Lea M.D. Delbridge,1 Vicky L. Benson,2 Rebecca H. Ritchie,3 andKimberley M. Mellor1,2,4

Diabetic Cardiomyopathy: The Case fora Role of Fructose in Disease EtiologyDiabetes 2016;65:3521–3528 | DOI: 10.2337/db16-0682

A link between excess dietary sugar and cardiac diseaseis clearly evident and has been largely attributed tosystemic metabolic dysregulation. Now a new paradigmis emerging, and a compelling case can be made thatfructose-associated heart injury may be attributed to thedirect actions of fructose on cardiomyocytes. Plasmaand cardiac fructose levels are elevated in patients withdiabetes, and evidence suggests that some uniqueproperties of fructose (vs. glucose) have specific car-diomyocyte consequences. Investigations to date havedemonstrated that cardiomyocytes have the capacity totransport and utilize fructose and express all of thenecessary proteins for fructose metabolism. When di-etary fructose intake is elevated and myocardial glucoseuptake compromised by insulin resistance, increasedcardiomyocyte fructose flux represents a hazard in-volving unregulated glycolysis and oxidative stress. Thehigh reactivity of fructose supports the contention thatfructose accelerates subcellular hexose sugar-relatedprotein modifications, such as O-GlcNAcylation and ad-vanced glycation end product formation. Exciting recentdiscoveries link heart failure to induction of the specifichigh-affinity fructose-metabolizing enzyme, fructokinase,in an experimental setting. In this Perspective, we reviewkey recent findings to synthesize a novel view of fructoseas a cardiopathogenic agent in diabetes and to identifyimportant knowledge gaps for urgent research focus.

Links between excess fructose consumption, diabetes in-cidence, and cardiovascular disease risk have been clearlydemonstrated (1–4). The systemic effects of high fructoseintake have been well described experimentally and includehyperglycemia, dyslipidemia, atherosclerosis, and in somecases hypertension (5). Diabetic cardiomyopathy is recognized

as a specific myocardial pathology, the occurrence of whichis independent of coronary and hypertensive disease. Di-abetic cardiomyopathy is generally characterized by earlysigns of diastolic dysfunction, which precede progression tosystolic failure (6,7).

While the relationship between excess fructose exposureand cardiac disease development has been identified, theunderlying mechanisms are as yet only partially under-stood. Aspects of diabetic cardiomyopathy that may beattributed specifically to high fructose intake or to selectivemyocardial fructose metabolic dysregulation have not beendetermined. Whether cardiac vulnerability associated withfructose exposure produces an injury response beyondeffects that may be attributed to general overnutrition orto overall excess consumption of refined sugar (eitherglucose or fructose) in different diabetic settings is alsonot yet known (8,9).

In this Perspective, these questions relating to fructose,diabetes, and the heart are examined, and the case for a roleof fructose in diabetic cardiomyopathy disease etiology isexplored. Evidence to support the proposition that fructoseis a distinctive cardiopathogenic agent in diabetes andstates of metabolic disturbance is considered. Findings froma diverse range of investigative approaches are reviewed tosynthesize a novel view of fructose (of exogenous and en-dogenous origin) as a perpetrator of cardiac damage. Newinsights into fructose-induced myocardial functional andsignaling dysregulation are discussed, and knowledge gapsfor priority research focus are identified.

DIETARY FRUCTOSE AND CARDIOMYOPATHY

Dietary Fructose Increases Cardiovascular RiskThe dramatic rise in the prevalence of diabetes has oc-curred in parallel with an escalation in dietary sugar

1Department of Physiology, University of Melbourne, Victoria, Australia2Department of Physiology, University of Auckland, Auckland, New Zealand3Heart Failure Pharmacology, Baker IDI Heart and Diabetes Institute, Victoria,Australia4Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand

Corresponding author: Lea M.D. Delbridge, lmd@unimelb.edu.au.

Received 31 May 2016 and accepted 9 September 2016.

© 2016 by the American Diabetes Association. Readers may use this article aslong as the work is properly cited, the use is educational and not for profit, and thework is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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PERSPECTIVESIN

DIA

BETES

consumption. In “westernized” cultures, the use of addedsweeteners containing fructose (sucrose and high-fructosecorn syrup) has increased by approximately 25% over thepast three decades (10). Meta-analyses of cohort studieshave determined that high intake of fructose-sweetenedbeverages is associated with a 26% greater risk of cardio-metabolic pathology (2). Experimental studies of hepaticfructose metabolism have shown that genetically modifiedrodents unable to metabolize fructose (fructokinase knock-out) are protected from high-carbohydrate–induced meta-bolic syndrome, supporting the contention that fructose isthe toxic component of the sugar complex (11,12). Althoughincreased cardiovascular disease risk may be partially attrib-uted to fructose-induced dyslipidemia, atherosclerosis, hy-pertension, obesity, or insulin resistance/diabetes/metabolicsyndrome (13,14), it is increasingly apparent that fructose-specific cardiac factors are important. Recent studies havedemonstrated that dietary fructose is not necessarily asso-ciated with changes in blood pressure (15), and the relation-ship between high sugar intake and increased risk for bothtype 2 diabetes and cardiovascular disease is independent ofBMI (2,16), which indicates that calorie intake and adiposedeposition are not the underlying etiology.

Emerging evidence suggests that cardiac complicationsin patients with diabetes (and their attenuation) are notalways linked to the degree of blood glucose control. Meta-analyses of large randomized controlled clinical trials reportthat drugs used to lower blood glucose levels in patients withdiabetes may exacerbate heart failure symptoms and in-crease the risk of heart failure (17,18). While some glucose-lowering agents (metformin, emphafliglozin) have beenshown to be cardioprotective in patients with diabetes,others do not improve cardiac dysfunction and can leadto increased heart failure risk (e.g., peroxisome proliferator–activated receptor agonists, dipeptidyl peptidase 4 inhibitors,thiazolidinediones). Thus negative cardiac impacts in di-abetes involve mechanisms not necessarily responsive tonormalization of circulating glucose levels. As cardiac tis-sue is both insulin sensitive and glycolysis dependent,increased cardiac vulnerability to fructose in the contextof metabolic dysregulation is plausible (5) and supportedby an accumulating experimental evidence base. As empha-sized in important recent commentaries (4,12), although ofcaloric equivalence, fructose and glucose are very differentsugars. The consequences of these differences in relation todiet-induced dysregulation of cardiomyocyte signaling, me-tabolism, and energetics are considered below.

Myocardial Metabolic Dysregulation With High DietaryFructose IntakeMyocardial signaling adaptations in response to highdietary fructose intake are reported. In animal models, tissueinsulin resistance is evident, characterized by downregulationof the phosphoinositide 3-kinase (PI3K)/Akt insulin sig-naling pathway (19). The PI3K/Akt pathway regulates GLUT4translocation, glucose uptake, and cardiac cell growth andsurvival, and thus suppression of this major signaling nexus

results in metabolic dysregulation and cell death vulnera-bility. Rodents fed a high-fructose diet for several monthsdisplay significant decreases in the levels of phosphory-lated Akt (Ser473) and the downstream signaling inter-mediate S6 (Ser235/236) with decreased PI3K activityand phosphorylation of Akt (19,20). Interestingly, insulingrowth factor 1 (IGF1) and IGF1 receptor expression areboth decreased in this setting, suggesting involvementfrom the IGF1 signaling pathway in addition to insulin-receptor–mediated effects (20). Fructose feeding also di-minishes cardiac glucose uptake (21). Thus despite elevatedextracellular glucose levels, intracellular glucose availabilityis reduced, which is associated with upregulation of cardiaclipid derivatives and transporters (22), indicative of a sub-strate shift from glucose to fatty acids for energy supply.

Energetic disturbances may manifest as triggers for oxi-dative stress in response to excess dietary fructose (23).Mitochondrial uncoupling is evident in hearts of fructose-fed rodents (24) and is associated with elevated myocar-dial production of reactive oxygen species (25). Impairedglucose uptake and utilization has also been linked to aninability to respond to an ischemic challenge. In contrastto controls, fructose-fed animals do not increase cardiomyo-cyte GLUT4 translocation and glycolytic flux in response toischemia (26), a response deficit that may underlie chronicischemic vulnerability in diabetic settings. Interestingly, twostudies have reported smaller infarct size in isolated heartsfrom fructose-fed rats (27,28), suggesting that metabolicadaptation involving modified routes of cardiomyocytehexose sugar uptake may actually have a role in acutecardioprotection.

Dietary Fructose–Induced Cardiac Cell Lossand DysfunctionDownregulation of the cardiomyocyte PI3K/Akt “cell sur-vival’’ pathway can promote cell death signaling as inhibi-tion of programmed cell death pathways via the PI3K/Aktaxis is relieved. Fructose feeding in rodents is associatedwith low-level constitutive loss of cardiomyocytes coupledwith increased collagen deposition, producing a progressivefibrotic replacement of viable myocardium (19). In feedinginterventions where the metabolic disturbance is moderate,apoptotic signaling pathways are not found to be activatedbut autophagy markers are significantly upregulated (19).Autophagy, a subcellular phagolysosomal degradation process,is essential for physiological turnover of macromolecules andorganelles. Sustained, high-level autophagic activity is con-sidered deleterious and is associated with induction of anonapoptotic form of programmed cell death (29–31).More work is required to establish the nature of the linksbetween dietary fructose, cardiomyocyte loss, and induc-tion of autophagy triggers. In rodent models where theextent of myocardial metabolic disturbance that developsin response to high-fructose feeding is more severe, acti-vation of apoptotic signaling is evident (20). These findingssuggest that loss of cardiomyocyte viability with fructoseinsult may be mediated initially through autophagic pathways,

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subsequently transitioning to apoptotic demise as cardio-pathology progresses.

The myocardial functional consequences of high fructoseintake have not been extensively studied. Some insightshave been gained from in vivo (hemodynamic) analyses andfrom in vitro cardiomyocyte contractility and Ca2+ handlingstudies. In vivo left ventricular dysfunction is evident inrodents administered fructose drinking solution (10%) foronly 2 weeks, as characterized by reduced left ventricularend-systolic elastance (a measure of intrinsic left ventricularcontractility independent of preload, afterload, and heartrate) (32). In cardiomyocytes isolated from fructose-fedmice, a marked Ca2+ handling disturbance is observed, evenwith maintenance of twitch contractile performance (33).Contractile myofilament sensitivity to Ca2+ is increased byhigh fructose intake (33), which may have important im-plications for impaired relaxation and diastolic dysfunctionin vivo. There is also recent evidence that high fructoseintake increases cardiomyocyte arrhythmogenic suscepti-bility. Cardiomyocytes obtained from animals exposed tofructose drinking solution exhibit Ca2+ handling defects,with increased instability of internal Ca2+ stores associ-ated with spontaneous arrhythmogenic events (34).

Collectively these clinical and experimental studies dem-onstrate the negative impacts of high fructose intake onmyocardial structural and functional integrity— effects thatmay not necessarily be contingent on systemic or cardiacinsulin resistance. Evidence suggests that the unique prop-erties of fructose, which differentiate this hexose sugarfrom glucose, have selective cardiomyocyte metabolic con-sequences that undermine cellular integrity. These specificaspects of fructose action are considered below.

SPECIFIC MYOCARDIAL FRUCTOSE ACTIONS

Cardiomyocyte Fructose Exposure—A Central Rolein Cardiac Pathology?Although systemic fructose levels are maintained withinthe micromolar range by hepatic clearance of absorbedfructose, plasma fructose concentration is elevated inpatients with diabetes (35). Thus it is feasible that elevatedplasma fructose levels exert cardiomyocyte influence. Workwith isolated cardiomyocytes has demonstrated that thesecells have the capacity to transport and utilize exogenouslysupplied fructose. A key study has shown that the high-affinity fructose-specific transporter, GLUT5, is expressedin adult rat cardiomyocytes (36). Importantly GLUT5-mediated glucose uptake is negligible, and thus the operationof this transporter is not influenced by fructose-glucose com-petition. In isolated cardiomyocytes, the contractile deficitinduced by inhibition of glucose oxidation is abrogated byfructose supplementation, providing direct evidence thatcardiomyocyte fructose uptake and utilization is operational(36). Production of fructose 1-phosphate (F1P) from exoge-nous fructose has been demonstrated in cultured neonatalcardiomyocytes using 13C-radiolabeled fructose (37). Thesefindings not only establish that fructose has a role in acutemodulation of cardiomyocyte fuel usage but also confirm

that fructose has direct cardiomyocyte “assault” access(36). Although not yet well characterized in cardiac tis-sues, increased fructose metabolic flux has the potentialto cause damage as a consequence of increased conversionof fructose to F1P. In noncardiac tissues, this reactionstep results in the ultimate production of uric acid andis linked with cell nucleotide depletion (4,38). Furtherinvestigation is required to fully characterize the extentand regulation of fructose fuel usage in the heart in bothphysiological and pathophysiological circumstances.

Endogenous fructose production is also potentially amajor factor in determining local exposure to this hexosesugar. In hepatic and renal tissues, there is clear evidenceof significant endogenous fructose production via aug-mented polyol pathway throughput (conversion of glucoseto fructose via sorbitol) in disease states (11,39). Condi-tions of enhanced polyol activity in myocardial tissues areless well described, but an important observation is thatmyocardial fructose content is measured to be 60-foldhigher in diabetic rats (40). This observation supportsthe proposition that stimulated intracellular productionof fructose via the polyol pathway in the diabetic heartmay also be significant and pathological. A recent pivotalreport has demonstrated that cardiac fructose uptake,transporter expression, and content are elevated in threemouse models of heart failure (1-kidney-1-clip [1K1C],transverse aortic constriction [TAC], and chronic isopro-terenol perfusion) and in cardiac biopsies from humanswith aortic stenosis and hypertrophic cardiomyopathy(37). Crucially, the finding that cardiac-specific knockdownof Sf3b1, a positive regulator of fructokinase (C isoform, alsoknown as ketohexokinase-C), attenuates 1K1C- and TAC-induced elevated cardiac fructose levels and cardiac dysfunc-tion and hypertrophy (37) demonstrates a central role forfructose metabolism in cardiac pathology. This study alsodetermined that TAC-induced cardiac dysfunction was pre-vented in global fructokinase knockout mice (37), a modelpreviously reported to exhibit elevated plasma fructose levels(11). Thus cardioprotection was achieved despite cardiomyo-cyte exposure to elevated plasma fructose. These findingssuggest that direct negative effects of fructose exposure oncardiomyocytes may be dependent on the pathological set-ting and involvement of hepatic fructose dysregulation (e.g.,extent of concomitant insulin resistance/diabetes, increasedlactic acid, increased uric acid). Clearly more work is neededto elucidate the hepatic dependent and independent aspectsof myocardial fructose vulnerability.

Increased intracellular fructose availability has thepotential to significantly modify cardiomyocyte metabolicprocesses. In contrast to the tightly regulated process ofglucose metabolism, fructose can bypass the glycolyticrate-limiting enzyme, phosphofructokinase, and proceedthrough glycolysis to pyruvate and lactate end productsin a relatively unregulated manner (41). Accumulation oflactate in particular has been shown to have adverse ef-fects in cardiomyocytes (42). Fructose can also enter thehexosamine biosynthesis pathway (HBP) to generate uridine

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diphosphate (UDP)-GlcNAc, the precursor for O-GlcNAcylation(see below). The importance of the HBP in myocardialmetabolic control and disease vulnerability is increas-ingly recognized (43,44). Regulatory factors that deter-mine the balance between glycolytic and HBP fructoseflux have not yet been identified. Qualitative and quan-titative shifts in cardiomyocyte fructose shunting likelyplay an important role in determining the impacts ofaltered intracellular fructose on cardiomyocytes. Newmetabolic studies in this area will be especially informativein relation to understanding adverse actions of cardiomyo-cyte fructose metabolism. In particular the application ofmetabolic tracing methodologies to track fructose uptakeand/or production and disposal in pathophysiological con-ditions will yield valuable insights (45).

Fructose and Cardiomyocyte O-GlcNAcylationin the HeartO-GlcNAcylation is a major posttranslational modificationinvolved in normal physiological signaling regulation andhas also been implicated in a number of pathological process-es (43,46). O-GlcNAcylation is a dynamic/reversible covalentattachment of an O-GlcNAc moiety onto serine or threonineresidues of target proteins, catalyzed by O-GlcNAc trans-ferase, and its removal is catalyzed by O-GlcNAcase. Attach-ment of the O-GlcNAc substrate can influence transcription,translation, nuclear transport, and cell signaling, and thereis evidence of interaction and/or competition for thetarget amino acid residues between phosphorylation andO-GlcNAcylation (47,48). O-GlcNAcylation has been iden-tified as an important mediator of diabetic heart pathol-ogy. Promotion of O-GlcNAc removal by overexpressionof O-GlcNAcase restores contractile function and Ca2+ han-dling in cardiomyocytes of diabetic rodents (47). More recently,it has been demonstrated that specific O-GlcNAcylation ofCa2+-dependent calmodulin kinase II, a key regulator ofmyocyte Ca2+ cycling and contractility, mediates cardiac dys-function and arrhythmias in diabetic hearts (49). ThusO-GlcNAcylation may prove to be an effective thera-peutic target in diabetic cardiomyopathy.

While glucose has been established as the main con-tributor toward O-GlcNAcylation, recent findings suggestthat fructose may also play a significant role. Fructose canbe converted to fructose 6-phosphate (F6P), the substratefor the HBP, providing for consequent production ofUDP-O-GlcNAc. This conversion is either via direct phos-phorylation of fructose by hexokinase to F6P (low affin-ity) (50,51) or via phosphorylation of fructose to F1P byfructokinase, followed by generation of F6P involvingintermediate steps via dihydroxyacetone phosphate orglyceraldehyde, glyceraldehyde-3-phosphate, and fructose1,6-biphosphate (51), as detailed in Fig. 1. Literaturereporting the direct effects of fructose on the HBP andO-GlcNAcylation is limited, and measurement of fructosemetabolic flux into the HBP is warranted. Left ventriculartissues from fructose-fed rodents exhibit significant elevationin the level of O-GlcNAcylation (52). Direct comparison of

cardiomyocyte glucose- and fructose-induced O-GlcNAcylationactivity in vitro has yet to be reported. In human hepa-tocarcinoma HepG2 lineage cells, incubation with eitherglucose or fructose produces a similar increase in UDP-O-GlcNAc levels in a 24-h period (51). Although involving non-cardiac cell types, these findings are consistent with thecontention that fructose can act as a substrate for the HBPand subsequent O-GlcNAcylation. These data suggest thatfructose can induce O-GlcNAcylation to a similar extent asglucose, but further work with cardiac cell types and map-ping fructose-induced O-GlcNAc to downstream cardiac con-sequences using in vivo experimental models is required.

Fructose-Induced Glycation of Cardiac ProteinsIn contrast to the dynamic, regulated nature ofO-GlcNAcylationreactions, advanced glycation end products (AGEs) are adducts

Figure 1—Pathways of glucose- and fructose-mediatedO-GlcNAcylationand glycolysis. Fructose phosphorylation by hexokinase to F6P directlyprovides substrate for the HBP. Glucose phosphorylation by glucoki-nase or hexokinase to glucose 6-phosphate (G6P) also produces F6P.Fructose can also be phosphorylated by fructokinase to F1P and canthen be further metabolized to generate F6P via dihydroxyacetonephosphate (DHAP) or glyceraldehyde (GA), both of which can be con-verted to glyceraldehyde 3-phosphate (G3P), fructose 1,6-bisphos-phate (F16BP), and F6P. G3P is also a substrate for glycolysis toproduce end products lactate and acetyl-CoA. F6P enters the gly-colytic pathway via conversion to F16BP, a step catalyzed by therate-limiting enzyme, phosphofructokinase (PFK). The HBP producesUDP-GlcNAc, and O-GlcNAc transferase (OGT) catalyzes the attach-ment of O-GlcNAc to a serine or threonine amino acid residue in aprotein. LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase.

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produced from the irreversible nonenzymatic glycationand oxidation of proteins and lipids. Clinical and experi-mental studies have demonstrated an association betweenAGE formation and dysfunction in the diabetic heart(53,54). In general, literature has focused on extracellularAGEs and in particular the cross-linking of collagen resultingin myocardial stiffness and diastolic dysfunction of extracel-lular matrix origin. There is some evidence that intracellularAGEs may also elicit significant impact on cardiomyocytefunction (55,56).

AGEs are formed from the attachment of a single hexosemolecule by its aldehyde group to the NH2-terminal of abasic amino acid residue (usually lysine or arginine) toform a Schiff base (57). Schiff bases are then rearrangedinto Amadori products, which can develop into reactiveintermediates such as 3-deoxyglucosone and glyoxal (58).A series of oxidation-based Maillard reactions involvingchemical cleavage, cross-linking, and conformational changetransform the reactive intermediates into irreversible AGEs(57), as detailed in Fig. 2. Not only do the reducing proper-ties of the bound AGE alter protein structure and function,but AGEs can also bind to cell membranes via receptors forAGEs (RAGEs) to activate signaling cascades involving oxi-dative stress, pathological growth, and induction of cell deathprocesses (53,59,60). The combination of hyperglycemia andreactive oxygen species in the diabetic heart provides a con-ducive environment for extracellular AGE production.

AGE formation within the extracellular matrix of thediabetic heart has been mostly attributed to hyperglycemia(53,61). But with evidence of intracellular AGEs in thecontext of impaired glucose uptake in diabetic cardiomyo-cytes, a recognition of the importance of alternative sub-strates for AGE production, including fructose, is emerging.In vitro studies with purified proteins have shown thatfructose-related AGEs (Fru-AGEs) are more reactive thantheir Glu-AGE equivalents (62,63). Fructose can undergononenzymatic condensation with protein amino groups toform Schiff bases in a similar manner to glucose (58,62,63),which subsequently undergo Heyns rearrangement to form

Heyns products (a fructose homolog to the glucose-derived Amadori product) (58). Fructose naturally existsin its open-chain conformation more often than glucose(63), which promotes faster glycation kinetics (58,62,64).Hence, the conversion of Heyns products into Fru-AGEsoccurs more rapidly than the conversion of the glucoseequivalent, which has significant implications for greaterFru-AGE production (65). Glu-AGEs are thought to bedeveloped over periods ranging from weeks to months,whereas Fru-AGE formation is believed to be much morerapid (Fig. 2) (62,64) and subsequently may have moresevere protein damage outcomes. New investigative initia-tives are required to understand the pathological impor-tance of Fru-AGEs and Glu-AGEs in the myocardium andthe cardiomyocyte. In diabetic cardiomyocytes, Glu-AGEs aredetected even on short-lived proteins involved in electrome-chanical transduction and Ca2+ handling (55,56), withreported half-life times of 3–8 days (66,67). Given theestablished timelines of AGE formation, this suggests thatAGEs may impair protein turnover—a positive feedbackscenario that would facilitate even more extensive AGE for-mation. In a cellular environment where fructose-drivenAGE formation is particularly promoted, the accumulationof Fru-AGE adducts conferring functional and structural de-formation of affected proteins could be much accelerated.

Using novel Fru-AGE antibodies, it has been demon-strated that patients with type 1 diabetes exhibit fourfoldhigher serum Fru-AGE levels than patients without non-diabetes (65). No studies to date have directly explored thepresence of intracellular Fru-AGEs in cardiomyocytes, butsome literature from in vitro studies working with purifiedproteins and using noncardiomyocyte cell culture experimentsis available. In experiments involving incubation of purifiedproteins with fructose, it has been shown that Fru-AGE for-mation is increased in parallel with significant modification ofthe protein function. In these experiments, Fru-AGE forma-tion is found to be markedly more rapid and/or more exten-sive than Glu-AGE formation and renders the protein moreresistant to biological enzymatic breakdown (62,64,65,68). Ina noncardiac cell culture system, when gene transfer methodsare used to promote intracellular fructose synthesis by stim-ulation of the polyol pathway, a coincident increase in thelevel of intracellular Fru-AGEs is observed (65). Together thesevarious experimental approaches demonstrate that intracel-lular formation of Fru-AGEs may be an important patho-physiological event with specific cellular structural andfunctional adverse outcomes. Exploration of the role of car-diomyocyte Fru-AGE formation as a substrate of heart dam-age, particularly in the context of high cardiac fructose indiabetes, is required. The development of selective and sen-sitive molecular tools for identifying fructose-specific adducttypes will allow new research, mapping the evolution offructose-dependent AGE pathology in the myocardium.

OVERVIEW AND NEW DIRECTIONS

Consideration of the literature from epidemiological, clinical,and experimental perspectives provides an abundance of

Figure 2—Fructose- and glucose-derived AGE formation. Both fruc-tose and glucose covalently attach to lysine or arginine residues inpeptides to form a Schiff base. These attachments can rearrange toform Amadori products and Heyns products for glucose and fructose,respectively. Fru-AGEs are produced from AGE precursors faster(days to weeks) than glucose-derived adducts (weeks to months).

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evidence attesting to fructose participation in the etiologyof diabetic cardiomyopathy—including involvement incardiac metabolic, structural, and electromechanicalpathologies. The findings indicate that when dietaryprovocation is a factor in diabetes induction, fructose(more than glucose) constitutes a particular “toxic” sugarchallenge. Moreover, in the insulin-resistant/deficientdiabetic cardiac milieu, abnormalities in fructose metabo-lism have the potential to contribute directly to myocardialdisease evolution. Bringing together key clinical andexperimental observations, the evidence suggests thatdysregulated tissue fructose metabolism, and not specifi-cally systemic glycemic exposure, is associated with theultimate progression of diabetic cardiomyopathy to car-diac failure state.

Fructose is increasingly recognized as a critical cellularenergy intermediate and signaling agent in many cell types.The available evidence suggests that cardiomyocyte fruc-tose vulnerability could arise from exposure to elevatedextracellular fructose (both direct and indirect conse-quences of dietary conditions) and to augmented in-tracellular fructose production (with polyol syntheticpathway involvement). In particular fructose-driven extra-cellular and intracellular posttranslational modifications,which exert both dynamic and permanent influence onmyocardial structure and function (Fig. 3), have been iden-tified as potential pathological provocateurs.

As urgent investigation priorities, fructose-driven AGEformation and O-GlcNAcylation processes, as well as theinvolvement of these events in inflicting cardiac damage,are highlighted. New studies that track diabetic diseaseinduction and parameters of cardiac function mappedagainst shifts in systemic and myocardial fructose han-dling are required. Defining the pathophysiological attri-butes of the fructose-damaged heart can potentiallyprovide impetus in establishing a case for dietary fructoseintake limitation as a cardioprotective measure. Charac-terizing the role of cardiomyocyte fructose dysregulationin the development of diabetic cardiomyopathy will pro-vide a substrate for identifying targeted interventions toachieve damage remediation.

Acknowledgments. We acknowledge Brendan Ma from the University ofMelbourne and Andrew Lim from the University of Auckland for their assistance inthe early stages of literature compilation for manuscript development. Weacknowledge funding support from the Diabetes Australia Research Trust.Duality of Interest. No potential conflicts of interest relevant to this articlewere reported.

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Figure 3—Potential pathways of direct fructose-induced cardiomyo-cyte actions. Fructose can enter cardiomyocytes via the GLUT5 fruc-tose-specific transporter and be produced from glucose via the polyolpathway to participate in AGE protein damage, O-GlcNAcylation ofsignaling proteins, and glycolytic disturbance.

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