NIH Public Access: Author Manuscript
NIH Public Access: Author Manuscript
NIH Public Access: Author Manuscript
Author Manuscript
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Published in final edited form as:
NIH-PA Author Manuscript
Abstract
Diabetes is associated with increased incidence of heart failure even after controlling for coronary
artery disease and hypertension. Thus, as diabetic cardiomyopathy has become an increasingly
recognized entity among clinicians, a better understanding of its pathophysiology is necessary for
early diagnosis and the development of treatment strategies for diabetes-associated cardiovascular
NIH-PA Author Manuscript
dysfunction. We will review recent basic and clinical research into the manifestations and the
pathophysiological mechanisms of diabetic cardiomyopathy. The discussion will be focused on
the structural, functional and metabolic changes that occur in the myocardium in diabetes and how
these changes may contribute to the development of diabetic cardiomyopathy in affected humans
and relevant animal models.
Keywords
Diabetic cardiomyopathy; Diastolic dysfunction; Substrate utilization; Mitochondrial dysfunction;
Uncoupling
1 Introduction
The concept of diabetic cardiomyopathy was first introduced by Rubler et al [1], and has
subsequently been widely used by epidemiologists and clinicians. Diabetic cardiomyopathy
describes diabetes-associated changes in the structure and function of the myocardium that
is not directly attributable to other confounding factors such as coronary artery disease
NIH-PA Author Manuscript
(CAD) or hypertension. It is important to note that in many patients, particularly those with
type 2 diabetes, diabetes associated changes are amplified by the existence of these co-
morbidities, which likely will augment the development of left ventricular hypertrophy,
increase the susceptibility of the heart to ischemic injury and increase the overall likelihood
of developing heart failure [2]. Several mechanisms have been implicated in the
pathogenesis of diabetic cardiomyopathy. Changes in myocardial structure, calcium
signaling and metabolism are early defects that have been described mainly in animal
models and may precede clinically manifest cardiac dysfunction. However, subtle functional
changes can be detected if specifically looked for.
Increased left ventricular (LV) mass is an independent risk factor for heart failure and may
occur independently of arterial blood pressure in Type 2 diabetes, and may contribute to
reduced myocardial compliance [3]. The Framingham study reported a significant increase
in LV wall thickness only in women with diabetes [4]. In contrast, the Strong Heart Study
conducted in Native Americans, found that both men and women with diabetes had higher
LV mass and wall thickness [5]. Furthermore, in a multi-ethnic population, the likelihood of
having LV mass that exceeds the 75th percentile is greater in patients with Type 2 diabetes,
after adjusting for various covariates including hypertension [6]. Indeed, in this same
population, increased LV mass was observed only in patients with diabetes but not in
patients with impaired fasting glucose or impaired glucose tolerance [7], suggesting that
changes in myocardial geometry in diabetes might not be an early defect but rather a
consequence of long term diabetes-associated changes such as hyperglycemia and/or
obesity. Eguchi et al. [6] described a significant interaction between diabetes and central
obesity on the risk for LVH. Furthermore, obesity promotes concentric LVH independently
of hypertension [8]. Emerging evidence has implicated cytokines, produced by the expanded
adipose tissue of obesity, in the development of LVH. For example, leptin is linked to
cardiac hypertrophy in obese humans and directly induces cardiomycyte hypertrophy in
vitro [9]. The mechanisms by which leptin induces LVH is not fully characterized but might
NIH-PA Author Manuscript
involve endothelin 1- mediated reactive oxygen species (ROS) generation [10]. Similarly,
resistin, which is also an adipokine that is released from macrophages, was shown to induce
cardiomyocyte hypertrophy in vitro via IRS-1 and MAPK signaling pathways [11].
Epidemiological studies have suggested a correlation between circulating levels of the
inflammatory cytokine interleukin 6, and the risk of obesity-associated heart failure [12].
Insulin resistance and hyperinsulinemia have been correlated with increased LV mass and
may partially account for the association of cardiac hypertrophy and obesity [13], and is also
correlated with increased risk of heart failure [14]. An increase in IRS1-associated PI3K
activity was recently reported in cardiac biopsies obtained from patients with Type 2
diabetes [15]. Insulin signaling might act as a growth factor in the heart, as genetic deletion
of insulin receptors leads to reduced cardiac size [16]. Taken together, these observations
raise the intriguing possibility that hyperinsulinemia might contribute to diabetes and
obesity-related LV hypertrophy.
reviewed in detail by us [17]. Thirty years ago, Regan et al [18] identified lipofuscin
deposits, which are brown lipid-containing pigment granules, in transmural LV biopsies
obtained from patients with Type 2 diabetes. Furthermore, myocardial triglyceride (TG) and
cholesterol content were significantly increased in these samples. Similarly, Oil Red O
staining of heart sections of non-ischemic failing hearts, revealed increased lipid deposition
that was exacerbated by diabetes [19]. Recent advances in magnetic resonance spectroscopy,
has enabled non-invasive assessment of myocardial triglyceride content. Diabetes, obesity,
insulin resistance and impaired glucose tolerance are associated with increased intra-
myocardial lipid that is independent of circulating concentrations of triglycerides [20]. This
increase in cardiac triglyceride accumulation is associated with diastolic but not systolic
dysfunction [20,21]. It is not clear if triglyceride accumulation is pathogenic per se or is a
marker of the underlying metabolic milieu. Increased myocardial triglycerides were not
observed in overweight but fairly well-controlled individuals with Type 2 diabetes [22]. This
contrasts with the findings in obese diabetics with poorer control [20]. Improvement in
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 3
An increase in myocardial fatty acid uptake and oxidation has been described in humans
with both Type 1 and Type 2 diabetes, as well as in many animal models [17,23,24].
Transgenic mouse models have suggested that an isolated increase in myocardial lipid
uptake is sufficient to precipitate cardiomyopathy in the absence of hyperglycemia. For
example, over-expression of proteins involved in cardiac FA transport such as long-chain
acyl-CoA synthetase, glycosylphosphatidylinositol (GPI) membrane-anchored form of
lipoprotein lipase or FA transport protein 1 resulted in lipotoxic cardiomyopathy in mice
[25,26]. The exact mechanisms by which increased myocardial lipid uptake induces
lipotoxicity and cardiac dysfunction are incompletely understood, but potential mechanisms
have been recently reviewed [17]. Lipid-induced cell death might be an important
contributor. For example, long-chain FA supplementation to chinese hamster ovary cells
(CHO) at pathophysiologic concentrations induced cell death that was associated with
increased de novo ceramide biosynthesis [27]. In parallel, inhibition of ceramide
biosynthesis prevented lipotoxic cardiomyopathy in mice over-expressing a
glycosylphosphatidylinositol (GPI) membrane-anchored form of lipoprotein lipase [28].
Since palmitate-induced cell death in CHO was not completely prevented by inhibition of
ceramide biosynthesis [27], additional mechanisms by which FA induced-cell death were
NIH-PA Author Manuscript
proposed. For example, long-chain fatty acids can change the dynamics of plasma and
mitochondrial membranes by altering phospholipid composition. Detachment of cytochrome
c from the mitochondrial inner membrane is a necessary step for cytochrome c release and
initiation of apoptosis. The saturated long chain FA, palmitate, induces apoptosis in rat
neonatal cardiomyocytes by diminishing the content of the mitochondrial anionic
phospholipid, cardiolipin [29]. In addition, changes in the composition of endoplasmic
reticulum (ER) membrane phospholipids have also been observed in lipotoxic conditions,
which precipitate ER swelling and ER stress [30,31].
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 4
Although a large fraction of total cellular ROS is generated in the mitochondria, enzymatic
systems capable of generating ROS in the cytosol such as NADPH oxidase can be
modulated by diabetes [35,36]. ROS can also interact with other molecules such as nitric
NIH-PA Author Manuscript
oxide (NO) to form nitrotyrosine species, which were found to be elevated in myocardial
biopsies of humans with Type 2 diabetes [37]. Finally, in addition to ROS-induced
cardiomyocyte cell death, these reactive molecules can also alter gene expression. In the
diabetic fatty ZDF rats, increased ROS contributes to the switch in cardiac myosin heavy-
chain gene expression from alpha to beta through the activation of NFkB, and antioxidant
treatment was able to prevent this switch [38].
understood. A role for leptin deficiency has been postulated because treatment of ob/ob mice
with leptin reduced apoptosis [40]. In addition to leptin deficiency, hyperglycemia has also
been implicated in triggering cell death via a Rac1 mediated increase in NADPH and
mitochondrial derived ROS in the hearts of db/db and STZ diabetic mice [41].
Activation of the renin-angiotensin system (RAS) correlated with increased oxidative stress,
apoptosis and necrosis in cardiomyocytes and endothelial cells in the hearts of patients with
diabetes and end stage heart failure, thereby representing another potential mechanism for
cell death [37,42]. In this regard, it is important to note that inhibition of the RAS, reduced
the rate of first hospitalization from heart failure and improved echocardiographic indices of
LV diastolic function in patients with Type 2 diabetes [43–45].
obtained from patients with Type 2 diabetes, who did not have significant CAD and
hypertension [46]. Furthermore, diastolic dysfunction detected in a population of
uncomplicated Type 2 diabetes correlated with pro-collagen type I carboxy-terminal peptide
[47,48], suggesting a mechanistic role for myocardial fibrosis in myocardial dysfunction in
diabetes. Similar to humans, some animal models with Type 2 diabetes also exhibited an
increase in cardiac fibrosis even prior to the onset of hyperglycemia. Thus, increased
extracellular fibrosis and collagen deposition was reported in the pre-diabetic stage in
OLETF rats, a genetic model of diabetes that resembles human Type 2 diabetes [49]. The
mechanisms for increased cardiac fibrosis in the diabetic heart are incompletely understood.
A recent study reported an increase in TGFβ1 receptor II density in the diabetic
myocardium. TGFβ is one of several cytokines the gene expression of which is enhanced by
diabetes [50]. Increased CTGF expression and collagen deposition has also been observed in
mouse models of STZ diabetes [51] that was associated with increased expression of
PKCβ2. Similar changes were observed in the hearts of mice that lack insulin receptors in
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 5
ob and db/db mice and the ZDF rat. These animal models exhibit obesity, insulin resistance
and mild or severe hyperglycemia and are suitable to investigate the effect of diabetes on
cardiac function independently of micro and macro vascular complications given the
absence of atherosclerosis in these models [57,58]. Thus, DD has been shown in db/db
hearts both in vivo (by echocardiography) [59] and ex vivo (in working heart preparations)
[60,61].
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 6
As summarized in Fig. 2 and recently reviewed by us [75], multiple mechanisms may lead to
impaired diastolic and systolic function and reduced contractile reserves in diabetic
cardiomyopathy. This includes accumulation of advanced glycation end products, [76],
adipokines [77], impaired myocardial insulin signaling [34], altered calcium homeostasis
[53,63] and lipotoxicity [62].
reviewed in detail elsewhere [23,24,78]. There are a number of mechanisms that are
responsible for this shift in substrate utilization. The earliest change that occurs in short term
studies of high-fat fed mice is reduced myocardial GLUT4 content and a defect in GLUT4
translocation. This in turns leads to reduced rates of glycolysis and glucose oxidation. FA
oxidation rates are subsequently increased most likely via the Randle cycle [79]. As high-fat
feeding becomes more prolonged and diabetes ensues, increased delivery of FA substrates
activate PPAR-alpha signaling pathways, which leads to transcriptional induction of
enzymes involved in beta oxidation and increased expression of pyruvate dehydrogenase
(PDH) kinase (PDK4), which further suppresses glucose oxidation by decreasing PDH
activity [79,80]. In humans with Type 2 diabetes and heart failure, myocardial lipotoxicity
was associated with evidence of activation of the PPAR alpha target gene carnitine
palmitoyl-transferase 1 (muscle isoform, mCPT1), which regulates mitochondrial FA uptake
[19].
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 7
GLUT4 and MEF2C mRNA were significantly down regulated in failing hearts from
diabetic subjects as opposed to failing hearts from non-diabetics [82]. Because fatty acids
are considered an inefficient substrate, increased FA oxidation in diabetic hearts is often
accompanied by an increase in myocardial oxygen consumption (MVO2) and reduced
cardiac efficiency in rodent models [83,84], and in obese and insulin resistant humans, as
well as humans with Type 1 diabetes [85,86].
The challenge of future studies will be to determine if therapies that normalize myocardial
substrate metabolism in diabetes mellitus will translate to lower prevalence of heart failure
or improved long-term survival.
years ago, Reagan et al. [18] observed an increase in mitochondrial number with
pleomorphism without swelling or distortion of cristae in the myocardium of patients with
diabetes. Furthermore, using 31P nuclear magnetic resonance spectroscopy, a number of
groups provided evidence for decreased cardiac energetics (decreased pCR/ATP ratios) in
Type 1 and Type 2 diabetic patients who were free of overt CAD [89–91]. However reduced
PCr/ATP ratios have not been seen in all studies [92]. A recent study, in which
mitochondrial function was directly measured in right atrial appendages obtained from
diabetics at the time of coronary artery bypass surgery revealed direct evidence of reduced
mitochondrial oxygen consumption and increased H2O2 emission [93]. Studies related to the
response of the diabetic heart to ischemic preconditioning (IPC) have also identified a defect
in the mitochondrial ATP-sensitive potassium channel that may impair the ability of the
diabetic heart to be preconditioned and may contribute to their increased risk for myocardial
infarction [94].
Our studies of the ob/ob and db/db mouse models of Type 2 diabetes identified
mitochondrial uncoupling as an additional defect that contributes to mitochondrial
dysfunction in obesity and insulin resistance [32,74]. We demonstrated increased state 4
respiration and reduced ATP synthesis in mitochondrial preparations obtained from ob/ob
NIH-PA Author Manuscript
and db/db hearts that were pre-perfused with palmitate. This mitochondrial uncoupling
further contributes to increasing oxygen consumption without a concomitant increase in
ATP production, which contributes to decreased cardiac efficiency in these hearts. The
mitochondrial uncoupling is largely mediated by uncoupling proteins and to a lesser extent
by the adenine nucleotide translocase. Mitochondrial ROS generation or lipid peroxides
such as hydroxynonenal have been shown to activate uncoupling proteins in heart muscle
mitochondria [95] and were found to be increased in the hearts of db/db mice [32].
Interestingly, mitochondrial uncoupling was not observed in the hearts of mice with Type 1
diabetes [33,96]. One difference between the hearts of models of Type 1 and Type 2
diabetes is the existence of myocardial insulin resistance in ob/ob mice versus normal
insulin sensitivity in the hearts of the Akita model of Type 1 diabetes, raising the possibility
that myocardial insulin resistance might be causally linked to mitochondrial uncoupling.
Indeed, our recent study of mitochondrial function in the hearts of mice with genetic
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 8
3 Conclusion
Although the increase in cardiovascular mortality and heart failure is due in part to
accelerated atherosclerosis, compelling epidemiological and clinical data indicate that
diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently
of other risk factors such as CAD and hypertension. The existence of diabetic
cardiomyopathy is becoming increasingly recognized and this review has summarized the
associated structural, functional and metabolic changes. As the mechanisms responsible for
diabetic cardiomyopathy continue to be elucidated, it is hoped that these insights will
provide the impetus for novel therapies that are tailored to reduce the risk of heart failure in
individuals with diabetes mellitus.
Acknowledgments
Dr. Boudina has been supported by the JDRF, and is currently supported by NIH P30 HL101310 and a Scientist
Development Award from the American Heart Association. Dr. Abel is an Established Investigator of the American
Heart Association and is supported by the American Diabetes Association and UO1 HL087947 (Animal Models of
Diabetes Complications Consortium).
NIH-PA Author Manuscript
References
1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of
cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972;30(6):595–602.
[PubMed: 4263660]
2. Hayat SA, Patel B, Khattar RS, Malik RA. Diabetic cardiomyopathy: mechanisms, diagnosis and
treatment. Clin Sci (Lond) 2004;107(6):539–57. [PubMed: 15341511]
3. Aneja A, Tang WH, Bansilal S, Garcia MJ, Farkouh ME. Diabetic cardiomyopathy: insights into
pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 2008;121(9):748–57.
[PubMed: 18724960]
4. Galderisi M, Anderson KM, Wilson PW, Levy D. Echocardiographic evidence for the existence of a
distinct diabetic cardiomyopathy (the Framingham Heart Study). Am J Cardiol 1991;68(1):85–9.
[PubMed: 2058564]
5. Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Lee ET, Welty TK, et al. Impact of diabetes
on cardiac structure and function: the strong heart study. Circulation 2000;101(19):2271–6.
[PubMed: 10811594]
6. Eguchi K, Boden-Albala B, Jin Z, Rundek T, Sacco RL, Homma S, et al. Association between
diabetes mellitus and left ventricular hypertrophy in a multiethnic population. Am J Cardiol
NIH-PA Author Manuscript
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 9
11. Kim M, Oh JK, Sakata S, Liang I, Park W, Hajjar RJ, et al. Role of resistin in cardiac contractility
and hypertrophy. J Mol Cell Cardiol 2008;45(2):270–80. [PubMed: 18597775]
12. Bahrami H, Bluemke DA, Kronmal R, Bertoni AG, Lloyd-Jones DM, Shahar E, et al. Novel
NIH-PA Author Manuscript
metabolic risk factors for incident heart failure and their relationship with obesity: the MESA
(Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol 2008;51(18):1775–83.
[PubMed: 18452784]
13. Karason K, Sjostrom L, Wallentin I, Peltonen M. Impact of blood pressure and insulin on the
relationship between body fat and left ventricular structure. Eur Heart J 2003;24(16):1500–5.
[PubMed: 12919774]
14. Ingelsson E, Sundstrom J, Arnlov J, Zethelius B, Lind L. Insulin resistance and risk of congestive
heart failure. Jama 2005;294 (3):334–41. [PubMed: 16030278]
15. Cook SA, Varela-Carver A, Mongillo M, Kleinert C, Khan MT, Leccisotti L, Strickland N, Matsui
T, Das S, Rosenzweig A, et al. Abnormal myocardial insulin signalling in type 2 diabetes and left-
ventricular dysfunction. Eur Heart J. 2009
16. Belke DD, Betuing S, Tuttle MJ, Graveleau C, Young ME, Pham M, et al. Insulin signaling
coordinately regulates cardiac size, metabolism, and contractile protein isoform expression. J Clin
Invest 2002;109(5):629–39. [PubMed: 11877471]
17. Wende AR, Abel ED. Lipotoxicity in the heart. Biochim Biophys Acta. 2009
18. Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, et al. Evidence for
cardiomyopathy in familial diabetes mellitus. J Clin Invest 1977;60(4):884–99. [PubMed: 893679]
19. Sharma S, Adrogue JV, Golfman L, Uray I, Lemm J, Youker K, et al. Intramyocardial lipid
NIH-PA Author Manuscript
accumulation in the failing human heart resembles the lipotoxic rat heart. Faseb J 2004;18(14):
1692–700. [PubMed: 15522914]
20. McGavock JM, Lingvay I, Zib I, Tillery T, Salas N, Unger R, et al. Cardiac steatosis in diabetes
mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 2007;116(10):1170–5.
[PubMed: 17698735]
21. Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, et al. Myocardial
steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll
Cardiol 2008;52(22):1793–9. [PubMed: 19022158]
22. van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, et al.
Pioglitazone improves cardiac function and alters myocardial substrate metabolism without
affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with
well-controlled type 2 diabetes mellitus. Circulation 2009;119(15):2069–77. [PubMed: 19349323]
23. Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity. Physiol Rev 2008;88(2):389–
419. [PubMed: 18391168]
24. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115(25):3213–23.
[PubMed: 17592090]
25. Chiu HC, Kovacs A, Ford DA, Hsu FF, Garcia R, Herrero P, et al. A novel mouse model of
lipotoxic cardiomyopathy. J Clin Invest 2001;107(7):813–22. [PubMed: 11285300]
NIH-PA Author Manuscript
26. Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y, et al. Lipoprotein lipase (LpL)
on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin
Invest 2003;111(3):419–26. [PubMed: 12569168]
27. Listenberger LL, Ory DS, Schaffer JE. Palmitate-induced apoptosis can occur through a ceramide-
independent pathway. J Biol Chem 2001;276(18):14890–5. [PubMed: 11278654]
28. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, et al. Ceramide is a cardiotoxin in
lipotoxic cardiomyopathy. J Lipid Res 2008;49(10):2101–12. [PubMed: 18515784]
29. Ostrander DB, Sparagna GC, Amoscato AA, McMillin JB, Dowhan W. Decreased cardiolipin
synthesis corresponds with cytochrome c release in palmitate-induced cardiomyocyte apoptosis. J
Biol Chem 2001;276(41):38061–7. [PubMed: 11500520]
30. Borradaile NM, Han X, Harp JD, Gale SE, Ory DS, Schaffer JE. Disruption of endoplasmic
reticulum structure and integrity in lipotoxic cell death. J Lipid Res 2006;47(12):2726–37.
[PubMed: 16960261]
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 10
31. Brookheart RT, Michel CI, Listenberger LL, Ory DS, Schaffer JE. The non-coding RNA gadd7 is
a regulator of lipid-induced oxidative and endoplasmic reticulum stress. J Biol Chem
2009;284(12):7446–54. [PubMed: 19150982]
NIH-PA Author Manuscript
32. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX, et al. Mitochondrial energetics in the
heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation
of uncoupling proteins. Diabetes 2007;56(10):2457–66. [PubMed: 17623815]
33. Bugger H, Boudina S, Hu XX, Tuinei J, Zaha VG, Theobald HA, et al. Type 1 diabetic akita
mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain
coupled despite increased uncoupling protein 3. Diabetes 2008;57(11):2924–32. [PubMed:
18678617]
34. Boudina S, Bugger H, Sena S, O’Neill BT, Zaha VG, Ilkun O, et al. Contribution of impaired
myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart.
Circulation 2009;119(9):1272–83. [PubMed: 19237663]
35. Li L, Renier G. Activation of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase
by advanced glycation end products links oxidative stress to altered retinal vascular endothelial
growth factor expression. Metabolism 2006;55(11):1516–23. [PubMed: 17046555]
36. Serpillon S, Floyd BC, Gupte RS, George S, Kozicky M, Neito V, et al. Superoxide production by
NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart
and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate
dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol 2009;297(1):H153–62.
[PubMed: 19429815]
37. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, et al. Myocardial cell death in
NIH-PA Author Manuscript
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 11
49. Mizushige K, Yao L, Noma T, Kiyomoto H, Yu Y, Hosomi N, et al. Alteration in left ventricular
diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a
type II diabetic rat model. Circulation 2000;101(8):899–907. [PubMed: 10694530]
NIH-PA Author Manuscript
50. Ban CR, Twigg SM. Fibrosis in diabetes complications: pathogenic mechanisms and circulating
and urinary markers. Vasc Health Risk Manag 2008;4(3):575–96. [PubMed: 18827908]
51. Way KJ, Isshiki K, Suzuma K, Yokota T, Zvagelsky D, Schoen FJ, et al. Expression of connective
tissue growth factor is increased in injured myocardium associated with protein kinase C beta2
activation and diabetes. Diabetes 2002;51(9):2709–18. [PubMed: 12196463]
52. McQueen AP, Zhang D, Hu P, Swenson L, Yang Y, Zaha VG, et al. Contractile dysfunction in
hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary
density. J Mol Cell Cardiol 2005;39(6):882–92. [PubMed: 16216265]
53. Van den Bergh A, Vanderper A, Vangheluwe P, Desjardins F, Nevelsteen I, Verreth W, et al.
Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases
ventricular stiffness. Cardiovasc Res 2008;77(2):371–9. [PubMed: 18006491]
54. Brooks BA, Franjic B, Ban CR, Swaraj K, Yue DK, Celermajer DS, et al. Diastolic dysfunction
and abnormalities of the microcirculation in type 2 diabetes. Diabetes Obes Metab 2008;10(9):
739–46. [PubMed: 17941867]
55. Shivalkar B, Dhondt D, Goovaerts I, Van Gaal L, Bartunek J, Van Crombrugge P, et al. Flow
mediated dilatation and cardiac function in type 1 diabetes mellitus. Am J Cardiol 2006;97(1):77–
82. [PubMed: 16377288]
56. Ozasa N, Furukawa Y, Morimoto T, Tadamura E, Kita T, Kimura T. Relation among left
ventricular mass, insulin resistance, and hemodynamic parameters in type 2 diabetes. Hypertens
NIH-PA Author Manuscript
63. Dong F, Zhang X, Yang X, Esberg LB, Yang H, Zhang Z, et al. Impaired cardiac contractile
function in ventricular myocytes from leptin-deficient ob/ob obese mice. J Endocrinol
2006;188(1):25–36. [PubMed: 16394172]
64. Stolen TO, Hoydal MA, Kemi OJ, Catalucci D, Ceci M, Aasum E, et al. Interval training
normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in
a mouse model of diabetic cardiomyopathy. Circ Res 2009;105(6):527–36. [PubMed: 19679837]
65. Fang ZY, Schull-Meade R, Leano R, Mottram PM, Prins JB, Marwick TH. Screening for heart
disease in diabetic subjects. Am Heart J 2005;149(2):349–54. [PubMed: 15846276]
66. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, et al. Tissue Doppler
echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously
delaying regional contraction after biventricular pacing therapy in heart failure. Circulation
2002;105(4):438–45. [PubMed: 11815425]
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 12
67. Yue P, Arai T, Terashima M, Sheikh AY, Cao F, Charo D, et al. Magnetic resonance imaging of
progressive cardiomyopathic changes in the db/db mouse. Am J Physiol Heart Circ Physiol
2007;292(5):H2106–18. [PubMed: 17122193]
NIH-PA Author Manuscript
68. Van den Bergh A, Flameng W, Herijgers P. Type II diabetic mice exhibit contractile dysfunction
but maintain cardiac output by favourable loading conditions. Eur J Heart Fail 2006;8(8):777–83.
[PubMed: 16716661]
69. Radovits T, Korkmaz S, Loganathan S, Barnucz E, Bomicke T, Arif R, et al. Comparative
investigation of the left ventricular pressure-volume relationship in rat models of type 1 and type 2
diabetes mellitus. Am J Physiol Heart Circ Physiol 2009;297(1):H125–33. [PubMed: 19429826]
70. Scognamiglio R, Avogaro A, Casara D, Crepaldi C, Marin M, Palisi M, et al. Myocardial
dysfunction and adrenergic cardiac innervation in patients with insulin-dependent diabetes
mellitus. J Am Coll Cardiol 1998;31(2):404–12. [PubMed: 9462586]
71. Ha JW, Lee HC, Kang ES, Ahn CM, Kim JM, Ahn JA, et al. Abnormal left ventricular
longitudinal functional reserve in patients with diabetes mellitus: implication for detecting
subclinical myocardial dysfunction using exercise tissue Doppler echocardiography. Heart
2007;93(12):1571–6. [PubMed: 17449503]
72. Palmieri V, Capaldo B, Russo C, Iaccarino M, Pezzullo S, Quintavalle G, et al. Uncomplicated
type 1 diabetes and preclinical left ventricular myocardial dysfunction: insights from
echocardiography and exercise cardiac performance evaluation. Diabetes Res Clin Pract
2008;79(2):262–8. [PubMed: 17996323]
73. Abe T, Ohga Y, Tabayashi N, Kobayashi S, Sakata S, Misawa H, et al. Left ventricular diastolic
dysfunction in type 2 diabetes mellitus model rats. Am J Physiol Heart Circ Physiol
NIH-PA Author Manuscript
efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile
dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 2005;146(12):
5341–9. [PubMed: 16141388]
81. Thai MV, Guruswamy S, Cao KT, Pessin JE, Olson AL. Myocyte enhancer factor 2 (MEF2)-
binding site is required for GLUT4 gene expression in transgenic mice. Regulation of MEF2 DNA
binding activity in insulin-deficient diabetes. J Biol Chem 1998;273(23):14285–92. [PubMed:
9603935]
82. Razeghi P, Young ME, Cockrill TC, Frazier OH, Taegtmeyer H. Downregulation of myocardial
myocyte enhancer factor 2C and myocyte enhancer factor 2C-regulated gene expression in
diabetic patients with nonischemic heart failure. Circulation 2002;106 (4):407–11. [PubMed:
12135937]
83. How OJ, Aasum E, Severson DL, Chan WY, Essop MF, Larsen TS. Increased myocardial oxygen
consumption reduces cardiac efficiency in diabetic mice. Diabetes 2006;55(2):466–73. [PubMed:
16443782]
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 13
84. Mazumder PK, O’Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC, et al. Impaired
cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts.
Diabetes 2004;53(9):2366–74. [PubMed: 15331547]
NIH-PA Author Manuscript
85. Peterson LR, Herrero P, McGill J, Schechtman KB, Kisrieva-Ware Z, Lesniak D, et al. Fatty acids
and insulin modulate myocardial substrate metabolism in humans with type 1 diabetes. Diabetes
2008;57(1):32–40. [PubMed: 17914030]
86. Peterson LR, Herrero P, Schechtman KB, Racette SB, Waggoner AD, Kisrieva-Ware Z, et al.
Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in
young women. Circulation 2004;109(18):2191–6. [PubMed: 15123530]
87. Boudina S, Abel ED. Mitochondrial uncoupling: a key contributor to reduced cardiac efficiency in
diabetes. Physiology (Bethesda) 2006;21:250–8. [PubMed: 16868314]
88. Bugger H, Chen D, Riehle C, Soto J, Theobald HA, Hu XX, et al. Tissue-specific remodeling of
the mitochondrial proteome in type 1 diabetic akita mice. Diabetes 2009;58(9):1986–97. [PubMed:
19542201]
89. Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, et al. Diastolic dysfunction is
associated with altered myocardial metabolism in asymptomatic normotensive patients with well-
controlled type 2 diabetes mellitus. J Am Coll Cardiol 2003;42 (2):328–35. [PubMed: 12875772]
90. Metzler B, Schocke MF, Steinboeck P, Wolf C, Judmaier W, Lechleitner M, et al. Decreased high-
energy phosphate ratios in the myocardium of men with diabetes mellitus type I. J Cardiovasc
Magn Reson 2002;4(4):493–502. [PubMed: 12549236]
91. Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P, et al.
Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes.
NIH-PA Author Manuscript
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 14
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Fig. 1.
Mechanisms for FA-induced cardiac dysfunction in diabetes. Increased FA uptake in
cardiomyocytes in vivo precipitates cardiomyocyte dysfunction by multiple mechanisms
including increased mitochondrial and cytosolic ROS generation and ER stress. FA-
mediated ROS generation leads to uncoupling of mitochondria, which reduces mitochondrial
ATP production. FFA: free fatty acids; ROS: reactive oxygen species; ER: endoplasmic
reticulum; Cyt. C: cytochrome c; FAOX: Fatty acid oxidation
NIH-PA Author Manuscript
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.
Boudina and Abel Page 15
NIH-PA Author Manuscript
Fig. 2.
Cellular mechanisms that contribute to cardiac contractile dysfunction in diabetes
NIH-PA Author Manuscript
NIH-PA Author Manuscript
Rev Endocr Metab Disord. Author manuscript; available in PMC 2010 September 1.