Proceedings of the Australian Physiological Society (2012) 43: 117-123
http://aups.org.au/Proceedings/43/117-123
© L.M.D. Delbridge 2012
Myocardial insulin resistance, metabolic stress and autophagy in diabetes
Kimberley M. Mellor, James R. Bell, Rebecca H. Ritchie* and Lea M.D. Delbridge*
Department of Physiology, University of Melbourne, Melbourne, VIC 3010, Australia
Summary
1. Clinical studies in humans strongly support a link
between insulin resistance and non-ischemic heart failure.
The occurrence of a specific insulin resistant
cardiomyopathy, independent of vascular abnormalities, is
now recognized. The progression of cardiac pathology
linked with insulin resistance is poorly understood.
2. Cardiac insulin resistance is characterized by
reduced availability of sarcolemmal Glut4 transporters and
consequent lower glucose uptake. A shift away from
glycolysis towards fatty acid oxidation for ATP supply is
apparent and is associated with myocardial oxidative stress.
Reliance of cardiomyocyte excitation-contraction coupling
on glycolytically-derived ATP supply potentially renders
cardiac function vulnerable to the metabolic remodelling
adaptations observed in diabetes development.
3. Findings from Glut4KO mice demonstrate that
cardiomyocytes with extreme glucose uptake deficiency
exhibit cardiac hypertrophy and marked excitation-
contraction coupling abnormalities characterized by
reduced sarcolemmal Ca2+
influx and sarcoplasmic
reticulum Ca2+ uptake. The ‘milder’ phenotype fructose-fed
mouse model of type 2 diabetes does not show evidence of
cardiac hypertrophy but cardiomyocyte loss linked with
autophagic activation is evident. Fructose feeding induces a
dramatic reduction in intracellular Ca2+ availability with
myofilament adaptation to preserve contractile function in
this setting.
4. The cardiac metabolic adaptations of two load-
independent models of diabetes, the Glut4 deficient mouse,
and the fructose-fed mouse are contrasted. The role of
autophagy in diabetic cardiopathology is evaluated and
anomalies of type 1
vs type 2 diabetic autophagic responses
are highlighted.
Introduction
The prevalence of insulin resistance and type 2
diabetes has increased dramatically in the past few decades
and has now reached epidemic levels in many countries.1,2
The Framingham Heart Study provided evidence of a link
between diabetes and non-ischemic heart failure 18 years
ago,3 but despite advances in treatments for heart failure,
mortality remains 40-80% higher for diabetic than non-
diabetic heart failure patients.4 Boyer
et al. reported that
diastolic dysfunction was evident in 75% of asymptomatic,
normotensive diabetic human subjects,5 and overlapping
diastolic and systolic dysfunction is commonly observed in
*
denotes equal senior authorship
diabetes.6 The myocardium is a major insulin-responsive
tissue and is thus especially vulnerable to diabetic
glucose/insulin homeostatic shifts. In diabetic hearts,
disturbances in myocardial energy metabolism are
apparent7,8 and may play a role in the greater mortality
observed in diabetic patients with heart failure.4 There is
some evidence that cardiomyocyte excitation-contraction
(EC) coupling is heavily reliant on glycolytically-derived
ATP,9,10 and the ATP supply shift away from glycolysis
towards β-oxidation of fatty acids evident in diabetes,11,12
has marked functional consequences. The purpose of this
review is to summarize the metabolic adaptations evident in
diabetic hearts and outline the cardiac features of two load-
independent models of diabetes, the Glut4 deficient mouse,
and the fructose-fed mouse. The role of autophagy in
diabetic cardiopathology is discussed and anomalies of type
1
vs type 2 diabetic autophagic responses are highlighted.
The diabetic heart
Cardiomyocyte metabolic substrates
Under normal conditions, cardiomyocyte fuel
preference is 30% glucose, 65% fatty acids, 5% ketone
bodies.13 Glucose uptake is mediated predominantly by
transporters from the Glut family, Glut1 and Glut4, and
fatty acids are transported across the sarcolemma mainly by
the long chain fatty acid transporter, CD36.14,15 The
sarcolemmal gradient of both glucose and fatty acids is
maintained by rapid enzyme-mediated conversion to
glucose-6-phosphate and acetyl-CoA respectively.14 Rodent
models of type 2 diabetes (
db/db mice, obese zucker rats,
high fat-fed rats) exhibit higher cardiomyocyte GLUT4
internalization coincident with increased sarcolemmal
localization of CD36.16-18 These transporter shifts are
associated with a marked reduction in cardiac glucose
uptake and an increase in uptake of fatty acids.18 In type 1
diabetic rat hearts (streptozotocin-induced), unchanged or
decreased Glut4 gene expression has been reported.19-21
Metabolic handling of glucose and fatty acids, and their
role in ATP production for EC-coupling processes has been
previously reviewed in Mellor
et al., 2010.22 Myocardial
oxidative stress induced by metabolic remodelling may play
a role in mediating cardiopathology in diabetes as high
peroxisomal processing of long-chain fatty acids and
mitochondrial dysfunction is associated with reactive
oxygen species excess.23,24
Recently, it has been demonstrated that fructose may
act as an alternative cardiomyocyte substrate.25 In diabetic
settings, and with high dietary fructose, plasma fructose is
elevated26,27 and it is feasible that fructose may have direct
Proceedings of the Australian Physiological Society (2012) 43
117
Diabetic cardiopathology and autophagy
cardiac metabolic consequences. The fructose-specific
transporter, Glut5, has recently been reported to be
expressed in rodent cardiomyocytes25,28 thus providing an
access route for plasma fructose uptake
via a non-glucose
competitive transporter.29 It has also been shown that
fructose acutely modulates cardiomyocyte excitation-
contraction coupling and may provide an alternative
glycolytic substrate when glucose supply is limited.25 How
fructose directly affects cardiomyocyte metabolism and EC
coupling in chronic settings has not been evaluated. Dietary
fructose excess has been shown to dramatically suppress
cardiomyocyte Ca2+
handling,28
potentially
via direct
cardiomyocyte fructose actions.
Fuel demand and EC coupling
Although myocardial energy is predominantly
oxidatively derived (up to 90%), there is some evidence that
cardiomyocyte EC-coupling is reliant on glycolysis.30
Glycolytic enzymes are closely associated with
sarcolemmal and sarcoplasmic reticulum (SR) Ca2+
handling proteins31 and intracellular Ca2+ regulation can be
altered by glycolytic intermediates (SR Ca2+ release
channel) and local glycolytic ATP supply (SR Ca2+ ATPase
(SERCA2a)).10
The Na+/Ca2+exchanger is indirectly
glycolysis-dependent
via the Na+/K+ATPase which
establishes the sarcolemmal Na+ electrochemical gradient.32
The Na+/K+ATPase pump is closely associated with
glycolytic enzymes at the sarcolemma and is dependent on
glycolytic ATP.31,33,34 Under normal conditions, SERCA2
has been estimated to require 15% of ATP produced by the
cardiomyocyte13,35 and is glycolysis-dependent.10 Thus
metabolic disturbances evident in the diabetic heart may
have dramatic consequences for cardiomyocyte EC-
coupling (discussed in detail below).
Cardiac pathology in diabetes
Lessons from the Glut4 deficient mouse
Type 2 diabetes is frequently observed coincident
with hypertension and obesity. Thus evaluating the cardiac
load-independent effects of insulin resistance is not possible
in many rodent models (
e.g. db/db mouse, high fat-fed
mouse/rat, zucker fatty rat,
ob/ob mouse). To inv estigate the
effects of cardiomyocyte insulin resistance, without
hemodynamic load complication, a Glut4 deficient mouse
has been utilised - this model has been constructed using a
Cre-LoxP system, with the genetic manipulation generating
two phenotypically distinct mice. The global Glut4
‘knockdown’ model (KD) exhibits 85% Glut4 protein
deletion in all tissues including heart, and the Glut4
‘knockout’ model (KO) exhibits further cardiomyocyte-
specific Glut4 deletion to achieve 99% protein deletion (see
Table 1 for a detailed comparison of Glut4KD and KO
models). Cardiomyocyte Glut4 deficiency is not offset by a
compensatory upregulation of the basal Glut1 transporter,
thus cardiac glucose uptake is significantly impaired in
these mice.36 Systemically, Glut4KD and Glut4KO mice
exhibit similar basal hyperinsulinemia but normal basal
plasma glucose and blood pressure relative to wildtype
controls.36 In the absence of systemic loading from
hypertension, cardiomyocyte Glut4 deficiency produces a
‘threshold’ hypertrophic effect. An 85% reduction in
cardiomyocyte Glut4 (Glut4KD) results in a 15% increase
in cardiac weight index (CWI), and Glut4 deletion (99%
reduction, Glut4KO) induces a 80% increase in CWI (see
Figure 1A).36 This growth abnormality is reversed by
treatment with the reactive oxygen species (ROS)
scavenger, tempol, confirming that oxidative stress plays a
role in mediating the cardiac hypertrophic effects of Glut4
deficiency (Figure 1B).37
HW
:BW
(m
g
/g
)
Glut4KO Glut4KO
+ Tempol
Control
Control +
Tempol
Glut4 Protein Levels (arbitary units)
B.
C
ard
ia
c W
eig
h
t In
d
ex
(m
g
/g
)
A.
Figure 1. Threshold hypertrophic effect of Glut4 defi-
ciency. A. Correlation of cardiac weight index and Glut4
protein expression in wildtype (white squares), Glut4KD
(grey squares) and Glut4KO (black squares). B. The
antioxidant, Tempol, abrogates cardiac hypertrophy in
Glut4KO mice. Reprinted from the Journal of Molecular
Endocrinology
200332 (1A) and the Journal of Molecular
and Cellular Cardiology
200733 (1B), with permission.
The cardiac insulin resistance generated by Glut4
deficiency is associated with a marked contractile deficit,
evident at the whole heart (
ex vivo) and cellular level.38,39
118
Proceedings of the Australian Physiological Society (2012) 43
K.M. Mellor, J.R. Bell, R.H. Ritchie & L.M.D. Delbridge
Table 1. Comparison of Glut4KO, Glut4KD and fructose-fed mouse models of cardiac insulin resistance.
Glut4KO
Glut4KD
Fructose-fed
mouse
Glut4 mRNA
∼99% ↓
∼85% ↓
↔/↓
cardiac weight index
∼80% ↑
∼15% ↑
↔
cardiomyocyte size
∼40% ↑
vs KD
-
↔
myocyte contractility (MRS, MRL)
∼30% ↓
vs KD
-
↔
SERCA2a
∼30% ↓
vs KD
-
∼20% ↓
Ca2+ transient amplitude
?
?
∼50% ↓
cardiac fibrosis
↑
↔
↑
cardiomyocyte number
?
?
↓
autophagy
?
?
↑
Arrows indicate change
vs control animal (
i.e. C57Bl/6 mouse for Glut4KO and KD data; control-fed C57Bl/6 mouse for
fructose-fed mouse data), unless specified otherwise. Abbreviations: maximum rate of shortening (MRS), maximum rate of
lengthening (MRL), sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). Data sourced from references: Kaczmarczyk
et al.
(2003)36
J. Mol. Endocrinol., Domenighetti
et al. (2010)38
J. Mol. Cell. Cardiol., Ritchie
et al. (2007)37
J. Mol. Cell. Car-
diol., Mellor
et al. (2011)41
J. Mol. Cell. Cardiol., Mellor
et al. (2012)28
Am. J. Physiol. Heart Circ. Physiol., Mellor
et al.
(2009)40
Nutrition.
Cardiac function can be restored to control values by
supplementation with the glycolytic end-product, pyruvate,
demonstrating a glycolytic dependence of cardiomyocyte
EC-coupling processes.39 Cardiomyocyte Ca2+ availability
(Ca2+ influx and SR Ca2+ uptake) is lower in Glut4 deficient
mouse hearts and adaptive Ca2+ and pH shifts are observed
with increased Na+Ca2+exchanger and Na+H+exchanger
(NHE) fluxes. Thus, a shift away from sarcoplasmic
reticulum towards sarcolemmal Ca2+ cycling is apparent.38
Increased NHE flux mediates an intracellular alkaline
environment (confirmed by intracellular pH measurements),
which has previously been shown to increase myofilament
Ca2+ responsiveness.38 This adaptive shift may partially
preserve cardiomyocyte contractility in this setting, at least
in the early stages of disease.
These findings with the Glut4KO mouse provide
valuable insight into the load-independent cardiac
phenotype of diabetes, in a relatively ‘extreme’ setting of
impaired cardiomyocyte glucose uptake. Yet, this genetic
approach based on manipulation of one transporter (Glut4)
which mediates supply of one substrate (glucose) represents
a rather artifically engineered cellular insulin resistance
scenario. To extend these observations to the more
pathophysiological context of type 2 diabetes, a different
approach using the fructose-fed mouse model has been
employed.
Lessons from the fructose-fed mouse
The fructose-fed mouse is normotensive and not
obese, thus systemic loading (pressure or volume) influence
is not a confounding factor.40,41 Mild basal hyperglycemia
is evident in the absence of hyperinsulinemia.41 It has
recently been demonstrated that chronic fructose feeding
induces cardiac insulin resistance, established through
decreased activation of downstream signalling
intermediates of the class I PI3K pathway (Akt and S6
phosphorylation).41
Dramatic reduction in insulin-
stimulated glucose uptake (50% decrease) has been
reported in response to fructose feeding,42 but there are
some discrepant findings relating to Glut4 expression. Qin
et al reported a ∼30% decrease in cardiac Glut4 mRNA in
fructose-fed rats,43 yet we observed no change in cardiac
Glut4 mRNA or total Glut4 protein content in fructose-fed
mice.41 Given the downregulation of the insulin signalling
intermediates, it is likely that Glut4 translocation is
reduced, but this is yet to be investigated in this model. The
cardiomyocyte EC-coupling phenotype associated with
these signalling alterations shows a profound reduction in
intracellular Ca2+ availability (lower diastolic Ca2+ and Ca2+
transient amplitude) without diminution of cardiomyocyte
contractility.28 The observed suppression in Ca2+ cycling
can be explained by a marked reduction in the expression of
Ca2+ handling proteins, SERCA2 and phospholamban,
coincident with upregulation of key cardiac phosphatase
subunits (PP2A-A and PP2A-C).28 The aetiology of these
expression shifts may correspond to the relative abundance
of reactive oxygen species (known to target important
signalling proteins involved in regulation of Ca2+
handling44). Increased myofilament responsiveness to Ca2+
is apparent, indicative of a specific cellular adaptation to
preserve contractile function (see Figure 2). Whether this
adaptive strategy can maintain ventricular function in the
whole heart has not been investigated. Few studies have
investigated the effects of fructose feeding on intact heart
function, and these reported findings are inconsistent.
Chang
et al. (2007) observed deteriorated cardiac function
using echocardiography after only 2 weeks fructose feeding
in rats.45 In contrast, Chess
et al. (2008) did not observe any
fructose-induced alterations in basal cardiac function in
mice but the contractile abnormalities induced by pressure-
overload hypertrophy were exacerbated by the fructose
diet.46 These findings suggest that although upregulated
myofilament responsiveness to Ca2+ may be successful as a
short-term adaptive strategy, the ability to respond to
Proceedings of the Australian Physiological Society (2012) 43
119
Diabetic cardiopathology and autophagy
A.
re 2.
100ms
8.0 µ
m
control
fructose
fructose
F360:380
100ms
B.
control
2.0
100ms
8
10
L
o
)
C.
2
4
6
8
Fructose
Control
%
S
h
o
rte
n
in
g
(n
o
rm
a
liz
e
d
to
L
3
4
5
6
0
Ca
2+
(Fura2 F360:380)
Figure 2. Dietary fructose suppresses cardiomyocyte Ca2+
handling and increases myofilament Ca2+ responsiveness.
A. Representative cardiomyocyte twitch profiles from con-
trol- and fructose-fed mice. B. Representative cardiomy-
ocyte Ca2+ transient profiles from control- and fructose-fed
mice. C. Representative Ca2+-shortening phase loops from
control- and fructose-fed mouse cardiomyocytes. Broken
arrow indicates progression of contractile cycle. Upper
arrow indicates left shift in phase loop in fructose-fed
mouse cardiomyocytes. Reprinted from the American Jour-
nal of Physiology: Heart and Circulation Physiology
201224
with permission.
cardiac stress is diminished. Longevity of the compensatory
myofilament adaptations with ongoing disease progression
is yet to be elucidated. The findings from these studies
demonstrate that significant underlying cellular EC
coupling disturbance may occur before cardiac functional
impact is observable
in vivo in the insulin resistant state
associated with high dietary fructose (see Table 1 for direct
comparison with Glut4KO and Glut4KD models).
In the relatively mild systemic diabetic environment
induced by a high fructose diet, no evidence of abnormal
cardiac growth is observed, but structural remodelling by
collagen infiltration is apparent.41 Evidence from human
and animal studies suggests that fibrosis infiltration occurs
in parallel with cardiomyocyte loss - the initial fibrotic
process is likely triggered by cell death events which
stimulate cytokine-mediated collagen ’infill’ responses. The
evidence of diffuse interstitial fibrosis throughout the
diabetic myocardium suggests widespread cardiomyocyte
attrition and cytokine activity. Indeed, a 4% reduction in
cardiomyocyte number during 12 weeks fructose treatment
was detected - a rate of myocyte loss which could be
expected to have marked cumulative functional impact with
extended dietary exposure and maintenance of cardiac
insulin resistance. A detailed investigation of myocyte death
responses elucidated a role for autophagy (and not
apoptosis) in mediating the observed myocyte dropout in
this setting.41,47
Autophagy in the diabetic heart
Cardiomyocyte autophagy is closely linked to energy
metabolism and is an essential myocardial adaptive
response to maintain energy homeostasis, particularly
during periods of cellular starvation.48,49 In excess, this
vacuolar destruction of proteins and organelles is
understood to lead to type 2 programmed cell death.50 The
intracellular environment of the insulin resistant heart may
be considered to be a state of ‘glucose deprivation’,
activating excessive autophagy. Glucose deprivation (
in
vitro) is a strong activator of AMPK in cardiomyocytes.51
This ‘nutrient sensor’ is activated by low ATP and
upregulates autophagy
via phosphorylation of mammalian
target of rapamycin (mTOR),52 thereby relieving mTOR’s
inhibition of autophagic initiation. If the Type 2 diabetic
heart is perceived as a form of sustained ’glucose
deprivation’, in contrast, the glucose excess environment of
type 1 diabetes might be expected to induce an entirely
different/opposite AMPK response. Xie
et al., (2011)
reported coincident downregulation of cardiac autophagy
and AMPK activity in two type 1 diabetic murine models
(STZ and OVE26).53 Thus opposite autophagic responses
are apparent in type 1 and type 2 diabetic hearts and direct
comparison of cardiomyocyte autophagy and energy stress
in these two disease settings is now required.
Conclusions
Clinical studies in humans strongly support the link
between insulin resistance and non-ischemic heart
failure,54,55 and a specific insulin resistant cardiomyopathy,
independent of vascular abnormalities, is now recognized.56
But the progression of cardiac pathology linked with insulin
120
Proceedings of the Australian Physiological Society (2012) 43
K.M. Mellor, J.R. Bell, R.H. Ritchie & L.M.D. Delbridge
resistance is poorly understood. Many experimental models
of insulin resistance and diabetes exhibit coincident
hypertension and/or obesity, thus selection of appropriate
‘load-independent’ models of diabetic cardiopathology is
crucial to advance this field. Findings from the Glut4
deficient and the fructose-fed mouse models have
demonstrated that specific cardiomyocyte EC-coupling
abnormalities are evident and myofilament adaptations may
act to preserve contractile function in the low Ca2+
intracellular environment observed in diabetic
cardiomyocytes. Identifying myocardial autophagy
activation as a key player in type 2 diabetic cardiopathology
opens a new area of investigation in this disease setting, and
provides potentially novel targets for treatment
development. Elucidating the cardiac phenotypes of type 1
vs type 2 diabetes, especially in relation to autophagic
processes, is a necessary next step in this field.
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Received 26 February 2012, in revised form 25 April 2012.
Accepted 14 May 2012.
© LMD Delbridge 2012.
Author for correspondence:
Prof LMD Delbridge
Department of Physiology
University of Melbourne
Parkville, VIC 3010
Australia
Tel: +61 3 83445853
Fax: +61 3 83445818
E-mail: lmd@unimelb.edu.au
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