Akt and with FOXO1
dephosphorylation and nuclear localization 128. It is important to put in context that the
usual rodent diet is significantly lower in fat than human diets. Thus caution is warranted in
extrapolating findings from rodent students in which a large increase in dietary fat is
imposed for variable periods of time, given that species-specific differences may exist in the
myocardial adaptations to a pathological lipid load, relative to those that might already be
partially adapted to diets that are higher in fat content. In studies of failing hearts in
experimental models, usually induced by transverse aortic constriction (on normal chow),
Akt phosphorylation is increased in concert with increased IRS-1 phosphorylation 114, 129.
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In one study, genetically reducing the expression of insulin receptors, Akt1 or inducing
systemic hypoinsulinemia reduced Akt phosphorylation and interestingly attenuated cardiac
hypertrophy, and prevented adverse LV remodeling and heart failure 114.
Limited availability of human heart tissue has hampered the ability of investigators to
evaluate changes in insulin signaling pathways in heart failure or insulin resistant states.
Early studies suggested dynamic regulation of uncoupling protein and GLUT4 content in
human heart atrial appendages in response to increasing circulating FA concentrations
indicating that increased myocardial lipid delivery could repress myocardial GLUT4 130.
Subsequently in an elegant study combining LV biopsy with metabolic analyses, Cook and
colleagues reported that a significant reduction in plasma membrane GLUT4 accounted for
the reduction in myocardial glucose utilization in humans with heart failure (average EF
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27%) or in subjects with type 2 diabetes without heart failure despite minimal changes in
overall GLUT4 content 131. The depletion of sarcolemmal GLUT4 was corroborated by
animal studies that revealed that only two weeks of high fat feeding significantly reduced
myocardial GLUT4 content and sarcolemmal translocation even prior to any weight gain
and at a time when myocardial insulin signaling was preserved 127. Importantly, the human
studies by Cook’s group also showed that PI3K and Akt signaling was substantially
increased in the hearts of subjects with type 2 diabetes or heart failure and positively
correlated with circulating insulin concentrations and with indices of insulin resistance.
These studies suggest a paradigm whereby insulin-mediated glucose uptake in the heart in
insulin resistant states could be dissociated from activation of insulin signaling to PI3K and
Akt. The mechanisms contributing to reduced GLUT4 expression and translocation in the
heart in obesity are incompletely understood, but could be due in part to altered regulation of
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SNARE proteins 131.
In contrast, in an analysis of left ventricular samples obtained from subjects with advanced
heart failure at the time of left ventricular assist device (LVAD) implantation, Schulze and
colleagues reported a significant repression in myocardial Akt phosphorylation that occurred
in concert with evidence of accumulated bio-active lipids such as diacyl glycerol and
ceramides leading to activation of protein kinase C isoforms that have been implicated as
mediators of impaired insulin signaling 24. In materials obtained after mechanical unloading

and following evidence of recovery of LV function, these signaling changes were reversed,
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leading to the conclusion that in end-stage heart failure there is significant repression of
insulin signaling pathways and that recovery correlated with improvement in insulin action.
In a study from a different group, mechanical unloading was associated with a decrease in
the phosphorylation of the Akt target FOXO3 in human hearts 132. This study did not
measure Akt phosphorylation, but in light of other studies that have reported activation of
Akt signaling in human failing hearts, the implications of this observation is that in some
cases ventricular unloading could potentially reduce myocardial Akt signaling.
The complexity of the Akt-FOXO interactions is further underscored by studies showing that
6-months of treatment with a 60% high fat diet leads to heart failure, which is associated
with reduced Akt phosphorylation and dephosphorylation and nuclear localization of
FOXO1 128. Genetic deletion of FOXO1 prevented the development of heart failure and the
associated metabolic abnormalities that was induced by high fat feeding. Interestingly
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genetic deletion of FOXO1 also restored insulin sensitivity by reducing serine

phosphorylation of IRS1 proteins and restoring Akt phosphorylation in cardiomyocytes in
response to insulin stimulation. Thus FOXO activation could represent an important
mechanism leading to impaired insulin signaling in heart failure that is induced by lipotoxic
cardiomyopathy. It is noteworthy that additional post-translational modifications of FOXO
proteins could potentially drive nuclear localization 133; therefore it will be of interest to
determine if nuclear FOXO localization precedes impaired insulin-IRS1-Akt signaling in
metabolic cardiomyopathy or occurs as a consequence of it.
Taken together, these studies underscore the complex responses of insulin signaling
pathways in the myocardium to the changes in the systemic metabolic milieu that
characterizes insulin resistant states or that accompany left ventricular remodeling in the
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failing heart. Current experimental data and studies in human samples could suggest a model
whereby an early adaptation of the heart to systemic insulin resistance or to heart failure
might be the repression of GLUT4 expression and GLUT4-mediated glucose transport. This
occurs at a time when proximal insulin signaling to PI3K and Akt might remain intact and
could potentially accelerate mal-adaptive ventricular hypertrophy. Over time, in response to
persistent nutrient overload or to ongoing ventricular remodeling, FOXO activation (i.e.
increased nuclear localization) might accelerate the desensitization of proximal insulin
signaling leading to loss of Akt signaling and reduction in pro-survival signaling pathways
that may further exacerbate cardiomyocyte loss. It has been proposed that myocardial insulin
resistance might represent a mechanism by which the heart attempts to protect itself against
nutrient overload in insulin resistant states134. Early on, attempts to over-ride myocardial
insulin resistance could exacerbate the early phases of adverse ventricular remodeling.
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However, it is possible that over time, a transition may take place in which there is
subsequent loss of proximal insulin signaling to Akt, which may exacerbate LV dysfunction
via additional mechanisms related to further loss of trophic effects of insulin signaling on
myocyte mass and mitochondrial capacity and loss of its anti-apoptotic actions, all of which
could accelerate or exacerbate LV dysfunction (Figure 3). We will next explore potential
mechanisms linking changes in myocardial insulin signaling to left ventricular dysfunction
and adverse LV remodeling. Given the potential bi-phasic changes in insulin signaling that
occur in the evolution of heart failure or systemic insulin resistance namely an activation of

Akt, followed later by loss of insulin-mediated Akt signaling, pathways by which Akt
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activation may promote heart failure versus mechanisms linking impaired insulin signaling
with heart failure will be discussed separately.
Excessive Insulin Signaling and Heart Failure

As summarized above, there is clear evidence that hyperactivation of proximal insulin
signaling pathways such as increased IRS-1 phosphorylation and Akt hyperactivation may
occur in the context of pathological cardiac hypertrophy and subsequent heart failure, and
that reduction of insulin or Akt signaling in this context might reverse LV remodeling and
preserve cardiac function 114. How might persistent activation of Akt lead to pathological
hypertrophy? Interesting insights have been obtained from various lines of mutant mice with
constitutive activation of various downstream components of the insulin signaling pathway.
These models mimic the effects of hyperinsulinemia in type 2 diabetes and obesity on
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myocardial insulin signaling. Although constitutive activation of PI3K leads to compensated

cardiac hypertrophy, our group recently showed that this leads to desensitization of insulin
mediated glucose uptake followed by impaired ability of insulin to activate Akt 54. Of note
this impairment in glucose uptake is due in part to a defect in activation of glucose transport
following insertion GLUT4 in the plasma membrane.
In mice with inducible transgenic overexpression of Akt, cardiac hypertrophy is reversible

and LV function preserved after short-term activation. However, if Akt expression is induced
long-term, heart failure ensues, in part to a failure of angiogenesis. Importantly if Akt
signaling is subsequently reduced in these failing hearts, the rate of progression to mortality
is accelerated 135. It is tempting to speculate that this temporal relationship between an
adverse consequence of Akt activation leading to pathological remodeling that is then
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exacerbated by reduction of Akt expression might parallel the temporal relationship between
an initial increase in Akt signaling in earlier stages of heart failure that subsequently
transitions to reduced Akt signaling in end-stage cardiomyopathy. We recently reported an
additional mechanism by which persistent Akt signaling impairs mitochondrial energy
metabolism that likely contributes to the Akt-mediated LV dysfunction. The mechanism for
mitochondrial dysfunction is due to Akt-dependent repression of the expression nuclear-
encoded mitochondrial genes via FOXO dependent and independent signaling pathways. We
also showed that short-term activation of Akt promotes a metabolic switch characterized by
increased glycolysis while impairing mitochondrial FA oxidation and we speculated that this
short term adaptation might represent a compensatory response to protect mitochondrial
integrity and capacity. Importantly the mitochondrial repression occurs early and is
independent of the Akt-induced cardiac hypertrophy 129. However, in the long-term, a
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mismatch between impaired mitochondrial capacity and the increase in energetic

requirements of Akt-mediated cardiac hypertrophy accelerates the onset of heart failure.
Partial reduction of insulin or Akt signaling in murine models of TAC-induced cardiac
hypertrophy prevents heart failure, which supports a model in which Akt-driven mechanisms
might contribute to adverse LV remodeling 114. It is important to emphasize though, that in
these studies Akt signaling was not abolished, but rather maintained at basal levels. In
contrast, when Akt1 or insulin receptor signaling is completely abolished, then in response
to stressors such as pressure overload, catecholamine toxicity or myocardial ischemia, all of

these models exhibit a more rapid progression to heart failure 136–139. Taken together, these
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observations suggest that whereas residual insulin-PI3K-Akt signaling is required to

maintain cardiomyocyte viability, excessive signaling by these pathways drives adverse LV
remodeling and ventricular dysfunction via multiple mechanisms.
We recently described that hyperinsulinemia may impair myocardial contractility via a

mechanism by which the G-protein receptor kinase (GRK2) leads to Gi biased β2AR
signaling that inhibits adenylate cyclase, cAMP generation and cardiac contractility 140. The
inhibition of βAR signaling via GRK2 by hyperinsulinemia requires insulin receptor and
IRS-1 mediated signaling pathways (Figure 3). Ob/ob mice or mice that have been treated
for 12-weeks with a 45% HFD, exhibit increased myocardial GRK2 content 141. GRK2
overexpression has been shown to reduce myocardial insulin signaling, and in germline
GRK2 heterozygous KO mice, GLUT4 content is increased, insulin signaling was enhanced
in aging mice or when these animals were placed on a high-fat diet 141, 142. Moreover,
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reduced GRK2 signaling promoted a “physiological cardiac hypertrophy” profile as animals

aged. Thus GRK2 activation might also contribute to impairing myocardial insulin signaling
with aging and in response to nutrient overload. GRK2 overactivation may also increase
mitochondrial-mediated apoptosis by increasing mitochondrial calcium sensitivity, MPTP
opening and cytochrome C release 142. Taken together, GRK2 activation could represent
another important mechanism linking hyperinsulinemia with adverse LV remodeling.
Although increased sympathetic activity is an established mechanism by which GRK2 is
induced in the heart, whether or not hyperinsulinemia induces GRK2 by this mechanism
remains to be definitively elucidated.
Suppression of PI3K signaling in the heart was reported to reduce signs of cardiac aging, in
part by sustaining physiological levels of autophagy 143. Kim and colleagues also recently
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reported that aging was associated with increasing expression of IGF-1 receptors in
cardiomyocytes and in mice with deficiency of myocardial IGF1R signaling, cardiac
senescence and age-dependent cardiac fibrosis was reduced 144. Finally, hyperactivation of
insulin signaling pathways will lead to autophagy suppression 145. Autophagy plays a
critical role in organellar quality control, thus as has been recently reviewed
hyperinsulinemic activation of Akt/mTOR signaling could suppress autophagy thereby
contributing to LV dysfunction 27. In addition to Akt/mTOR-mediated suppression of
autophagy, we also reported a novel mechanism that may occur in insulin resistant states and
the metabolic syndrome by which bioactive lipids that accumulate in the heart will activate
NOX2 via a PKC-dependent mechanism that ultimately inhibits lysosomal function and
autophagic flux 146. In this model autophagic flux was impaired despite reduced
phosphorylation of mTOR. Recent reports of the time course of autophagy following TAC
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suggests that although autophagy might be transiently induced, a repression of autophagy

coincides with the transition from compensated hypertrophy to heart failure 147. Consistent
with this model are many observations that mouse models with impaired expression of
autophagy mediators develop LV dysfunction either at baseline or more rapid
decompensation following pressure overload 148, 149. Thus constitutive repression of
myocardial autophagy could represent a plausible mechanism by which hyperinsulinemia
and activation of Akt signaling could impair left ventricular function and accelerate adverse
LV remodeling. Impaired autophagy might also impair mitochondrial quality control.

Whether or not insulin signaling specifically regulates mitophagy remains incompletely

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understood, and whether or not they are linked in heart failure is currently unknown.
Decreased Insulin Signaling and LV Remodeling

Mechanisms that are distinct from those associated with hyperactivation of insulin signaling
pathways might also contribute to promoting LV dysfunction when insulin-PI3K and Akt
signaling ultimately become impaired. In this regard, valuable insights have been obtained
from genetic knockouts of components of the insulin signaling pathway (Table 1). It is
important to emphasize that there is significant redundancy in insulin and IGF-1 signal
transduction pathways 77. Thus, there is clear crosstalk between insulin and IGF-1R
signaling pathways in the heart, which might reflect the relatively benign phenotypes of
single knockouts of the IGF-1R or the IR respectively 42, 78. This is also true for IRS
isoforms in that loss of IRS1 or IRS2 individually do not precipitate LV dysfunction in
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unstressed hearts and indeed we observed no differences in the ability of insulin to activate
Akt or promote glucose uptake 76. However, combined deletion of IR and IGF-1receptors or
IRS1 and IRS2 leads to catastrophic heart failure due in part to unrestrained autophagy,
apoptosis and profound mitochondrial dysfunction 43, 150. Similar phenotypes have been
observed in animals with targeted loss of the phosphoinositide dependent protein kinase
(pdpk1), which is required for IR or IGF-1R dependent activation of Akt 80.
The second mechanism by which reduced insulin signaling might contribute to LV

dysfunction is by persistent nuclear localization of FOXO1. Guo and colleagues in mice
with cardiomyocyte-restricted deletion of IRS1 and IRS2 showed that they could ameliorate
the heart failure in part by genetically deleting FOXO1 expression 150, 151. Similarly heart
failure associated with long-term high-fat feeding could also be prevented when FOXO1 was
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deleted 128. It is likely that the mechanism by which persistent nuclear localization of FOXO
proteins might lead to LV dysfunction is multifactorial. Mechanisms by which FOXO may
mediate LV remodeling include myosin isoform switching, FOXO mediated activation of
autophagic and atrophic pathways and FOXO-mediated activation of lipid metabolism
pathways that would promote lipotoxicity 128, 132, 151. The potential bi-phasic response in
insulin signaling is also of particular importance for the design of future studies. Therefore,
it is of great interest to perform time course studies, especially in the context heart failure
and insulin resistance.
Implications for Therapy and Future Research

Taken together, this review of the field identifies an important need for uniformity in
determining changes in the specific components of the insulin signaling cascade at varying
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stages in the evolution from compensated cardiac hypertrophy to decompensated cardiac

hypertrophy and ultimately to heart failure. Furthermore, a careful analysis of the
relationship between altered myocardial insulin signaling in models of generalized insulin
resistance in concert with cardiac adaptations to hemodynamic stress will advance our
understanding of the complex interactions between generalized insulin resistance,
myocardial insulin signaling and heart failure. To more closely mimic human disease,
studies in which heart failure is induced in animals that have developed generalized insulin

resistance would be informative. Generalized insulin resistance is usually evident in high-fat

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fed rodent models after high-fat diets of >10-week duration. We would also suggest that
measuring glucose uptake in response to insulin gives only a partial picture of changes in
insulin signaling in the heart and as such it is important to evaluate the phosphorylation
states of IRS1/2, Akt1/2 and FOXO proteins under conditions of ambient insulinemia and in
response to an insulin stimulus. These analyses would be informative if determined in
conjunction with assays of signaling defects in skeletal muscle, adipose tissue and liver, as
they will not only identify differences in the adaptations of these tissues to insulin resistance
but also the potential for crosstalk between these classical insulin signaling targets and the
heart in models of heart failure. Moreover, they will test the hypothesis that changes in
insulin signaling, either an increase in the early stages followed by impaired signaling in
late-stage heart failure, may independently contribute to the pathophysiology of heart failure.
Modulation of myocardial insulin signaling is not currently a consideration in the

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management of heart failure. As discussed above, there are profound changes in myocardial
insulin signaling that develop in the failing heart and are also present in subjects with
generalized insulin resistance that may sensitize the heart to LV dysfunction. This raises
important questions regarding whether or not modulation of generalized insulin resistance,
normalization of hyperinsulinemia and other disturbances in the metabolic milieu will alter
the prognosis of heart failure. Second, it remains to be determined if strategies that will
directly correct the changes in myocardial insulin signaling described above will reverse
heart failure. Oxidative stress is a widely accepted mechanism for cardiac dysfunction in
insulin resistant states and it was recently reported that targeted anti-oxidant therapy may
partially restore abnormal insulin signaling and improve cardiac structure and function 152.
Combined treatment with polyphenols resveratrol and S17834 also significantly restored
cardiac function in diet-induced heart failure in rodent models via multiple mechanisms
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including reducing oxidative stress, reversing oxidative modifications of proteins, reducing

hyperinsulinemia and increasing circulating adiponectin concentrations 153. As alluded to
above, GRK2 could represent an attractive target that could ameliorate pathological LV
remodeling via mechanisms that could involve direct modulation of insulin signaling
pathways within cardiomyocytes as well as by effects on systemic metabolic
homeostasis 141, 142, 154. Whereas ventricular unloading improved myocardial insulin
signaling and lipotoxicity, it is not clear if the myocardial changes were primary or
secondary to improvement in peripheral insulin resistance 24. It is probable that ventricular
unloading by reversing some of the mechanisms that promote generalized insulin resistance
in subjects with heart failure might have contributed to a feed-forward mechanism to
increase myocardial recovery.
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An important conundrum that has been increasingly recognized is the unique challenges in
managing heart failure in the patient with type 2 diabetes and insulin resistance. Although it
is clear that diabetic patients with heart failure will respond to conventional heart failure
therapies, many recent clinical trials have revealed a disturbing association between multiple
diabetes therapies and worsening of heart failure or increased heart failure hospitalization.
This topic has been the subject of recent reviews 155, 156. However, it is clear that many
diabetes therapies including thiazolidinediones and even insulin might be associated with
volume expansion, which may exacerbate heart failure. Similar effects have also been

observed with certain DDPIV inhibitors. Specifically, treatment with the DDPIV inhibitor
saxagliptin resulted in increased heart failure hospitalization157. DPPIV degrades GLP-1 and
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other vasoactive peptides158 including brain natriuretic peptide (BNP), which though
increased in heart failure could represent an adaptive response159. Moreover, the increase in
circulating concentrations of insulin that occur as a result of incretin therapy could lead to
ligand-dependent activation of insulin signaling pathways. Thus, if hyperactivation of insulin
signaling indeed contributes to adverse ventricular remodeling in heart failure then a
plausible mechanism for the relationship between these therapies and heart failure
exacerbation could be the increase in myocardial insulin signaling and Akt hyperactivation.
In contrast, metformin, which acts as an insulin sensitizer and reduces hyperinsulinemia
might afford some degree of protection in terms of heart failure 160. Even though not directly
proven, decreased circulating insulin levels following metformin treatment might attenuate
cardiac insulin signaling and provide a potential explanation for the cardioprotective effects
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observed. A recent trial using a novel class of diabetes therapeutic, an inhibitor of the renal
sodium glucose co-transporter (SGLT2) had a dramatic impact on subsequent risk of
hospitalization for heart failure 161. It is not known if this beneficial effect was secondary to
the mild volume depletion or anti-hypertensive effects of this agent or to effects on altering
the metabolic milieu such as reducing circulating levels of insulin. Thus additional studies
are required to determine if therapeutic strategies that directly impact the abnormal systemic
milieu that characterizes the insulin resistant state will impact LV structure and function in
heart failure and impact prognosis and survival.
Concluding Remarks
The heart is an insulin responsive organ and insulin signaling plays an important role in
cardiovascular homeostasis. Cardiac hypertrophy and heart failure are associated with
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profound changes in myocardial insulin signaling. Moreover, heart failure is an insulin

resistant state that leads to an altered metabolic milieu that will influence myocardial
structure and function via mechanisms that are dependent or independent of alterations in
myocardial insulin signaling. It is possible that strategies that might correct the systemic
metabolic disturbances that are associated with insulin resistance could have an impact on
the outcome and prognosis of subjects with heart failure. An important imperative for the
future will be to design trials that can rigorously test this hypothesis. Second, an important
opportunity for the future will be to identify and evaluate therapeutic strategies that might
directly influence changes in myocardial insulin signaling that accompany heart failure.
Given the dynamic nature of these changes, it will be important that subjects are carefully
stratified or phenotyped to determine which insulin signaling pathways are perturbed and the
pathophysiological mechanisms that will most likely benefit from targeted therapies.
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Acknowledgments
Work in the Abel Laboratory has been supported by the following grants from the National Institutes of health
R01HL10837, RO1 HL12357, R01 HL127764, R01 HL112413, R01DK092065, U01 HL087947, RO1 HL73167,
R21DK073590 and by grants to trainees from the American Heart Association and the JDRF. EDA is an established
investigator of the AHA. CR was supported by a postdoctoral grant from the German Research Foundation (DFG).

Nonstandard Abbreviations and Acronyms

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FA Fatty Acids
EAT Epicardial adipose tissue
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Figure 1. Schematic of insulin signaling pathway

Simplified summary of key elements involved in insulin signal transduction that ultimately
regulate multiple cellular processes. Upon binding to its ligand, insulin and IGF-1 receptors
undergo autophosphorylation, which increases their tyrosine kinase activities. Tyrosine
phosphorylation and activation of the docking proteins insulin receptor substrates 1 and 2
(IRS1/2), engages regulatory subunits of the phosphatidylinositol-3-kinase (PI3K) that
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generates phosphatidylinositol 3,4,5 tris phosphate (PIP3) from phosphatidylinositol 3,4, bis
phosphate (PIP2). The serine threonine kinases phosphoinositide dependent protein kinase 1
(PDPK1) and Akt1 or Akt2 bind to PIP3 by their PH domains. PDPK1 phosphorylates Akt
on Thr 308 and mTORC2 phosphorylates Akt1/2 on Ser 473. Once activated, Akt in turn
phosphorylates multiple targets of which a subset is shown. Phosphorylation of these targets
induces pleiotropic cellular responses: Bcl2 phosphorylation inhibits apoptosis, FOXO
protein phosphorylation promotes nuclear exclusion, thereby repressing the expression of

FOXO-regulated transcripts that mediate autophagy and apoptosis. TSC1/2 phosphorylation

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promotes mTOR activation, which increases mRNA translation, promotes protein synthesis,
cell growth, mitochondrial fusion and also inhibits autophagy. Phosphorylation of glycogen
synthase kinase (GSK) removes the repression of glycogen synthase, which in concert with
increased availability of glucose promotes glycogen synthesis. Phosphorylation of
endothelial nitric oxide synthase (NOSIII) or eNOS by Akt increases the generation of nitric
oxide (NO) to promote vasodilation. Akt phosphorylation mediates the translocation of
vesicles containing the GLUT4 glucose transporter in part by phosphorylating downstream
targets such as AS160 (not shown), leading to increased glucose transport following
insertion into the plasma membrane. Akt also mediates in part, translocation of the fatty acid
translocase CD36. Insulin signaling also promotes activation of the mitogen activated
protein kinases (ERK1/2) to increase the expression of various genes.
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Figure 2. Summary of mechanisms that lead to insulin resistance in heart failure or in the
metabolic syndrome
Signaling events in skeletal muscle, liver, adipose tissue and brain (not shown) impair
insulin signaling in each respective organ leading to metabolic perturbations as illustrated,
which alter the systemic milieu in ways that may adversely impact cardiac structure and
function.
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Figure 3. Molecular mechanisms linking increased or decreased insulin signaling with adverse
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left ventricular (LV) remodeling and heart failure progression

In early stages of heart failure mediated by pressure overload, or in the early stages of the
metabolic syndrome, hyperinsulinemia leads to activation of insulin receptor substrate
1(IRS1) and Akt1 to promote pathological hypertrophy, mitochondrial dysfunction and
decreased autophagy, which contribute to accelerated LV remodeling. As heart failure
progresses, despite systemic hyperinsulinemia insulin signaling pathways may become
desensitized leading to loss of cytoprotective consequences of Akt signaling and persistent

nuclear localization of forkhead (FOXO) proteins that will accelerate heart failure by various
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mechanisms such as increased apoptosis and exacerbation of lipotoxicity.

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Table 1
Rodent models for perturbed insulin / IGF-1 signaling
Basal phenotype Phenotype following superimposed pathological

stressor
Riehle and Abel
Signaling Genetic Cardiac Contractile Notes Ref Stressor Cardiac Contractile Notes Ref
molecule Manipul size Function size Function
ation /
Treatme
nt
IR/IGF-1R
IR CKO ↓ =/ age-dependent 42, 73, 78, 137 ISO = ↓ catecholamine- 138

↓ mitochondrial mediated injury ↑
dysfunction
AC = ↓ susceptibility to 137
heart failure ↑
MI = ↓ left ventricular 139
dysfunction post MI
↑
STZ ↓ = mitochondrial 162
dysfunction ↑ /
cardiac efficiency ↓
IPC efficacy of IPC to 163
reduce infarct size ↑
CKO het = = 114 AC ↓ ↑ 114
IGF-1R CKO = = 78
MKO ↑ = 164

IR/IGF- MKO ↓ ↓↓ 164
1R DKO
IRS
IRS1 CKO ↓ = 76
IRS2 CKO = = 76
IRS1/2 CKO =/↓ ↓↓ 43, 150

DKO
MKO = ↓↓ 165
GKO ND ND embryonic lethal? 166

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stressor
ation /
Treatme
nt
Riehle and Abel
CKOi ↓ ↓↓ 151
IRS3 GKO = 167
IRS4 GKO NR 168
PI3K
p85 p85α ↓ = 169

MKO
p85β
GKO
p110α dn ↓ = 170, 171 AC = ↓ 170, 172
MI = ↓ 173
DCM ↓ survival following cross ↓ 172
ca ↑ = 171 AC = ↑ 172
MI = ↑ 173
DCM ↑ survival following cross ↑ 172
p110γ GKO = ↑ 174 AC ↓ 175
ISO ↑ 174

PDK1
PDK1 CKO ↓↓ β1-adrenergic 176, 177

receptor ↓
MKO ↓ ↓↓ Dilated 178
cardiomyopathy
Akt
Akt1 GKO = = 79, 136 AC ↑ ↓ 136
GKO het = 114 AC ↑ 114

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stressor
ation /
Treatme
nt
Riehle and Abel
Akt2 GKO =/↑ =/ age-dependent 30, 79, 179 AC = = 30

↓ hypertrophy and
contractile
dysfunction
ISO ↑ = 179
MI ↓ infarct size ↑ 180
Akt3 COE ↑ ↓ age-dependent 181

contractile
dysfunction
GKO = 182
kdAkt kd = = 183
caAkt ca ↑ ↓ age-dependent 183

contractile
dysfunction
myrAkt ↑ = 184 MI infarct size ↓ 184
GSK-3β
GSK-3β ca = 185 AC ↓ 185
dn ↑ = 186 AC = ↑ 186

mTOR
mTOR Rapamyc = = 187, 188 AC ↓ =/↑ 187, 188

in
MI ↓ ↑ LV remodelling and cell 189
death ↓
CKO ↓ ↓↓ embryonic lethal 190
(mTOR)
CKOi ↓↓ 191 AC ↓ ↓↓ rapid development of 191
(mTOR) heart failure post AC
CKOi ↓ autophagy ↑, 192 AC ↓ ↓↓ rapid development of 192
(raptor) Glucose oxidation ↑, heart failure post AC
Palmitate oxidation ↓
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stressor
ation /
Treatme
nt
Riehle and Abel
CKOi = ↓ Glucose oxidation ↑, 193

(mTOR) Palmitate oxidation ↓
ca = = 194
kd = ↓ 194 ISO = = hypertrophic response 194

similar to WT
p70S6K
p70S6K1 TG ↑ = mutant with higher 195 AC = 195

basal activity
kd = = 195
GKO = 195 AC = 195
p70S6K2 kd = = 195
GKO = 195 AC = 195
p70S6K1 GKO = 195 AC = 195

/2
GLUT4
GLUT4 CKO ↑ = 123, 196
MKO ↑ ↓ age-dependent 197, 198

(α-actin- contractile
Cre) dysfunction
Changes are expressed compared to WT controls same treatment; ↑ increased; ↓ decreased; = no difference observed.
AC, aortic constriction; ca, constitutively active mutant; CKO het, cardiac-specific heterozygous knockout (αMHC-Cre); CKO, cardiac-specific knockout (αMHC-Cre); CKOi, inducible cardiac-specific
knockout; COE, cardiac-specific overexpression; DCM, cross to transgenic mouse model of dilated cardiomyopathy; dn, dominant-negative mutant; GKO het, global heterozygous knockout; GKO, global
knockout; IPC, ischemic preconditioning; ISO, Isoproterenol treatment; kd, kinase-deficient mutant; MI, Myocardial infarction; MKO, muscle-specific knockout (MCK-Cre, unless otherwise indicated);
myrAkt, myristoylated Akt; STZ, streptozotocin treatment; TG, transgenic model; ND, not determined.
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Insulin Signaling and Heart Failure

treating or preventing heart failure will be discussed.

A relatively understudied signaling pathway that could represent an important contributor to

In contrast, a number of studies reported a significant increase in survival in obese subjects

Circ Res. Author manuscript; available in PMC 2017 April 01.

of generalized insulin resistance and hyperinsulinemia per se remains incompletely

Insulin Signaling Pathways

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Among other components, mTOR Complex 1 (mTORC1) is composed of Raptor

mTOR) is part of mTOR Complex 2 (mTORC2)34. mTOR mediated phosphorylation of 70

discussion of the pathophysiological consequences of insulin signaling in heart failure.

Insulin Signaling in the Vasculature

insulin signaling per-se 46–48. Another important consideration in understanding impaired

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hyperinsulinemia, thereby leading to increased vasoconstriction 49–51. Similarly, in vascular

Insulin Signaling and the Regulation of Substrate Metabolism in

Like skeletal muscle, activation of insulin signaling pathways in cardiomyocytes leads to an

Transmembrane uptake of fatty acids (FA) in cardiomyocytes is mediated in part by fatty

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hyperinsulinemic states that is often associated with increased availability of triglycerides

Insulin may also directly regulate mitochondrial metabolism by promoting mitochondrial

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are incompletely understood; however, increased endoplasmic reticulum stress, ROS

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as ceramide in their skeletal muscles, adipose tissue inflammation and hypo-

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Cardiac Muscle Insulin Signaling in Insulin Resistant States or in Heart

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SNARE proteins 131.

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genetic deletion of FOXO1 also restored insulin sensitivity by reducing serine

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Excessive Insulin Signaling and Heart Failure

myocardial insulin signaling. Although constitutive activation of PI3K leads to compensated

In mice with inducible transgenic overexpression of Akt, cardiac hypertrophy is reversible

mismatch between impaired mitochondrial capacity and the increase in energetic

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observations suggest that whereas residual insulin-PI3K-Akt signaling is required to

We recently described that hyperinsulinemia may impair myocardial contractility via a

reduced GRK2 signaling promoted a “physiological cardiac hypertrophy” profile as animals

suggests that although autophagy might be transiently induced, a repression of autophagy

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Whether or not insulin signaling specifically regulates mitophagy remains incompletely

Decreased Insulin Signaling and LV Remodeling

The second mechanism by which reduced insulin signaling might contribute to LV

Implications for Therapy and Future Research

stages in the evolution from compensated cardiac hypertrophy to decompensated cardiac

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resistance would be informative. Generalized insulin resistance is usually evident in high-fat

Modulation of myocardial insulin signaling is not currently a consideration in the

including reducing oxidative stress, reversing oxidative modifications of proteins, reducing

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profound changes in myocardial insulin signaling. Moreover, heart failure is an insulin

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Nonstandard Abbreviations and Acronyms

journal of the American Medical Association. 1979; 241:2035–2038. [PubMed: 430798]

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Circ Res. Author manuscript; available in PMC 2017 April 01.