Cardiac Metabolism Diabetic Cardiomyopathy

doi: 10.1152/ajpheart.00278.2006291:H1489-H1506, 2006. First published 2 June 2006;Am J Physiol Heart Circ Physiol

Ding An and Brian Rodriguesdiabetic cardiomyopathyRole of changes in cardiac metabolism in development of

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Invited Review

Role of changes in cardiac metabolism in developmentof diabetic cardiomyopathy

Ding An and Brian RodriguesDivision of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences,The University of British Columbia, Vancouver, British Columbia, Canada

An, Ding, and Brian Rodrigues. Role of changes in cardiac metabolism in devel-opment of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 291: H1489–H1506, 2006. First published June 2, 2006; doi:10.1152/ajpheart.00278.2006.—Inpatients with diabetes, an increased risk of symptomatic heart failure usually developsin the presence of hypertension or ischemic heart disease. However, a predisposition toheart failure might also reflect the effects of underlying abnormalities in diastolicfunction that can occur in asymptomatic patients with diabetes alone (termed diabeticcardiomyopathy). Evidence of cardiomyopathy has also been demonstrated in animalmodels of both Type 1 (streptozotocin-induced diabetes) and Type 2 diabetes (Zuckerdiabetic fatty rats and ob/ob or db/db mice). During insulin resistance or diabetes, theheart rapidly modifies its energy metabolism, resulting in augmented fatty acid anddecreased glucose consumption. Accumulating evidence suggests that this alteration ofcardiac metabolism plays an important role in the development of cardiomyopathy.Hence, a better understanding of this dysregulation in cardiac substrate utilizationduring insulin resistance and diabetes could provide information as to potential targetsfor the treatment of cardiomyopathy. This review is focused on evaluating the acute andchronic regulation and dysregulation of cardiac metabolism in normal and insulin-resistant/diabetic hearts and how these changes could contribute toward the develop-ment of cardiomyopathy.

heart disease; diabetes; insulin resistance; lipoprotein lipase; fatty acid transporters;PPARs; lipotoxicity; mitochondria dysfunction

HEART DISEASE is a leading cause of death in diabetic patients(226, 253), with coronary vessel disease and atherosclerosisbeing primary reasons for the increased incidence of cardio-vascular dysfunction (151, 225, 253). However, a predisposi-tion to heart failure might also reflect the effects of underlyingabnormalities in diastolic function that can be detected inasymptomatic patients with diabetes alone (24, 61, 74). Theseobservations suggest a specific impairment of heart muscle(termed diabetic cardiomyopathy). Rodent models of chronicdiabetes demonstrate abnormalities in diastolic left ventricularfunction, with or without systolic left ventricular dysfunction(73, 205, 219). Because diastolic dysfunction is also seen inpatients with both Type 1 and Type 2 diabetes, it can beproposed that the diabetic state can directly induce abnormal-ities in cardiac tissue independent of vascular defects. Severaletiological factors have been put forward to explain the devel-opment of diabetic cardiomyopathy, including an increasedstiffness of the left ventricular wall associated with accumula-tion of connective tissue and insoluble collagen (9, 204, 212)and abnormalities of various proteins that regulate ion flux,specifically intracellular calcium (90, 235). More recently, theview that diabetic cardiomyopathy could also occur as aconsequence of metabolic alterations has been put forward(146, 147, 149).

Because uninterrupted contraction is a unique feature of theheart, cardiac muscle has a high demand for provision ofenergy. Under normal physiological conditions, hearts canutilize multiple substrates, including fatty acids (FA), carbo-hydrate, amino acids, and ketones (15). Among these sub-strates, carbohydrates and FA are the major sources fromwhich the heart derives most of its energy. In a normal heart,70% of ATP generation is through FA oxidation, whereasglucose and lactate account for �30% of energy provided tothe cardiac muscle (86, 173, 210). It should be noted that theheart can rapidly switch its substrate selection to accommodatedifferent physiological and pathphysiological conditions in-volving altered extracellular hormones, substrate availability, andworkload (energy demand) (11, 130, 204, 217, 227). Acutely orchronically, this regulation occurs through various mechanisms.Although substrate switching is essential to ensure continuousATP generation to maintain heart function, it has also beenassociated with deleterious consequences (17, 267).

In Type 1 and Type 2 diabetes mellitus, glucose uptake,glycolysis, and pyruvate oxidation are impaired. Additionally,lack of insulin function augments lipolysis and release of FAfrom adipose tissue. Under these conditions, the heart rapidlyadapts to using FA exclusively for ATP generation. Chroni-cally, this maladaptation is believed to play a key role in thedevelopment of cardiomyopathy. Hence, it is essential to identifyand understand the mechanisms that control substrate utilizationin the diabetic heart. This review discusses the acute and chroniccellular changes that modify cardiac metabolism and elucidatetheir roles in the development of cardiomyopathy.

Address for reprint requests and other correspondence: B. Rodrigues, Div. ofPharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The Univ.of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3(e-mail: [email protected]).

Am J Physiol Heart Circ Physiol 291: H1489–H1506, 2006.First published June 2, 2006; doi:10.1152/ajpheart.00278.2006.

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DIABETIC CARDIOMYOPATHY

The central basis for diabetic heart failure is coronarydisease associated with atherosclerosis (151, 225, 253). Be-cause diabetes is often accompanied by hypertension and/orischemic heart disease, which often causes diastolic dysfunc-tion, it is difficult to attribute heart failure in these patients todiabetes alone (23). On the other hand, Type 1 or Type 2diabetic patients have also been diagnosed with reduced orlow-normal diastolic function and left ventricular hypertrophyin the absence of coronary heart disease or hypertension,identified as cardiomyopathy (24, 81, 192, 195, 200, 231).These abnormalities in asymptomatic diabetic patients poten-tially might predispose them to symptomatic heart failure whenthey develop hypertension or ischemic heart disease, particu-larly after myocardial infarction.

In animal models of Type 1 diabetes, either streptozotocin(STZ)-induced rats or genetic nonobese diabetic mice, systolicand diastolic dysfunction have been demonstrated using in vivoor in vitro measurements (177, 185, 232, 239). For example,systolic and diastolic dysfunction have been detected by usingechocardiography in STZ diabetic animals (123, 177). With theuse of in vivo catheterization of these animals, elevated leftventricular end-diastolic pressure and reduced left ventricularsystolic pressure with diminished increase or decrease pressureover time (�dP/dt) were observed (124). Reduced peak leftventricular pressure and �dP/dt were confirmed in ex vivoperfused STZ hearts (239). Recently, evidence of cardiomyop-athy has also been reported in animal models of insulinresistance and Type 2 diabetes (ZDF rats and ob/ob or db/dbmice) (5, 21, 30, 266). In db/db mice, systolic and diastolicdysfunction were detected by echocardiography (218). Withthe use of ex vivo perfused hearts from db/db mice, augmentedleft ventricular end-diastolic pressure and reduced cardiacoutput and cardiac power have also been observed (21). Giventhat rodents are resistant to atherosclerosis, these models pro-vided strong evidence for the occurrence of diabetic cardiomy-opathy. However, in another study, no evidence of impairmentin cardiac function was detected using in ex vivo Langendorffperfusions of hearts from insulin resistant and obese Zuckerrats (224) and Type 2 diabetic Zucker diabetic fatty (ZDF) rats(250). It is likely that such inconsistencies arose due to therodent models used and the methods employed for evaluatingheart function in the different studies.

It should be acknowledged that the features of cardiomyop-athy between human diabetic patients and rodent diabeticmodels might be different. The development of diabetic car-diomyopathy is influenced by the severity and duration ofalterations in plasma parameters such as insulin, leptin, glu-cose, and lipids. Given the discrepancy in changes in thesehormones and substrates between human diabetic patients androdent models of Type 1 and Type 2 diabetes, the etiology andseverity of diabetic cardiomyopathy may vary (196). For ex-ample, STZ-induced diabetes exhibit severe hypoinsulinemia,whereas ob/ob mice show leptin deficiency, which are rare inhuman diabetes. Additionally, it has been suggested that STZcan directly impair the cardiac contractile function of isolatedventricular myocytes (256). Finally, although db/db mice andZucker and ZDF rats exhibit hyperinsulinemia, hyperleptine-mia, and hyperglycemia, the severity of these alterations varybetween animal models and patients with diabetes (196).

Taken together, experimental data obtained using animalsmodels of diabetes should be used with caution when extrap-olating to the human condition.

Cardiomyopathy is a complicated disorder, and several fac-tors have been associated with its development. These includeincreased stiffness of the left ventricular wall associated withaccumulation of connective tissue and insoluble collagen (204,212), depressed autonomic function (73), impaired endothe-lium function and sensitivity to various ligands (e.g., �-ago-nists) (23), and abnormalities of various proteins that regulateion flux, specifically intracellular calcium (90, 235). Morerecently, there is a generalized view that diabetic cardiomyop-athy also occurs as a consequence of altered fuel metabolism.During insulin resistance or diabetes, glucose utilization iscompromised. This alteration, together with increased FA sup-ply, switches cardiac energy generation to utilization of FA.High FA uptake and metabolism not only augment accumula-tion of FA intermediates and triglycerides but also increaseoxygen demand and generation of reactive oxygen species(ROS), leading to cardiac damage. Interestingly, increasing FAuptake through overexpression of cardiac human lipoproteinlipase (LPL) (260) or FA transport protein (47), or augmentingFA oxidation through overexpression of cardiac peroxisomeproliferator-activated receptor (PPAR)-� (79) or long-chainacyl CoA synthase (48), results in a cardiac phenotype resem-bling diabetic cardiomyopathy. Conversely, normalizing car-diac metabolism in diabetic animals reverses the developmentof cardiomyopathy (21, 272). Taken together, these studiesstrongly support the role of altered metabolism in the devel-opment of diabetic cardiomyopathy.

CARDIAC METABOLISM

Glucose Uptake and Oxidation

Under normal physiological conditions, glucose is one of themajor carbohydrates utilized by the heart. Glucose metabolismis regulated through multiple steps, including uptake, glycoly-sis, and pyruvate decarboxylation (Fig. 1). Cardiac glucoseuptake is dependent on the transmembrane glucose gradientand the content of sarcolemmal glucose transporters (GLUT1and GLUT4) (132, 154, 189). GLUT1 has a more pronouncedsarcolemmal localization and represents basal cardiac uptake.When compared with GLUT1, GLUT4 is the dominant trans-porter in the adult heart, and under basal conditions, a majorityof this transporter is located in an intracellular pool (154). Itstranslocation from an intracellular compartment to the sar-colemmal membrane requires insulin (154). Other than recruit-ing GLUT to the sarcolemmal membrane, insulin also influ-ences glucose transport through its regulation of GLUT geneexpression (137, 183). It should be noted that GLUT-mediatedglucose uptake could also be stimulated through insulin-inde-pendent mechanisms. For example, recent studies have dem-onstrated that AMP-activated protein kinase (AMPK) alsopromotes GLUT4 redistribution to the sarcolemmal membrane(143, 261).

Once inside the cardiomyocyte, glucose is broken downthrough glycolysis, a sequence of reactions that convert glu-cose into pyruvate. Phosphofructokinase-1 (PFK1), the enzymethat catalyzes the generation of fructose 1,6-bisphosphate fromfructose 6-phosphate, is a rate-limiting enzyme controllingglycolysis (57, 202). PFK-1 is inhibited by low pH, high

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intracellular citrate, or ATP and is activated by ADP, AMP,phosphate, and fructose 2,6-bisphosphate (57, 202, 228). Fruc-tose 2,6-bisphosphate is formed from fructose 6-phosphatecatalyzed by PFK-2 (110). Given that PFK-2 is phosphorylatedand activated by hormones, such as insulin (25, 58) andglucagon (228) or kinases such as AMPK (109, 161), stimu-lation of PFK-2 through these mechanism increases fructose2,6-bisphosphate generation, activates PFK-1, and subse-quently promotes glycolysis. In an aerobic heart, glycolysiscontributes �10% of total ATP generated, with no oxygenconsumption.

After glycolysis, the pyruvate generated has three destina-tions: carboxylation to oxaloacetate or malate, reduction tolactate, and most importantly, decarboxylation to acetyl-CoA.To be oxidized, pyruvate is transported into the mitochondriaand decarboxylated to acetyl-CoA through pyruvate dehydro-genase (PDH), a multienzyme complex. PDH is phosphory-lated and inactivated by pyruvate dehydrogenase kinase (PDK)

(107, 258), which is inhibited by pyruvate and stimulated byhigh mitochondrial acetyl-CoA-to-CoA and NADH-to-NAD(�) ratios (29, 104). Acetyl-CoA then enters the tricar-boxylic acid cycle and is eventually broken down to H2O andCO2 for ATP generation. Oxidation of one glucose provides 30ATP with 6 oxygen consumed, which combined with 2 glyco-lytic ATPs produces a phosphate-to-oxygen ratio of 2.58 ATP/oxygen atom. Although glucose is the focus in this review,other carbohydrates like lactate also make an importantcontribution toward cardiac energy generation (39). In fact,as greater lactate compared with glucose utilization is ob-served in the isolated working heart (119, 127, 148), theinclusion of lactate in the perfusion buffer is recommendedin future studies.

FA Uptake and Utilization

When compared with glucose, FA is the preferred substrateand accounts for �70% of ATP generated in an aerobic heart.FA metabolism includes multiple steps and can be regulated byboth acute and chronic mechanisms, with or without modula-tion of gene expression (Fig. 2).

Lipoprotein lipase. Because the heart has limited capacity tosynthesize and store FA, it relies on continuous exogenoussupply. FA supplied to the heart from the circulation is fromtwo sources: albumin-bound FA and triglyceride (TG)-richlipoproteins. It should be noted that the molar concentration ofFA in lipoprotein-TG is �10-fold larger than FA bound toalbumin (165). Lipoprotein lipase (LPL) is the key enzyme thathydrolyzes lipoproteins to release FA. Thus, when lipoproteinsare hydrolyzed by LPL, a large amount of FA are released andare believed to be the principle source of FA supplied to theheart (14, 237). LPL is produced in cardiomyocytes and sub-sequently secreted onto heparan sulfate proteoglycan bindingsites on the myocyte cell surface (33, 68, 70). From here, LPLis transported onto comparable binding sites on the luminalsurface of coronary endothelial cells (193). At these sites, LPLhydrolyzes TG-rich lipoproteins, such as very-low-density li-poprotein (VLDL) and chylomicrons, to release FA. Perfusionof working hearts with VLDL or chylomicrons, in the absenceor presence of FA, has revealed that, compared with chylomi-crons, VLDL is a poor substrate for LPL (100). In addition,utilization of chylomicrons was inhibited by free FA, whichfailed to affect cardiac VLDL utilization (100). Given theimportant role that LPL plays in regulating FA delivery,alteration in its level is able to change FA delivery andsubsequent oxidation. Indeed, overexpression of LPL in theheart or skeletal muscle accelerates FA uptake (141, 260).Conversely, tissue-specific knockout of LPL in the heartswitches the cardiac substrate selection preference to glucose(12, 13). Other than hydrolysis by LPL, lipoproteins can alsobe transported into the cardiac tissue with help of the lipopro-tein receptor, with VLDL uptake through this mechanismbeing more substantial compared with chylomicrons (178). Inperfused working hearts, inhibition of the lipoprotein receptorsignificantly reduced FA oxidation without altering FA uptake,suggesting that lipoprotein receptor mediated FA uptake chan-nels FA toward oxidation, whereas LPL mediated FA uptakechannels FA toward both oxidation and TG storage (178).

FA transporters. Although FA can translocate into the cellthrough passive diffusion across the plasma membrane, FA

Fig. 1. Glucose utilization in the cardiomyocyte. Glucose uptake into cardio-myocyte occurs through GLUT1 and GLUT4 transporters. Once inside, glu-cose is broken down through glycolysis, a sequence of reactions that convertglucose into pyruvate. Phosphofructokinase-1 (PFK1), the enzyme that cata-lyze the generation of fructose 1,6-bisphosphate from fructose 6-phosphate, isa rate-limiting enzyme controlling glycolysis. PFK1 is activated by 2,6-bisphosphate, which is formed from fructose 6-phosphate catalyzed by PFK-2.After glycolysis, the pyruvate generated is transported into mitochondria anddecarboxylated to acetyl-CoA through pyruvate dehydrogenase (PDH), amultienzyme complex. PDH is phosphorylated and inactivated by pyruvatedehydrogenase kinase (PDK). Acetyl-CoA then enters tricarboxylic acid cycle(citric acid cycle) and is eventually broken down to H2O and CO2 for ATPgeneration.

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uptake shows saturation kinetics and is inhibited by proteases(7, 158, 159, 230). Thus FA transporters are also likely re-quired to support this process. In the heart, three FA transport-ers have been identified and these include CD36, FA transportprotein (FATP), and FA binding protein plasma membrane(FABPpm) (157). Given that 55–80% of FA transport wasblocked using general transporter inhibitors (131, 158) and thatoverexpression of CD36 or FATP has been found to dramati-cally increase FA metabolism (47, 113), these FA transportersare believed to play a key role in FA delivery to the cardiactissue.

Regulation of FA transport proteins occurs through differentmechanisms. In severe STZ-induced diabetes, expression ofcardiac CD36 and FABPpm were augmented (152), suggestingtranscriptional modification of these transporters. At present,the mechanisms that induce this change have yet to be eluci-dated. Additionally, because muscle contraction or acute insu-lin treatment does not change protein but simply relocatesCD36 from an intracellular pool to the sarcolemmal membrane(155, 156), posttranslational regulation of this transporter hasalso been suggested.

Acyl-CoA synthase. Acyl-CoA synthase (ACS) catalyzes theesterification of FA to fatty acyl-CoA, the initial step of FAmetabolism. Fatty acyl-CoA can be transported into the mito-chondria for oxidation or used for intracellular TG synthesis.The fate of fatty acyl-CoA is influenced by the location ofdifferent ACS isoforms, energy demand, and the availability ofFA (37). Moreover, ACS not only functions as an enzyme-catalyzing esterification but is also actively involved in con-trolling FA homeostasis (48). Recent studies have demon-strated that ACS is associated with CD36 or FATP on thecytosolic side of the sarcolemmal membrane (84, 201, 214),suggesting that ACS also influences FA uptake. Several studiesalso suggest that FATP1 is a very long chain ACS (53).Overexpression of ACS in the heart or fibroblast causes dra-matically augmented FA uptake and intracellular TG accumu-lation (48).

Under normal conditions, 70–90% of the esterified FA thatenters cardiomyocytes is oxidized for ATP generation, whereas10–30% is converted to TG (228). The TG pool is not static,with lipolysis and esterification taking place continuously(240). In a normal heart, intracellular TG level is constant,indicating a balance of lipogenesis and lipolysis (210). Insituations where FA supply supercedes the cellular oxidativecapacity, such as obesity or diabetes, intracellular TG accumu-lates and is associated with lipotoxicity (240). Although TG isunlikely to be a direct mediator of cell apoptosis, its augmentedlipolysis expands fatty acyl-CoA levels, which may be a keyfactor mediating cell apoptosis (117, 240). Thus TG is oftenused as a marker of lipotoxicity.

PPARs. PPARs are a group of ligand-activated transcrip-tional factors belonging to the superfamily of nuclear recep-tors. They are activated by either natural ligands like FA ornumerous pharmacological ligands (80). Once activated,PPARs form complexes with retinoid X receptors and bind tothe promoter regions of a number of target genes that encodethe proteins involved in controlling FA metabolism (76, 78).Through regulation of expression of these genes, PPARs mod-ulate FA utilization at the transcriptional level. PPARs havethree isoforms: PPAR-�, PPAR-� (or -�), and PPAR-�.PPAR-� is extensively expressed in tissues with high FAmetabolism like the heart (17). Activated by elevated intracel-lular FA levels, PPAR-� promotes expression of genes thatregulate FA oxidation at various steps, such as FA uptake andbinding (LPL, CD36, and FA binding protein), FA esterifica-tion (ACS), and FA oxidation (carnitine palmitoyltrans-ferase-1, acyl-CoA oxidase, long-chain acyl-CoA dehydroge-nase, and very-long-chain acyl-CoA dehydrogenase) (76, 78,111). Knocking out cardiac PPAR-� abolishes fasting-inducedoverexpression of FA metabolic genes and switches substrateselection from FA to glucose (140, 172). Overexpression ofcardiac PPAR-� augments FA uptake and oxidation (77, 79).Taken together, PPAR-� is believed to be the primary regula-tor of FA metabolism in the heart. Similar to PPAR-�, PPAR-�

Fig. 2. Control of fatty acid (FA) delivery andutilization in the cardiomyocyte. FA, either fromadipose tissue or released from triglyceride(TG)-rich lipoproteins through hydrolysis by li-poprotein lipase (LPL), is taken up into thecardiomyocyte by three FA transporters: CD36,FA transport protein (FATP), and FA bindingprotein plasma membrane (FABPpm). FA is con-verted to fatty acyl-CoA, which is transportedinto the mitochondria through CPT1/CPT2. In-side the mitochondria, fatty acyl-CoA undergoes�-oxidation to generate acetyl-CoA, which isfurther oxidized in the tricarboxylic acid cycle.Utilization of FA is regulated through differentmechanisms. FA, through activation of peroxi-some prolferator-activated receptor-� (PPAR-�), increases the expression of a number ofenzymes involved in FA oxidation. Malonyl-CoA, which is generated through carboxylationof acetyl-CoA catalyzed by acetyl-CoA carbox-ylase (ACC), inhibits CPT-1 and FA oxidation.AMP-activated kinase (AMPK) inhibits ACC,relieves its inhibition on CPT-1, and promotesFA oxidation. Similarly, malonyl-CoA decar-boxylase (MCD), through decreasing malonyl-CoA by decarboxylating it to acetyl-CoA, en-hances CPT-1 and FA oxidation.

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(or -�) is expressed abundantly in the cardiac tissue (17).Activated by elevated intracellular FA (45), PPAR-� (or -�)augments expression of a group of genes that promote FAutilization (63, 169). Cardiac-specific knockout of PPAR-�also decreases FA oxidative gene expression and FA oxidation(46). Although the targets of PPAR-� and PPAR-� are par-tially overlapping (169), their unique roles and interactionremains unclear in the heart. PPAR-�, the third number of thePPAR family, is highly expressed in adipose tissue. Throughpromoting lipogenic gene expression, PPAR-� controls lipo-genesis. Loss and gain of function experiments have demon-strated that PPAR-� is necessary for adipose tissue prolifera-tion and differentiation (16, 238). In isolated cardiomyocytes,the expression of PPAR-� is barely detectable (89), suggestinga limited direct role for this nuclear receptor in regulatingcardiac metabolism. However, the ability of PPAR-� agoniststo normalize elevated plasma concentrations of glucose and FAin diabetic animals will have a profound indirect effect oncardiac metabolism.

AMP-activated protein kinase. As an energy sensor, AMP-activated protein kinase (AMPK) is activated following a risein the intracellular AMP-to-ATP ratio (97). Once stimulated,AMPK switches off energy-consuming processes like proteinsynthesis, whereas ATP-generating mechanisms, such as FAoxidation and glycolysis, are turned on (96, 105). In heart andskeletal muscle, AMPK facilitates FA utilization through itscontrol of acetyl-CoA carboxylase (ACC) (133, 134). As ACCcatalyzes the conversion of acetyl-CoA to malonyl-CoA,AMPK by inhibiting ACC is able to decrease malonyl-CoAand minimize its inhibition of CPT-1, the rate-limiting en-zyme-controlling FA oxidation. AMPK has also been impli-cated in FA delivery to cardiomyocytes through its regulationof the FA transporter CD36 (155). Additionally, results fromour laboratory have demonstrated a strong correlation betweenactivation of whole heart AMPK and increases in coronary

lumen LPL activity (8). Interestingly, recent studies usingtransgenic mice with a dominant negative form of AMPK hasdemonstrated that the lack of AMPK does not affect cardiacmetabolism under physiological conditions (209, 259). Atpresent, it is unclear as to what compensatory mechanisms areactivated following knockout of AMPK. Additionally, it isunknown whether overexpression of AMPK could affect car-diac lipid homeostasis and metabolism.

Malonyl-CoA decarboxylase. In addition to AMPK, malo-nyl-CoA decarboxylase (MCD) is also known to promote FAoxidation through its lowering of malonyl-CoA. MCD cata-lyzes the degradation of malonyl-CoA to acetyl-CoA, leadingto reduction of malonyl-CoA (65). This action relieves theinhibition of CPT-1 by malonyl-CoA and favors FA oxidation.Recent studies have suggested that inhibition of cardiac MCDleads to accumulation of malonyl-CoA and reduced FA oxida-tion (66).

Interaction Between Glucose and FA Metabolism

Regulation of glucose and FA metabolism does not occurindependently, and numerous studies have reported a “cross-talk” between the utilization of these substrates (Fig. 3) (199,211, 233). Randle et al. (199) demonstrated that FA impairsbasal and insulin-stimulated glucose uptake and oxidation, anevent that is known as the “Randle cycle” (199). FA influencesglucose utilization at multiple levels. Accumulation of FAimpairs insulin-mediated glucose uptake through inhibition ofinsulin receptor substrate and protein kinase B (94, 115, 187).Accumulation of FA leads to augmented intracellular FAderivatives, such as fatty acyl CoA, diacylglycerol, and cer-amide. These FA metabolites activate a serine kinase cascade,which involves protein kinase C- and IB kinase-� (inhibitorof NF-B kinase-�), leading to serine phosphorylation of IRS(129, 269). Serine phosphorylation of IRS-1 reduces tyrosine

Fig. 3. Inhibition of glucose oxidation by FAutilization. Accumulation of FA impairs in-sulin-mediated glucose uptake through inhi-bition of insulin receptor substrate (IRS) andprotein kinase-B (PKB). Increased intracellu-lar FA also activates PPAR-�. As a conse-quence, PPAR-� promotes the expression ofgenes involved in FA oxidation, as well asPDK4, known to inhibit PDH and pyruvateflux. Increased acetyl-CoA and NADHcaused by the high rate of FA oxidationactivate PDK4, leading to further inactivationof PDH. Augmented acetyl-CoA also causesaccumulation of citrate in the cytosol, whichsubsequently inhibits PFK1 and glycolysis.

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phosphorylation and interferes with its ability to phosphorylateand activate phosphatidylinositol 3-kinase and protein kinase B(206). Increased intracellular FA also activates PPAR-�. As aconsequence, PPAR-� promotes the expression of genes in-volved in FA oxidation, as well as pyruvate dehydrogenasekinase-4 (PDK4), which is known to inhibit PDH and pyruvateflux (257). Moreover, increased acetyl-CoA-to-free CoA andNADH-to-NAD� ratios caused by the high rate of FA oxida-tion are also known to activate PDK4, leading to inactivationof PDH (29, 104). Augmented acetyl-CoA-to-free CoA ratioalso causes accumulation of citrate in the cytosol, whichsubsequently inhibits PFK and glycolysis (85, 175). Con-versely, inhibition of FA oxidation through elevation of mal-onyl-CoA levels, or using pharmacological inhibitors, favorsglucose oxidation.

ALTERATION OF CARDIAC METABOLISM DURING DIABETES

Changes in Plasma Substrates

Glucose and lipids are the major substrates affected bydiabetes. Hyperglycemia is a consequence of decreased glu-cose clearance and augmented hepatic glucose production,whereas enhanced lipolysis in adipose tissue and higher li-poprotein synthesis in the liver dramatically increases circulat-ing free FA and TG. Because glucose entry into the cell islargely dependent on insulin, whereas FA transport acrossplasma membrane does not require any hormone, the aug-mented circulating lipids increase FA delivery to the cardio-myocyte. With the increase of intracellular FA, cardiac tissuerapidly adapts to promote FA utilization. In addition to diabe-tes, augmentation of plasma lipids by fasting or intralipid-heparin infusion also increases cardiac FA oxidation (52, 266).Under conditions where FA supply supercedes the oxidativecapacity of the heart, the FA is converted to lipids like TG orceramide, with an end result being lipotoxicity (272). In obeseZDF rats, lowering of plasma lipids with a PPAR-� agonistreduced cardiac TG and ceramide and improved heart function(272). Overall, these studies suggest that alterations in plasmalipids may drive changes in cardiac metabolism. It should benoted that a recent study using 4-wk-old ob/ob and db/db micedemonstrated altered cardiac metabolism without any changein plasma substrates (30). Hence, in these genetic mice models,intrinsic changes in the cardiomyocyte, rather than changes incirculating substrates, initiate alterations in cardiac metabolismat this early time point.

Defects in Cardiac Carbohydrate Utilization

In the obese or diabetic heart, myocardial glucose utilizationis compromised at several points. In noninsulin-controlledType 1 diabetic animals, reduced GLUT gene and proteinexpression compromises cardiac glucose uptake and oxidation(34). In obese or Type 2 diabetic animals, although there ishyperglycemia and hyperinsulinemia, cardiac glucose uptake isreduced as a consequence of reduced GLUT4 protein andimpaired insulin signaling (38, 266). With the use of ob/ob anddb/db mice, a recent study (30) reported that cardiac glucoseoxidation is reduced at 4 wk of age and was associated withincreased FA oxidation. Interestingly, this lower glucose oxi-dation occurred before the onset of impaired insulin signalingin the heart and development of hyperglycemia. Thus this early

reduction in glucose utilization is likely due to suppression byhigh FA oxidation rather than impaired cardiac-specific insulinsignaling. In another study that used db/db mice at differentages, increased cardiac FA oxidation preceded the reduction inglucose oxidation (5). Higher FA oxidation increases citrate,which is known to inhibit PFK, the rate-limiting enzyme inglycolysis. Elevated intracellular FA is also known to increasePDK-4 expression, which phosphorylates and inhibits PDH.Finally, high rates of FA oxidation augment acetyl-CoA thatinhibits PDH either allosterically or through activation of PDK.

When compared with animal models, the use of carbohy-drates in the human diabetic hearts is more controversial. InType 1 diabetic patients, decreased myocardial carbohydrateuptake is reported (15, 62). With the use of an euglycemicinsulin clamp, another study (179) has shown that cardiacglucose uptake is normal in these patients, suggesting thatinsulin is the major limiting factor that influences cardiacglucose uptake and no cardiac-specific insulin resistance isevident, as observed in skeletal muscle. In Type 2 diabetes,cardiac expression of GLUT4 is compromised likely due toelevated FA (10). However, a number of studies have alsoreported that cardiac tissue from Type 2 diabetic patientsrespond normally to insulin and show regular glucose uptake,suggesting that myocardial insulin resistance is not a commonfeature of Type 2 diabetes (118, 160, 242). Interestingly, arecent study has suggested that impaired myocardial glucoseuptake is only observed in Type 2 diabetic patients withhypertriglyceridemia, suggesting that myocardial insulin resis-tance in these patients is associated with hypertriglyceridemiaand augmented plasma FA levels (168).

Cardiac lactate utilization is also compromised followingdiabetes. In STZ-induced Type 1 diabetes, cardiac utilizationof lactate is reduced to a greater extent when compared withglucose oxidation (41, 42). Moreover, hearts from 12-wk-oldZDF rats also showed lower carbohydrate oxidation, and thiswas almost entirely due to a reduction in lactate rather thanglucose oxidation (43, 250). The mechanisms that mediate theinhibition of lactate utilization are unclear but is likely inde-pendent of any alterations in lactate dehyrogenase or lactatetransporter (41).

The shift of cardiac energy substrate utilization from carbo-hydrate to lipids increases the intracellular glycogen pool,probably through augmented glycogen synthesis, or impairedglycogenolysis, or a combination of both processes (103, 136,167, 223). Emerging evidence indicates that glycogen, inaddition to its role as energy storage, is also able to regulatemetabolism. At least in skeletal muscle, accumulation of gly-cogen acutely alters glycogen synthesis and glucose metabo-lism (59, 120–122). Chronically, glycogen accumulation mayalso impair insulin signaling in skeletal muscle (121). Whethercardiac glycogen accumulation also influences insulin signal-ing and metabolism is unknown. In addition, recent studieshave identified a glycogen-binding domain in the �-subunit ofAMPK and suggests that this domain links AMPK and glyco-gen (108). Although an association between high glycogenlevels and repressed AMPK activity in human and rat skeletalmuscle have been documented (254, 255), it is still unclearwhether glycogen is able to regulate metabolism throughAMPK.

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Alterations in FA Utilization

Utilization of FA by cardiac tissue increases followingobesity and diabetes. This change occurs not only as a conse-quence of increased FA supply but also through an intrinsicadaptation/maladaptation to elevated FA (234, 267). It must beacknowledged that some studies have also observed a reduced,rather than augmented, FA oxidation in Zucker fatty or ZDFrats (266, 272). In human diabetic patients, obese womendemonstrate increased FA utilization, associated with aug-mented cardiac oxygen consumption, and reduced cardiacefficiency (190). Moreover, elevated cardiac TG and increasedexpression of PPAR-� target genes have been observed inpatients without ischemic heart disease, very similar to lipo-toxic ZDF rat hearts (220).

Lipoprotein lipase. The amount of FA supplied to the heartthrough LPL is influenced by multiple factors, including LPLactivity and plasma lipoprotein concentration and composition.The relative contribution of cardiac LPL activity to the deliveryof free FA to the diabetic heart is inconclusive. Thus LPLimmunoreactive protein or activity has been reported to beunchanged, increased, or decreased in the diabetic rat heart. Inpart, this variability between different studies could be due tothe diversity in the rat strains used, the dosage of STZ used toinduce diabetes, and the duration of the diabetic state (203). Inaddition, many of the above investigations utilized proceduresthat did not distinguish between functional (i.e., heparin-releas-able component localized on capillary endothelial cells that isimplicated in the hydrolysis of circulating TG) and cellular(i.e., non-heparin-releasable pool that represents a storage formof the functional enzyme) pools of cardiac LPL because cel-lular LPL activity or protein levels have largely been obtainedusing whole heart homogenates. Rodrigues et al. (203) havepreviously reported that in STZ (55 mg/kg)-induced moderatediabetic Wistar rat hearts, HR-LPL activity is significantlyincreased. Induction of more severe diabetes using 100 mg/kgSTZ did not influence HR-LPL (203). In another study usinghearts from 65 mg/kg STZ-induced diabetic rats, HR-LPLdecreased and was associated with reduced VLDL-TG lipoly-sis (182). Acute treatment of these diabetic rats with insulinenhanced both HR-LPL and VLDL-TG lipolysis (182). Inmouse models of diabetes, although there is no change ofcardiac HR-LPL activity in either STZ or db/db hearts, utili-zation of chylomicron-TG increases (174). Hence, the mecha-nisms that control cardiac LPL during diabetes are complexand have yet to be completely resolved.

It should be noted that even though LPL may not changefollowing obesity or diabetes, increased circulating lipopro-teins through LPL cleavage could still elevate FA supply to thecardiac tissue. However, increased concentration could beoffset by changes in lipoprotein composition or lipoproteinreceptor number. Binding of lipoproteins containing apoli-poprotein (apo) CII to LPL enhances lipolysis (181), whereasbinding of lipoproteins containing apoCIII or apoE suppressesLPL activity (1, 2). A recent study has shown that overexpres-sion of HDL-associated apo AV accelerates hydrolysis ofTG-rich lipoproteins, indicating the importance of this apolipoprotein in stimulating LPL (166, 188). O’Looney et al.(181) have shown that induction of diabetes by STZ changeslipoprotein composition, with reduced apoCII levels, leading toimpaired VLDL-TG lipolysis. A recent study has reported that

expression of VLDL receptor decreases following STZ-in-duced diabetes (116).

FA transporters. During obesity and diabetes, the high rateof FA uptake is facilitated by FA transporters, leading toaugmented FA oxidation and TG storage. In STZ-induceddiabetes, the increase in plasmalemmal CD36 and FABPpm

amplifies FA uptake, an effect resulting from increased CD36and FABPpm protein expression (152). In Zucker fatty rats,without a change in total protein, permanent relocation ofCD36 and FABPpm to the cardiomyocyte plasmalemmal mem-brane augments FA uptake (55, 56, 153). The mechanism forthis permanent repositioning of FA transporters at the plasmamembrane is still unknown. Interestingly, in young (4 wk)ob/ob or db/db mice, cardiac FA oxidation increases withoutany change in circulating substrates (30). Given that the highrate of FA oxidation requires coordinated FA uptake, augmen-tation of CD36-mediated FA supply is suggested to be in-volved in facilitating FA oxidation at this early stage of insulinresistance.

PPAR-�. As the principle regulator of cardiac FA metabo-lism, PPAR-� plays an important role in controlling FA oxi-dation during obesity and diabetes. Activation of this nuclearreceptor in the heart has been reported in almost all obese ordiabetic animal models, including STZ-induced diabetic rats,ZDF rats, and ob/ob and db/db mice (30, 79, 220). Given thatFA and its derivatives activate PPAR-�, higher cardiacPPAR-� activity is always observed when circulating lipids areaugmented (30, 171). Hence, in ob/ob and db/db mice, activa-tion of PPAR-�, evidenced by elevated expression of itsdownstream targets, is only observed at 12 wk and is associ-ated with augmented plasma lipid (30). A similar associationbetween plasma lipids and PPAR-� is also seen in hearts fromSTZ-induced diabetic rats, with only chronic (6 wk) but notacute (4 days) diabetes demonstrating activation of PPAR-�(unpublished data). Interestingly, in acute STZ diabetes or4-wk ob/ob or db/db mice, increased FA oxidation is observedeven in the absence of any change in cardiac PPAR-� and itsdownstream targets, suggesting PPAR-� independent controlof FA oxidation. Identification of these mechanisms requiresfurther studies.

After activation, cardiac PPAR-� promotes the expressionof a group of genes involved in various steps of FA oxidation.Simultaneously, activation of PPAR-� also reduces expressionof genes involved in glucose uptake, glycolysis, and oxidationthrough direct or indirect mechanisms (77, 79). With the use oftransgenic mice, a recent study (186) demonstrated that knock-ing out cardiac PPAR-� prevented suppression of GLUT4expression and glucose uptake by elevated plasma FA andimproved myocardial recovery from ischemia following STZdiabetes induction, high-fat feeding, or fasting. Taken together,activation of cardiac PPAR-� not only favors FA oxidation butalso inhibits glucose uptake and utilization, leading to aug-mented susceptibility to ischemic damage.

MCD. In STZ-induced diabetes, overexpression of cardiacMCD protein was observed and could contribute to the highrate of FA oxidation (213). It is unknown whether MCD alsoplays a role in augmenting cardiac FA oxidation in obese andType 2 diabetes. Nevertheless, given that PPAR-� increasesMCD expression (138, 265), higher MCD protein levels areexpected following PPAR-� activation during obesity andType 2 diabetes.

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Limitations of Metabolic Measurements UsingRadiolabeled Substrate

The majority of metabolic data in the above studies wereobtained by using radiolabeled substrate perfusion of isolatedhearts. In these methods, [3H]glucose and [14C]glucose wereused to evaluate glycolysis and glucose oxidation, whereas[3H]FA or [14C]FA was used to estimate FA oxidation bymeasuring the generation of 3H2O and 14CO2. Although thismeasurement allows for the manipulation of substrate concen-tration, there are limitations. First, the substrates used inperfused hearts do not truly reflect what the heart receives invivo. For example, lipoproteins, lactate, and ketone bodies thatare important substrates for the heart in vivo (39, 98, 165) arerarely used to examine metabolism in perfused hearts. Inaddition, most metabolic data of diabetic hearts are obtained byusing normal concentrations of glucose and/or palmitate,which differ from the elevated concentrations seen in thediabetic conditions in vivo. Another drawback is that diabetichearts always have an elevated intracellular TG pool. Aug-mented intracellular TG turnover in diabetic hearts could diluteutilization of exogenous radiolabeled palmitate oxidation, re-sulting in an underestimation of FA oxidation (180). Finally,hormonal effects on energy metabolism are usually not con-sidered (20), and lack of hormones in the in vitro perfusate maycontribute to functional abnormalities that are not recapitulatedin intact models.

CONSEQUENCES OF ALTERED METABOLISM INDIABETIC HEARTS

Impaired Cardiac Function

Emerging evidence supports the concept that alterations inmetabolism contribute toward cardiac contractile dysfunction.In STZ-induced diabetes, a larger number of studies haveimplicated metabolic abnormalities (FA oxidation providesalmost 100% of ATP, with a dramatic decrease of glucoseutilization) in cardiac contractile dysfunction (219, 227, 234,267). In these animals, contractile failure begins as diastolicdysfunction, followed by severe systolic dysfunction (196,219). Normalizing energy metabolism in these hearts reversesthe impaired contractility (40, 176, 248). Animal models ofobesity and Type 2 diabetes also exhibit cardiac dysfunctionassociated with altered cardiac metabolism (5, 21, 218). Somestudies have observed both impaired diastolic and systolicfunction (3, 218), whereas other studies argue that no change insystolic function is present (6, 18, 164, 197). This discrepancycould be due to the severity of diabetes or the methods used toevaluate cardiac function. In diabetic patients, left ventricularhypertrophy and impaired isovolumic relaxation and ventricu-lar filling are the most common abnormalities diagnosed (196).

During diabetes, changes in cardiac metabolism occur earlyand precede the development of cardiomyopathy. For example,in STZ-induced diabetes, altered cardiac metabolism is ob-served as early as 4 days following diabetes induction (88),whereas evidence of cardiomyopathy is only apparent after4–6 wk. Similarly, in ob/ob and db/db mice, changes incardiac metabolism are evident much before confirmation ofcardiac dysfunction (5, 30). To validate the role of alteredmetabolism in provoking cardiac dysfunction, several studieshave treated 6- or 9-wk-old db/db mice with either PPAR-� or

PPAR-� agonists for 3–6 wk (3, 4, 36). Even though thesetreatments normalized cardiac metabolism, they failed to im-prove cardiac function in these mice, suggesting that metabo-lism may be unrelated to heart failure or that the treatment wasnot initiated in time. Interestingly, when ZDF rats were treatedwith a PPAR-� agonist at 6 wk of age [when insulin resistancecompared with 6-wk-old db/db mice is milder (37)], improve-ments of cardiac metabolism and heart function were observed(272). In a different study, changing cardiac metabolic profileby treating ZDF rats with PPAR-� agonist also improvedcontractile function (91). Additionally, overexpression ofGLUT4 in db/db mice not only normalized cardiac metabolismbut also improved heart function (21, 218). These studiessuggest that acute changes in metabolism likely induce earlyand reversible damage to cardiac tissue. Even though theseearly alterations are inadequate to produce cardiac functionalchanges, early interventions would be favored to provideprotection against development of cardiomyopathy in the laterstages of the disease.

The role of abnormal cardiac metabolism in cardiac dys-function is also supported by studies using transgenic mice.Overexpression of cardiac PPAR-� increased FA uptake andoxidation (79). The hearts from these transgenic mice exhibit ametabolic phenotype similar to diabetic hearts (79). Measure-ment of heart function revealed systolic dysfunction and ven-tricular hypertrophy in these hearts, indicating that, in theabsence of systemic metabolic disturbances, alteration of car-diac metabolism is sufficient to induce cardiac contractiledysfunction (79). This concept is further substantiated bytransgenic mice overexpressing cardiac ACS, FATP1, or LPL(47, 48, 260). These transgenic mice have shown increased FAuptake, utilization, or lipid accumulation, and these changescorrelated well with contractile dysfunction.

In contrast, several studies have reported that altered metab-olism has no impact on contractile function (224, 250). Itshould be noted that, in these studies, heart function wasevaluated using a Langendorff heart perfusion. Given thatdiabetic hearts exhibit reduced mitochondrial oxidative capac-ity and cardiac efficiency (28, 106), it is possible that withincreased workload and energy requirement, cardiac functionwould be compromised.

In addition to heart dysfunction per se, diabetic patients alsohave a greater incidence and severity of angina and acutemyocardial infarction (147). After a myocardial infarction,diabetic patients have almost twice the rate of mortality com-pared with nondiabetics (229). Alterations in myocardial en-ergy metabolism during diabetes are probably an importantcontributing factor in explaining this increased susceptibility toischemic damage. In obese or diabetic animals, increasedischemic damage is also observed (5, 60, 93, 147), and nor-malization of cardiac metabolism in hearts from these animalshas been shown to improve functional recovery followingischemia-reperfusion (147, 224, 270). Interestingly, a numberof studies have also reported contradictory results, with de-creased susceptibility to ischemia-reperfusion damage beingreported in STZ or ZDF hearts (145, 150, 236, 249). Althoughthe mechanisms for this observation are still unclear, decreasedglycolysis and glycolytic products, a lower Na�-Ca2� activity,and a decreased clearance of protons via the Na�/H� ex-changer have been proposed to explain this inconsistency (75).

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Although changes in metabolism have been implicated indiabetic cardiac dysfunction, the mechanisms responsible arestill unclear. Several factors have been proposed, and theseinclude changes in Ca2� homeostasis, decreased cardiac effi-ciency, lipotoxicity, and myocardial mitochondrial damage(Fig. 4).

Effects on Ca2� Homeostasis

Within the cell, enzymes that catalyze glycolysis are locatedclose to the sarcoplasmic reticulum and sarcolemma (71, 251),and ATP generated through glycolysis is preferentially used byion transporters [like Ca2�-ATPase (SERCA2a) and Na�-K�-ATPase] in these membrane fractions (71, 228, 252). Thusinhibition of cardiac glycolysis by high rates of FA oxidationduring obesity and diabetes may impair intracellular Ca2�

homeostasis, a defect that has been proposed to contributetoward the development of cardiomyopathy. Altered Ca2�

homeostasis can also result from glycolysis-independent mech-anisms. For example, decreased cardiac expression ofSERCA2a or Na�/Ca2� exchanger have been observed inType 1 (99, 126) and Type 2 diabetic animals (22). Althoughthe mechanisms for this reduction in gene expression areunclear, several studies have suggested that accumulation ofglucose metabolites due to dissociation of glucose influx andpyruvate oxidation plays a role (51). Conversely, decreasingglucose metabolites has been shown to prevent the decrease inSERCA2a following diabetes (207). In other studies, a de-crease in the activity of SERCA2a and Na�/Ca2� exchanger,without any change in expression or protein levels, have also

been documented (215, 271). Irrespective of the mechanism,suppression of SERCA2a and the Na�/Ca2� exchanger resultsin poor calcium handling associated with impaired heart func-tion (6, 22, 49). Interestingly, overexpression of SERCA2a inthe diabetic heart improved Ca2� handling (243) and cardiacfunction (239).

Decreased Cardiac Efficiency

When compared with glucose, oxidation of FA consumesmore oxygen (2.58 vs. 2.33 ATP/oxygen atom). Cardiac effi-ciency, the ratio of cardiac work to myocardial oxygen con-sumption, changes with the type of substrate. Thus, in perfusedhearts, provision of FA decreases cardiac efficiency comparedwith when glucose is the sole substrate (31, 162, 245). Addi-tionally, decreased cardiac efficiency is also observed in hu-man or experimental animals with obesity or diabetes (106,162, 191). This reduction in cardiac efficiency and increasedoxygen demand makes the heart especially vulnerable to dam-age following increased workload or ischemia. Interestingly,even though oxidation of FA requires 10% more oxygencompared with glucose, cardiac oxygen consumption is over30% higher in ob/ob or db/db mice compared with controlhearts, suggesting that other mechanisms also contribute tohigher oxygen consumption and lower cardiac efficiency (37).A recent study reported oxygen wasting for noncontractilepurposes in the diabetic heart (106). The mechanisms for thisoxygen wasting are unknown, and uncoupled proteins (UCPs)are suggested as a potential target. In hearts from STZ-induceddiabetic rats and ob/ob and db/db mice, augmented geneexpression or protein levels of UCP2 or UCP3 have beenreported (30, 102, 170, 171, 268). Other studies demonstrate noassociation between change in cardiac UCP protein levels andthe onset of cardiac inefficiency (28, 30). Hence, additionalstudies are required to identify the targets that cause oxygenwasting observed in hearts from obese and diabetic animals.

Lipotoxicity

A number of studies have suggested that excessive FAoverload induces lipotoxicity and contributes to the initiationand development of cardiomyopathy (194, 272). With the useof transgenic mice, studies have shown that elevation of FAuptake or utilization induces lipotoxicity in the absence of anysystemic metabolic disturbance. Cardiac-specific overexpres-sion of LPL or FATP1 significantly increased FA delivery withensuing lipid storage, lipotoxic cardiomyopathy, and contrac-tile dysfunction (47, 260). Moreover, elevating FA utilizationby cardiac-specific overexpression of PPAR-� or ACS alsocauses cardiomyopathy and cardiac dysfunction, similar to thatseen during diabetes (48, 79). Conversely, reducing FA supplyor utilization prevented the development of cardiomyopathy inobese or diabetic animals. In ZDF or transgenic mice withcardiac overexpression of LPL, a PPAR-� agonist decreasedplasma and cardiac intracellular lipids and ameliorated cardio-myopathy (244, 272). A recent study also demonstrated thatincreasing lipoprotein excretion by overexpressing humanapoB reduced cardiac lipids and improved cardiomyopathy(264). Taken together, these studies provide convincing evi-dence that augmented FA supply during obesity or diabetesimpairs cardiac lipid homeostasis and leads to lipotoxicitycardiomyopathy.

Fig. 4. Consequences of changes in cardiac metabolism during diabetes. Afterinsulin resistance or diabetes, augmented cardiac FA uptake promotes FAutilization and storage, which contributes toward a reduction in glycolysis andglucose oxidation. As ATP generated through glycolysis is preferentially usedby ion transporters (like Ca2�-ATPase), inhibition of cardiac glycolysis im-pairs intracellular Ca2� homeostasis. High rate of FA oxidation increasesreactive oxygen species (ROS) generation, along with augmented lipid storage,leading to lipotoxicity and mitochondrial dysfunction. High rate of FA oxida-tion also increases oxygen demand and reduces cardiac efficiency. All of thesechanges can eventually contribute to the development of diabetic cardiomy-opathy.

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Although limited evidence is available of the existence oflipotoxicity in human diabetic patients, some studies havedocumented similarities between rodent lipotoxicity and thehuman metabolic syndrome (240). In a subgroup of patientswith heart failure, Sharma et al. (220) have identified severemetabolic dysregulation characterized by intracellular TG ac-cumulation and alterations in gene expression, similar to thelipotoxic rat heart. Increased apoptosis was also detected inventricular biopsies from Type 2 diabetic patients (82). Addi-tionally, cardiac PCr-to-ATP ratio was decreased in Type 2diabetic patients and correlated well with plasma FA concen-trations (216).

The mechanisms that mediate cardiac lipotoxicity are stillnot completely understood. One potential target is over pro-duction of ROS (79). High rate of FA oxidation increasesmitochondrial action potential, leading to augmented ROSgeneration. Under normal physiological conditions, ROS isremoved by cellular antioxidants. In the event of excessivegeneration of ROS, as observed in STZ-induced diabetic rats,ZDF rats, and db/db mice (19, 32, 272), it causes cardiomyo-cyte cell damage and augmented apoptosis. Another potentialmechanism for lipotoxicity is accumulation of lipids, when FAuptake supercedes its oxidation. Regarding accumulation ofTG, the role of this neutral lipid in inducing contractile dys-function is still unknown, although a strong association be-tween TG storage and lipotoxicity has been established in bothanimal models and human studies (50, 220, 272). Interestingly,a recent study suggested that TG formation actually providesprotection against the deleterious effects of fatty acyl-CoA(144). Besides TG, excessive FA also leads to ceramide gen-eration, an intracellular messenger known to trigger apoptosis(272). Accumulation of ceramide has been found in ZDF rats(272) or in isolated cardiomyocytes incubated with high fat(67, 101). Ceramide upregulates inducible nitric oxide synthasethrough activation of NF-B, leading to increased generationof nitric oxide and peroxynitrite (241, 272). As a highlyreactive molecule, peroxynitrite causes opening of the mito-chondrial permeability transition pore and release of cyto-chrome c. Additionally, ceramide directly interacts with cyto-chrome c, leading to its release from the mitochondria (87). Asa consequence, caspase is activated, which initiates the apop-totic pathway in cells. Additionally, with the use of isolatedcardiomyocytes, high FA impairs cardiolipin and leads toceramide-independent cell apoptosis (184). Finally, accumula-tion of FA metabolites has also been associated with insulinresistance. FA derivatives, such as fatty acyl CoA, diacylglyc-erol, or ceramide may activate a serine kinase cascade, whichinvolves protein kinase C- and IB kinase-� (inhibitor ofNF-B kinase-�), leading to serine phosphorylation of IRS(44, 114, 128, 129, 269). Following this, tyrosine phosphory-lation of IRS and its ability to activate phosphatidylinositol3-kinase and protein kinase B are compromised (206). Futurestudies are required to substantiate the roles of these FAderivatives in the development of insulin resistance, especiallyin the heart.

Hyperglycemia

In addition to hyperlipidemia-induced lipotoxicity, hyper-glycemia also provokes glucotoxicity, which could contributeto cardiac tissue injury. Hyperglycemia promotes the produc-

tion of reactive oxygen and nitrogen species, leading to cyto-chrome c-mediated caspase 3 activation and myocardial apop-tosis (32). Hyperglycemia-induced oxidative stress also acti-vates poly(ADP-ribose) polymerase-1 (PARP) (64). Mildactivation of PARP regulates multiple cellular reactions suchas DNA repair, gene expression, and cell survival (246).However, overactivation of PARP could initiate a series ofcellular processes, leading to cellular damage. Through deple-tion of NAD�, an ATP-consuming process, PARP may causeenergy deficit and cell death (69). PARP, through inhibition ofglyceraldehyde phosphate dehydrogenase (GAPDH), divertsglucose from glycolytic pathways into alternative fates, includ-ing advanced glycation end product (AGE) formation, hex-osamine, polyol pathway flux, and protein kinase C (PKC)activation, which are believed to mediate hyperglycemia-in-duced cardiac tissue damage (64, 196). In this regard, increasedformation of AGE forms irreversible cross-links with manymacromolecules such as collagen, leading to tissue fibrosis,inactivation of SERCA2a, and ryanodine receptor calcium-release channel, impaired cardiac relaxation, contractility, andventricular stiffness (26, 27, 35, 54). Increased hexosamineinflux reduces SERCA2a protein levels, resulting in prolongedcalcium transients and delayed myocardial relaxation (51).Increased hexosamine influx also impairs insulin signal trans-duction and contributes to insulin resistance (163). Increasedpolyol flux is associated with a decrease in intracellular gluta-thione levels and an augmentation in cell apoptosis (83).Conversely, inhibition of polyol flux protects hearts fromischemic injury (125, 198). Finally, activation of PKC-�2 leadsto left ventricular hypertrophy, cardiac myocyte necrosis, mul-tifocal fibrosis, and decreased left ventricular performance,resulting in cardiomyopathy (247). Taken together, hypergly-cemia, through multiple pathways, causes cardiac cellular andfunctional changes, possibly contributing to the developmentof cardiomyopathy.

Mitochondrial Dysfunction

Mitochondria are the primary source of energy generationwithin cells. Acetyl-CoA generated from FA �-oxidation orglycolysis is used by the tricarboxylic acid cycle for productionof NADH and FADH2. These electron carriers transfer elec-trons to the mitochondria electron transport chain, where ATPis ultimately generated. Thus cardiac mitochondrial dysfunc-tion is expected to induce deleterious cellular effects, ulti-mately leading to heart disease. Indeed, humans with inheritedor acquired mitochondrial defects develop cardiomyopathy(112, 208). With the use of transgenic mice models, mitochon-drial dysfunction is also associated with heart disease. Forinstance, knock out of Ant1 (which controls exchange ofmitochondrial ATP with cytosolic ADP) or Tfam (a mitochon-drial transcription factor that regulates mitochondrial biosyn-thesis and gene expression) results in a cardiac energy deficitand cardiomyopathy (92, 142). Mice with cardiac-specificdeletion of mitochondrial genes involved in FA oxidation alsodisplay a cardiomyopathic phenotype (72, 135). Interestingly,the opposite is also true with overexpression of PPAR-�(which regulates the expression of mitochondrial enzymesinvolved in FA oxidation) (79) or PGC1 (which controlsmitochondrial biosynthesis) (139) resulting in mitochondrialdysfunction and cardiomyopathy. In Type 1 or Type 2 diabetic

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rats, impaired mitochondrial function has been demonstrated(222, 262), an observation similar to hearts from transgenicmice. Given the similarity between transgenic mice and modelsof diabetes, these studies strongly suggest that impairment ofmitochondrial function contributes to the development of car-diomyopathy.

The mechanisms by which mitochondrial dysfunction con-tributes toward cardiomyopathy are still unclear. One potentialtarget is ROS. Augmented ROS generation following high FAoxidation induces oxidative stress and cell damage. Inhibitionof ROS by overexpression of metallothionein, MnSOD, orcatalase has been shown to protect against mitochondrial dys-function and cardiomyopathy (221, 262, 263). Another target isceramide, a sphingolipid that has been shown to accumulatefollowing FA overload. Ceramide, through inhibition of mito-chondrial respiratory chain, or inducing cytochrome c releasefrom mitochondria and apoptosis, is suggested to provoke thedevelopment of cardiomyopathy (67, 95). Augmented expres-sion of PGC1 in hearts from obese or diabetic animals mayincrease mitochondrial proliferation, mitochondrial ultrastruc-tural abnormalities and dysfunction, and ultimately cardiomy-opathy (139). Finally, following end stage diabetes, dysfunc-tion of mitochondria causes energetic starvation, leading toheart failure (208).

Summary

In this review, we document that both insulin resistance andType 1 and Type 2 diabetes exhibit similar alterations incardiac metabolism through extrinsic and intrinsic mecha-nisms. The predominant change is a suppression of cardiacglucose utilization and a switch to excessive FA utilizationassociated with lipid storage. It should be noted that, in themajority of these studies, metabolic outcomes were obtainedusing ex vivo perfused working hearts. Additionally, only twosubstrates (glucose and fatty acid) were present in the perfusionbuffer, and lactate, lipoproteins, ketone bodies, and relevanthormones were excluded. Hence, cardiac metabolism mea-sured through this method may not reflect the in vivo situation.Despite these drawbacks, many studies have documented astrong correlation between altered cardiac metabolism andcardiac dysfunction observed during insulin resistance or dia-betes. This correlation was further substantiated using trans-genic mice with lipid oversupply in the absence of systemicinterference. Regarding heart function, both diastolic and sys-tolic dysfunction are observed in Type 1 diabetic animals. Thisis likely a consequence of prolonged hypoinsulinemia andhyperglycemia. With Type 2 diabetic models, there are con-flicting reports, with some studies documenting both impairedsystolic and diastolic function, whereas other studies argueagainst a change in systolic function. It is possible with Type2 diabetic models, this discrepancy could be due to the severityor duration of hyperinsulinemia, and eventual hyperglycemia,or the techniques used to measure cardiac function. Finally,during diabetes, changes in cardiac metabolism occur early andprecede the development of cardiomyopathy. Even thoughaltered metabolism is inadequate to produce cardiac functionalchanges at this early time, it is likely that early metabolicdamage is occurring at the cellular or subcellular levels. Over-time, these cumulative defects could be contributing to diabeticcardiomyopathy. Identification of this early damage could

facilitate proper interventions and provide protection againstdevelopment of diabetic cardiomyopathy in the later stages ofthe disease.

GRANTS

This work was supported by operating grants from Heart and StrokeFoundation of BC and Yukon and Canadian Diabetes Association.

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