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Accepted Manuscript

Molecular mechanisms of cardiac pathology in diabetes –

Experimental insights

U. Varma, P. Koutsifeli, V.L. Benson, K.M. Mellor, L.M.D.


PII: S0925-4439(17)30412-X
DOI: doi:10.1016/j.bbadis.2017.10.035
Reference: BBADIS 64947
To appear in:
Received date: 28 July 2017
Revised date: 9 October 2017
Accepted date: 27 October 2017

Please cite this article as: U. Varma, P. Koutsifeli, V.L. Benson, K.M. Mellor, L.M.D.
Delbridge , Molecular mechanisms of cardiac pathology in diabetes – Experimental
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Molecular mechanisms of cardiac pathology in diabetes – experimental insights

Varma U,2 Koutsifeli P,1,2 Benson VL,1 Mellor KM,*1,2,3 Delbridge LMD*2
1. Department of Physiology, University of Auckland, New Zealand
2. Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia
3. Auckland Bioengineering Institute, University of Auckland, New Zealand

*Authors contributed equally.

Word count: 5112
Figures: 2

Tables: 1
References: 200 NU
Keywords: diabetes, heart, metabolism, autophagy, oxidative stress

Corresponding Author:
Prof LMD Delbridge
Department of Physiology
University of Melbourne
Parkville, Victoria
Australia 3010
Ph.: +61 3 83445853


Diabetic cardiomyopathy is a distinct pathology independent of co-morbidities such as coronary

artery disease and hypertension. Diminished glucose uptake due to impaired insulin signaling and

decreased expression of glucose transporters is associated with a shift towards increased reliance on

fatty acid oxidation and reduced cardiac efficiency in diabetic hearts. The cardiac metabolic profile

in diabetes is influenced by disturbances in circulating glucose, insulin and fatty acids, and

alterations in cardiomyocyte signaling. In this review, we focus on recent preclinical advances in

understanding the molecular mechanisms of diabetic cardiomyopathy. Genetic manipulation of

cardiomyocyte insulin signaling intermediates has demonstrated that partial cardiac functional

rescue can be achieved by upregulation of the insulin signaling pathway in diabetic hearts.
Inconsistent findings have been reported relating to the role of cardiac AMPK and β-adrenergic

signaling in diabetes, and systemic administration of agents targeting these pathways appear to elicit

some cardiac benefit, but whether these effects are related to direct cardiac actions is uncertain.

Overload of cardiomyocyte fuel storage is evident in the diabetic heart, with accumulation of

glycogen and lipid droplets. Cardiac metabolic dysregulation in diabetes has been linked with

oxidative stress and autophagy disturbance, which may lead to cell death induction, fibrotic

‘backfill’ and cardiac dysfunction. This review examines the weight of evidence relating to the

molecular mechanisms of diabetic cardiomyopathy, with a particular focus on metabolic and

signaling pathways. Areas of uncertainty in the field are highlighted and important knowledge gaps

for further investigation are identified.

1. Introduction

Diabetic patients have a high risk of cardiovascular disease and mortality. A distinct

cardiomyopathy has been identified in patients with type 1 and type 2 diabetes (T1D, T2D),

characterized by cardiac dysfunction, fibrosis, oxidative stress and metabolic disturbance. Although

extensive co-morbidities are common in diabetic patients, the occurrence of diabetic

cardiomyopathy is independent of vascular abnormalities such as coronary artery disease, and

hypertension [1-4]. Cardiac outcomes are influenced by diabetic systemic insult including

hyperglycemia, dyslipidemia and hyperinsulinemia (T2D)/hypoinsulinemia (T1D), resulting in

altered cardiomyocyte molecular signaling and metabolism [5]. Additionally, volume-loading from

obesity can elicit significant effects on cardiac structural remodeling, with subsequent functional

Diastolic dysfunction is an early manifestation of diabetic cardiomyopathy, prevalent in more than

50% of asymptomatic diabetic patients [6-8], and linked to an increased risk of heart failure and

mortality, independent of systolic functional decline [9]. Impaired heart relaxation involves

increased ventricular wall stiffness and abnormal cardiac filling [10, 11]. The early occurrence of

diastolic dysfunction in asymptomatic diabetic patients is evident even in patients with normal

blood pressure, no vascular complications and normal contractility during systole [7, 12, 13].

Although hyperglycemia certainly elicits marked effects on cardiomyocyte function, evidence


suggests that glycemic status is not necessarily predictive of early cardiac functional decline [14].

Treatment options targeting diastolic dysfunction are limited and understanding the molecular basis

for dysfunction in the diabetic heart is an important priority.

Clinically, diabetic patients exhibit worse outcomes post-ischemia, with a higher incidence of

post-ischemic heart failure despite smaller infarct size, and are less responsive to the protective

effects of ischemic preconditioning [15-17]. Experimental studies with diabetic rodent models have

reported inconsistent findings relating to post-ischemic outcomes and pre-conditioning (reviewed in

[16]), with some reports suggesting that the diabetic heart is resistant to ischemic injury and

progression to heart failure [18-21]. Further work is required to elucidate the interaction between

diabetes and ischemic events, with particular focus on aligning the animal models with clinical

phenotypes for mechanistic interrogation.

At the molecular level, the energy stress associated with diabetes has been shown to induce

alterations in myocardial substrate and energy metabolism [22]. Increased free fatty acids, oxidative

stress and impaired protein clearance have been implicated in activating the endoplasmic reticulum

stress response, linked with activation of autophagy and apoptotic cell death in the diabetic heart

(reviewed in [23]). High extracellular glucose has been linked to formation of cross-linking

advanced glycation end-products (AGEs) on proteins such as collagens, contributing to ventricular

stiffness, and more recently AGE modification of intracellular proteins has been identified which

may provide a novel route of cellular damage in diabetic cardiomyopathy [24-26]. Glucose-

mediated post-translational modifications have been well-described in diabetes, in the heart and

other tissues. O-GlcNAcylation of key Ca2+ handling proteins and signaling kinases has been shown

to play an important role in mediating cardiac dysfunction in diabetes (reviewed in [24, 27]). Ca2+

handling disturbance appears to be a key feature of diabetic cardiomyocytes, involving prolonged

SERCA2-mediated Ca2+ removal from the cytosol during diastole, changes in myofilament Ca2+

sensitivity, and heightened ryanodine receptor-mediated Ca2+ leak from the sarcoplasmic reticulum

contributing to arrhythmia susceptibility [28, 29]. From an epigenetics perspective, dysregulation of


miRNAs has recently received attention for contributing to changes in expression of genes involved

in diabetic cardiomyopathy (reviewed in [30]). An understanding of the key miRNAs and their

targets is emerging and may open up new therapeutic opportunities in the field.

The focus of this review is on the molecular mechanisms of diabetic cardiomyopathy, with

comprehensive analysis of the literature relating to cardiomyocyte metabolic and signaling

pathways, accumulation of fuel stores (glycogen and lipid droplets), oxidative stress, and autophagy

disturbance. We highlight areas of uncertainty in the field and identify important knowledge gaps

for further investigation.

2. Metabolic disturbances in the diabetic heart

Adult cardiomyocytes preferentially use fatty acid oxidation for ATP production, with a smaller

contribution from glucose metabolism (up to 40%) [31]. Sarcolemmal glucose uptake is primarily

mediated by insulin-independent glucose transporter (GLUT) 1 and insulin-dependent GLUT4

transporters. Decreased expression of GLUT1 and GLUT4, and reduced insulin-stimulated GLUT4

translocation to the sarcolemma, are associated with decreased glucose uptake in both T1D and

T2D rodent hearts [32, 33]. Sodium-glucose co-transporters (SGLTs) are upregulated in the kidney
and intestinal tissue of human diabetic patients and rodent diabetic models, facilitating glucose

absorption [34]. Specifically, SGLT1 is increased in hearts of T2D patients and obese insulin

resistant mice (ob/ob), but decreased in T1D mice [35]. Cardiac SGLT1 expression is increased

with exposure to leptin [35], and upregulation of SGLT1 in T2D may provide an alternate route for

glucose uptake when GLUT1 and GLUT4 are downregulated. Systemic inhibition of SGLT1 and/or

SGLT2 has been advanced as an effective anti-hyperglycemic therapy (reviewed in [34]) and

multiple clinical trials are underway investigating the cardiac therapeutic potential of SGLT1

inhibition. In T1D mice, pharmacological inhibition of histone deacetylases (HDACs) increases


cardiac expression of both GLUT1 and GLUT4 and improves cardiac function [36], suggesting that

GLUT downregulation may be linked to HDAC regulation and constitutes a central component of

diabetic cardiomyopathy.

Transporters for galactose (GLUT1,3,8,11) and fructose (GLUT5,8,11) are also expressed in

cardiomyocytes and may provide alternative fuel sources in energy stress settings [37, 38]. In

glucose-deprived isolated adult cardiomyocytes, exposure to fructose facilitates contractile function,

indicating that cardiomyocytes have the capacity to transport and utilize fructose [39]. Cardiac
fructose content is increased in diabetes [40, 41] and may influence protein glycation damage and

metabolic disturbance [42]. Cardiomyocyte fructose accumulation may be due to over-activation of

the sorbitol pathway and/or endogenous fructose exposure from dietary sources. Understanding the

nuances of alternative fuel sources in the diabetic heart may provide new opportunities for


Coincident with impaired glucose uptake, reduced glucose oxidation is a common observation in

diabetic cardiomyocytes [43], associated with a shift towards increased reliance on fatty acid

oxidation [22] (Figure 2). Additionally, increased fatty acid oxidation (driven by increased fatty

acid uptake) might further suppress glucose oxidation via the Randle cycle [44]. In genetic mouse

models of obesity (ob/ob) and T2D (db/db), decreased glucose oxidation is observed by 4 weeks of
age, associated with an increase in fatty acid oxidation and reduced cardiac efficiency, preceding

hyperglycemia [43]. Interventions to upregulate glucose oxidation, eg. via dichloroacetic acid-

induced increased pyruvate dehydrogenase activity, have been shown to improve cardiac function

in both T2D (high fat diet) and T1D (STZ) rats [45, 46]. Similarly, rosiglitazone-induced PPAR-γ

activation in db/db mice improved cardiac efficiency associated with increased glucose oxidation

and decreased fatty acid oxidation [47]. Together, these findings suggest that normalization of the

metabolic profile in the diabetic heart may be an important target for ameliorating cardiac function

in diabetes.

Given that de novo synthesis of fatty acids in the heart is limited, intracellular fatty acid availability

is reliant on circulating levels of fatty acids, uptake kinetics, and intracellular lipid depots [48]. An

increase in circulating fatty acids has been observed clinically and in T2D rodent models, associated

with impaired glucose tolerance and insulin sensitivity in muscle tissue [49]. Fatty acyl-CoA-

mediated inhibition of insulin receptor substrate signaling pathways, hexokinase inhibition and

peroxisome proliferator-activated receptor α (PPAR-α) activation may be involved [49]. PPAR-α

activation stimulates fatty acid transport while suppressing glucose utilization, further promoting

the shift towards fatty acid oxidation [50]. High fat-fed mice with global PPAR-α gene deletion

exhibit improved insulin sensitivity compared to their wildtype counterparts. Cardiac outcomes

were not investigated in this study [51]. In contrast, db/db mice with long term exposure to a PPAR-

α agonist exhibit enhanced cardiac glucose uptake and utilization associated with a normalization of

blood glucose and insulin, but stabilization of the cardiac metabolic profile in this setting does not

lead to functional improvement [52, 53]. HDACs may also play an important role via PPARα-

mediated regulation of glucose and lipid homeostasis. HDAC inhibitors have gained attention as a

promising therapeutic intervention to improve systemic insulin resistance and glucose handling

[54], and an understanding of their role in the diabetic heart is emerging. Streptozotocin (STZ)-

induced T1D rats treated with HDAC inhibitor, MPT0E104, exhibit improved in vivo cardiac

function and electrocardiogram profile linked with restored cardiac expression of PPARα [55].
Whether these effects are secondary to the observed improvement in systemic glucose and lipid

profile, or mediated by intrinsic cardiomyocyte mechanisms is not yet clear, and investigation into

cardiac-specific modulation of HDACs is required.


Collectively, the metabolic adaptations in the diabetic heart appear to have a detrimental impact on

cardiac efficiency and function and may be attributed to changes in circulating glucose, insulin and

fatty acids. Advanced knowledge of the complex signaling networks connecting glucose utilization

and fatty acid oxidation might yield valuable therapeutic targets to stabilize the metabolic profile in

the diabetic heart.


3. Cardiac metabolic signaling dysregulation in diabetes

3.1 Insulin signaling

Cardiac insulin signaling mediates cellular homeostasis via control of substrate utilization, protein

synthesis, autophagy and cell survival. Suppression of this pathway is associated with increased

cardiac dysfunction and susceptibility to stress-induced heart failure [56]. Physiologically, binding

of the insulin ligand to the sarcolemmal insulin receptor (IR) activates insulin receptor substrates

(IRS1 and 2) and downstream phosphoinositide-3-kinase class I (PI3K(I))-protein kinase B (Akt)

pathways. Akt activation stimulates the translocation of GLUT4 to the cell membrane and

subsequent uptake of glucose [32]. The mechanisms mediating impaired insulin signaling in T2D

are not well understood. Recently, an E3 ubiquitin ligase, MG53, has been implicated as an

important regulator of the insulin signaling pathway [57]. Multiple rodent diabetic models (db/db

mice and high fat diet (HFD) mice) exhibit elevated cardiac MG53 protein content, linked with

increased proteosomal degradation of IR and IRS1, and activation of PPARα [57, 58]. Cardiac-

specific overexpression of MG53 induces a phenotype which mimics many of the features of

diabetic cardiomyopathy including downregulation of the insulin signaling pathway, increased

fibrosis and cardiac dysfunction [58]. However, low MG53 expression in the human myocardium

makes it an unlikely cardiac specific therapeutic target in diabetes [59].

Some insights into the role of insulin signaling in diabetic cardiac pathology have been gained via

genetic manipulation of signaling intermediates. Cardiac insulin receptor knockout (α-myosin heavy

chain (αMHC) promotor) decreases cardiomyocyte glucose uptake, increases cardiac oxidative

stress, and reduces mitochondrial function and cardiac efficiency [60-62]. Similarly, cardiac double

knockout of IRS1 and IRS2 (α-MHC promotor) reduces cardiomyocyte ATP content, increases

fibrosis, impairs cardiac metabolism and function, and increases apoptosis leading to eventual

cardiac failure [63]. STZ-induced T1D cardiac pathology is exacerbated in IR-KO mice, with a

greater extent of mitochondrial dysfunction and reduced cardiac efficiency relative to WT mice

[62]. These gene deletion studies suggest that the upstream components of the insulin signaling

pathway (IR, IRS1, IRS2) play an important role in diabetes-associated cardiac pathology, and

investigation of the efficacy of overexpression of these proteins in providing a metabolic rescue

strategy would be informative.

Impaired glucose uptake in the diabetic heart is often linked with reduced expression or activity of

the downstream intermediates in the insulin signaling pathway (Figure 2). Decreased cardiac basal

and insulin-stimulated phosphorylation of Akt is evident in diabetic rodent models [64-66] and

studies using genetic manipulation of the PI3K-Akt nexus in diabetic mice have demonstrated that

these signaling intermediates play a central role in diabetic cardiac pathology. STZ-induced T1D

cardiac pathology is exacerbated in mice with downregulated cardiomyocyte PI3K activity

(dominant-negative PI3K(I) mice, αMHC promotor), and prevented in mice with upregulated

cardiomyocyte PI3K activity (constitutively active PI3K(I) mice, αMHC promotor) [67]. Similarly,

upregulation of PI3K via administration of constitutively active PI3K(I) viral constructs in mice

with established diabetic cardiac pathology (STZ-induced T1D), partially rescued cardiac

dysfunction [68]. Surprisingly, insulin-stimulated glucose uptake has been observed to be decreased
by upregulation of cardiomyocyte PI3K-Akt signaling (via inducible constitutively active PI3K and

myristoylated (active) Akt, αMHC promotor) [69], suggesting that cardiac functional rescue

induced by increased PI3K activity may not be related to restoration of glucose uptake. Given that

PI3K is an important signaling focal point for regulation of multiple pathways, it is likely that

favorable cardiac outcomes are related to altered metabolism, protein synthesis and/or cell survival.

Interestingly, not all animal studies suggest that diabetes is detrimental in the context of a secondary

cardiac insult. In response to pressure overload surgery, diabetic mice (induced by STZ, db/db, high

fat diet) exhibit less severe (or even abrogated) systolic dysfunction, attributed to the absence of

insulin-dependent Akt activation of downstream hypertrophic signaling pathways [21, 70-72].

IR-KO mice and Akt1-deficient mice also exhibit preserved systolic function following pressure

overload, suggesting that the insulin pathway plays an important role in mediating the progression

to heart failure induced by pressure overload [21]. These findings have important implications for

the possible adverse effects of insulin supplementation in settings of high pressure-mediated cardiac

remodeling such as in hypertensive diabetic patients.

3.2 AMPK signaling

AMP-activated kinase (AMPK) is composed of a catalytic α subunit and regulatory β and γ

subunits, and is activated in conditions of stress and starvation via an increase in cellular AMP

concentration [73]. The binding of AMP to AMPK promotes the auto-phosphorylation of threonine

172 and prevents dephosphorylation of AMPK by phosphatases [73]. AMPK is involved in

numerous cellular processes including regulation of glycolysis and fatty acid oxidation, autophagy

initiation, and lipid, glycogen and protein synthesis [74] (Figure 2). AMPK mediates tight

regulation of glucose handling via promoting GLUT4 translocation [75], GLUT4-independent

glucose uptake [76], and glycogen synthase phosphorylation [77, 78]. AMPK also binds to

glycogen via its β subunit carbohydrate domain [79, 80], although the role of AMPK in regulating
glycogen content in the heart is not well understood.

Clinically, AMPK activators such as metformin have been used extensively to control

hyperglycemia in T2D patients for over 60 years [81]. Trials are currently underway to evaluate the

therapeutic cardiac effects of metformin in T1D patients [82] and numerous studies have

demonstrated that metformin treatment improves cardiac outcomes in T1D and T2D rodent models

[83, 84]. Cardiac AMPK downregulation has been reported in animal models of T1D and T2D and

may be an important intervention target [84, 85]. However not all studies have reported decreased

AMPK activity with diabetes. Obese insulin resistant mice (ob/ob) exhibit increased cardiac AMPK

phosphorylation (Thr172) which can be restored by captopril treatment, suggesting involvement

from the renin-angiotensin system [86]. Interestingly, cardiac AMPK modulation in T1D appears

dependent on diabetes duration - AMPK phosphorylation is increased in STZ rats at 4 days post-

injection, yet not different from control at 6 weeks post-STZ injection [87]. Activation of AMPK

via metformin treatment in cultured cardiomyocytes exposed to high glucose improves cell survival

relative to high glucose alone, an effect associated with a pro-autophagic/anti-apoptotic dissociation

of Beclin-Bcl2 [88]. Whether cardiac benefit observed with AMPK activation is secondary to

systemic improvement, or due to intrinsic cardiomyocyte mechanisms is yet to be elucidated.

3.3 β-adrenergic signaling

Diabetic patients exhibit impaired exercise capacity, sympathetic activity and blunted inotropic

response to β‐adrenergic stimulation [89, 90]. Experimentally, β-adrenergic involvement in diabetic

cardiomyopathy appears to be different in T1D and T2D settings. In STZ-induced T1D rodents,

cardiac β-adrenergic receptors are observed to be desensitized and downregulated [91-95]. In obese

T2D rats, heightened sensitivity to β1- but not β2-adrenergic receptor-mediated chronotropy is

evident [96]. Interestingly, global deletion of the β2 receptor prevented both diastolic and systolic
dysfunction in high fat-fed mice via inhibition of insulin-mediated activation of phosphodiesterase

4D [97]. Given that β2-adrenergic receptors are present in only ~5% of ventricular cardiomyocytes

[98], β2-receptor knockout-induced cardiac outcomes may be related to systemic or atrial changes.

The relationship between β-adrenergic signaling and insulin resistance is emerging as an important

focal point in diabetic cardiac pathology (Figure 2). Short term stimulation of the β-adrenergic

pathway in cultured cardiomyocytes increases insulin-dependent glucose uptake through

phosphorylation of Akt via protein kinase A [99]. In contrast, long term β-adrenergic stimulation

inhibits insulin-dependent glucose uptake in cultured cardiomyocytes [99]. In vivo, sustained


systemic activation of the β-adrenergic receptor (daily injections of isoproterenol) induces insulin

resistance, and reduces glucose uptake and GLUT4 expression in cardiac tissue; effects which could

be ameliorated with β-blocker treatment [100]. Hyperinsulinemia may play a role in dysregulation

of β-adrenergic signaling in T2D, although the mechanisms are not clear. Insulin-treated neonatal

mouse cultured cardiomyocytes exhibit G protein-coupled receptor kinase 2-mediated

phosphorylation and internalization of β2 receptors [101]. In contrast, numerous studies have

suggested that hyperinsulinemia promotes β-adrenergic signaling leading to hypertrophy and failure

[102]. Together, these findings indicate a complex relationship between β-adrenergic and insulin

signaling pathways in the diabetic heart, with each pathway playing an integral role in the

development of the cardiac pathology [102, 103].

4. Perturbed cardiomyocyte fuel storage in diabetes

4.1 Glycogen storage

Disruption of metabolic signaling pathways, coupled with altered substrate accessibility and

utilization is associated with irregular fuel storage in the diabetic heart. Glycogen is an important

fuel depot for glucose, well characterized in the liver and skeletal muscle, but its role in the heart is
not well understood. Physiologically, glycogen is regulated via two key enzymes: glycogen

synthase which adds glucose monomers to glycogen chains, and glycogen phosphorylase which

releases glucose-1-phosphate from glycogen [104]. In skeletal muscle, glycogen particles exhibit a

high surface area-to-volume ratio, thus facilitating rapid breakdown in situations where a swift

glucose surge is required [105]. Experimentally, in response to fasting, glycogen content is depleted

in skeletal muscle [106], but unchanged or even increased [17, 106, 107] in cardiac muscle. It has

been suggested that nutrient deprivation may re-direct glucose to critical tissues such as the heart

and brain for preservation of function in acute stress circumstances.


In the diabetic context, insulin-sensitive tissues such as cardiac and skeletal muscle are subjected to

a state of glucose deprivation due to impaired glucose uptake induced by insulin deficiency (T1D)

or cellular insulin resistance (T2D). Thus, an expected decrease in skeletal muscle glycogen content

is evident in diabetic subjects [108, 109]. In contrast and paradoxically, increased glycogen in the

human diabetic heart is evident, first documented in early work by Warren (1930), and subsequent

studies in humans and rodents have mostly corroborated this finding [110-136]. However, some

reports of unchanged [129, 137-141] or decreased [140, 142, 143] glycogen are evident (Table 1).

Interestingly, exercise training has been shown to both elevate [125] and attenuate [132] cardiac

glycogen accumulation in T2D rodents. These inconsistent findings may relate to differences in

diabetes duration, dose, species or age of the animal models. Aged animals appear to be more

susceptible to glycogen accumulation associated with T2D [144], and the dose of streptozotocin

administration is positively correlated with cardiac glycogen content in T1D rats [140]. It could be

expected that glycogen accumulation is a result of increased synthesis and/or decreased

degradation. Yet it appears that cardiac glycogen accumulation in diabetes is not explained by

changes in glycogen regulatory enzymes - lower glycogen synthase activity and unchanged or

increased activity of glycogen phosphorylase in various rodent models of T1D and T2D has been

reported [113, 117, 121, 125, 145]. These findings suggest that glycogen accumulation may be

initiated early in disease progression, and snapshot measures at later time points may capture a later
compensatory response, rather than an initial causative enzyme modulatory effect. Alternatively,

other pathways involved in regulating glycogen content may play a role.

Electron micrographs have depicted glycogen in double-membrane phagosomal structures in the


heart, indicative of an autophagy-mediated degradation breakdown process [146]. The process of


glycogen autophagy (‘glycophagy’) has been identified in skeletal muscle, liver and the heart [147-

149]. Glycophagy involves starch-binding domain-containing protein 1 (STBD1) tagging glycogen


and recruiting it to the forming autophagosome via binding to γ-aminobutyric acid receptor-

associated protein-like 1 (GABARAPL1), an ATG8 homologue. The glycogen-containing


autophagosome fuses with a lysosome where acid α-glucosidase (GAA) degrades glycogen to its

glucose monomers [150]. GAA deficiency in Pompe disease, and inherited lysosome-associated

protein (LAMP2) deficiency, result in severe myocardial glycogen accumulation and cardiac

dysfunction, thus highlighting the importance of lysosomal glycogen breakdown in the heart [151,

152]. In cultured primary cardiomyocytes, glycophagy is modulated by extracellular glucose and

insulin, coincident with glycogen accumulation [153]. Disturbances in glycophagy may play a role

in mediating glycogen accumulation in the diabetic heart in vivo, and further investigation is


4.2 Lipid storage

A shift in reliance on fatty acid oxidation in the diabetic heart is linked with increased fatty acid

availability driven by sarcolemmal fatty acid uptake [154]. Experimentally, diabetes-induced

upregulation of genes involved in lipid metabolism is evident early in disease progression, detected

at 48 hours post-injection of streptozotocin to induce T1D [155]. Despite increased metabolism of

lipids, cardiac accumulation of lipid stores has been reported in mouse models of T2D (db/db

mouse) [156] and insulin resistance (high fat-fed mouse) [157], suggesting that upregulation of fatty
acid oxidation is not sufficient to maintain intracellular lipid homeostasis in this setting of increased

fatty acid uptake. Lipid droplets consist of a neutral lipid core containing triacylglycerols and

cholesteryl esters, surrounded by a monolayer of phospholipids serving as an anchor-point for

perilipins [158, 159]. Perilipin 5 is increased in the hearts of T2D (db/db) and T1D (STZ-treated

and Akita) mice and cardiac triacylglycerol accumulation and reduced fractional shortening in STZ

mice is abrogated by global perilipin5 knockout [160]. Interestingly, evidence of increased lipid

droplets in T2D cardiomyocytes was observed prior to the onset of diastolic dysfunction in 12 week

old male db/db mice [161]. Thus lipid accumulation may be an early, and perhaps primary,

manifestation of diabetic cardiomyopathy and further investigation into the relationship between

excess lipids and diastolic functional pathology is now warranted.

Within the cardiomyocyte cytosol, lipid droplets increase in size via fusion, which is mediated by a

multitude of protein complexes, including membrane fusion proteins from the soluble NSF

attachment protein receptor (SNARE) family. In HL-1 cultured cardiomyocytes, oleic acid

incubation increases the lipid droplet-associated pool of the SNARE family protein, soluble NSF

attachment protein 23 (SNAP23), at the expense of the plasma membrane-associated SNAP23 pool

[162]. Given that SNARE proteins are also involved in GLUT4 translocation, it has been suggested

that increased demand for lipid droplet fusion in diabetes may decrease the availability of SNARE

proteins for GLUT4 vesicle transport thus decreasing insulin sensitivity [162, 163]. Whether this

mechanism plays a role in the development of cardiac insulin resistance in vivo is yet to be

investigated. Fatty acid availability for ATP synthesis is driven by hydrolyzing stored lipids via

adipose triglyceride lipase (Atgl) and hormone sensitive lipase (Hsl) [164]. Cardiac-specific

overexpression of Atgl in T1D (STZ) mice improved the cardiac lipid profile, restored glucose

oxidation and improved functional parameters, whereas Atgl knockdown exacerbated diabetic

cardiac pathology [165]. Similarly, cardiac-specific overexpression of Hsl in T1D (STZ) mice

prevented diabetes-induced lipotoxicity and cardiac fibrosis by facilitating lipid breakdown [166].

Bulk lipid droplet degradation via microtubule-associated protein light chain 3B (LC3B)-mediated
autophagy has been identified in non-cardiac cell types [167], but the role of autophagy in lipid

metabolism in the heart is not yet established. Interestingly, genetic knockout of the autophagy

regulator, forkhead box protein O1 (FoxO1), in T2D mice was associated with reduced lipid

accumulation and lipotoxicity, preserved metabolic substrate selectivity and cardiac function, and

improved mortality compared to wild-type T2D mice [168]. Although this study did not directly

investigate autophagy-mediated lipid degradation, FoxO1 has been implicated as a key regulator of

transcription of autophagy proteins in the heart [169]. Given that autophagy plays an important role

in energy stress responses in cardiomyocytes, further investigation into cardiomyocyte lipid-


selective autophagy pathways in the diabetic setting would be informative.

5. Energy stress adaptations in the diabetic cardiomyocyte

5.1 Reactive oxygen species generation

Extracellular hyperglycemia, impaired glucose uptake, disturbed glycogen handling and metabolic

dysregulation creates an environment of energy stress in the diabetic cardiomyocyte. The

augmented reliance on fatty acid oxidation evident in diabetic mouse hearts, is coincident with

increased myocardial oxygen consumption and reduced cardiac efficiency [170, 171]. Dysregulated

metabolism may be linked to increased production of reactive oxygen species (ROS) and

development of cardiac oxidative stress in diabetes [172]. A disruption in the homeostatic balance

of ROS management leads to oxidative damage of DNA, proteins and lipids as well as activating

stress-sensitive pathways. Cardiac oxidative stress has been observed in patients with diabetes [173]

and diabetic animals models [68, 174, 175], and urinary levels of oxidation markers have been

proposed as potential biomarkers of micro- and macro-vascular complications in diabetic patients

[173, 176]. Production of ROS in diabetic hearts and high glucose-incubated cultured

cardiomyocytes has been largely attributed to increased activity of nicotin-amide adenine

dinucleotide phosphate (NADPH) oxidase [177-179] and uncoupling of the mitochondria and
subsequent leakage of the mitochondrial electron transport chain, implicated in declining cardiac

function [180-182]. Other sources of ROS production in the heart include uncoupling of nitric oxide

synthase, activation of protein kinase C, lipoxygenase, and xanthine oxidase [1, 183].

Antioxidant treatment strategies have demonstrated some cardiac benefit in experimental animal

models of diabetes. In obese insulin resistant mice, mitochondria-specific antioxidant treatment

reduced ROS and oxidation of cardiac myofilament proteins, leading to an improvement in cardiac

diastolic function [182]. Similarly, systemic administration of the antioxidant coenzyme Q10 in

STZ-treated dominant-negative PI3K(p110α) transgenic mice with upregulated NADPH oxidase,


limits diabetes-induced diastolic dysfunction, fibrosis and hypertrophy [175]. ROS production can

also mediate autophagy, a process of cellular ‘self-digestion’ implicated in the development of

diabetic cardiomyopathy. Induction of oxidative stress via hydrogen peroxide treatment in cultured

H9c2 cardiomyoblasts increases autophagy, an effect reversed by treatment with the antioxidant

resveratrol [184]. In the early phase of energy deprivation, cardiomyocyte autophagy induction has

been linked to NADPH oxidase isoform Nox4-derived ROS production in the endoplasmic

reticulum [185, 186]. Evidence suggests that autophagy induction may be a compensatory response
to oxidative stress with a negative feedback action. Elevated myocardial ROS production and

autophagy activity with lipopolysaccharide (LPS)-induced sepsis in mice is attenuated by

antioxidant treatment, and conversely, activation of autophagy with rapamycin in this setting

attenuates ROS production [187]. Whether a similar mechanism is evident in diabetic hearts is yet

to be investigated.

5.2 Autophagic activity

Autophagy is a highly conserved and tightly regulated homeostatic process vital for cell growth and

survival. An excess level of autophagic activity has been linked to induction of programmed cell

death [188]. Impaired autophagy is associated with an accumulation of dysfunctional mitochondria

and can trigger stress-response pathways and subsequent cell death via apoptosis [189, 190]. An
understanding of cargo-selective autophagy is emerging - specific degradation processes targeting

proteins (macrophagy), mitochondria (mitophagy), glycogen (glycophagy) and lipids (lipophagy) -

and may play an important role in diabetes-induced cardiac pathology [191]. Conflicting literature

reports of increased, decreased and unchanged cardiac autophagy in rat and mouse models of

diabetic cardiomyopathy have emerged, with no apparent consistency within species, strain,

duration or type of diabetes (previously reviewed in [191]). For example, increased LC3B-positive

myocytes, LC3BII protein expression, phagosome number (from electron micrographs) and

decreased p62 protein expression is evident in atrial biopsies from human T2D patients with

ischemic heart disease [192]. In contrast, decreased Atg5 protein expression and no change in LC3B

is observed in T2D patients with coronary artery disease but without overt signs of cardiomyopathy

[193]. Interestingly, despite similar increases in autophagosome number and expression of

autophagy marker LC3BII, T1D rat hearts exhibit increased lysosome number, while T2D mouse

hearts (db/db) exhibit decreased lysosome number [194], suggesting that lysosomal availability

and/or function may play an important role. Inconsistent findings from animal models of diabetes

could be due to differences in severity and type of diabetes, but even highly constrained in vitro

culture experiments where cardiomyocytes are exposed to high glucose (30mM) yield conflicting

results. Autophagy activation (via rapamycin) exacerbates cell death, and autophagy inhibition (via

3-methyladenine) attenuates cell death in high glucose primary neonatal rat cardiomyocytes [153,

195]. These findings suggest that suppression of autophagy in this context may be a favorable

adaptive response to preserve cell viability. In contrast, activation of autophagy (via metformin-

treatment) decreases high glucose-induced apoptosis in cultured H9c2 cardiomyoblasts [88]. The

differences in these studies could be attributed to the different cell types used. The ‘control’ culture

conditions of ~5mM glucose (for comparison with 30mM glucose) are well-tolerated by primary

neonatal rat ventricular myocytes but may pose a ‘starvation’ challenge to H9c2 cells routinely

maintained in 25mM glucose.
Interventions manipulating cardiac autophagy in experimental diabetic settings have also generated

contradictory findings on the role of autophagy in diabetic cardiomyopathy. Activation of


autophagy via systemic administration of pharmacological agents (metformin [88], resveratrol

[194], fenofibrate [196]) has proved beneficial in ameliorating diabetes-induced cardiac


dysfunction. But inhibition of autophagy via systemic administration of chloroquine [197], or


global genetic knockdown of autophagy initiation proteins (Beclin 1 or Atg16L1 [198]) has also

improved cardiac dysfunction in diabetes. However, the cardiac effects observed in these studies

may be secondary to the systemic impact of these interventions. Cardiac-specific Beclin 1

overexpression in T1D STZ-treated mice (via α-MHC cardiac promotor with tetracycline-controlled

transactivator) increases autophagosomal clearance and exacerbates diabetes-induced cardiac

pathology [198]. Given that STZ-induced T1D increases lysosomal content [194], interventions

which upregulate early-autophagy proteins such as Beclin 1 could be detrimental in this disease

setting of heightened lysosomal throughput, but might prove therapeutic in type 2 diabetic db/db

mice where lysosomal availability is more limited. Understanding specific points of disruption in

the autophagic process and how they differ between T1D and T2D is an important priority.


6. Conclusions

Diabetic cardiomyopathy is a distinct pathology independent of co-morbidities such as coronary

artery disease and hypertension. Experimental investigations of diabetic cardiomyopathy have

provided considerable mechanistic and molecular insight into disease characteristics. Diabetes-

related systemic disturbances in glucose, insulin and fatty acids, facilitate shifts in the cardiac

metabolic profile and alterations in key cardiac signaling pathways. Decreased insulin signaling,

and an aberrant response to β-adrenergic stimulation, impact on cardiomyocyte substrate utilization,

storage of glucose and lipids, and cell death via apoptosis and autophagy. AMPK signaling

disturbance is evident but not well characterized in the diabetic heart. Disruptions in these signaling
pathways, and energy stress responses such as oxidative stress and autophagy dysregulation, are

likely contributors to cardiomyocyte death and to impaired functional performance in the diabetic

heart (Figure 1). Genetic manipulation of cardiac metabolic pathways, signaling intermediates, and

autophagy proteins have provided important insights into the molecular mechanisms of diabetic

cardiac pathology. Despite these advances, an understanding of the etiology of diabetic


cardiomyopathy has not yet been achieved. In some cases, pre-clinical findings have not translated

to the human patient setting. Relative ischemic cardioprotection observed in some diabetic rodent

models is not evident in diabetic patients where worse outcomes post-ischemia are evident [17].

Impaired cardiac glucose uptake and utilization, well-described in obese and lean diabetic rodents,

are evident in T2D male but not female patients [199]. Interestingly, metformin treatment

exacerbated glucose handling abnormalities in male T2D patients, despite evidence of some

improvement in cardiac function [200]. Thorough investigation at the pre-clinical level

characterizing sex differences and interrogation of the translational value of rodent models of

disease is an important priority in this field.

1. K. Huynh, B.C. Bernardo, J.R. McMullen, R.H. Ritchie, Diabetic cardiomyopathy:
mechanisms and new treatment strategies targeting antioxidant signaling pathways,
Pharmacol Ther 142 (2014) 375-415.
2. C.S. Lam, Diabetic cardiomyopathy: An expression of stage B heart failure with preserved
ejection fraction, Diab Vasc Dis Res 12 (2015) 234-238.
3. H. Bugger, E.D. Abel, Molecular mechanisms of diabetic cardiomyopathy, Diabetologia 57
(2014) 660-671.
4. B.M. Fisher, G. Gillen, G.B. Lindop, H.J. Dargie, B.M. Frier, Cardiac function and coronary
arteriography in asymptomatic type 1 (insulin-dependent) diabetic patients: evidence for a
specific diabetic heart disease, Diabetologia 29 (1986) 706-712.
5. G. Jia, A. Whaley-Connell, J.R. Sowers, Diabetic cardiomyopathy: a hyperglycaemia- and

insulin-resistance-induced heart disease, Diabetologia (2017)
6. S. Dandamudi, J. Slusser, D.W. Mahoney, M.M. Redfield, R.J. Rodeheffer, H.H. Chen, The
prevalence of diabetic cardiomyopathy: a population-based study in Olmsted County,

Minnesota, J Card Fail 20 (2014) 304-309.
7. V.C. Patil, H.V. Patil, K.B. Shah, J.D. Vasani, P. Shetty, Diastolic dysfunction in

asymptomatic type 2 diabetes mellitus with normal systolic function, Journal of
cardiovascular disease research 2 (2011) 213-222.
8. M. Shimabukuro, N. Higa, T. Asahi, K. Yamakawa, Y. Oshiro, M. Higa, H. Masuzaki,
Impaired glucose tolerance, but not impaired fasting glucose, underlies left ventricular
diastolic dysfunction, Diabetes Care 34 (2011) 686-690.
9. A.M. From, C.G. Scott, H.H. Chen, The development of heart failure in patients with
diabetes mellitus and pre-clinical diastolic dysfunction a population-based study, J Am Coll

Cardiol 55 (2010) 300-305.

10. J.E. Liu, V. Palmieri, M.J. Roman, J.N. Bella, R. Fabsitz, B.V. Howard, T.K. Welty, E.T.
Lee, R.B. Devereux, The impact of diabetes on left ventricular filling pattern in
normotensive and hypertensive adults: the Strong Heart Study, J Am Coll Cardiol 37 (2001)

11. L. van Heerebeek, N. Hamdani, M.L. Handoko, I. Falcao-Pires, R.J. Musters, K.

Kupreishvili, A.J. Ijsselmuiden, C.G. Schalkwijk, J.G. Bronzwaer, M. Diamant, A. Borbely,


J. van der Velden, G.J. Stienen, G.J. Laarman, H.W. Niessen, W.J. Paulus, Diastolic
stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end
products, and myocyte resting tension, Circulation 117 (2008) 43-51.

12. K.J. Nadeau, J.G. Regensteiner, T.A. Bauer, M.S. Brown, J.L. Dorosz, A. Hull, P. Zeitler,
B. Draznin, J.E. Reusch, Insulin resistance in adolescents with type 1 diabetes and its
relationship to cardiovascular function, J Clin Endocrinol Metab 95 (2010) 513-521.

13. T.J. Bradley, C. Slorach, F.H. Mahmud, D.B. Dunger, J. Deanfield, L. Deda, Y. Elia, R.L.
Har, W. Hui, R. Moineddin, H.N. Reich, J.W. Scholey, L. Mertens, E. Sochett, D.Z.
Cherney, Early changes in cardiovascular structure and function in adolescents with type 1
diabetes, Cardiovasc Diabetol 15 (2016) 31.
14. M. Diamant, H.J. Lamb, Y. Groeneveld, E.L. Endert, J.W. Smit, J.J. Bax, J.A. Romijn, A.
de Roos, J.K. Radder, Diastolic dysfunction is associated with altered myocardial
metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes
mellitus, J Am Coll Cardiol 42 (2003) 328-335.
15. A.S. Jaffe, J.J. Spadaro, K. Schechtman, R. Roberts, E.M. Geltman, B.E. Sobel, Increased
congestive heart failure after myocardial infarction of modest extent in patients with
diabetes mellitus, American heart journal 108 (1984) 31-37.
16. A. Goyal, N. Agrawal, Ischemic preconditioning: Interruption of various disorders, J Saudi
Heart Assoc 29 (2017) 116-127.

17. M.E. Reichelt, K.M. Mellor, J.R. Bell, C. Chandramouli, J.P. Headrick, L.M. Delbridge,
Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus, Am
J Physiol Heart Circ Physiol 305 (2013) H779-792.
18. B.A. Christopher, H.M. Huang, J.M. Berthiaume, T.A. McElfresh, X. Chen, C.M. Croniger,
R.F. Muzic, Jr., M.P. Chandler, Myocardial insulin resistance induced by high fat feeding in
heart failure is associated with preserved contractile function, American journal of
physiology Heart and circulatory physiology 299 (2010) H1917-1927.
19. J.H. Rennison, T.A. McElfresh, X. Chen, V.R. Anand, B.D. Hoit, C.L. Hoppel, M.P.
Chandler, Prolonged exposure to high dietary lipids is not associated with lipotoxicity in
heart failure, Journal of molecular and cellular cardiology 46 (2009) 883-890.
20. J.H. Rennison, T.A. McElfresh, I.C. Okere, E.J. Vazquez, H.V. Patel, A.B. Foster, K.K.
Patel, Q. Chen, B.D. Hoit, K.Y. Tserng, M.O. Hassan, C.L. Hoppel, M.P. Chandler, High-

fat diet postinfarction enhances mitochondrial function and does not exacerbate left
ventricular dysfunction, American journal of physiology Heart and circulatory physiology
292 (2007) H1498-1506.

21. I. Shimizu, T. Minamino, H. Toko, S. Okada, H. Ikeda, N. Yasuda, K. Tateno, J. Moriya, M.
Yokoyama, A. Nojima, G.Y. Koh, H. Akazawa, I. Shiojima, C.R. Kahn, E.D. Abel, I.
Komuro, Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by

pressure overload in rodents, The Journal of clinical investigation 120 (2010) 1506-1514.
22. W.C. Stanley, G.D. Lopaschuk, J.G. McCormack, Regulation of energy substrate
metabolism in the diabetic heart, Cardiovasc Res 34 (1997) 25-33.
23. L. Yang, D. Zhao, J. Ren, J. Yang, Endoplasmic reticulum stress and protein quality control
in diabetic cardiomyopathy, Biochim Biophys Acta 1852 (2015) 209-218.
24. K.M. Mellor, M.A. Brimble, L.M. Delbridge, Glucose as an agent of post-translational

modification in diabetes--New cardiac epigenetic insights, Life Sci 129 (2015) 48-53.
25. K.R. Bidasee, K. Nallani, Y. Yu, R.R. Cocklin, Y. Zhang, M. Wang, U.D. Dincer, H.R.
Besch, Jr., Chronic diabetes increases advanced glycation end products on cardiac ryanodine
receptors/calcium-release channels, Diabetes 52 (2003) 1825-1836.

26. K.R. Bidasee, Y. Zhang, C.H. Shao, M. Wang, K.P. Patel, U.D. Dincer, H.R. Besch, Jr.,
Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic

reticulum Ca2+-ATPase, Diabetes 53 (2004) 463-473.

27. J.L. McLarty, S.A. Marsh, J.C. Chatham, Post-translational protein modification by O-

linked N-acetyl-glucosamine: its role in mediating the adverse effects of diabetes on the
heart, Life Sci 92 (2013) 621-627.
28. K.M. Mellor, I.R. Wendt, R.H. Ritchie, L.M. Delbridge, Fructose diet treatment in mice

induces fundamental disturbance of cardiomyocyte Ca2+ handling and myofilament

responsiveness, Am J Physiol Heart Circ Physiol 302 (2012) H964-972.
29. L. Pereira, G. Ruiz-Hurtado, A. Rueda, J.J. Mercadier, J.P. Benitah, A.M. Gomez, Calcium

signaling in diabetic cardiomyocytes, Cell Calcium 56 (2014) 372-380.

30. P.K. Mishra, W. Ying, S.S. Nandi, G.K. Bandyopadhyay, K.K. Patel, S.K. Mahata, Diabetic
Cardiomyopathy: An Immunometabolic Perspective, Front Endocrinol (Lausanne) 8 (2017)
31. H. Taegtmeyer, C.R. Wilson, P. Razeghi, S. Sharma, Metabolic energetics and genetics in
the heart, Annals of the New York Academy of Sciences 1047 (2005) 208-218.
32. E.D. Abel, Glucose transport in the heart, Front Biosci 9 (2004) 201-215.
33. L. Szablewski, Glucose transporters in healthy heart and in cardiac disease, International
journal of cardiology 230 (2017) 70-75.
34. P. Song, A. Onishi, H. Koepsell, V. Vallon, Sodium glucose cotransporter SGLT1 as a
therapeutic target in diabetes mellitus, Expert Opin Ther Targets 20 (2016) 1109-1125.
35. S.K. Banerjee, K.R. McGaffin, N.M. Pastor-Soler, F. Ahmad, SGLT1 is a novel cardiac
glucose transporter that is perturbed in disease states, Cardiovascular research 84 (2009)
36. Y. Chen, J. Du, Y.T. Zhao, L. Zhang, G. Lv, S. Zhuang, G. Qin, T.C. Zhao, Histone
deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac
remodeling in diabetic mice, Cardiovascular diabetology 14 (2015) 99.
37. D. Shao, R. Tian, Glucose Transporters in Cardiac Metabolism and Hypertrophy, Compr
Physiol 6 (2015) 331-351.
38. K.M. Mellor, R.H. Ritchie, A.J. Davidoff, L.M.D. Delbridge, Elevated dietary sugar and the
heart: experimental models and myocardial remodeling., Can J Physiol Pharmacol 88 (2010)
39. K.M. Mellor, J.R. Bell, I.R. Wendt, A.J. Davidoff, R.H. Ritchie, L.M. Delbridge, Fructose
modulates cardiomyocyte excitation-contraction coupling and Ca(2)(+) handling in vitro,
PloS one 6 (2011) e25204.
40. S. Lal, W.C. Randall, A.H. Taylor, F. Kappler, M. Walker, T.R. Brown, B.S. Szwergold,

Fructose-3-phosphate production and polyol pathway metabolism in diabetic rat hearts,
Metabolism 46 (1997) 1333-1338.
41. A. Kashiwagi, T. Obata, M. Suzaki, Y. Takagi, Y. Kida, T. Ogawa, Y. Tanaka, T. Asahina,

M. Ikebuchi, Y. Saeki, et al., Increase in cardiac muscle fructose content in streptozotocin-
induced diabetic rats, Metabolism 41 (1992) 1041-1046.
42. L.M. Delbridge, V.L. Benson, R.H. Ritchie, K.M. Mellor, Diabetic Cardiomyopathy: The

Case for a Role of Fructose in Disease Etiology, Diabetes 65 (2016) 3521-3528.
43. J. Buchanan, P.K. Mazumder, P. Hu, G. Chakrabarti, M.W. Roberts, U.J. Yun, R.C.
Cooksey, S.E. Litwin, E.D. Abel, Reduced cardiac efficiency and altered substrate
metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse
models of insulin resistance and obesity, Endocrinology 146 (2005) 5341-5349.
44. L. Hue, H. Taegtmeyer, The Randle cycle revisited: a new head for an old hat, American

journal of physiology Endocrinology and metabolism 297 (2009) E578-591.

45. L.M. Le Page, O.J. Rider, A.J. Lewis, V. Ball, K. Clarke, E. Johansson, C.A. Carr, L.C.
Heather, D.J. Tyler, Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic
Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and

Echocardiography Study, Diabetes 64 (2015) 2735-2743.

46. T.A. Nicholl, G.D. Lopaschuk, J.H. McNeill, Effects of free fatty acids and dichloroacetate

on isolated working diabetic rat heart, The American journal of physiology 261 (1991)

47. O.J. How, T.S. Larsen, A.D. Hafstad, A. Khalid, E.S. Myhre, A.J. Murray, N.T. Boardman,
M. Cole, K. Clarke, D.L. Severson, E. Aasum, Rosiglitazone treatment improves cardiac
efficiency in hearts from diabetic mice, Arch Physiol Biochem 113 (2007) 211-220.

48. M. Bayeva, K.T. Sawicki, H. Ardehali, Taking diabetes to heart--deregulation of myocardial

lipid metabolism in diabetic cardiomyopathy, Journal of the American Heart Association 2
(2013) e000433.

49. H. Taegtmeyer, P. McNulty, M.E. Young, Adaptation and maladaptation of the heart in
diabetes: Part I: general concepts, Circulation 105 (2002) 1727-1733.
50. B.N. Finck, J.J. Lehman, T.C. Leone, M.J. Welch, M.J. Bennett, A. Kovacs, X. Han, R.W.
Gross, R. Kozak, G.D. Lopaschuk, D.P. Kelly, The cardiac phenotype induced by
PPARalpha overexpression mimics that caused by diabetes mellitus, J Clin Invest 109
(2002) 121-130.
51. D.R. Cha, J.Y. Han, D.M. Su, Y. Zhang, X. Fan, M.D. Breyer, Y. Guan, Peroxisome
proliferator-activated receptor-alpha deficiency protects aged mice from insulin resistance
induced by high-fat diet, American journal of nephrology 27 (2007) 479-482.
52. E. Aasum, D.D. Belke, D.L. Severson, R.A. Riemersma, M. Cooper, M. Andreassen, T.S.
Larsen, Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM
17.0744, a novel PPAR-alpha activator, Am J Physiol Heart Circ Physiol 283 (2002) H949-

53. A.N. Carley, L.M. Semeniuk, Y. Shimoni, E. Aasum, T.S. Larsen, J.P. Berger, D.L.
Severson, Treatment of type 2 diabetic db/db mice with a novel PPARgamma agonist
improves cardiac metabolism but not contractile function, American journal of physiology
Endocrinology and metabolism 286 (2004) E449-455.
54. S. Sharma, R. Taliyan, Histone deacetylase inhibitors: Future therapeutics for insulin
resistance and type 2 diabetes, Pharmacological research : the official journal of the Italian
Pharmacological Society 113 (2016) 320-326.
55. T.I. Lee, Y.H. Kao, W.C. Tsai, C.C. Chung, Y.C. Chen, Y.J. Chen, HDAC Inhibition
Modulates Cardiac PPARs and Fatty Acid Metabolism in Diabetic Cardiomyopathy, PPAR
Res 2016 (2016) 5938740.
56. C. Riehle, E.D. Abel, Insulin Signaling and Heart Failure, Circulation research 118 (2016)

57. R. Song, W. Peng, Y. Zhang, F. Lv, H.K. Wu, J. Guo, Y. Cao, Y. Pi, X. Zhang, L. Jin, M.
Zhang, P. Jiang, F. Liu, S. Meng, C.M. Cao, R.P. Xiao, Central role of E3 ubiquitin ligase
MG53 in insulin resistance and metabolic disorders, Nature 494 (2013) 375-379.

58. F. Liu, R. Song, Y. Feng, J. Guo, Y. Chen, Y. Zhang, T. Chen, Y. Wang, Y. Huang, C.Y. Li,
C. Cao, Y. Zhang, X. Hu, R.P. Xiao, Upregulation of MG53 Induces Diabetic
Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated

Receptor alpha, Circulation 131 (2015) 795-804.
59. Y. Zhang, H.K. Wu, F. Lv, R.P. Xiao, MG53, biological function and potential as a
therapeutic target, Molecular pharmacology (2017)
60. D.D. Belke, S. Betuing, M.J. Tuttle, C. Graveleau, M.E. Young, M. Pham, D. Zhang, R.C.
Cooksey, D.A. McClain, S.E. Litwin, H. Taegtmeyer, D. Severson, C.R. Kahn, E.D. Abel,
Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein

isoform expression, J Clin Invest 109 (2002) 629-639.

61. S. Boudina, H. Bugger, S. Sena, B.T. O'Neill, V.G. Zaha, O. Ilkun, J.J. Wright, P.K.
Mazumder, E. Palfreyman, T.J. Tidwell, H. Theobald, O. Khalimonchuk, B. Wayment, X.
Sheng, K.J. Rodnick, R. Centini, D. Chen, S.E. Litwin, B.E. Weimer, E.D. Abel,

Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and

oxidative stress in the heart, Circulation 119 (2009) 1272-1283.

62. H. Bugger, C. Riehle, B. Jaishy, A.R. Wende, J. Tuinei, D. Chen, J. Soto, K.M. Pires, S.
Boudina, H.A. Theobald, I. Luptak, B. Wayment, X. Wang, S.E. Litwin, B.C. Weimer, E.D.

Abel, Genetic loss of insulin receptors worsens cardiac efficiency in diabetes, J Mol Cell
Cardiol 52 (2012) 1019-1026.
63. Y. Qi, Z. Xu, Q. Zhu, C. Thomas, R. Kumar, H. Feng, D.E. Dostal, M.F. White, K.M.

Baker, S. Guo, Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by
p38alpha MAPK during insulin resistance, Diabetes 62 (2013) 3887-3900.
64. M. Shum, K. Bellmann, P. St-Pierre, A. Marette, Pharmacological inhibition of S6K1

increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice,
Diabetologia 59 (2016) 592-603.
65. H. Liu, H.Y. Liu, Y.N. Jiang, N. Li, Protective effect of thymoquinone improves
cardiovascular function, and attenuates oxidative stress, inflammation and apoptosis by
mediating the PI3K/Akt pathway in diabetic rats, Molecular medicine reports 13 (2016)
66. Q. Chen, T. Xu, D. Li, D. Pan, P. Wu, Y. Luo, Y. Ma, Y. Liu, JNK/PI3K/Akt signaling
pathway is involved in myocardial ischemia/reperfusion injury in diabetic rats: effects of
salvianolic acid A intervention, American journal of translational research 8 (2016) 2534-
67. R.H. Ritchie, J.E. Love, K. Huynh, B.C. Bernardo, D.C. Henstridge, H. Kiriazis, Y.K.
Tham, G. Sapra, C. Qin, N. Cemerlang, E.J. Boey, K. Jandeleit-Dahm, X.J. Du, J.R.
McMullen, Enhanced phosphoinositide 3-kinase(p110alpha) activity prevents diabetes-

induced cardiomyopathy and superoxide generation in a mouse model of diabetes,
Diabetologia 55 (2012) 3369-3381.
68. D. Prakoso, M.J. DeBlasio, C. Qin, S. Rosli, H. Kiriazis, H. Qian, X.J. Du, K.L. Weeks, P.
Gregorevic, J.R. McMullen, R.H. Ritchie, Phosphoinositide 3-Kinase (p110alpha) Gene
Delivery Limits Diabetes-induced Cardiac NADPH Oxidase and Cardiomyopathy in a
Mouse Model with Established Diastolic Dysfunction, Clin Sci (Lond) 131 (2017) 1345-
69. Y. Zhu, R.O. Pereira, B.T. O'Neill, C. Riehle, O. Ilkun, A.R. Wende, T.A. Rawlings, Y.C.
Zhang, Q. Zhang, A. Klip, I. Shiojima, K. Walsh, E.D. Abel, Cardiac PI3K-Akt impairs
insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation, Mol
Endocrinol 27 (2013) 172-184.
70. D. Abdurrachim, M. Nabben, V. Hoerr, M.T. Kuhlmann, P. Bovenkamp, J. Ciapaite, I.M.E.

Geraets, W. Coumans, J. Luiken, J.F.C. Glatz, M. Schafers, K. Nicolay, C. Faber, S.
Hermann, J.J. Prompers, Diabetic db/db mice do not develop heart failure upon pressure
overload: a longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural,

and functional adaptations, Cardiovascular research 113 (2017) 1148-1160.
71. R.E. Brainard, L.J. Watson, A.M. Demartino, K.R. Brittian, R.D. Readnower, A.A. Boakye,
D. Zhang, J.D. Hoetker, A. Bhatnagar, S.P. Baba, S.P. Jones, High fat feeding in mice is

insufficient to induce cardiac dysfunction and does not exacerbate heart failure, PloS one 8
(2013) e83174.
72. D.J. Chess, R.J. Khairallah, K.M. O'Shea, W. Xu, W.C. Stanley, A high-fat diet increases
adiposity but maintains mitochondrial oxidative enzymes without affecting development of
heart failure with pressure overload, American journal of physiology Heart and circulatory
physiology 297 (2009) H1585-1593.

73. D. Grahame Hardie, AMP-activated protein kinase: a key regulator of energy balance with
many roles in human disease, Journal of internal medicine 276 (2014) 543-559.
74. S.C. Bairwa, N. Parajuli, J.R. Dyck, The role of AMPK in cardiomyocyte health and
survival, Biochimica et biophysica acta 1862 (2016) 2199-2210.

75. R.R. Russell, 3rd, R. Bergeron, G.I. Shulman, L.H. Young, Translocation of myocardial
GLUT-4 and increased glucose uptake through activation of AMPK by AICAR, Am J

Physiol 277 (1999) H643-649.

76. C.T. Lee, J.R. Ussher, A. Mohammad, A. Lam, G.D. Lopaschuk, 5'-AMP-activated protein

kinase increases glucose uptake independent of GLUT4 translocation in cardiac myocytes,

Canadian journal of physiology and pharmacology 92 (2014) 307-314.
77. S.B. Jorgensen, J.N. Nielsen, J.B. Birk, G.S. Olsen, B. Viollet, F. Andreelli, P. Schjerling, S.

Vaulont, D.G. Hardie, B.F. Hansen, E.A. Richter, J.F. Wojtaszewski, The alpha2-5'AMP-
activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is
responsive to glucose loading, Diabetes 53 (2004) 3074-3081.

78. R. Halse, L.G. Fryer, J.G. McCormack, D. Carling, S.J. Yeaman, Regulation of glycogen
synthase by glucose and glycogen: a possible role for AMP-activated protein kinase,
Diabetes 52 (2003) 9-15.
79. A. McBride, S. Ghilagaber, A. Nikolaev, D.G. Hardie, The glycogen-binding domain on the
AMPK beta subunit allows the kinase to act as a glycogen sensor, Cell metabolism 9 (2009)
80. G. Polekhina, A. Gupta, B.J. Michell, B. van Denderen, S. Murthy, S.C. Feil, I.G. Jennings,
D.J. Campbell, L.A. Witters, M.W. Parker, B.E. Kemp, D. Stapleton, AMPK beta subunit
targets metabolic stress sensing to glycogen, Current biology : CB 13 (2003) 867-871.
81. H. An, L. He, Current understanding of metformin effect on the control of hyperglycemia in
diabetes, The Journal of endocrinology 228 (2016) R97-106.
82. J.R. Petrie, N. Chaturvedi, I. Ford, M. Brouwers, N. Greenlaw, T. Tillin, I. Hramiak, A.D.
Hughes, A.J. Jenkins, B.E.K. Klein, R. Klein, T.C. Ooi, P. Rossing, C.D.A. Stehouwer, N.
Sattar, H.M. Colhoun, R.S. Group, Cardiovascular and metabolic effects of metformin in
patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled
trial, Lancet Diabetes Endocrinol 5 (2017) 597-609.
83. S. Verma, J.H. McNeill, Metformin improves cardiac function in isolated streptozotocin-
diabetic rat hearts, Am J Physiol 266 (1994) H714-719.
84. Z. Xie, K. Lau, B. Eby, P. Lozano, C. He, B. Pennington, H. Li, S. Rathi, Y. Dong, R. Tian,
D. Kem, M.H. Zou, Improvement of cardiac functions by chronic metformin treatment is
associated with enhanced cardiac autophagy in diabetic OVE26 mice, Diabetes 60 (2011)
85. A. Daniels, M. van Bilsen, B.J. Janssen, A.E. Brouns, J.P. Cleutjens, T.H. Roemen, G.
Schaart, J. van der Velden, G.J. van der Vusse, F.A. van Nieuwenhoven, Impaired cardiac
functional reserve in type 2 diabetic db/db mice is associated with metabolic, but not
structural, remodelling, Acta Physiol (Oxf) 200 (2010) 11-22.

86. I. Tabbi-Anneni, J. Buchanan, R.C. Cooksey, E.D. Abel, Captopril normalizes insulin
signaling and insulin-regulated substrate metabolism in obese (ob/ob) mouse hearts,
Endocrinology 149 (2008) 4043-4050.

87. G. Kewalramani, D. An, M.S. Kim, S. Ghosh, D. Qi, A. Abrahani, T. Pulinilkunnil, V.
Sharma, R.B. Wambolt, M.F. Allard, S.M. Innis, B. Rodrigues, AMPK control of
myocardial fatty acid metabolism fluctuates with the intensity of insulin-deficient diabetes, J

Mol Cell Cardiol 42 (2007) 333-342.
88. C. He, H. Zhu, H. Li, M.H. Zou, Z. Xie, Dissociation of Bcl-2-Beclin1 complex by activated
AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in
diabetes, Diabetes 62 (2013) 1270-1281.
89. R. Scognamiglio, A. Avogaro, D. Casara, C. Crepaldi, M. Marin, M. Palisi, R. Mingardi, G.
Erle, G. Fasoli, S. Dalla Volta, Myocardial dysfunction and adrenergic cardiac innervation

in patients with insulin-dependent diabetes mellitus, Journal of the American College of

Cardiology 31 (1998) 404-412.
90. S. Paolillo, G. Rengo, G. Pagano, T. Pellegrino, G. Savarese, G.D. Femminella, M. Tuccillo,
A. Boemio, E. Attena, R. Formisano, L. Petraglia, F. Scopacasa, G. Galasso, D. Leosco, B.

Trimarco, A. Cuocolo, P. Perrone-Filardi, Impact of diabetes on cardiac sympathetic

innervation in patients with heart failure: a 123I meta-iodobenzylguanidine (123I MIBG)

scintigraphic study, Diabetes care 36 (2013) 2395-2401.

91. O. Gotzsche, The adrenergic beta-receptor adenylate cyclase system in heart and

lymphocytes from streptozotocin-diabetic rats. In vivo and in vitro evidence for a

desensitized myocardial beta-receptor, Diabetes 32 (1983) 1110-1116.
92. P.R. Sundaresan, V.K. Sharma, S.I. Gingold, S.P. Banerjee, Decreased beta-adrenergic

receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones,

Endocrinology 114 (1984) 1358-1363.
93. J.J. Savarese, B.A. Berkowitz, beta-Adrenergic receptor decrease in diabetic rat hearts, Life

sciences 25 (1979) 2075-2078.

94. C.E. Heyliger, G.N. Pierce, P.K. Singal, R.E. Beamish, N.S. Dhalla, Cardiac alpha- and
beta-adrenergic receptor alterations in diabetic cardiomyopathy, Basic research in
cardiology 77 (1982) 610-618.
95. Y. Nishio, A. Kashiwagi, Y. Kida, M. Kodama, N. Abe, Y. Saeki, Y. Shigeta, Deficiency of
cardiac beta-adrenergic receptor in streptozocin-induced diabetic rats, Diabetes 37 (1988)
96. R.F. Cook, C.T. Bussey, K.M. Mellor, P.A. Cragg, R.R. Lamberts, beta1 -Adrenoceptor, but
not beta2 -adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo,
Experimental physiology (2017)
97. Q. Wang, Y. Liu, Q. Fu, B. Xu, Y. Zhang, S. Kim, R. Tan, F. Barbagallo, T. West, E.
Anderson, W. Wei, E.D. Abel, Y.K. Xiang, Inhibiting Insulin-Mediated beta2-Adrenergic
Receptor Activation Prevents Diabetes-Associated Cardiac Dysfunction, Circulation 135
(2017) 73-88.
98. B.E. Myagmar, J.M. Flynn, P.M. Cowley, P.M. Swigart, M.D. Montgomery, K. Thai, D.
Nair, R. Gupta, D.X. Deng, C. Hosoda, S. Melov, A.J. Baker, P.C. Simpson, Adrenergic
Receptors in Individual Ventricular Myocytes: The Beta-1 and Alpha-1B Are in All Cells,
the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent,
Circulation research 120 (2017) 1103-1115.
99. C. Morisco, G. Condorelli, V. Trimarco, A. Bellis, C. Marrone, J. Sadoshima, B. Trimarco,
Akt mediates the cross-talk between beta-adrenergic and insulin receptors in neonatal
cardiomyocytes, Circulation research 96 (2005) 180-188.
100. S. Mangmool, T. Denkaew, S. Phosri, D. Pinthong, W. Parichatikanond, T. Shimauchi, M.
Nishida, Sustained betaAR Stimulation Mediates Cardiac Insulin Resistance in a PKA-
Dependent Manner, Mol Endocrinol 30 (2016) 118-132.
101. Q. Fu, B. Xu, D. Parikh, D. Cervantes, Y.K. Xiang, Insulin induces IRS2-dependent and

GRK2-mediated beta2AR internalization to attenuate betaAR signaling in cardiomyocytes,
Cellular signalling 27 (2015) 707-715.
102. Q. Fu, Q. Wang, Y.K. Xiang, Insulin and beta Adrenergic Receptor Signaling: Crosstalk in

Heart, Trends in endocrinology and metabolism: TEM 28 (2017) 416-427.
103. S. Mangmool, T. Denkaew, W. Parichatikanond, H. Kurose, beta-Adrenergic Receptor and
Insulin Resistance in the Heart, Biomolecules & therapeutics 25 (2017) 44-56.

104. C. Chandramouli, U. Varma, E.M. Stevens, R.P. Xiao, D.I. Stapleton, K.M. Mellor, L.M.
Delbridge, Myocardial glycogen dynamics: new perspectives on disease mechanisms,
Clinical and experimental pharmacology & physiology 42 (2015) 415-425.
105. J.H. Ryu, J. Drain, J.H. Kim, S. McGee, A. Gray-Weale, L. Waddington, G.J. Parker, M.
Hargreaves, S.H. Yoo, D. Stapleton, Comparative structural analyses of purified glycogen
particles from rat liver, human skeletal muscle and commercial preparations, Int J Biol

Macromol 45 (2009) 478-482.

106. E. Kokubun, S.M. Hirabara, J. Fiamoncini, R. Curi, H. Haebisch, Changes of glycogen
content in liver, skeletal muscle, and heart from fasted rats, Cell Biochem Funct 27 (2009)

107. M.C. Gannon, F.Q. Nuttall, Effect of prolonged starvation on glycogen synthase and
glycogen synthase phosphatase activity in rat heart, J Nutr 114 (1984) 2147-2154.

108. J. He, D.E. Kelley, Muscle glycogen content in type 2 diabetes mellitus, Am J Physiol
Endocrinol Metab 287 (2004) E1002-1007.

109. A.W. Thorburn, B. Gumbiner, F. Bulacan, G. Brechtel, R.R. Henry, Multiple defects in
muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin
dependent diabetes mellitus, J Clin Invest 87 (1991) 489-495.

110. R.A. Rizza, M.F. Crass, 3rd, J.C. Shipp, Effect of insulin treatment in vivo on heart
glycerides and glycogen of alloxan-diabetic rats, Metabolism: clinical and experimental 20
(1971) 539-543.

111. S. Penpargkul, T. Schaible, T. Yipintsoi, J. Scheuer, The effect of diabetes on performance

and metabolism of rat hearts, Circulation research 47 (1980) 911-921.
112. M. Nakao, T. Matsubara, N. Sakamoto, Effects of diabetes on cardiac glycogen metabolism
in rats, Heart Vessels 8 (1993) 171-175.
113. T.B. Miller, Jr., Altered regulation of cardiac glycogen metabolism in spontaneously
diabetic rats, Am J Physiol 245 (1983) E379-383.
114. C. Malfitano, A.L. de Souza Junior, M. Carbonaro, A. Bolsoni-Lopes, D. Figueroa, L.E. de
Souza, K.A. Silva, F. Consolim-Colombo, R. Curi, M.C. Irigoyen, Glucose and fatty acid
metabolism in infarcted heart from streptozotocin-induced diabetic rats after 2 weeks of
tissue remodeling, Cardiovascular diabetology 14 (2015) 149.
115. N.P. Lebkova, O.E. Kolesova, V.D. Gorbunova, I. Bobkov Iu, A. Petrovich Iu, [Intracellular
transformation of fatty acids into glycogen in alloxan diabetic rats, based on electron
autoradiographic data], Biulleten' eksperimental'noi biologii i meditsiny 98 (1984) 734-736.

116. N.P. Lebkova, M.F. Bondarenko, O.E. Kolesova, G.P. Azarian, [Ultrastructural
manifestations of early metabolic disorders in the myocardium of dogs with alloxan
diabetes], Biulleten' eksperimental'noi biologii i meditsiny 89 (1980) 614-617.
117. M.R. Laughlin, W.A. Petit, Jr., R.G. Shulman, E.J. Barrett, Measurement of myocardial
glycogen synthesis in diabetic and fasted rats, Am J Physiol 258 (1990) E184-190.
118. O. Kraupp, L. Adler-Kastner, H. Niessner, B. Plank, The effects of starvation and of acute
and chronic alloxan diabetes on myocardial substrate levels and on liver glycogen in the rat
in vivo, Eur J Biochem 2 (1967) 197-214.
119. Y.C. Hsiao, K. Suzuki, H. Abe, T. Toyota, Ultrastructural alterations in cardiac muscle of
diabetic BB Wistar rats, Virchows Archiv A, Pathological anatomy and histopathology 411
(1987) 45-52.
120. M. Higuchi, K. Miyagi, J. Nakasone, M. Sakanashi, Role of high glycogen in underperfused

diabetic rat hearts with added norepinephrine, J Cardiovasc Pharmacol 26 (1995) 899-907.
121. M. Dervisevik, S. Dinevska-Kovkarovska, M. Dimitrovska, N. Cipanovska, B. Miova, High
dose of aspirin moderates diabetes-induced changes of heart glycogen/glucose metabolism

in rats, The journal of physiological sciences : JPS 64 (2014) 411-420.
122. V. Chen, C.D. Ianuzzo, B.C. Fong, J.J. Spitzer, The effects of acute and chronic diabetes on
myocardial metabolism in rats, Diabetes 33 (1984) 1078-1084.

123. S. Bhimji, D.V. Godin, J.H. McNeill, Myocardial ultrastructural changes in alloxan-induced
diabetes in rabbits, Acta anatomica 125 (1986) 195-200.
124. C. Alfarano, S. Suffredini, O. Fantappie, A. Mugelli, E. Cerbai, M.E. Manni, L. Raimondi,
The effect of losartan treatment on the response of diabetic cardiomyocytes to ATP
depletion, Pharmacol Res 63 (2011) 225-232.
125. J. Shearer, K.D. Ross, C.C. Hughey, V.L. Johnsen, D.S. Hittel, D.L. Severson, Exercise

training does not correct abnormal cardiac glycogen accumulation in the db/db mouse model
of type 2 diabetes, Am J Physiol Endocrinol Metab 301 (2011) E31-39.
126. M. Sakakibara, A. Hirashiki, X.W. Cheng, Y. Bando, K. Ohshima, T. Okumura, H.
Funahashi, S. Ohshima, T. Murohara, Association of diabetes mellitus with myocardial

collagen accumulation and relaxation impairment in patients with dilated cardiomyopathy,

Diabetes research and clinical practice 92 (2011) 348-355.

127. P. Rosen, L. Herberg, H. Reinauer, Different types of postinsulin receptor defects contribute
to insulin resistance in hearts of obese Zucker rats, Endocrinology 119 (1986) 1285-1291.

128. M. Reyes, M.E. Steinhelper, J.A. Alvarez, D. Escobedo, J. Pearce, J.W. Valvano, B.H.
Pollock, C.L. Wei, A. Kottam, D. Altman, S. Bailey, S. Thomsen, S. Lee, J.T. Colston, J.H.
Oh, G.L. Freeman, M.D. Feldman, Impact of physiological variables and genetic

background on myocardial frequency-resistivity relations in the intact beating murine heart,

American journal of physiology Heart and circulatory physiology 291 (2006) H1659-1669.
129. J.A. Povlsen, B. Lofgren, C. Dalgas, R.I. Birkler, M. Johannsen, N.B. Stottrup, H.E. Botker,

Protection against myocardial ischemia-reperfusion injury at onset of type 2 diabetes in

Zucker diabetic fatty rats is associated with altered glucose oxidation, PLoS One 8 (2013)
130. E. Plante, A. Menaouar, B.A. Danalache, T.L. Broderick, M. Jankowski, J. Gutkowska,
Treatment with brain natriuretic peptide prevents the development of cardiac dysfunction in
obese diabetic db/db mice, Diabetologia 57 (2014) 1257-1267.
131. J.L. Liang, Z.K. Feng, X.Y. Liu, Q.X. Lin, Y.H. Fu, Z.X. Shan, J.N. Zhu, S.G. Lin, X.Y.
Yu, Effect of impaired glucose tolerance on cardiac dysfunction in a rat model of
prediabetes, Chinese medical journal 124 (2011) 734-739.
132. C. Lajoie, A. Calderone, F. Trudeau, N. Lavoie, G. Massicotte, S. Gagnon, L. Beliveau,
Exercise training attenuated the PKB and GSK-3 dephosphorylation in the myocardium of
ZDF rats, J Appl Physiol (1985) 96 (2004) 1606-1612.
133. C. Lajoie, L. Beliveau, F. Trudeau, N. Lavoie, G. Massicotte, S. Gagnon, A. Calderone, The
rapid onset of hyperglycaemia in ZDF rats was associated with a widespread alteration of
metabolic proteins implicated in glucose metabolism in the heart, Can J Physiol Pharmacol
84 (2006) 1205-1213.
134. M. Eto, K. Watanabe, M. Sekiguchi, Y. Iwashima, A. Morikawa, E. Oshima, K. Ishii,
Metabolic and morphological changes of the heart in Chinese hamsters (CHAD strain) with
spontaneous long-term diabetes, Diabetes research and clinical practice 3 (1987) 297-305.
135. A. Virkamaki, H. Yki-Jarvinen, Allosteric regulation of glycogen synthase and hexokinase
by glucosamine-6-phosphate during glucosamine-induced insulin resistance in skeletal
muscle and heart, Diabetes 48 (1999) 1101-1107.
136. J. He, M.T. Quintana, J. Sullivan, L.P. T, J.G. T, J.C. Schisler, J.A. Hill, C.C. Yates, R.F.
Mapanga, M.F. Essop, W.E. Stansfield, J.R. Bain, C.B. Newgard, M.J. Muehlbauer, Y. Han,
B.A. Clarke, M.S. Willis, MuRF2 regulates PPARgamma1 activity to protect against
diabetic cardiomyopathy and enhance weight gain induced by a high fat diet, Cardiovascular

diabetology 14 (2015) 97.
137. Z.J. Wang, Q. Liu, P.P. Li, C.H. Zou, Z.F. Shen, Effect of GCP-02, a PPARalpha/gamma
dual activator, on glucose and lipid metabolism in insulin-resistant mice, European journal

of pharmacology 580 (2008) 277-283.
138. W.C. Stanley, J.L. Hall, K.R. Smith, G.D. Cartee, T.A. Hacker, J.A. Wisneski, Myocardial
glucose transporters and glycolytic metabolism during ischemia in hyperglycemic diabetic

swine, Metabolism 43 (1994) 61-69.
139. L.S. Mansor, K. Mehta, D. Aksentijevic, C.A. Carr, T. Lund, M.A. Cole, L. Le Page, L.
Sousa Fialho Mda, M.J. Shattock, E. Aasum, K. Clarke, D.J. Tyler, L.C. Heather, Increased
oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia
signalling and metabolic adaptation, The Journal of physiology 594 (2016) 307-320.
140. L.S. Mansor, E.R. Gonzalez, M.A. Cole, D.J. Tyler, J.H. Beeson, K. Clarke, C.A. Carr, L.C.

Heather, Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with
low dose streptozotocin, Cardiovascular diabetology 12 (2013) 136.
141. I. Das, Studies on glycogen metabolism in normal and diabetic rat heart in vivo, Can J
Biochem 51 (1973) 637-641.

142. B.L. Leonard, R.N. Watson, K.M. Loomes, A.R. Phillips, G.J. Cooper, Insulin resistance in
the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes,

Acta diabetologica 42 (2005) 162-170.

143. M.C. Gannon, C.B. Niewoehner, F.Q. Nuttall, Effect of insulin administration on cardiac

glycogen synthase and synthase phosphatase activity in rats fed diets high in protein, fat or
carbohydrate, J Nutr 115 (1985) 243-251.
144. L.G. Chuffa, F.R. Seiva, Combined effects of age and diet-induced obesity on biochemical

parameters and cardiac energy metabolism in rats, Indian J Biochem Biophys 50 (2013) 40-
145. T.B. Miller, Jr., A dual role for insulin in the regulation of cardiac glycogen synthase, J Biol

Chem 253 (1978) 5389-5394.

146. D.J. Kondomerkos, S.A. Kalamidas, O.B. Kotoulas, A.C. Hann, Glycogen autophagy in the
liver and heart of newborn rats. The effects of glucagon, adrenalin or rapamycin, Histology
and histopathology 20 (2005) 689-696.
147. P.J. Roach, A.A. Depaoli-Roach, T.D. Hurley, V.S. Tagliabracci, Glycogen and its
metabolism: some new developments and old themes, Biochem J 441 (2012) 763-787.
148. S. Jiang, C.D. Wells, P.J. Roach, Starch-binding domain-containing protein 1 (Stbd1) and
glycogen metabolism: Identification of the Atg8 family interacting motif (AIM) in Stbd1
required for interaction with GABARAPL1, Biochem Biophys Res Commun 413 (2011)
149. M.E. Reichelt, K.M. Mellor, C.L. Curl, D. Stapleton, L.M. Delbridge, Myocardial
glycophagy - A specific glycogen handling response to metabolic stress is accentuated in the
female heart, J Mol Cell Cardiol 65 (2013) 67-75.

150. L.M. Delbridge, K.M. Mellor, D.J. Taylor, R.A. Gottlieb, Myocardial autophagic energy
stress responses--macroautophagy, mitophagy, and glycophagy, American journal of
physiology Heart and circulatory physiology 308 (2015) H1194-1204.
151. A. Fayssoil, Cardiomyopathy in Pompe's disease, European journal of internal medicine 19
(2008) 57-59.
152. Z. Cheng, Q. Fang, Danon disease: focusing on heart, Journal of human genetics 57 (2012)
153. K.M. Mellor, U. Varma, D.I. Stapleton, L.M. Delbridge, Cardiomyocyte glycophagy is
regulated by insulin and exposure to high extracellular glucose, American journal of
physiology Heart and circulatory physiology 306 (2014) H1240-1245.
154. J.J. Luiken, Y. Arumugam, D.J. Dyck, R.C. Bell, M.M. Pelsers, L.P. Turcotte, N.N. Tandon,
J.F. Glatz, A. Bonen, Increased rates of fatty acid uptake and plasmalemmal fatty acid

transporters in obese Zucker rats, J Biol Chem 276 (2001) 40567-40573.
155. G.A. Cook, E.N. Lavrentyev, K. Pham, E.A. Park, Streptozotocin diabetes increases mRNA
expression of ketogenic enzymes in the rat heart, Biochim Biophys Acta 1861 (2017) 307-

156. D. Abdurrachim, M. Nabben, V. Hoerr, M.T. Kuhlmann, P. Bovenkamp, J. Ciapaite, I.M.E.
Geraets, W. Coumans, J. Luiken, J.F.C. Glatz, M. Schafers, K. Nicolay, C. Faber, S.

Hermann, J.J. Prompers, Diabetic db/db mice do not develop heart failure upon pressure
overload: A longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural,
and functional adaptations, Cardiovasc Res (2017)
157. D. de Gonzalo-Calvo, R.W. van der Meer, L.J. Rijzewijk, J.W. Smit, E. Revuelta-Lopez, L.
Nasarre, J.C. Escola-Gil, H.J. Lamb, V. Llorente-Cortes, Serum microRNA-1 and
microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes, Sci

Rep 7 (2017) 47.

158. K. Tauchi-Sato, S. Ozeki, T. Houjou, R. Taguchi, T. Fujimoto, The surface of lipid droplets
is a phospholipid monolayer with a unique Fatty Acid composition, J Biol Chem 277 (2002)

159. H. Wang, U. Sreenivasan, D.W. Gong, K.A. O'Connell, E.R. Dabkowski, P.A. Hecker, N.
Ionica, M. Konig, A. Mahurkar, Y. Sun, W.C. Stanley, C. Sztalryd, Cardiomyocyte-specific

perilipin 5 overexpression leads to myocardial steatosis and modest cardiac dysfunction, J

Lipid Res 54 (2013) 953-965.

160. K. Kuramoto, F. Sakai, N. Yoshinori, T.Y. Nakamura, S. Wakabayashi, T. Kojidani, T.

Haraguchi, F. Hirose, T. Osumi, Deficiency of a lipid droplet protein, perilipin 5, suppresses
myocardial lipid accumulation, thereby preventing type 1 diabetes-induced heart

malfunction, Mol Cell Biol 34 (2014) 2721-2731.

161. V.G. Demarco, D.A. Ford, E.J. Henriksen, A.R. Aroor, M.S. Johnson, J. Habibi, L. Ma, M.
Yang, C.J. Albert, J.W. Lally, C.A. Ford, M. Prasannarong, M.R. Hayden, A.T. Whaley-

Connell, J.R. Sowers, Obesity-related alterations in cardiac lipid profile and nondipping
blood pressure pattern during transition to diastolic dysfunction in male db/db mice,
Endocrinology 154 (2013) 159-171.
162. P. Bostrom, L. Andersson, M. Rutberg, J. Perman, U. Lidberg, B.R. Johansson, J.
Fernandez-Rodriguez, J. Ericson, T. Nilsson, J. Boren, S.O. Olofsson, SNARE proteins
mediate fusion between cytosolic lipid droplets and are implicated in insulin sensitivity, Nat
Cell Biol 9 (2007) 1286-1293.
163. T.H. Sollner, Lipid droplets highjack SNAREs, Nat Cell Biol 9 (2007) 1219-1220.
164. I.J. Goldberg, C.M. Trent, P.C. Schulze, Lipid metabolism and toxicity in the heart, Cell
Metab 15 (2012) 805-812.
165. T. Pulinilkunnil, P.C. Kienesberger, J. Nagendran, T.J. Waller, M.E. Young, E.E. Kershaw,
G. Korbutt, G. Haemmerle, R. Zechner, J.R. Dyck, Myocardial adipose triglyceride lipase
overexpression protects diabetic mice from the development of lipotoxic cardiomyopathy,
Diabetes 62 (2013) 1464-1477.
166. M. Ueno, J. Suzuki, Y. Zenimaru, S. Takahashi, T. Koizumi, S. Noriki, O. Yamaguchi, K.
Otsu, W.J. Shen, F.B. Kraemer, I. Miyamori, Cardiac overexpression of hormone-sensitive
lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice, Am J
Physiol Endocrinol Metab 294 (2008) E1109-1118.
167. R. Singh, S. Kaushik, Y. Wang, Y. Xiang, I. Novak, M. Komatsu, K. Tanaka, A.M. Cuervo,
M.J. Czaja, Autophagy regulates lipid metabolism, Nature 458 (2009) 1131-1135.
168. P.K. Battiprolu, B. Hojayev, N. Jiang, Z.V. Wang, X. Luo, M. Iglewski, J.M. Shelton, R.D.
Gerard, B.A. Rothermel, T.G. Gillette, S. Lavandero, J.A. Hill, Metabolic stress-induced
activation of FoxO1 triggers diabetic cardiomyopathy in mice, The Journal of clinical
investigation 122 (2012) 1109-1118.
169. S. Paula-Gomes, D.A. Goncalves, A.M. Baviera, N.M. Zanon, L.C. Navegantes, I.C.
Kettelhut, Insulin suppresses atrophy- and autophagy-related genes in heart tissue and

cardiomyocytes through AKT/FOXO signaling, Hormone and metabolic research =
Hormon- und Stoffwechselforschung = Hormones et metabolisme 45 (2013) 849-855.
170. O.J. How, E. Aasum, D.L. Severson, W.Y. Chan, M.F. Essop, T.S. Larsen, Increased

myocardial oxygen consumption reduces cardiac efficiency in diabetic mice, Diabetes 55
(2006) 466-473.
171. P.K. Mazumder, B.T. O'Neill, M.W. Roberts, J. Buchanan, U.J. Yun, R.C. Cooksey, S.

Boudina, E.D. Abel, Impaired cardiac efficiency and increased fatty acid oxidation in
insulin-resistant ob/ob mouse hearts, Diabetes 53 (2004) 2366-2374.
172. A. Faria, S.J. Persaud, Cardiac oxidative stress in diabetes: Mechanisms and therapeutic
potential, Pharmacology & therapeutics 172 (2017) 50-62.
173. X. Liu, W. Gan, Y. Zou, B. Yang, Z. Su, J. Deng, L. Wang, J. Cai, Elevated Levels of
Urinary Markers of Oxidative DNA and RNA Damage in Type 2 Diabetes with

Complications, Oxidative medicine and cellular longevity 2016 (2016) 4323198.

174. D. Liang, P. Zhong, J. Hu, F. Lin, Y. Qian, Z. Xu, J. Wang, C. Zeng, X. Li, G. Liang, EGFR
inhibition protects cardiac damage and remodeling through attenuating oxidative stress in
STZ-induced diabetic mouse model, J Mol Cell Cardiol 82 (2015) 63-74.

175. M.J. De Blasio, K. Huynh, C. Qin, S. Rosli, H. Kiriazis, A. Ayer, N. Cemerlang, R. Stocker,
X.J. Du, J.R. McMullen, R.H. Ritchie, Therapeutic targeting of oxidative stress with

coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of

diabetes with diminished PI3K(p110alpha) signaling, Free Radic Biol Med 87 (2015) 137-

176. T. Nishikawa, T. Sasahara, S. Kiritoshi, K. Sonoda, T. Senokuchi, T. Matsuo, D. Kukidome,
N. Wake, T. Matsumura, N. Miyamura, M. Sakakida, H. Kishikawa, E. Araki, Evaluation of

urinary 8-hydroxydeoxy-guanosine as a novel biomarker of macrovascular complications in

type 2 diabetes, Diabetes care 26 (2003) 1507-1512.
177. K. Huynh, H. Kiriazis, X.J. Du, J.E. Love, K.A. Jandeleit-Dahm, J.M. Forbes, J.R.

McMullen, R.H. Ritchie, Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte

hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes, Diabetologia
55 (2012) 1544-1553.
178. J.R. Privratsky, L.E. Wold, J.R. Sowers, M.T. Quinn, J. Ren, AT1 blockade prevents
glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and
NADPH oxidase, Hypertension 42 (2003) 206-212.
179. M. Zhang, A.L. Kho, N. Anilkumar, R. Chibber, P.J. Pagano, A.M. Shah, A.C. Cave,
Glycated proteins stimulate reactive oxygen species production in cardiac myocytes:
involvement of Nox2 (gp91phox)-containing NADPH oxidase, Circulation 113 (2006)
180. S.S. Bombicino, D.E. Iglesias, I.A. Mikusic, V. D'Annunzio, R.J. Gelpi, A. Boveris, L.B.
Valdez, Diabetes impairs heart mitochondrial function without changes in resting cardiac
performance, The international journal of biochemistry & cell biology 81 (2016) 335-345.

181. G. Koncsos, Z.V. Varga, T. Baranyai, K. Boengler, S. Rohrbach, L. Li, K.D. Schluter, R.
Schreckenberg, T. Radovits, A. Olah, C. Matyas, A. Lux, M. Al-Khrasani, T. Komlodi, N.
Bukosza, D. Mathe, L. Deres, M. Bartekova, T. Rajtik, A. Adameova, K. Szigeti, P. Hamar,
Z. Helyes, L. Tretter, P. Pacher, B. Merkely, Z. Giricz, R. Schulz, P. Ferdinandy, Diastolic
dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress, American
journal of physiology Heart and circulatory physiology 311 (2016) H927-H943.
182. E.M. Jeong, J. Chung, H. Liu, Y. Go, S. Gladstein, A. Farzaneh-Far, E.D. Lewandowski,
S.C. Dudley, Jr., Role of Mitochondrial Oxidative Stress in Glucose Tolerance, Insulin
Resistance, and Cardiac Diastolic Dysfunction, Journal of the American Heart Association 5
183. Y. Kayama, U. Raaz, A. Jagger, M. Adam, I.N. Schellinger, M. Sakamoto, H. Suzuki, K.
Toyama, J.M. Spin, P.S. Tsao, Diabetic Cardiovascular Disease Induced by Oxidative

Stress, Int J Mol Sci 16 (2015) 25234-25263.
184. C.Y. Huang, W.J. Ting, J.Y. Yang, W.T. Lin, Resveratrol attenuated hydrogen peroxide-
induced myocardial apoptosis by autophagic flux, Food & nutrition research 60 (2016)

185. S. Sciarretta, M. Volpe, J. Sadoshima, NOX4 regulates autophagy during energy
deprivation, Autophagy 10 (2014) 699-701.

186. S. Sciarretta, P. Zhai, D. Shao, D. Zablocki, N. Nagarajan, L.S. Terada, M. Volpe, J.
Sadoshima, Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes
cardiomyocyte autophagy and survival during energy stress through the protein kinase
RNA-activated-like endoplasmic reticulum kinase/eukaryotic initiation factor
2alpha/activating transcription factor 4 pathway, Circ Res 113 (2013) 1253-1264.
187. H. Yuan, C.N. Perry, C. Huang, E. Iwai-Kanai, R.S. Carreira, C.C. Glembotski, R.A.

Gottlieb, LPS-induced autophagy is mediated by oxidative signaling in cardiomyocytes and

is associated with cytoprotection, Am J Physiol Heart Circ Physiol 296 (2009) H470-479.
188. G.W. Dorn, 2nd, Apoptotic and non-apoptotic programmed cardiomyocyte death in
ventricular remodelling, Cardiovasc Res 81 (2009) 465-473.

189. D.A. Kubli, A.B. Gustafsson, Unbreak my heart: targeting mitochondrial autophagy in
diabetic cardiomyopathy, Antioxidants & redox signaling 22 (2015) 1527-1544.

190. C. Zhang, T.W. Syed, R. Liu, J. Yu, Role of Endoplasmic Reticulum Stress, Autophagy, and
Inflammation in Cardiovascular Disease, Frontiers in cardiovascular medicine 4 (2017) 29.

191. L.M.D. Delbridge, K.M. Mellor, D.J. Taylor, R.A. Gottlieb, Myocardial stress and
autophagy: mechanisms and potential therapies, Nature reviews Cardiology (2017)
192. P.E. Munasinghe, F. Riu, P. Dixit, M. Edamatsu, P. Saxena, N.S. Hamer, I.F. Galvin, R.W.

Bunton, S. Lequeux, G. Jones, R.R. Lamberts, C. Emanueli, P. Madeddu, R. Katare, Type-2

diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated
pathway, Int J Cardiol 202 (2016) 13-20.

193. D. Montaigne, X. Marechal, A. Coisne, N. Debry, T. Modine, G. Fayad, C. Potelle, J.M. El

Arid, S. Mouton, Y. Sebti, H. Duez, S. Preau, I. Remy-Jouet, F. Zerimech, M. Koussa, V.
Richard, R. Neviere, J.L. Edme, P. Lefebvre, B. Staels, Myocardial contractile dysfunction
is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not
in obese patients, Circulation 130 (2014) 554-564.
194. H. Kanamori, G. Takemura, K. Goto, A. Tsujimoto, A. Mikami, A. Ogino, T. Watanabe, K.
Morishita, H. Okada, M. Kawasaki, M. Seishima, S. Minatoguchi, Autophagic adaptations
in diabetic cardiomyopathy differ between type 1 and type 2 diabetes, Autophagy 11 (2015)
195. S. Kobayashi, X. Xu, K. Chen, Q. Liang, Suppression of autophagy is protective in high
glucose-induced cardiomyocyte injury, Autophagy 8 (2012) 577-592.
196. J. Zhang, Y. Cheng, J. Gu, S. Wang, S. Zhou, Y. Wang, Y. Tan, W. Feng, Y. Fu, N. Mellen,
R. Cheng, J. Ma, C. Zhang, Z. Li, L. Cai, Fenofibrate increases cardiac autophagy via

FGF21/SIRT1 and prevents fibrosis and inflammation in the hearts of Type 1 diabetic mice,
Clin Sci (Lond) 130 (2016) 625-641.
197. X. Yuan, Y.C. Xiao, G.P. Zhang, N. Hou, X.Q. Wu, W.L. Chen, J.D. Luo, G.S. Zhang,
Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic
mice, Drug Des Devel Ther 10 (2016) 2729-2737.
198. X. Xu, S. Kobayashi, K. Chen, D. Timm, P. Volden, Y. Huang, J. Gulick, Z. Yue, J.
Robbins, P.N. Epstein, Q. Liang, Diminished autophagy limits cardiac injury in mouse
models of type 1 diabetes, J Biol Chem 288 (2013) 18077-18092.
199. L.R. Peterson, P. Herrero, A.R. Coggan, Z. Kisrieva-Ware, I. Saeed, C. Dence, D. Koudelis,
J.B. McGill, M.R. Lyons, E. Novak, V.G. Davila-Roman, A.D. Waggoner, R.J. Gropler,
Type 2 diabetes, obesity, and sex difference affect the fate of glucose in the human heart,
Am J Physiol Heart Circ Physiol 308 (2015) H1510-1516.

200. M.R. Lyons, L.R. Peterson, J.B. McGill, P. Herrero, A.R. Coggan, I.M. Saeed, C. Recklein,
K.B. Schechtman, R.J. Gropler, Impact of sex on the heart's metabolic and functional
responses to diabetic therapies, Am J Physiol Heart Circ Physiol 305 (2013) H1584-1591.


Figure Legends

Figure 1. Mechanisms of diastolic dysfunction in the diabetic heart. Diabetes is associated with

impaired glucose uptake and utilization, a shift towards fatty acid oxidation and accumulation of

glycogen and lipids. Metabolic dysregulation may trigger energy stress responses such as oxidative

stress and autophagy disturbance linked with increased cell death, fibrosis and ultimately leading to

impaired cardiac relaxation and diastolic dysfunction in diabetes.

Figure 2. Molecular mechanisms of diabetic cardiomyopathy. Diabetes is associated with

increased circulating fatty acids, increased glucose, either insulin deficiency (T1D) or
hyperinsulinemia (T2D) and increased catecholamines from heightened sympathetic activity. These

systemic perturbations lead to increased cardiac fatty acid uptake, impaired glucose uptake and

dysregulated insulin and β-adrenergic signaling. A shift towards fatty acid oxidation and

accumulation of glycogen and lipids are common observations in the diabetic heart and although

inconsistent findings have been reported relating to AMPK and autophagic processes, disturbances

in these pathways may exacerbate the metabolic mismanagement in the heart. ‘+’, upregulation; ‘-’,

downregulation, ‘mTOR’ mammalian target of rapamycin.



cardiac metabolic dysregulation:
• impaired glucose uptake & utilization
• shift towards fatty acid oxidation
• accumulation of fuel stores (glycogen and lipids)

energy stress responses:

• oxidative stress
• autophagy disturbance

impaired cardiac relaxation

• activation of cell death pathways
• fibrosis and ventricular stiffness

Diastolic Dysfunction

Figure 1. Mechanisms of diastolic dysfunction in the diabetic heart. Diabetes is associated with
impaired glucose uptake and utilization, a shift towards fatty acid oxidation and accumulation of
glycogen and lipids. Metabolic dysregulation may trigger energy stress responses such as oxidative
stress and autophagy disturbance linked with increased cell death, fibrosis and ultimately leading to

impaired cardiac relaxation and diastolic dysfunction in diabetes.



- insulin (T1D)
+ fatty acids + glucose + insulin (T2D) + catecholamines

- IR β1 +/- ?
- IRS1/2 cAMP
fatty acid - glycolysis
+ oxidation acute
- - PKA

oxidation PI3K/Akt
lipid chronic
+ droplets + glycogen
mTOR Ca2+

AMPK autophagy
+/- ? +/- ?

cardiomyocyte death, fibrosis

and cardiac dysfunction

Figure 2. Molecular mechanisms of diabetic cardiomyopathy. Diabetes is associated with increased circulating fatty
acids, increased glucose, either insulin deficiency (T1D) or hyperinsulinemia (T2D) and increased catecholamines from
heightened sympathetic activity. These systemic perturbations lead to increased cardiac fatty acid uptake, impaired

glucose uptake and dysregulated insulin and β-adrenergic signaling. A shift towards fatty acid oxidation and accumulation
of glycogen and lipids are common observations in the diabetic heart and although inconsistent findings have been
reported relating to AMPK and autophagic processes, disturbances in these pathways may exacerbate the metabolic

mismanagement in the heart. ‘+’, upregulation; ‘-’, downregulation, ‘mTOR’ mammalian target of rapamycin.


Table 1. Reports of cardiac glycogen content in models of diabetes.
Cardiac glycogen Phenotype
Phenotype Species Model Reference
content duration
nr Human Diabetic Patient Chronic [162]
T1D Rat Alloxan inj Short term [77, 84]
T1D Rat Alloxan inj Chronic [82, 85]
T1D Rat STZ inj Short term [79, 87-89]
[78, 81, 87-89,
T1D Rat STZ inj Chronic
91, 164]
T1D Rat BB Wistar Chronic [86]
T1D Dog Alloxan inj Chronic [83]
↑ T1D Rabbit Alloxan inj nr [90]

T2D Human T2D Patient Chronic [93]
T2D Rat ZDF Chronic [94, 99, 100]

T2D (late) Rat ZDF Chronic [96]
T2D Rat STZ inj (low dose) Chronic [98]
T2D Mouse db/db Chronic [92, 95, 97]

T2D Hamster CHAD strain Chronic [101]
Ins res +
Rat Glucosamine inj Short term [102]
T1D Rat STZ inj nr [108]
T1D Swine STZ inj Chronic [105]
HFD + STZ inj
T2D Rat Chronic [107]
(mod dose)

T2D Rat HFD + STZ inj Chronic [106]

↔ T2D (early) Rat ZDF Chronic [96]
Ins res +
Mouse MSG inj Chronic [104]

Ins res +
Mouse HFD Chronic [103]

HFD + STZ inj (low

T2D Rat Chronic [107] [165]

↓ T2D Rat ZDF Chronic [109]

Ins res +
Rat HFD Short term [110]

HFD + STZ inj (low

T2D Rat Chronic [166]
Ins res +
Rat Hypercaloric diet# Chronic [111]

T1D, type I diabetes; T2D, type II diabetes; ins res, insulin resistance; inj, injection; STZ, streptozotocin;
HFD, high fat diet; ZDF, Zucker diabetic fatty; nr, not recorded. Short term  1 week. Chronic > 1 week.
For genetic models, duration of disease is equivalent to final age. #With 30% sucrose.


 Diabetes-related systemic disturbances facilitate alterations in cardiac metabolism.
 Dysregulation of cardiac insulin, AMPK and β-adrenergic signaling is well documented.
 Diabetes alters cardiac substrate utilization and storage of glucose and lipids.
 Cardiac energy stress responses in diabetes (eg. oxidative stress and autophagy) are linked with
cell death.
 Molecular disturbances ultimately culminate in impaired relaxation and functional performance
in the diabetic heart.