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Abstract

Type 2 diabetes mellitus escalates the risk of heart failure partly via its ability to induce a cardiomyopathic state that is independent of coronary artery disease and hypertension. Although the pathogenesis of diabetic cardiomyopathy has yet to be fully elucidated, aberrations in cardiac substrate metabolism and energetics are thought to be key drivers. These aberrations include excessive fatty acid utilisation and storage, suppressed glucose oxidation and impaired mitochondrial oxidative phosphorylation. An appreciation of how these abnormalities arise and synergise to promote adverse cardiac remodelling is critical to their effective amelioration. This review focuses on disturbances in myocardial fuel (fatty acids and glucose) flux and energetics in type 2 diabetes, how these disturbances relate to the development of diabetic cardiomyopathy and the potential therapeutic agents that could be used to correct them.

Keywords

Metabolism energetics diabetes

Introduction

Type 2 diabetes mellitus (T2DM) is a global pandemic that is associated with a more than 2-fold greater risk of developing heart failure (HF),¹ and a 60%–80% greater probability of death in those with established HF.^2,3 While accelerated coronary artery disease and hypertension largely explain these statistics,⁴ evidence suggests that T2DM itself can drive adverse cardiac remodelling and give rise to a diabetic cardiomyopathy (DiCM).^5–7 Although hotly debated, DiCM is reportedly evident in up to 60% of patients with T2DM and is characterised by unexplained myocardial hypertrophy and fibrosis, with left ventricular (LV) diastolic (±systolic) impairment.^8–11 At the cardiomyocyte level, defects in excitation–contraction coupling, calcium mishandling and increased oxidative stress are present.^12–14 More importantly, profound alterations in myocardial substrate metabolism and energetics have been shown.^15,16 Crucially, these metabolic derangements not only precede cardiac structural and functional changes, but their early correction in animal models of T2DM aborted the development of DiCM.^15,17 Consequently, metabolic abnormalities of the heart are promising therapeutic targets whose amelioration might improve outcomes in T2DM.

Here, after recounting normal myocardial metabolism and energetics, we review how these processes are disturbed in T2DM, how disturbances relate to the genesis of DiCM and the potential therapeutic agents that could be used to ameliorate them.

Normal myocardial metabolism

Cardiac energetics

The heart is an astonishing organ. Over an average human lifespan, it beats ~2–3 billion times and circulates ~200 million litres of blood. To sustain such a high workload, the heart can consume up to 30 kg of adenosine triphosphate (ATP) daily (~75–100 times its own weight) which is equivalent to the energy needed to climb a 100-storey building.¹⁸ Thus, the heart is the highest energy consuming organ of the body, and subtle energetic deficits can rapidly induce contractile dysfunction.^19,20 Uninterrupted ATP generation is dependent on the continuous supply of oxygen and fuel substrates and on the integrity of oxidative phosphorylation (OxPhos) which produces virtually all the hearts’ ATP.^21,22 Of the generated ATP, ~60%–70% fuels cardiac contractions with the remainder used for ion pumps such as the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA). While the heart can switch its substrate [fatty acids (FAs), glucose, ketones, lactate, amino acids] preference depending on workload, oxygen supply and hormones, its two main energetic substrates are FAs and glucose.²²

FA uptake and utilisation

FAs are the preferred fuel substrates and account for 70%–90% of myocardial ATP generation (Figure 1).²³ They circulate in plasma as triglyceride (TG)-rich lipoproteins and, to a lesser extent, bound to albumin. Endothelial lipoprotein lipases cleave lipoproteins to release free FAs which then enter cardiomyocytes via specific transporters.²⁴ Once in the cytosol, free FAs are esterified to fatty acyl-CoA which is either stored in the intracellular TG pool (10%–30%) or transported into the mitochondrion for β-oxidation (70%–90%).²⁵ Carnitine palmitoyltransferase (CPT)-I is the rate-limiting enzyme of FA metabolism. It translocates fatty acyl-CoA into mitochondria by converting it to fatty acyl-carnitine. Once in the mitochondrion, fatty acyl-carnitine is converted back to fatty acyl-CoA by CPT II for β-oxidation.²⁴ Overall, FA metabolism is principally regulated by the transcription factor peroxisome proliferator-activated receptor-α (PPAR-α) which, upon activation by high myocardial FA levels, upregulates FA uptake and utilisation and suppresses glucose oxidation.²⁶ In turn, increased glucose oxidation can reduce FA utilisation. This reciprocal inhibition is termed the ‘Randle cycle’.²⁷ Although FAs generate more ATP than glucose for each molecule metabolised, the ATP production to oxygen consumption ratio is lower for FAs (2.33 vs 2.58). Thus, increased FA oxidation reduces cardiac efficiency (cardiac work/myocardial oxygen consumption).^24,28

Figure 1.

Fatty acid and glucose metabolism in type 2 diabetic cardiomyocytes. Substrate uptake occurs via specific transporters. Fatty acids (FAs) principally undergo β-oxidation in mitochondria under the control of peroxisome proliferator-activated receptor (PPAR)-α. Glucose molecules flux through diverse metabolic fates but mainly undergo glycolysis (pathway in bold). Arrows in parentheses denote the direction of change in type II diabetic cardiomyocytes compared to normal cells. Potential therapeutic agents are listed in the black boxes.

Glucose uptake and utilisation

Glucose oxidation accounts for 10%–30% of cardiac ATP production. It is initiated by glucose entry into cardiomyocytes via glucose transporter (GLUT)-1 and -4 (Figure 1). GLUT-1 mediates basal insulin-independent glucose uptake, while GLUT-4 is insulin responsive.²⁹ Once in the cell, limited amounts of glucose (<5%) enter the polyol (or sorbitol-aldose reductase) pathway which consumes reducing equivalents [nicotinamide adenine dinucleotide phosphate (NADPH)] to generate sorbitol.³⁰ However, the vast majority of imported glucose is converted to glucose-6-phosphate by glucokinase. Glucose-6-phosphate is then channelled into glycolysis (~85%), glycogenesis (<5%), the pentose phosphate pathway (PPP; <5%) for nucleic acid and NADPH synthesis³¹ or the hexosamine biosynthetic pathway (HBP; <5%) for the production of precursors of glycosaminoglycans.³² During glycolysis, phosphofructokinase (PFK)-1 catalyses the rate-limiting step of early glycolytic reactions that generate pyruvate which is then oxidatively decarboxylated by pyruvate dehydrogenase (PDH) to form acetyl-CoA. PDH is a critical site of regulation. It is inhibited by pyruvate dehydrogenase kinase (PDK) and stimulated by pyruvate dehydrogenase phosphatase (PDP). In turn, PDK is stimulated by PPAR-α, FAs, acetyl-CoA and nicotinamide adenine dinucleotide (NADH), while PDP is stimulated by elevated intracellular Ca²⁺ levels.^33,34 Under anaerobic conditions, pyruvate is converted to lactate or shuttled into anaplerotic pathways (Figure 1).

Krebs cycle and mitochondrial OxPhos

Irrespective of substrate preference, the final end-product of fuel oxidation is acetyl-CoA which enters the Krebs cycle to generate reducing equivalents [NADH and flavin adenine dinucleotide (FADH₂)] for OxPhos which produces >95% of myocardial ATP (Figure 2).³⁵ Because Krebs intermediates are continuously siphoned off for amino acid, lipid and nucleic acid biosynthesis (cataplerotic processes), uninterrupted NADH and FADH₂ production depends on anapleurosis, which is the replenishment of Krebs moieties independently of acetyl-CoA.³⁶ Once formed, NADH and FADH₂ release electrons to the electron transport chain (ETC), inducing sequential redox reactions that generate the proton gradient that drives ATP synthesis (Figure 2). Phosphocreatinine (PCr) then links ATP production to ATP consumption. Even under normal conditions, OxPhos is not fully efficient as 1%–2% of electrons leak from the ETC to form reactive oxygen species (ROS), and uncoupling proteins (UCPs) partially dissipate the proton gradient to generate heat.³⁷ Besides Krebs cycle flux, molecular oxygen, ETC proteins and coenzyme Q₁₀, OxPhos is also dependent on iron. This is because iron is a component of haem within ETC and Krebs cycle enzymes and of iron–sulfur clusters that execute the electron transfer function of most ETC complexes.^38,39 Consistent with its high energy demands, the myocardium has the highest mitochondrial density (35% of cardiomyocyte volume versus 3%–8% in skeletal and smooth muscle cells) of any organ, and its mitochondria exhibit the greatest number of cristae which enhance OxPhos.^40–42

Figure 2.

Mitochondrial oxidative phosphorylation in type 2 diabetic cardiomyocytes. Substrate oxidation generates reducing equivalents via the Krebs cycle which feed electrons (e⁻) into the ETC. Electron flow drives a proton gradient which powers ATP synthesis. Mitochondrial and cytostolic ROS impair oxidative phophosphorylation, myofilament function and calcium homeostasis. Iron mediates electron transfer in many ETC complexes. Arrows in parentheses denote the direction of change in type II diabetic cardiomyocytes compared to normal cells. Potential mitochondrial therapeutic agents are listed in the black box.

Myocardial metabolism in T2DM

Abnormal cardiac FA uptake and utilisation in T2DM

The hearts’ preference for FAs as energetic substrates is exaggerated in T2DM. This is due to the increase in plasma FA levels as a result of increased lipolysis from insufficient insulin action, increased hepatic TG production and inefficient adipocyte TG storage. The enhanced delivery of FAs to the sarcolemma then elevates myocardial FA uptake and TG stores.⁴³ As a result, myocardial FA abundance activates PPAR-α which amplifies the reliance on FAs further by upregulating FA uptake, storage and β-oxidation, while suppressing glucose utilisation.²⁶ Increased PPAR-α activity is evident in rodent models of DiCM, and hearts from PPAR-α knock-out mice do not remodel when rendered insulin resistant.⁴⁴ In patients with T2DM, a twofold increase in cardiac FA oxidation has been described,⁴⁵ and aberrant FA metabolism has been correlated to adverse cardiac changes (Figure 3).

Figure 3.

Changes in metabolism and their relevance to diabetic cardiomyopathy. Fatty acid (FA) abundance impairs glycolysis, shunts glucose towards more pathological pathways and leads to other abnormalities that plausibly drive diabetic cardiomyopathy. Hyperglycaemia augments levels of oxidative stress and advanced glycation end-products (AGE).

Excessive FA storage is thought to be cytotoxic and myocardial steatosis is associated with cardiac dysfunction in T2DM. Up to twofold increases in myocardial TG content have been shown in patients with T2DM, with higher TG levels related to lower LV diastolic and systolic function.^46–48 FA accumulation within the heart is postulated to increase mitochondrial ROS by augmenting β-oxidation and ETC activity.⁴⁹ Elevated ROS levels are, in turn, implicated in myocardial hypertrophy, defective excitation–contraction coupling and cardiac inefficiency via mitochondrial uncoupling (Figure 2).^28,50 Additionally, increased lipid intermediary metabolites such as ceramide and diacylglycerol can derange signalling and can trigger cardiomyocyte apoptosis directly or via cytochrome c release.⁵¹ These events underlie ‘lipotoxicity’ which is implicated in the genesis of DiCM.⁵² Because of its higher oxygen cost (~86% greater myocardial oxygen consumption compared to glucose), increased FA metabolism further diminishes cardiac mechanoenergetic efficiency.⁵³

Abnormal cardiac glucose uptake and utilisation in T2DM

Despite systemic hyperglycaemia, and appropriate glucose uptake in some studies, cardiac glucose oxidation is reduced by 30%–40% in patients with T2DM.^45,54–56 This is largely attributed to FA excess in the myocardium. FAs reduce pyruvate synthesis by inhibiting glucokinase and PFK-1 and attenuate pyruvate oxidation by inhibiting PDH directly, and indirectly via augmented PPAR-α, acetyl-CoA and NADH levels.^57–60 Reductions in glycolysis are accompanied by decreases in PPP flux and increases in polyol, HBP and glycogeneic pathways that may have pathological relevance.^61–64

Hyperglycaemia and the end-products of abnormal glucose disposition possibly mediate some of the features of DiCM. Hyperglycaemia elevates cardiomyocyte glucose levels which can non-enzymatically glycate proteins to form advanced glycation end-products (AGEs). AGEs enhance ROS production and can cross-link and damage macromolecules such as collagen (leading to myocardial fibrosis and stiffness), SERCA (leading to diastolic impairment) and the ryanodine receptor (leading to contractile impairment).^65–67 Increased polyol flux and decreased PPP activity reduce NADPH levels which increases oxidative stress.^61,62 Augmented HBP flux increases the production of glycosaminoglycans, which can contribute to matrix remodelling, myocardial fibrosis and impaired SERCA activity.⁶³

Cardiac mitochondrial OxPhos defects in T2DM

Cardiac mitochondria exhibit diminished rates of OxPhos and a greater uncoupling of respiration from ATP generation in T2DM. This occurs despite evidence of increased cellular anaplerosis⁶⁸ and an increased delivery of Krebs cycle end-products (NADH and FADH₂) to the ETC. This implies that factors downstream of the Krebs cycle limit OxPhos. Indeed, in the hearts of animals and humans with T2DM, a consistent reduction in the amount and catalytic activity of ETC complexes have been shown, and ETC dysfunction has been linked to oxidative stress.^69–73 Reductions in OxPhos also result from FA-mediated upregulation of UCPs which uncouple mitochondria, and to attenuations in mitochondrial density (only in animal models), size and internal complexity.^14,74–77 In patients with T2DM, reductions in mitochondrial size relate to impaired mitochondrial fusion with decreased mitofusin-2 expression.⁷⁵ In rodent models, lower PCr replenishment by creatine kinase has also been shown,⁷⁸ suggesting that defects in energy transduction might accompany those in energy generation.

Mitochondrial dysfunction is associated with abnormal myocardial structure and function in T2DM. Reductions in OxPhos manifest in decreases in myocardial PCr and ATP content which have been shown in animals and humans with T2DM. Greater energetic deficits, as reflected by lower cardiac PCr/ATP ratios, related to lower ETC activities, lower exercise capacity and poorer diastolic function.^16,79,80 Moreover, in atrial trabeculae excised from surgical patients with T2DM, reductions in OxPhos were associated with impaired contractility.⁷¹ While mitochondrial dysfunction could be deleterious solely via its ability to limit ATP supply to myofibrils (leading to systolic impairment) and SERCA (leading to diastolic impairment), it also augments ROS production which is implicated in cardiac remodelling.^72,73 Increased ROS production results from the abundance of electrons delivered to the ETC (due to increased FA oxidation) which, because the ETC is defective, increasing leak to form ROS. Although mitochondrial dysfunction, lipotoxicity and glucotoxicity plausibly contribute to DiCM, it is unclear whether they are markers or mediators of cardiac remodelling. This uncertainty reflects the paucity of trials targeting cardiac metabolism in patients with T2DM.

Therapeutic targeting of cardiac metabolism in T2DM

Diabetic and HF medications

As unexplained cardiomyopathy is possibly driven by T2DM itself, good diabetic control seems intuitively important for preventing DiCM. However, only animal studies have shown that achieving early euglycaemia arrests the development of DiCM, and that certain diabetic drugs can have specific anti-remodelling effects.^15,17 For example, in ex vivo mice hearts, glucose–insulin infusions improved glucose oxidation and contractile efficiency, while incretin-based therapies (Liraglutide and Exendin-4) reversed steatosis, oxidative stress and SERCA downregulation.^81–84 Limited data exist in humans, and some of them are at odds with findings in animals. In a retrospective analysis, biguanide (metformin) use was associated with reduced natiuretic peptide levels and lower cardiovascular morbidity and mortality.⁸⁵ In contrast, glucose–insulin–potassium trials yielded inconsistent results,^86–88 and increased hospitalisations for HF were documented with thiazolidinediones (e.g. rosiglitazone), incretin-based therapies (e.g. saxagliptin) and sulfonyureas (e.g. glicazide).^89–91 Thus, glycaemic control alone might not be sufficient for preventing or managing DiCM.

Because systolic dysfunction develops as DiCM progresses, and can itself accelerate DiCM by independently inducing mitochondrial dysfunction and oxidative stress, the mandated use of HF specific therapies is critical. They not only disrupt the vicious cycle between systolic failure and DiCM but certain agents such as β-blockers directly suppress oxidative stress and FA metabolism.^92,93 However, because these agents are not mandated in the majority of DiCM patients (as their LV ejection fractions are adequate), alternative strategies are needed.

Strategies to modulate cardiac substrate utilisation

Increased FA utilisation is a key feature of deranged metabolism in T2DM. Besides statins to reduce cholesterol levels, excessive FA metabolism can also be targeted (Figure 1) by drugs that reduce plasma-free FA levels (lipoprotein lipase inhibitors), mitochondrial FA uptake (CPT1 inhibitors) or FA oxidation (β-oxidation inhibitors). In rats with T2DM, acipimox and etomoxir reduced serum lipid levels and augmented SERCA expression.⁹⁴ In patients with T2DM and HF, trimetazidine reduced natiuretic peptides and improved exercise capacity and LV function despite no change in cardiac perfusion.⁹⁵ In a large clinical trial, ranolazine relieved angina more in diabetic than in non-diabetic patients.⁹⁶ It also recovered LV function quicker in diabetic than in non-diabetic rats after myocardial infarction, with the benefits related to activation of the energy sensor, adenosine monophosphate kinase.⁹⁷ Although perhexiline improved cardiac energetics and function in small HF and hypertrophic cardiomyopathy cohorts, it was not beneficial in patients undergoing cardiac surgery and has not been studied in T2DM.^98–100 Besides inhibiting FA utilisation, directly stimulating glucose oxidation with dichloroacetate, a PDH activator, could also rebalance cardiac substrate use in T2DM.¹⁰¹ However, no studies have been done.

Strategies to improve mitochondrial OxPhos

Mitochondrial oxidative stress is implicated in the reduction in ETC activity, and mitochondrial-targeted antioxidants (e.g. SS-31, MitoQ) preferentially accumulate in mitochondria to reduce ROS generation.^102,103 In cell models of glucotoxicity and gluco-lipotoxicity, MitoQ reduced oxidative stress, increased OxPhos and promoted survival.¹⁰² Alternatively, oxidative stress could be dampened by boosting antioxidant defences with agents such as resveratrol which improved cardiac OxPhos in a rat model of T2DM.¹⁰⁴ Besides attenuating oxidative stress, direct ETC stimulation could also augment OxPhos.

Electron transfer from reducing equivalents to molecular oxygen is the limiting step in OxPhos. Coenzyme Q₁₀, also known as ubiquinone, carries electrons from their sites of donation (complexes I and II) to complex III and is also a potent antioxidant. In 420 patients with chronic HF, coenzyme Q₁₀ was shown to improve New York Heart Association (NYHA) class and survival.¹⁰⁵ While no studies in patients with T2DM have been done, coenzyme Q₁₀ attenuated LV remodelling and diastolic dysfunction in a mice model of T2DM.¹⁰⁶ Theoretically, iron could also be used to augment OxPhos. It is a functional component of many ETC and Krebs cycle proteins, and its deficiency impairs exercise capacity, induces LV hypertrophy and leads to diastolic and systolic dysfunction.^{38,39,107,108} Systemic and myocardial iron deficiency is evident in patients with chronic heart failure, is associated with greater exercise intolerance and mortality and its correction improves functional status.^{107,109–111} To date, iron status in T2DM is largely unknown. Because the rate of PCr regeneration by creatine kinase is also unknown in humans with T2DM, agents that improve energy transduction such as allopurinol and creatine may be relevant once more data are available.

Summary

The metabolic phenotype of the type 2 diabetic heart is characterised by excessive FA utilisation and storage, suppressed glucose oxidation and impaired OxPhos. Myocardial FA excess is posited to play a pivotal role. By inducing steatosis and an abundance of ROS and toxic intermediary metabolites, FAs can trigger adverse cardiac remodelling. By inhibiting key glycolytic enzymes, FAs can shunt glucose towards more pathological pathways that plausibly aggravate remodelling. Further research, particularly in human subjects, is needed to clarify whether defective myocardial metabolism and energetics truly drive unexplained cardiomyopathy in T2DM.

Footnotes

Declaration of conflicting interests

Dr Amaral has no conflicts of interest. Dr Okonko has received research support from Pharmacosmos A/S.

Funding

The authors are supported by the British Heart Foundation. Dr Okonko has also received research support from Pharmacosmos A/S.

References

Kannel

McGee

. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979; 241: 2035–2038.

Cubbon

Adams

Rajwani

. Diabetes mellitus is associated with adverse prognosis in chronic heart failure of ischaemic and non-ischaemic aetiology. Diab Vasc Dis Res 2013; 10: 330–336.

MacDonald

Petrie

Varyani

. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) programme. Eur Heart J 2008; 29: 1377–1385.

Buse

Ginsberg

Bakris

.; American Heart Association; American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007; 30: 162–172.

Rubler

Dlugash

Yuceoglu

. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972; 30: 595–602.

Devereux

Roman

Paranicas

. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation 2000; 101: 2271–2276.

Miki

Yuda

Kouzu

. Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev 2013; 18: 149–166.

Di Bonito

Moio

Cavuto

. Early detection of diabetic cardiomyopathy: usefulness of tissue Doppler imaging. Diabet Med 2005; 22: 1720–1725.

Schannwell

Schneppenheim

Perings

. Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology 2002; 98: 33–39.

10.

Andersen

Poulsen

Eiskjaer

. Decreased left ventricular longitudinal contraction in normotensive and normoalbuminuric patients with Type II diabetes mellitus: a Doppler tissue tracking and strain rate echocardiography study. Clin Sci 2003; 105: 59–66.

11.

Ernande

Rietzschel

Bergerot

. Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle tracking imaging study. J Am Soc Echocardiogr 2010; 23: 1266–1272.

12.

Ward

Crossman

. Mechanisms underlying the impaired contractility of diabetic cardiomyopathy. World J Cardiol 2014; 6: 577–584.

13.

Pereira

Ruiz-Hurtado

Rueda

. Calcium signaling in diabetic cardiomyocytes. Cell Calcium. Epub ahead of print 17 August 2014. DOI: 10.1016/j.ceca.2014.08.004.

14.

Boudina

Sena

Theobald

. Mitochondrial energetics in the heart in obesity related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 2007; 56: 2457–2466.

15.

Belke

Larsen

Gibbs

. Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab 2000; 279: e1104–e1113.

16.

Scheuermann-Freestone

Madsen

Manners

. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 2003; 107: 3040–3046.

17.

Zhou

Grayburn

Karim

. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA 2000; 97: 1784–1789.

18.

Ashrafian

Neubauer

. Metabolomic profiling of cardiac substrate utilization: fanning the flames of systems biology? Circulation 2009; 119: 1700–1702.

19.

Weiss

Maslov

. Normal myocardial metabolism: fueling cardiac contraction. Adv Stud Med 2004; 4: S457–S463.

20.

Neubauer

. The failing heart – an engine out of fuel. N Engl J Med 2007; 356: 1140–1151.

21.

Taegtmeyer

Golfman

Sharma

. Linking gene expression to function: metabolic flexibility in the normal and diseased heart. Ann NY Acad Sci 2004; 1015: 202–213.

22.

Neely

Rovetto

Oram

. Myocardial utilization of carbohydrate and lipids. Prog Cardiovasc Dis 1972; 15: 289–329.

23.

Wisnecki

Gertz

Neese

. Myocardial metabolism of free fatty acids: studies with 14C labelled substrates in humans. J Clin Invest 1987; 79: 359–366.

24.

Lopaschuk

Ussher

Folmes

. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010; 90: 207–258.

25.

Saddik

Lopaschuk

. Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 1991; 266: 8162–8170.

26.

Ferre

. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 2004; 53: S43–S50.

27.

Randle

Garland

Hales

. The glucose fatty-acid cycle, its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 281: 785–789.

28.

Fillmore

Lopaschuk

. Impact of free fatty acids on cardiac efficiency. Heart Metab 2011; 53: 33–37.

29.

Depre

Vanoverschelde

Taegtmeyer

. Glucose for the heart. Circulation 1999; 99: 578–588.

30.

Cotter

Cameron

Robertson

. Polyol pathway mediated changes in cardiac muscle contractile properties: studies in streptozotocin-diabetic and galactose-fed rats. Exp Physiol 1992; 77: 829–838.

31.

Wamelink

Struys

Jakobs

. The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. J Inherit Metab Dis 2008; 31: 703–717.

32.

Schleicher

Weigert

. Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int 2000; 77: S13–S18.

33.

Hansford

Cohen

. Relative importance of pyruvate dehydrogenase interconversion and feed-back inhibition in the effect of fatty acids on pyruvate oxidation by rat heart mitochondria. Arch Biochem Biophys 1978; 191: 65–81.

34.

McCormack

Halestrap

Denton

. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 1990; 70: 391–425.

35.

Papa

Martino

Capitanio

. The oxidative phosphorylation system in mammalian mitochondria. Adv Exp Med Biol 2012; 942: 3–37.

36.

Des Rosiers

Labarthe

Lloyd

. Cardiac anaplerosis in health and disease: food for thought. Cardiovasc Res 2011; 90: 210–219.

37.

Murphy

. How mitochondria produce reactive oxygen species. Biochem J 2009; 417: 1–13.

38.

Beard

. Iron biology in immune function, muscle metabolism, and neuronal functioning. J Nutr 2001; 131: 568–580.

39.

Crack

Green

Thomson

. Iron-sulfur cluster sensor-regulators. Curr Opin Chem Biol 2012; 16: 35–44.

40.

Park

Gifford

Andtbacka

. Cardiac, skeletal, and smooth muscle respiration: are all mitochondria created equal? Am J Physiol Heart Circ Physiol 2014; 307: 346–352.

41.

Lemieux

Hoppel

. Mitochondria in the human heart. J Bioenerg Biomembr 2009; 41: 99–106.

42.

Zick

Rabl

Reichert

. Cristae formation-linking ultrastructure and function of mitochondria. Biochim Biophys Acta 2009; 1793: 5–19.

43.

Labbe

Grenier-Larouche

Noll

. Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans. Diabetes 2012; 61: 2701–2710.

44.

Cha

Han

. Peroxisome proliferator-activated receptor-alpha deficiency protects aged mice from insulin resistance induced by high-fat diet. Am J Nephrol 2007; 27: 479–482.

45.

Rijzewijk

Van der Meer

Lamb

. Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J Am Coll Cardiol 2009; 54: 1524–1532.

46.

McGavock

Lingvay

Zib

. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 2007; 116: 1170–1175.

47.

Rijzewijk

Van der Meer

Smit

. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 2008; 52: 1793–1799.

48.

Delgado

Bertini

. Myocardial steatosis and biventricular strain and strain rate imaging in patients with type 2 diabetes mellitus. Circulation 2010; 122: 2538–2544.

49.

Edelstein

Obici

. Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 2006; 116: 1071–1080.

50.

Hafstad

Nabeebaccus

Shah

. Novel aspects of ROS signalling in heart failure. Basic Res Cardiol 2013; 108: 359.

51.

Perry

Hannun

. The role of ceramide in cell signaling. Biochim Biophys Acta 1998; 1436: 233–243.

52.

Drosatos

Schulze

. Cardiac lipotoxicity: molecular pathways and therapeutic implications. Curr Heart Fail Rep 2013; 10: 109–121.

53.

How

Aasum

Severson

. Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 2006; 55: 466–473.

54.

Hafstad

Solevåg

Severson

. Perfused hearts from type 2 diabetic (db/db) mice show metabolic responsiveness to insulin. Am J Physiol Heart Circ Physiol 2006; 290: 1763–1769.

55.

Armoni

Harel

Bar-Yoseph

. Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements. J Biol Chem 2005; 280: 34786–34795.

56.

Utriainen

Takala

Luotolahti

. Insulin resistance characterizes glucose uptake in skeletal muscle but not in the heart in NIDDM. Diabetologia 1998; 41: 555–559.

57.

Schummer

Werner

Tennagels

. Dysregulated pyruvate dehydrogenase complex in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 2008; 294: 88–96.

58.

Bowker-Kinley

Davis

. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 1998; 329: 191–196.

59.

Holness

Sugden

. Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans 2003; 31: 1143–1151.

60.

Thompson

Cooney

. Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance. Diabetes 2000; 49: 1761–1765.

61.

Chung

Lam

. Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 2003; 14: 233–236.

62.

Sochor

Gonzalez

McLean

. Regulation of alternative pathways of glucose metabolism in rat heart in alloxan diabetes: changes in the pentose phosphate pathway. Biochem Biophys Res Commun 1984; 118: 110–116.

63.

McNulty

. Hexosamine biosynthetic pathway flux and cardiomyopathy in type 2 diabetes mellitus. Focus on ‘Impact of type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart’. Am J Physiol Cell Physiol 2007; 292: 1243–1244.

64.

Laughlin

Petit

Jr Shulman

. Measurement of myocardial glycogen synthesis in diabetic and fasted rats. Am J Physiol 1990; 258: 184–190.

65.

Petrova

Yamamoto

Muraki

. Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes. J Mol Cell Cardiol 2002; 34: 1425–1431.

66.

Brownlee

. Advanced protein glycosylation in diabetes and aging. Annu Rev Med 1995; 46: 223–234.

67.

Arai

. Advanced glycation endproducts and their receptor: do they play a role in diabetic cardiomyopathy? J Mol Cell Cardiol 2002; 34: 1305–1308.

68.

Roche

Farfari

Witters

. Long-term exposure of beta-INS cells to high glucose concentrations increases anaplerosis, lipogenesis, and lipogenic gene expression. Diabetes 1998; 47: 1086–1094.

69.

Anderson

Kypson

Rodriguez

. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 2009; 54: 1891–1898.

70.

Croston

Thapa

Holden

. Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart. Am J Physiol Heart Circ Physiol 2014; 307: 54–65.

71.

Montaigne

Marechal

Coisne

. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 2014; 130: 554–564.

72.

Andreyev

Kushnareva

Starkov

. Mitochondrial metabolism of reactive oxygen species. Biochem Mosc 2005; 70: 200–214.

73.

Nishikawa

Edelstein

. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787–790.

74.

Giardino

Edelstein

Brownlee

. BCL-2 expression or antioxidants prevent hyperglycemia induced formation of intracellular advanced glycation endproducts in bovine endothelial cells. J Clin Invest 1996; 97: 1422–1428.

75.

Zorzano

Liesa

Palacín

. Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes. Int J Biochem Cell Biol 2009; 41: 1846–1854.

76.

Sheu

Robotham

. Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res 2008; 79: 341–351.

77.

Williamson

Dabkowski

Baseler

. Enhanced apoptotic propensity in diabetic cardiac mitochondria: influence of subcellular spatial location. Am J Physiol Heart Circ Physiol 2010; 298: 633–642.

78.

Savabi

. Mitochondrial creatine phosphokinase deficiency in diabetic rat heart. Biochem Biophys Res Commun 1988; 154: 469–475.

79.

Savabi

Kirsch

. Alteration of the phosphocreatine energy shuttle components in diabetic rat heart. J Mol Cell Cardiol 1991; 23: 1323–1333.

80.

Diamant

Lamb

Groeneveld

. 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: 328–335.

81.

Hafstad

Khalid

How

. Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice. Am J Physiol Endocrinol Metab 2007; 292: 1288–1294.

82.

Monji

Mitsui

Bando

. Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol Heart Circ Physiol 2013; 305: 295–304.

83.

Liu

Chen

. Glucagon-like peptide-1 analog liraglutide protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway. J Diabetes Res 2013; 2013: 630537.

84.

Younce

Burmeister

Ayala

. Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am J Physiol Cell Physiol 2013; 304: 508–518.

85.

Rosiak

Postula

Kaplon-Cieslicka

. Metformin treatment may be associated with decreased levels of NT-proBNP in patients with type 2 diabetes. Adv Med Sci 2013; 58: 362–368.

86.

Malmberg

Ryden

Hamsten

. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. DIGAMI Study Group. Diabetes Insulin-Glucose in Acute Myocardial Infarction. Eur Heart J 1996; 17: 1337–1344.

87.

Malmberg

Ryden

Wedel

. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005; 26: 650–661.

88.

Selker

Beshansky

Sheehan

. Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA 2012; 307: 1925–1933.

89.

Home

Pocock

Beck-Nielsen

.; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised open-label trial. Lancet 2009; 373: 2125–2135.

90.

Scirica

Bhatt

Braunwald

. SAVOR-TIMI 53 Steering Committee and Investigators Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369: 1317–1326.

91.

Nagendran

Oudit

Bakal

. Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes? Diabetes Obes Metab 2013; 15: 1022–1028.

92.

Panchal

Stanley

Kerner

. Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure. J Card Fail 1998; 4: 121–126.

93.

Huang

Shan

Pan

. Carvedilol protects early diabetic rat hearts through reducing oxidative stress. Conf Proc IEEE Eng Med Biol Soc 2005; 1: 929–932.

94.

Rupp

Elimban

Dhalla

. Modification of myosin isozymes and SR Ca(2⁺)-pump ATPase of the diabetic rat heart by lipid-lowering interventions. Mol Cell Biochem 1994; 132: 69–80.

95.

Belardinelli

Cianci

Gigli

. Effects of trimetazidine on myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy. J Cardiovasc Pharmacol 2008; 51: 611–615.

96.

Kosiborod

Arnold

Spertus

. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina). J Am Coll Cardiol 2013; 61: 2038–2045.

97.

Mourouzis

Mantzouratou

Galanopoulos

. The beneficial effects of ranolazine on cardiac function after myocardial infarction are greater in diabetic than in nondiabetic rats. J Cardiovasc Pharmacol Ther 2014; 19: 457–469.

98.

Lee

Campbell

Scheuermann-Freestone

. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation 2005; 112: 3280–3288.

99.

McKenna

Phan

Nallur-Shivu

. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 2010; 122: 1562–1569.

100.

Drury

Howell

Calvert

. The effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre, randomized, double-blind, placebo-controlled trial. Eur J Cardiothorac Surg. 2015; 47: 464–472.

101.

Bersin

Wolfe

Kwasman

. Improved haemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol 1994; 23: 1617–1624.

102.

Lim

Rashid

Jang

. Mitochondria-targeted antioxidants protect pancreatic β-cells against oxidative stress and improve insulin secretion in glucotoxicity and glucolipotoxicity. Cell Physiol Biochem 2011; 28: 873–886.

103.

Dai

Chen

Szeto

. Mitochondrial targeted antioxidant peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 2011; 58: 73–82.

104.

Beaudoin

Perry

Arkell

. Impairments in mitochondrial palmitoyl-CoA respiratory kinetics that precede development of diabetic cardiomyopathy are prevented by resveratrol in ZDF rats. J Physiol 2014; 592: 2519–2533.

105.

Mortensen

Rosenfeldt

Kumar

. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. Epub ahead of print 1 October 2014. DOI: 10.1016/j.jchf.2014.06.008.

106.

Huynh

Kiriazis

. Coenzyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes. Diabetologia 2012; 55: 1544–1553.

107.

Okonko

Mandal

Missouris

. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity and survival. J Am Coll Cardiol 2011; 58: 1241–1251.

108.

Naito

Tsujino

Matsumoto

. Adaptive response of the heart to long-term anemia induced by iron deficiency. Am J Physiol Heart Circ Physiol 2009; 296: 585–593.

109.

Okonko

Grzeslo

Witkowski

. Effect of intravenous iron sucrose on exercise tolerance in anemic and non-anemic patients with symptomatic chronic heart failure and iron deficiency (FERRIC-HF): a randomized, controlled, observer-blinded trial. J Am Coll Cardiol 2008; 51: 103–112.

110.

Anker

Comin Colet

Filippatos

. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361: 1–13.

111.

Maeder

Khammy

dos Remedios

. Myocardial and systemic iron depletion in heart failure implications for anemia accompanying heart failure. J Am Coll Cardiol 2011; 58: 474–480.

Metabolic abnormalities of the heart in type II diabetes

Abstract

Keywords

Introduction

Normal myocardial metabolism

Cardiac energetics

FA uptake and utilisation

Glucose uptake and utilisation

Krebs cycle and mitochondrial OxPhos

Myocardial metabolism in T2DM

Abnormal cardiac FA uptake and utilisation in T2DM

Abnormal cardiac glucose uptake and utilisation in T2DM

Cardiac mitochondrial OxPhos defects in T2DM

Therapeutic targeting of cardiac metabolism in T2DM

Diabetic and HF medications

Strategies to modulate cardiac substrate utilisation

Strategies to improve mitochondrial OxPhos

Summary

Footnotes

Declaration of conflicting interests

Funding

References