resistencia insulina consecuencias en el corazon

Insulin Resistance: Metabolic mechanisms and consequences inthe heart

E. Dale Abel, MD, PhD1, Karen M. O'Shea, PhD2, and Ravichandran Ramasamy, PhD2

1Division of Endocrinology, Metabolism and Diabetes and Program in Molecular Medicine,University of Utah School of Medicine, Salt Lake City, Utah2Diabetes Research Program, Department of Medicine, New York University Langone MedicalCenter, New York, NY 10016

AbstractInsulin resistance is a characteristic feature of obesity and Type 2 diabetes and impacts the heart invarious ways. Impaired insulin-mediated glucose uptake is a uniformly observed characteristic ofthe heart in these states, although changes in upstream kinase signaling are variable and dependenton the severity and duration of the associated obesity or diabetes. The understanding of thephysiological and pathophysiological role of insulin resistance in the heart is evolving. Tomaintain its high energy demands, the heart is capable of utilizing many metabolic substrates.Although, insulin signaling may directly regulate cardiac metabolism, its main role is likely theregulation of substrate delivery from the periphery to the heart. In addition to promoting glucoseuptake, insulin regulates long chain fatty acid uptake, protein synthesis, and vascular function inthe normal cardiovascular system. Recent advances in understanding the role of metabolic,signaling, and inflammatory pathways in obesity have provided opportunities to better understandthe pathophysiology of insulin resistance in the heart. This review will summarize our currentunderstanding of metabolic mechanisms for and consequences of insulin resistance in the heartand discuss potential new areas for investigating novel mechanisms that contribute to insulinresistance in the heart.

IntroductionUnder physiological circumstances, insulin regulates substrate utilization in multiple tissuesincluding the heart, skeletal muscle, liver, and adipose tissue. In the heart, insulin stimulatesglucose uptake and oxidation and although it increases FA uptake, it inhibits fatty acidutilization for energy. Generalized insulin resistance occurs primarily as a result of obesity, aconsequence of caloric excess, physical inactivity, genetics, and age. Insulin resistance isassociated with many serious medical conditions, such as type 2 diabetes, hypertension,atherosclerosis, and metabolic syndrome1, 2. In diabetes and insulin resistant states,metabolic, structural and functional changes in the heart and vasculature lead to diabeticcardiomyopathy, coronary artery disease and myocardial ischemia, and ultimately heart

Address correspondence to: Ravichandran Ramasamy, PhD, Diabetes Research Program, Department of Medicine, New YorkUniversity Langone Medical Center, New York, NY 10016, Tel: 212-263-9475, [email protected], Or E. Dale Abel, MD PhD,Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, 15N2030E, Bldg. 533, Rm. 3110, Salt Lake City, UT 84112,Tel: (801) 585-3353, [email protected].

Disclosures: None

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NIH Public AccessAuthor ManuscriptArterioscler Thromb Vasc Biol. Author manuscript; available in PMC 2013 September 01.

Published in final edited form as:Arterioscler Thromb Vasc Biol. 2012 September ; 32(9): 2068–2076. doi:10.1161/ATVBAHA.111.241984.

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failure3, 4. There are many molecular mechanisms that contribute to the association betweeninsulin resistance and increased cardiovascular disease. These include the impact of insulinresistance to induce impaired vascular function, which leads to impaired nitric oxidemediated vasorelaxation, which may contribute to hypertension and to increased risk ofatherosclerosis5-8. Moreover, genetic manipulation of insulin action in the vasculature willincrease atherosclerosis9-12. Insulin resistance via multiple mechanisms may contribute tomacrophage accumulation in the vessel wall to increase atherosclerosis and instability ofvulnerable plaques13. Finally, insulin resistance has been shown in many human and animalstudies to increase the extent of myocardial injury in the context of myocardial ischemia,which may contribute to the increased risk of heart failure in affected individuals14. Theinteractions between insulin resistance and vascular disease will be the subject of otherreviews in this series. The present review will focus on the mechanisms by which insulinresistance develops and contributes to structural heart disease. Although incompletelyunderstood, these mechanisms involve the combination of changes insulin signaltransduction pathways in the heart acting in concert with changes in mitochondrial functionand metabolism glucose and free fatty acids 14.

Insulin Signaling in the Heart and the Molecular Changes in Insulin ResistanceInsulin release from pancreatic β-cells, induces glucose uptake into cardiomyocytes, skeletalmuscle and adipose tissue upon binding by insulin to the cell surface insulin receptor (IR).The IR undergoes autophosphorylation after insulin binding, which initiates a signalingcascade initiated by tyrosine phosphorylation of insulin receptor substrates (IRS), followedby phosphorylation of phosphatidyl-inositol-3 kinase (PI3K), phosphoinositide-dependentkinase 1 (PDK1), Akt, and protein kinase C (PKC). These events result in glucosetransporter type 1 and type 4 (GLUT1 and GLUT4) translocation to the membrane tofacilitate glucose uptake into the cell3, 15. Although insulin mediated translocation ofGLUT4 translocation is a major regulator of glucose utilization in glycolytic and oxidativeskeletal muscle, in the heart it is likely that contractile mediated translocation of GLUT4represents the major mechanism that regulates glucose entry in the beating heart, withGLUT1 playing a lesser role16. Thus insulin stimulation in isolated working hearts or invivo increases myocardial glucose utilization by 40-60%17, 18, in contrast with a 3-8foldincrease in insulin-treated skeletal muscle in vivo or in vitro19, 20. In addition to glucoseuptake, insulin-mediated activation of PI3K and Akt regulates many other cellular processessuch as cellular hypertrophy, protein translation, nitric oxide generation, apoptosis andautophagy by activating other intracellular signaling intermediates such as mTOR, S6K,forkhead transcription factors e.g. FOXO1/3, GSK3β and NOSIII21. Changes in many ofthese signaling pathways as develops in insulin resistant states could contribute to increasingthe risk for cardiac hypertrophy, adverse left ventricular remodeling or heart failure.

In discussing the concept of myocardial insulin resistance it is important to distinguishbetween effects that are secondary to the disturbed systemic milieu in insulin resistant states(hyperinsulinemia, hyperglycemia, hyperlipidemia), and changes that occur in insulinsignaling pathways that are intrinsic to the cardiac tissue. The earliest and most consistentchange that develops in the hearts in animal models, in the evolution of insulin resistance isimpairment in the ability of insulin to increase glucose transport18. This early change occursprior to any defect in the ability of insulin to increase PI3K and Akt signaling and occurs asa consequence of both reduced GLUT4 protein and impaired GLUT4 translocation. Similarchanges have been reported in ventricular muscle biopsies obtained from subjects with type2 diabetes22. Indeed in this human study diabetes was associated increased signaling to Aktand PI3K despite reduced GLUT4 translocation to the plasma membrane. A recent study inmice also revealed that the generalized insulin resistance and hyperinsulinemia that developsin the context of pressure overload cardiac hypertrophy drives excessive myocardial insulin

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signaling to Akt that contributes to accelerated LV remodeling and the transition to heartfailure23. In support of this concept, decreased myocardial insulin signaling may represent amechanism for the potential benefit of high-fat diets in ameliorating heart failure in rodentmodels of pressure overload or post-myocardial infarction left ventricular remodeling24.Thus in considering the impact of insulin resistance on the heart it is important to distinguishbetween effects that are secondary to hyperactivation of signaling pathways that may remainresponsive to insulin, versus changes that are the consequence of an impaired ability ofinsulin to modulate glucose metabolism. In animal models with longer term exposure tohigh-fat diets or in genetic models of severe insulin resistance such as ob/ob and db/db mice,clear evidence exists for an impaired ability of insulin to activate intracellular signalingkinases such as Akt or FOXO1, which might also contribute to LV dysfunction25-27. Indeedgenetic inactivation of insulin signaling in the heart as been shown to contribute to LVdysfunction by increasing mitochondrial dysfunction, decreasing angiogenesis andincreasing fibrosis particularly in response to hemodynamic stressors17, 28-31. Thus given thebroad spectrum of abnormalities that may characterize “cardiac insulin resistance” it iscritical to dissect and distinguish between those mechanisms that are a consequence ofincreased or decreased signal transduction to intracellular kinases, changes that aresecondary to intrinsic regulation of substrate metabolism or changes that are secondary toaltered delivery of substrates to the heart.

Because of its high and tightly regulated energy demands changes in systemic insulinsensitivity or changes in myocardial insulin action can significantly impact cardiacmetabolism and function. The constant demand for mechanical power in the heart is met byhigh rates of ATP production from fat and carbohydrate oxidation32, 33. The myocardiumrapidly adjusts to fluctuations in circulating substrate concentrations34, 35, giving the heartthe metabolic flexibility needed for feeding, fasting, and intense exercise. Insulin resistanceimpairs the ability of the heart to adjust to changing energy demands by increasing thedelivery of fatty acids to the heart and by reducing the ability of the heart to use glucose,thereby shifting the heart towards a greater reliance on fatty acids for energy36, 37. As aresult, the diabetic heart undergoes cellular stress, including elevated reactive oxygenspecies (ROS) production, mitochondrial dysfunction, and apoptosis. These changes inmyocardial metabolism that occur as a result of insulin resistance may contribute todownstream structural and functional alterations in the heart that can lead to cardiomyopathyand heart failure3. While there are many aspects of insulin resistance that impact the heart,this review will focus on the mechanisms of insulin resistance in the heart related to glucoseand fatty acid metabolism.

Glucose and Fatty Acid Metabolism in the HeartUpon insulin-mediated uptake of glucose into the cell, glucose is converted to glucose-6-phosphate by hexokinase in heart, skeletal muscle, and adipose tissue. Glucose-6-phosphatehas several fates in the cell, but the two primary fates are glycolysis for energy productionand glycogen for storage, both of which are augmented by insulin signaling. Under ambientphysiological conditions, a small percentage of glucose is shunted to the hexosaminebiosynthesis pathway, pentose phosphate pathway, or the polyol pathway and glycolysis andsubsequent glucose oxidation accounts for approximately 20% of total myocardial energygeneration38. Short-term hyperglycemia can increase total myocardial glucose utilization to60-70% of total energy generation38. However, in the context of diabetes, these changes arenot long lasting because of downregulation of glucose transport and increased delivery offatty acids to the heart39.

Circulating FFAs contribute to the development of insulin resistance via a number ofmechanisms. Circulating concentrations of plasma FFAs are determined to a large extent bythe release by lipolysis of adipocyte triglyceride stores by adipose triglyceride lipase

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(ATGL) and hormone-sensitive lipase40. (HSL)-stimulated release of FFAs fromtriglyceride stores in adipose tissue, is tightly controlled by hormones that are regulated bythe metabolic status33. During conditions such as fasting, when blood glucose is low orwhen energy demands are increased, glucagon, glucocorticoids and catecholamines lead toactivation of HSL to promote hydrolysis of triglycerides to FFAs. By contrast, in the fedstate insulin inactivates HSL and inhibits lipolysis33. In vivo, the majority of FFAs that aredelivered to tissues arise from hydrolysis of a triglycerides, which are transported in plasmain chylomicrons or very-lowdensity lipoproteins (VLDL) particles and the remainder exist inthe non-esterified form bound to albumin. Plasma FFAs can increase in healthy individualsdue to adrenergic stimulation brought on by exercise, stress, fasting, ischemia, or diabetes.The release of FFAs from chylomicrons or VLDL by lipoprotein lipases in these situationsalso increases plasma FFAs33.

After FAs are taken up by target tissues, they have three major fates in the cell. They can beesterified into triglycerides, diglycerides, or phospholipids; converted to sphingolipids; oroxidized for energy41. FFAs are transported across the sarcolemma and into thecardiomyocyte by either passive diffusion or transport proteins (fatty acid translocase orfatty acid binding proteins)33. Since the majority of FFAs that enter the heart are used forenergy (70-90%)42, they must enter the mitochondrial matrix for β-oxidation. FFAs aretransported across the outer and inner mitochondrial membrane by carnitine palmitoyltransferase 1 (CPT1), which is the rate-limiting step of fatty acid oxidation, and CPT2. Theacetyl-CoA resulting from β-oxidation enters the tricarboxylic acid cycle, yielding NADHand FADH2, which enter the electron transport chain to produce ATP33. Persistent exposureof tissues to increased concentrations of fatty acids, and associated changes in the metabolicfate of fatty acids are an important cause of insulin resistance.

Obesity, Lipotoxicity, and Insulin ResistanceObesity is the leading cause of insulin resistance, and obese individuals tend to have higherplasma FFAs as a result of decreased suppression of lipolysis by insulin resistance. It is alsobelieved that an impaired ability of adipocytes to store excess calories as triglycerides alsocontributes to increased accumulation of lipids and their metabolites in other tissues that arenot necessarily adapted to lipid storage such as muscle and liver. As a consequence, theaccumulation of lipid metabolic intermediates incites a variety of cellular abnormalities suchas apoptosis, oxidative stress, and ER stress, which impairs cellular function.

FFAs are the main substrate for ATP production in the heart under normal conditions. FFAsundergo β-oxidation to yield 60-70% of the energy needed to maintain cardiac work37. Thelevel of circulating FFAs largely determines FFA uptake in the heart33, 42, 43. In situationswhere FFAs are elevated, myocardial lipid accumulation can occur, which is detrimental toleft ventricular function. Myocardial lipid accumulation occurs as a result of a mismatchbetween FA uptake and oxidative metabolism, which increases the partitioning of lipids intoother metabolic pathways that may contribute to impaired insulin action in the heart such asreduced insulin-stimulated glucose transport and impaired insulin signaling1. Increasedavailability and utilization of FFAs lead to the accretion of triglycerides and lipidmetabolites, such as long chain acyl-CoAs and diacylglycerol (DAG) in the heart and othertissues, including liver and skeletal muscle44. Although triglyceride accumulation is ofteninterpreted as a cause of lipotoxicity, it is likely that the triglycerides per se might notrepresent the toxic lipid moiety but may represent a mechanism by which the tissue isattempting to sequester the excess lipids into a relatively inert pool45. However lipidmetabolites, such as DAG stimulates protein kinase C Φ (PKC)1, 46, a serine/threoninekinase that may inhibit insulin signaling by increasing the serine phosphorylation of IRSproteins47, 48. In mice fed a high fat diet for 10 weeks, cardiac insulin resistance asevidenced by a decrease in glucose oxidation was associated with an increase in DAG, but

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not triacylglycerol, ceramide, or long chain acyl-CoA49, suggesting that DAG accumulationmay play a role in high fat diet-induced insulin resistance in the heart.

Lipid-induced cardiac dysfunction (cardiac lipotoxicity) may contribute to apoptosis50,impaired mitochondrial function51, and ultimately to cardiac dysfunction. The heart has alimited capacity to store triglycerides, thereby increasing its susceptibility to theconsequence of accumulation of toxic lipid species52. An underappreciated mechanism thatmay contribute to lipotoxicity in the insulin resistant state is hyperinsulinemia itself. Asdiscussed earlier, the ability of insulin to activate Akt, may be relatively preserved in theheart. Akt activation promotes the translocation of CD36 go the plasma membrane, whichwould increase the uptake of fatty acids53. However the concurrent inhibition ofmitochondrial FA oxidation increases the flux of FAs into lipid storage pathways, therebycontributing to lipotoxicity. Transcription factors related to lipid metabolism have also beenimplicated in the pathogenesis of liptoxicity. Peroxisome proliferator activated receptors(PPARs), which are members of the nuclear receptor superfamily of transcription factors,are key regulators of fatty acid metabolism54. There are three major PPAR isoforms:PPARα, PPARβ/δ, and PPARγ, which have distinct but overlapping functions in regulatingfatty acid metabolism and are differentially expressed in various tissues. Transgenic miceoverexpressing cardiac-specific PPARγ display augmented expression of fatty acidoxidation genes, dilated cardiomyopathy, and enhanced lipid deposition in the heart55.Cardiac-specific overexpression of PPARα in mice leads to enhanced β-oxidation of fattyacids and reduced glucose oxidation and accumulation of triglycerides 56. Myocardialinsulin resistance may also contribute to contractile dysfunction in these hearts57.Conversely, PPARα-null mice have reduced rates of β-oxidation of fatty acids, elevatedrates of glucose oxidation, cardiac fibrosis, and they cannot maintain cardiac output duringconditions of increased workload58, 59.

Another transcription factor involved in lipotoxicity is sterol regulatory element binding-protein (SREBP)-1c, which regulates hepatic lipogenesis and converts glucose to fatty acidsand triglycerides during conditions of over-nutrition60, 61. SREBP1c is activated by insulinduring insulin resistance62. Furthermore, there is a correlation between reduced ejectionfraction and lipid accumulation within cardiomyocytes of patients with the metabolicsyndrome and increased levels of SREBP-1c and PPARγ in the heart63. This suggests thatSREBP-1c may promote lipid deposition in cardiomyocytes in the metabolic syndrome byupregulating PPARγ, which promotes lipotoxicity and contractile dysfunction.

Ceramide is a sphingolipid that is a key mediator of cellular stress pathways that induceapoptosis and mitochondrial dysfunction. In normal physiology, ceramide is derived from denovo synthesis or can be derived from sphingomyelin hydrolysis. Ceramide acts as alipotoxic intermediate when it builds up as a result of elevated circulating FFAs. The role ofceramide in insulin resistance in skeletal muscle has been studied more closely than in theheart. Ceramide and ceramide metabolites interfere with insulin signaling by activatingPKCζ64, blocking Akt activation and subsequently reducing glucose uptake65. In skeletalmuscle, ceramide decreases GLUT4 translocation to the membrane66, 67 and inhibition ofserine palmitoyl transferase 1 (SPT1) reverses insulin resistance68. We recently showed thatceramide also plays an important role in the pathogenesis of obesity-mediated vasculardysfunction via a mechanism that involves PP2A mediated dephosphorylation of NOSIII5.Moreover, treatment of mice with lipotoxic cardiomyopathy with the inhibitor of ceramidesynthesis myriocin, reversed contractile dysfunction in a mouse model of lipotoxiccardiomyopathy69. Taken together, it is therefore likely that ceramide accumulation maycontribute to the pathogenesis of cardiac dysfunction in insulin resistant states.

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Other Mediators of the Interaction of Insulin Resistance and Cardiac DysfunctionRecent studies have implicated novel mechanisms that may directly contribute to thepathophysiology of insulin resistance and its cardiovascular complications48 such as changesin AMPK signaling70, oxidative stress71, inflammation72, advanced glycation end products(AGEs)73, endoplasmic reticulum (ER) stress74, autophagy75, and changes in adipokines76.Some of these mechanisms are discussed in more detail below.

AMP-activated Protein KinaseAMP-activated protein kinase (AMPK) is an important mediator of energy balance invarious tissues, including the heart77. Under conditions of inhibited ATP production orelevated ATP consumption, such as ischemia or exercise, the AMP/ATP ratio is elevatedand AMPK is stimulated. As a result, AMPK acts to maintain ATP production andcontractile function by increasing glucose and fatty acid uptake and oxidation in theheart78-80. AMPK directly impacts fatty acid metabolism through inhibition of acetyl-CoAcarboxylase (ACC), which is responsible for the synthesis of malonyl CoA, a potentinhibitor of carnitine palmitoyl transferase 1. AMPK directly enhances insulin signaling inendothelial cells, protecting from insulin resistance81. It is possible that obesity-relatedimpairment of AMPK function may contribute to insulin resistance in the heart. Moreover, areduced circulating level of adiponectin, which is a characteristic of obesity, is associatedwith impaired AMPK signaling and mitochondrial biogenesis82. These observations raisethe possibility that reduced activity of AMPK might contribute to mitochondrial dysfunctionin the heart in obesity and insulin resistant states.

Reactive Oxygen Species and Insulin ResistanceObesity is associated with increased oxidative stress in the heart and vasculature14. Thesources of ROS are mitochondrial and extramitochondrial. For example, hyperglycemia maycontribute to ROS production by activation of NADPH oxidase in cardiomyocytes 83.Ceramide may also contribute to ROS by reducing the mitochondrial ubiquinone pool ofcomplex III84, 85 and increasing NADPH oxidase activity in endothelial cells86. Althoughthe mitochondria are largely responsible for generating ROS, they can also be damaged byROS. Oxidative stress has also been implicated in the pathophysiology of insulin resistanceboth in animals as well as in cultured cells48. It is not yet known if oxidative stress willimpair myocardial insulin action. However there is strong evidence that oxidative stress maycontribute to mitochondrial dysfunction in obesity and insulin resistant states87. ROS in theheart can act as a second messenger, initiating hypertrophic signaling, extracellular matrixremodeling, and apoptosis88.

Inflammation and Insulin ResistanceIt is generally accepted that systemic inflammation contributes to insulin resistance 89.Proinflammatory cytokines induce insulin resistance, which may influence the fate ofglucose and fatty acid utilization via direct and indirect mechanisms. By inducing insulinresistance, inflammation will increased the reliance of the heart on triglycerides from theliver and free fatty acids from adipose tissue for energy90. Obesity is accompanied byincreased in circulating concentrations of inflammatory cytokines such as interleukin-6(IL-6) and tumor necrosis factor (TNF)-α. These are believed to be derived in large partfrom macrophage infiltration of adipose tissue60. Given the well-documented associationsbetween inflammation, obesity, and insulin resistance in other tissues91, inflammation in theheart may be a contributor to myocardial insulin resistance. Inflammatory cytokines impairinsulin signaling by activating intracellular signaling kinases such as Jun N terminal kinase(JNK) that impairs insulin signaling by increasing the serine phosphorylation of IRSproteins48. It is possible that this mechanism may potentially occur in cardiomyocytes. Ko et

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al. reported that high fat feeding increased inflammation in the obese mouse heart, asevidenced by interleukin 6-mediated increases in macrophage and cytokine infiltration intothe heart92. In addition, glucose oxidation was reduced as a result of cardiac inflammation inan IL-6-dependent manner92. It remains to be demonstrated if the local increase inmyocardial inflammation directly contributes to impaired myocardial insulin action or if itthe metabolic changes are secondary to systemic changes.

Advanced Glycation End Products and Insulin ResistanceSeveral studies have reported interesting associations between advanced glycation endproduct (AGE) levels and insulin resistance, even in the absence of diabetes. Studies by Tanand colleagues, in healthy non-diabetic subjects, showed an association between AGElevels, inflammatory markers and insulin resistance (the latter by the homeostatic modelassessment index or HOMA-IR)93. Tahara and colleagues reported correlation betweenserum AGE levels and HOMA-IR in Japanese subjects94. Sarkar and colleagues found ahighly significant correlation between the degree of insulin resistance and pre-AGE carbonyllevels in type 2 diabetic subjects95. Recent animal studies demonstrated that flux via thealdose reductase (AR) pathway in hyperglycemia contributes to driving formation of pre-AGE methylglyoxal and oxidative stress. In an AGE-enriched environment of aging,treatment with AR inhibitors reduce levels of methylglyoxal and AGEs96. Interaction ofAGEs with its receptor RAGE has been linked to poor outcome after ischemic stress indiabetic and non-diabetic hearts97-99. AGE precursor generating AR pathway has also beendemonstrated to play a key role in mediating ischemic injury and cardiovascularcomplications in diabetes100-102. These data suggest that examination of AR and RAGE islikely to be useful in determining potential relationships to impaired myocardial insulinaction.

Therapeutic ImplicationsTherapies that modulate generalized insulin resistance such as PPARγ or PPARα agonistshave been shown in animal models to improve myocardial function in part by decreasingcirculating levels of fatty acids and switching myocardial substrate metabolism towardsglucose14, 103. However, thiazolidinediones also induce cardiac hypertrophy via mechanismsthat might be independent of effects on myocardial insulin signaling, which mightindependently contribute to increased heart failure risk104. Moreover, recent analyses of thistherapeutic class in humans have indicated an independent increase in cardiovascularmortality resulting from increased coronary events105. Fewer studies have directly examinedthe impact of insulin sensitizers on cardiac structure, function and metabolism in humanswith diabetes. In a study of well-controlled subjects with type 2 diabetes, pioglitazonemodestly improved diastolic dysfunction in association with increased glucose utilization,while metformin treatment was without effect106. However, metformin on the other handmay have a potentially beneficial impact on cardiovascular outcomes via mechanisms thatmight not only be related to its impact to improve systemic metabolic homeostasis, but viamechanisms that may include beneficial impact of increasing AMPK signaling and therepression of autophagy107-109. The notion that excessive insulin signaling andhyperinsulinemia may accelerate left ventricular remodeling on the basis of hyperactivationof Akt22, 23 raises a therapeutic conundrum in that one consequence of achieving metaboliccontrol in subjects with type 2 diabetes is the use of increased doses of insulin that willincrease hyperinsulinemia and increase Akt signaling in the heart. Indeed analyses of theimpact of tight metabolic control on the outcomes on cardiovascular outcomes or heartfailure have been disappointingly neutral110 or in the case of heart failure, could potentiallyworsen heart failure risk111. Thus it is imperative to explore the impact of novel therapeuticstrategies for treating diabetes such as agents that modulate GLP1 signaling on theinteractions between insulin resistance and cardiac structure, metabolism and function.

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Moreover, additional studies in humans are required to investigate the impact of therapiesthat modulate inflammation, ER stress, autophagy and other novel mediators of insulinresistance on cardiovascular outcomes in insulin resistant states.

Concluding RemarksThe mechanisms for and consequences of insulin resistance in the heart are complex andmultifactorial. Whereas, impaired insulin stimulated glucose uptake is a commonobservation, changes in upstream signaling kinases are variable, and may be increased ordecreased, with varied impact on cardiac structure and function. The heart requires aconstant, tightly regulated supply of energy, relying primarily on fatty acid oxidation to meetthis demand. Glucose oxidation also contributes to the energy demand of the heart; however,in insulin resistant states the contribution of glucose is decreased, while that of FAs isproportionately increased. The main cause of insulin resistance is obesity and the associatedincrease in FFA delivery to the heart precipitates many problems in the cardiomyocyte,including lipotoxicity, ROS production, oxidative stress, and changes in insulin signaling.One unexplored territory in the field of cardiac insulin signaling is the role of advancedglycation end products, its receptor RAGE and the pre-AGE generating AR pathway. Thepotential interplay between known metabolic mediators of insulin resistance and theunexplored pathways are summarized in Figure 1. In conclusion, the development of newtherapeutic targets that may normalize impaired myocardial insulin action may contribute tonovel strategies for treatment of diabetic heart disease.

AcknowledgmentsWork in the authors laboratories are supported by the National Institutes of Health, the American Heart Associationand the Juvenile Diabetes Research Foundation.

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Figure 1.Proposed scheme linking metabolic and signaling pathways to insulin resistance in the heart.Enhanced supply of fatty acids results in enhanced fatty acid uptake into the heart, which inturn, leads to an increase in mitochondrial uptake of long chain fatty acyl CoA . β-oxidationof long chain acyl CoA in the heart is increased in insulin resistance, and may exceed thecapacity of the TCA cycle and the electron transport chain to utilize β-oxidation products,leading to increased oxidative stress and ROS production. A mismatch between β-oxidationand the TCA cycle and electron transport chain leads to a buildup of products of incompleteβ-oxidation. ROS and products of incomplete oxidation impact signaling cascade such asPKC, JNK and IKK, as well as that of IRS-1 and downstream signaling mediators in theinsulin signaling pathway, such as PI3 kinase, Akt and AS160, resulting in reduced GLUT4translocation and consequently a decrease in glucose uptake in to the heart. However,GLUT4 translocation has also been shown to be impaired in the heart in insulin resistantstates in the absence of defects in PI3K and Akt signaling. In these circumstances,hyperactivation of Akt may further exacerbate lipotoxicity by increasing the translocation ofCD36 to the plasma membrane. Increased β-oxidation leads to increased production ofacetyl-CoA, NADH, AND FADH2, and citrate, which inhibit PDH and PFK respectively.Generation of Advanced glycation end product (AGE) precursors and AGEs due toincreased flux of glucose via the aldose reductase pathway, are an unexplored pathway ininsulin resistance. These pathways have been shown to impact signaling via PKC and PI3K/Akt and ROS generation.

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resistencia insulina consecuencias en el corazon

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