This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Poornima, I. G. Articles by Shannon, R. P. Search for Related Content PubMed PubMed Citation Articles by Poornima, I. G. Articles by Shannon, R. P. Related Collections Congestive Myocardial cardiomyopathy disease Type 1 diabetes Type 2 diabetes

(Circulation Research. 2006;98:596.)
© 2006 American Heart Association, Inc.

Reviews

Diabetic Cardiomyopathy

The Search for a Unifying Hypothesis

Indu G. Poornima, Pratik Parikh, Richard P. Shannon

From the Department of Medicine, Allegheny General Hospital, Pittsburgh; and the Drexel University College of Medicine, Philadelphia, Pa.

Correspondence to Richard P. Shannon, MD, Department of Medicine, Allegheny General Hospital, 320 East North Ave, Pittsburgh, PA 15212. E-mail rshannon{at}wpahs.org

This Review is part of a thematic series on Adipocyte Signaling in the Cardiovascular System, which includes the following articles:

Adipose Tissue, Inflammation, and Cardiovascular Disease

Adipocyte Signaling and Lipid Homeostasis: Sequelae of Insulin Resistant Adipose Tissue

Diabetic Cardiomyopathy: The Search for a Unifying Hypothesis

Adipocyte Signaling and the Vasculature

PPAR Activation and Effects on the Vasculature
Phillip Scherer Guest Editor

	Abstract

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
Although diabetes is recognized as a potent and prevalent risk factor for ischemic heart disease, less is known as to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Left ventricular systolic and diastolic dysfunction, left ventricular hypertrophy, and alterations in the coronary microcirculation have all been observed, although not consistently, in diabetic cardiomyopathy and are not fully explained by the cellular effects of hyperglycemia alone. The recent recognition that diabetes involves more than abnormal glucose homeostasis provides important new opportunities to examine and understand the impact of complex metabolic disturbances on cardiac structure and function.

Key Words: insulin resistance • diabetic cardiomyopathy • diastolic function • cardiac hypertrophy

	Introduction

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
The conventional wisdom holds that diabetes causes myocardial contractile dysfunction through accelerated atherosclerosis and hypertension. Much less appreciated and more controversial is the notion that diabetes mellitus affects cardiac structure and function, independent of blood pressure or coronary artery disease. Diabetic cardiomyopathy is a clinical condition, diagnosed when ventricular dysfunction develops in patients with diabetes in the absence of coronary atherosclerosis and hypertension.^1–4 Despite the potential importance of this disease entity, the complex and multifactorial nature of the cellular and molecular perturbations that predispose to altered myocardial structure and function remain incompletely understood.

The epidemiological link between diabetes mellitus and the development of heart failure, independent of atherosclerotic cardiovascular disease, has been evident for the better part of three decades. The increased risk of heart failure persists in the diabetic patients after considering age, blood pressure, weight, cholesterol, as well as history of coronary artery disease.^5,6 Notably, there is a significant association between diabetes and diastolic dysfunction leading to congestive heart failure in the absence of impaired systolic function.^7,8 More recently, patients with unexplained idiopathic dilated cardiomyopathy were found to be 75% more likely to have diabetes than age matched controls.⁹ The association between diabetes and cardiomyopathy was strongest among individuals with microvascular complications of diabetes that parallels the duration and the severity of hyperglycemia. However, it has been difficult to ascertain from these epidemiological correlations the causal relationship between the commonly observed metabolic abnormalities and the specific cardiac phenotype. In this review, we provide an update of our current understanding of the complexities of diabetic cardiomyopathy with a special emphasis on the relationship between the metabolic perturbations that accompany diabetes and the cellular consequences leading to altered myocardial structure and function.

	Cellular Mechanisms Predisposing to Diabetic Cardiomyopathy

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
The 3 characteristic metabolic disturbances evident in diabetic states are hyperlipidemia (usually in the form of increased triglycerides and nonesterified fatty acids [NEFAs]) and early hyperinsulinemia followed by pancreatic ß-cell failure, leading eventually to hyperglycemia. Type 1 diabetes differs principally from type 2 diabetes in that it is unaccompanied by a period of hyperinsulinemia and is characterized by early- as opposed to late-onset hyperglycemia. Alterations in body mass (obesity) and adipocytokines (leptin, adiponectin) have also been implicated in the cardiovascular pathophysiology observed in diabetes. As such, the effects of increased NEFAs, altered insulin action, and hyperglycemia can be considered triggers to the cardiac phenotype in diabetes. An understanding of the cellular effects of these metabolic disturbances on cardiomyocytes should be useful in predicting the structural and functional cardiac consequences.

Extensive cellular and molecular studies have identified putative mediators, effectors, and targets of these metabolic triggers in the pathogenesis of cardiac dysfunction in diabetes (Figure 1). We review the cellular signaling pathways associated with these metabolic triggers that lead to altered myocardial structure and function.

View larger version (50K): [in this window] [in a new window]   Figure 1. The relationship between diabetic metabolic disturbances (triggers) and the mediators, effectors, and intracellular targets that lead to a diabetic cardiomyopathic phenotype.

	Increased NEFAs

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
NEFAs play a critical role in triggering the development of cellular insulin resistance but also have been implicated in the development of myocardial contractile dysfunction. NEFAs play a central role in altering cellular insulin signaling through several mechanisms leading to insulin resistance and compensatory hyperinsulinemia^10–12 (Figure 2). In turn, hyperinsulinemia is an important trigger to the development of cardiac hypertrophy in diabetic cardiomyopathy (see below).

View larger version (25K): [in this window] [in a new window]   Figure 2. Role of increased NEFAs in the pathogenesis of cellular insulin resistance. There are several putative mechanisms including the induction of atypical PKC, phosphorylation, and activation of IB kinase which serine phosphorylates and deactivates IRS-1. NEFAs may also activate the phosphatase PTEN, decreasing the tris-inositol phosphates to which the pleckstrin domain of Akt-1 binds. Finally, NEFAs can contribute to ceramide production, triggering cellular apoptosis.

NEFAs induce the activation of atypical protein kinase C (PKC) , a serine/threonine kinase that phosphorylates and subsequently activates IB kinase. IB kinase phosphorylates serine residues on insulin receptor substrate-1 (IRS-1), inhibiting its ability to bind SH2 domains of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), impairing insulin signal transduction.¹² Although this mechanism is active in skeletal muscle and adipose tissue, it has been less clear whether similar mechanisms are apparent in cardiac muscle.

Increases in intracellular NEFAs can also alter insulin signaling without affecting IRS-1/PI3K activation (Figure 2). Akt-1 activation is critically dependent on the generation of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P₃) to bind the N-terminal pleckstrin domain and activate membrane bound kinases responsible for the phosphorylation of serine and threonine residues on Akt-1 that confer catalytic and regulatory properties.^13–16 NEFAs are natural ligands for the nuclear receptor, peroxisome proliferator-activated receptor (PPAR) , and can induce the upregulation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) which dephosphorylates PtdIns(3,4,5)P₃, preventing the activation of Akt-1.¹⁶

NEFAs can directly alter myocardial contractility independent of altered insulin action by increasing NEFA flux into the myocardium.¹⁷ Recent evidence¹⁸ suggests that increases in fatty acyl coenzyme A (CoA) esters within cardiac myocytes may modulate the contractile state of the myocardium by opening of the K_ATP channel. Activation of the K_ATP channel leads to shortening of the action potential and reduces transsarcolemmal calcium flux and subsequently myocardial contractility.

Finally, the increased intracellular accumulation of NEFAs may directly contribute to cell death under circumstances in which accumulating intracellular NEFAs do not undergo ß oxidation. The reaction between palmityol-CoA, an intracellular intermediate of NEFAs, and serine leads to the generation of the sphingolipid ceramide, and this reaction may be facilitated by the cytokine, tumor necrosis factor (TNF) .¹⁹ Ceramide can induce cellular apoptosis through the induction of nuclear factor B, caspase 3 activation, and cytochrome c release and can inhibit DNA repair by blocking poly (ADP ribose) polymerase.²⁰ Under these circumstances, increased NEFAs are said to cause lipotoxicity.¹⁷ Although lipotoxicity has been implicated in the reduction in pancreatic ß-cell reserves, the relevance of these findings in the myocardium remain controversial.

Thus, NEFAs play a central role not only in inducing cellular insulin resistance but also in directly affecting myocardial contractility and, under specific circumstances, in the promotion of cardiomyocyte cell death.

	Hyperinsulinemia

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
Cellular insulin resistance may presage frank diabetes by a decade or more and requires compensatory increases in plasma insulin levels to maintain glucose homeostasis in the face of impaired cellular insulin action, principally in skeletal muscle and liver.¹⁰ The nature and extent of the cellular insulin resistance may be selective to certain organ systems and may vary in terms of the metabolic, mitogenic, prosurvival, and vascular actions of insulin.

How then can hyperinsulinemia cause cardiac hypertrophy^21–24 if the cellular actions of insulin are attenuated? The paradox is reconciled by the recognition that systemic hyperinsulinemia may accentuate cellular insulin action in insulin responsive tissues, such as the myocardium, that do not manifest cellular insulin resistance. In this regard, the mitogenic actions of insulin on myocardium during chronic systemic hyperinsulinemia bear directly the commonly observed finding of cardiac hypertrophy in diabetic cardiomyopathy.^21–23

There are at least 3 cellular mechanisms whereby hyperinsulinemia mediates cardiomyocyte hypertrophy (Figure 3). Acutely, insulin stimulates growth through the same PI3K/Akt-1 pathway by which it mediates glucose uptake. Akt-1 phosphorylates and inactivates glycogen synthases kinase-3ß (GSK-3ß), a well-recognized inhibitor of nuclear transcription governing the hypertrophic process via the nuclear factor in activated lymphocytes (NFAT-3).^25,26 In addition, Akt-1 activates the mammalian target of rapamycin (mTOR) that activates the p70 ribosomal subunit S6kinase-1, leading to increased protein synthesis.^27–30 However, these mitogenic actions mediated through the insulin receptor may be mitigated when insulin signaling through the PI3K/Akt-1 pathway is impaired during chronic hyperinsulinemia

View larger version (38K): [in this window] [in a new window]   Figure 3. Alternative pathways whereby compensatory hyperinsulinemia contributes to myocyte hypertrophy through the sympathetic nervous system activation and MAP kinase/ERK pathways at a time when insulin receptor mediated Akt-1 activation is impaired.

However, chronic hyperinsulinemia may augment myocardial Akt-1 activation indirectly through increased sympathetic nervous system activation.^26,31–33 Recent evidence suggests that chronic Akt-1 activation in cardiac myocytes is mediated through ß₂-adrenergic receptors via protein kinase A and Ca²⁺-calmodulin dependent kinase (CaMK),²⁶ and these mechanisms may predominate when insulin signaling is attenuated through the PI3K pathway.

In addition, there are other insulin-mediated, but Akt-1–independent, pathways that may be operative, most notably the extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinase pathways.^34,35 Significant cellular evidence exists for an insulin-induced activation of the p38 MAP kinase pathway,³⁴ as well as prenylation of both Rho and Ras in the setting of hyperinsulinemia, leading to myocyte hypertrophy and expansion of the extracellular matrix (Figure 3). These redundant pathways provide a strong mechanistic basis for the development of cardiac hypertrophy associated with chronic hyperinsulinemia as an early accompaniment of type 2 diabetes, even though the glucoregulatory effects of insulin are attenuated.

	Hyperglycemia

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
The mechanism whereby hyperglycemia mediates tissue injury through the generation of reactive oxygen species has been elucidated largely through the work of the Brownlee and colleagues.^36–38 Hyperglycemia leads to increased glucose oxidation and mitochondrial generation of superoxide.^37,39,40 In turn, excess superoxide leads to DNA damage and activation of poly (ADP ribose) polymerase (PARP) as a reparative enzyme.³⁶ However, PARP also mediates the ribosylation and inhibition of glyceraldehyde phosphate dehydrogenase (GAPDH), diverting glucose from its glycolytic pathway and into alternative biochemical pathways that are considered the mediators of hyperglycemia induced cellular injury. These include increases in advanced glycation end products (AGEs), increased hexosamine and polyol flux, and activation of classical isoforms of protein kinase C. Table 1 summarizes the effects of these alternative biochemical fates of glucose on cardiac structure and function in states of hyperglycemia.^41–51 Taken together, these data provide mechanistic evidence linking hyperglycemia to altered expression and function of both the ryanodine receptor (RyR) and sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA2) that may contribute to decreased systolic and diastolic function. In addition, hyperglycemia contributes to altered cardiac structure through posttranslational modification of the extracellular matrix.

View this table: [in this window] [in a new window]   Table 1. Alternative Metabolic Fates of Glucose Leading to Cardiac Structural and Functional Abnormalities in Hyperglycemia

	Cardiac Phenotypes in Experimental Models of Type 1 and Type 2 Diabetes Mellitus

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
The altered cardiac phenotypes associated with diabetic cardiomyopathy have been investigated in a wide array of experimental animal models.^52,53 From a mechanistic perspective, the manifestations of diabetic cardiomyopathy should be predictable based on the duration and the severity of the abnormalities in NEFAs, insulin, and glucose homeostasis. However, the experimental conditions under which the models are studied add significant complexity to our understanding. In particular, the nature of the available substrates and hormonal milieu may be limited in isolated myocytes or isolated heart preparations and contribute to functional abnormalities that are not recapitulated in intact models. Table 2 summarizes the biochemical, structural, and functional abnormalities reported in these models.

View this table: [in this window] [in a new window]   Table 2. Metabolic and Cardiac Phenotypes in Experimental Models of Diabetic Cardiomyopathy

	Models of Hyperglycemia Without Hyperinsulinemia

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
Streptozotocin (STZ) and alloxan are the 2 of the most common islet cell toxins that are used to induce type I diabetes in experimental animal models. The metabolic features^52,53 include the prompt development of profound hyperglycemia (25 to 30 mmol/L), modest hypertriglyceridemia (200 to 400 µmol/L), ketosis, and markedly reduced plasma insulin levels (<20 pmol/L). As such, the model is particularly useful in examining the effects of hyperglycemia in the absence hyperinsulinemia.

STZ- and alloxan-induced diabetes have been associated with myocardial atrophy as opposed to hypertrophy.^54,55 This is associated with loss of contractile proteins, myocyte dropout without reparative fibrosis,⁵⁶ consistent with the absence of the mitogenic and prosurvival effects of insulin. Decreases in cardiac mass have also been noted with cardiac specific knockout of the insulin receptor⁵⁷ associated with ventricular dilatation and impaired left ventricular (LV) systolic performance. There has been consistent evidence of intramyocardial lipid accumulation reflecting a compensatory shift in myocardial preference for fatty acids in the absence of insulin mediated glucose uptake.^54,56

Alterations in SERCA2 have been reported in association with the hyperglycemia in STZ induced diabetes leading to decreased SR calcium sequestration and intracellular calcium overload.^54,55 Decreases in contractile proteins such as -actin and myosin ATPase activity^54,55 have also been noted in association with shifts in myosin heavy chain isoforms from to ß,^53,54,58,59 contributing to decreased systolic tension development.

The functional consequences of these cellular effects have been studied in cardiomyocytes, isolated perfused hearts and in vivo in rats with STZ induced diabetes. Abnormalities in diastolic function (increased LV end-diastolic pressure and operating chamber stiffness) can be observed in isolated heart preparations within 7 days, with significant decreases in LV systolic pressure, LV developed pressure, and LV dP/dt max evident within 3 weeks⁵⁶ and progressing to profound systolic function over 1 year.^60–62 Notably, these impairments in diastolic and systolic dysfunction occur in the absence of significant changes in myocardial perfusion.^56,60 These important observations indicate that diastolic abnormalities, both impaired relaxation and increased stiffness, occur in the absence of hypertrophy and precede by weeks the onset of systolic dysfunction.⁶⁰ Equally important is the observation that administration of insulin in type 1 diabetic rats partially corrects the systolic abnormalities in association with restoration of contractile proteins, even though modest hyperglycemia persists.^61,62

These studies suggest that experimental type 1 diabetes, characterized principally by hyperglycemia is associated with altered calcium handling, impaired diastolic function, altered contractile proteins, and progressive systolic dysfunction as the magnitude and duration of the hyperglycemia progresses.^54,55,58,59 These abnormalities occur in the absence of myocyte hypertrophy or fibrosis. The findings are consistent with a dominant influence of hyperglycemia and the absence of the influence of insulin. Thus, hyperglycemia alone is sufficient to account for the functional, but not necessarily the structural, changes observed in diabetic cardiomyopathy.

	Models of Hyperinsulinemia With or Without Hyperglycemia

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
Models of type 2 diabetes are metabolically distinct from type 1 diabetes largely related to increased plasma insulin levels associated with altered cellular insulin action. Increased NEFAs and marked hyperinsulinemia are early accompaniments, whereas hyperglycemia is a later development attributable to exhaustion of pancreatic ß-cell reserves. However, the cardiac manifestations in experimental models of type 2 diabetes vary considerably based on the onset and severity of these metabolic perturbations, as well as the complex interactions of intramyocardial lipids, insulin, and glucose on the cardiomyocyte structure and function.

Many of the commonly used experimental models of type 2 diabetes are associated with obesity caused by genetic perturbations in the Ob gene and its product, leptin.^63–67 Leptin is a 16-kDa peptide produced by adipocytes that acts via specific receptors on the hypothalamus to inhibit food intake and increase energy expenditure. Notably, leptin receptors have been identified in the rat myocardium^63,64 and regulate fatty acid oxidation independent of effects on the acetyl CoA-malonyl CoA axis.⁶⁵ Leptin has also been shown to stimulate myocyte hyperplasia in rats⁶⁶ and humans⁶⁷ through both PI3-K– and ERK1/2-dependent mechanisms, similar to insulin. The metabolic phenotype associated with both leptin-deficient (ob^–/ob^–) and the leptin receptor–deficient (db^–/db^–) mice include obesity, insulin resistance, compensatory hyperinsulinemia, hypertriglyceridemia, and various degrees of hyperglycemia.

The cardiac phenotype of the ob^–/ob^– (leptin-deficient) mice has been studied both early and later in its development with varying results. There is evidence of LV hypertrophy and intramyocardial lipid accumulation both early⁶⁸ and late,⁶⁹ suggesting that hyperleptinemia is not necessary for the development of LV hypertrophy. At 3 months with normal fasting glucose but impaired glucose tolerance, LV systolic, diastolic, and developed pressures are normal, but there is evidence of decreased cardiac power in isolated, working heart preparations.⁶⁸ Notably, the degree of functional impairment varies depending on the concentrations of palmitate and insulin in the perfusate.⁶⁹ In contrast, LV systolic function is preserved at both 3 months⁷⁰ and 6 months⁷¹ when intact ob^–/ob^– mice are studied in vivo by echocardiography, whereas impaired diastolic function has been noted in some studies.

The hyperleptinemic db^–/db^– (leptin receptor–deficient) mice have a similar metabolic phenotype, but more profound hyperglycemia (30 to 50 mmol/L) manifest earlier in development. The hyperglycemic db^–/db^– mice have no cardiac hypertrophy at 3 months,⁷² despite combined hyperinsulinemia and hyperleptinemia, but develop LV hypertrophy later.⁶⁹ In isolated working hearts, db^–/db^– mice have normal LV systolic and developed pressures but increased ventricular stiffness and impaired cardiac power.⁷² However, systolic function is preserved in db^–/db^– mice at 6 months when studied in vivo.⁶⁹ The conflicting data as to the nature and extent of cardiac functional abnormalities between working heart and intact preparations can be reconciled by considering differences in substrate availability between the preparations. Hormone and substrate concentrations are limited in the isolated, crystalloid perfused hearts,^68,72 whereas alternative substrates (lactate and pyruvate) and metabolic hormones are available in physiological concentrations in the intact models.⁶⁹ Under circumstances in which a full array of substrates is available, LV systolic function is preserved. Notably, both models are associated with the development of cardiac hypertrophy independent of plasma leptin levels or action, suggesting that hyperleptinemia is not necessary for the development of cardiac hypertrophy in type 2 diabetes. Finally, in contrast to the cardiac phenotype in models of type 1 diabetes, systolic performance is largely preserved even in the presence of profound hyperglycemia, provided that insulin is present. Instead, myocardial hypertrophy is the most commonly observed abnormality with increased chamber stiffness seen in some cases.

A similar evolution in cardiac phenotype is evident in genetically engineered rat models involving the absence of a functional leptin receptor. The Zucker fatty (ZF) rat is characterized metabolically by hyperleptinemia and consequent obesity, hyperlipidemia, and marked hyperinsulinemia with the late onset of hyperglycemia. As such, the model is characteristic of obesity and insulin resistance early (3 to 6 months). In contrast, the Zucker diabetic fatty (ZDF) rat has a similar genetic background but demonstrates earlier hyperglycemia, consistent with metabolic features of type 2 diabetes.

The morphological features of the ZF rat include increased intramyocardial lipid and increased myocardial mass.^73–75 Hypertrophy is evident in individual myocytes⁷⁵ and whole hearts⁸³ where there is an associated expansion in the extracellular matrix.⁷⁶ However, cardiac functional abnormalities have been observed inconsistently in isolated heart preparations with decreased cardiac power⁷³ and systolic wall stress⁷⁴ in some studies, whereas LV pressures and LV dP/dt⁷⁷ and the rate-pressure product⁷⁸ are maintained in others. Diastolic abnormalities have been noted early with prolonged isovolumic relaxation,⁷⁶ whereas chamber stiffness was reported to be normal at 12 months.⁷⁴

In contrast to the ZF rats, the ZDF rats do not demonstrate consistent increases in cardiac mass.^79–81 At 2 months, there is increased mass in the presence of marked hyperinsulinemia at a time when glucose levels are normal.⁸² However, by 3 months, there is no increase in mass when plasma glucose levels are high (27 mmol/L) and plasma insulin levels are reduced.⁸⁰ Fredersdorf et al⁸³ established the importance of the balance between hyperglycemia and hyperinsulinemia in 5-month old ZDF rats by controlling hyperglycemia with exogenous insulin and demonstrating increased cardiac mass, whereas ZDF rats that remained persistent hyperglycemic had no increase in mass. In isolated heart preparations, the magnitude of systolic dysfunction in ZDF rats tends to be greater when accompanied by severe hyperglycemia.^79,82 These effects are dependent on the substrate availability in the perfusate.⁷⁹ In contrast, studies in intact ZDF reveal intact systolic function^83–85 myocardial hypertrophy,⁸³ impaired flow reserve,⁸⁴ and diastolic relaxation.⁸⁵

Thus, hyperinsulinemic ZF rats have myocardial hypertrophy and variable degrees of diastolic abnormalities, whereas the diabetic ZDF rats have smaller increases in cardiac mass and impairments in LV systolic function in isolated hearts but not intact models. These findings are consistent with the cellular effects of hyperinsulinemia to induce cardiac hypertrophy in contrast to the effects of hyperglycemia that mitigate hypertrophy and affect systolic dysfunction to a greater extent. Whether the observed abnormalities in diastolic function are a consequence of hypertrophy or hyperglycemia remains unresolved.

	Models of Increased Intramyocardial Lipid Without Hyperinsulinemia or Hyperglycemia

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
The model of cardiac specific overexpression of PPAR in mice is associated with cardiac contractile dysfunction that is mediated by increased NEFA uptake and intracellular accumulation.^86,87 Although the cardiac phenotype is dramatic both at baseline and in response to a superimposed cardiac insult, the model does not possess characteristic features of diabetes. However, this model is particularly useful in studying the contribution of excess intracellular lipid accumulation to cardiac contractile dysfunction, in the absence of hyperglycemia and hyperinsulinemia.⁸⁶ Recent data using transgenic murine models of cardiac specific overexpression of fatty acid transport protein (FATP) demonstrated a cardiac phenotype that features diastolic dysfunction.⁸⁸ Taken together, it is abundantly clear that increased circulating NEFAs, a ubiquitous feature of both type 1 and 2 diabetes, contribute fundamentally not only to the development of both insulin resistance and compensatory hyperinsulinemia but also can directly affect cardiac function.

	Cardiovascular Manifestations in Humans With Type 1 and Type 2 Diabetes

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
The most commonly observed cardiac abnormalities in clinical studies of asymptomatic diabetics included LV hypertrophy and impairment in both isovolumic relaxation and ventricular filling, particularly among diabetic women.^9,89,90 Recently, there is evidence to suggest that this gender preference may relate to estrogen-induced activation of Akt-1 and its transcriptional effects in cardiomyocytes.^91,92 In addition, clinical studies have demonstrated consistent abnormalities in coronary flow reserve in patients with diabetes in the absence of epicardial coronary artery disease.^70,93–96 Both findings correlate closely with microvascular complications, particularly autonomic dysfunction.^95,96 What is surprising is the fact that the clinical manifestations are similar in both type 1^71,97,98 and type 2⁹³ diabetics. How do we reconcile these clinical findings with the phenotypic distinction noted in experimental animal models? The principal explanation involves the fact that type 1 diabetic patients are treated with insulin and are therefore not truly hypoinsulinemic as in the STZ models. Insulin has been shown to mitigate systolic dysfunction in STZ-induced diabetes in rats.⁶¹ Notably, systolic dysfunction at rest and during exercise in type 1 diabetes is observed most commonly in patients with microvascular complications, a reflection of poor glycemic control.⁹⁸

	Unifying Hypothesis

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
There is an extensive body of epidemiological, clinical, and experimental evidence that supports the existence of a distinct form of cardiomyopathy related to pathogenic cellular and molecular changes that accompany diabetes mellitus. Figure 4 provides a unifying hypothesis as to the relationship between the common metabolic perturbations in diabetes and altered cardiac phenotypes. Specifically, the magnitude of ventricular hypertrophy may depend on the magnitude and duration of hyperinsulinemia that, in turn, may depend on magnitude and distribution of increasing NEFAs. In contrast, the extent of systolic dysfunction may depend more on the magnitude and duration of hyperglycemia and the presence or absence of insulin. Diastolic abnormalities may occur as a consequence of either hypertrophy or hyperglycemia. As such, hypertrophy and diastolic abnormalities are observed most commonly and earlier than systolic abnormalities and thus dominate the clinical findings. The paradigm reconciles the distinctive cardiovascular features attributable to type 1 (hypoinsulinemic/hyperglycemiasystolic dysfunction) and type 2 (hyperinsulinemic/hyperglycemichypertrophy and diastolic dysfunction) diabetes in experimental models studied in vivo. In humans with type 1 diabetes, systolic dysfunction is less evident than in STZ-induced models because these patients receive exogenous insulin, making them metabolically akin to a type 2 diabetic from this mechanistic perspective. These findings are generally consistent with the established cellular consequences of increased NEFAs, hyperinsulinemia, and hyperglycemia on cardiac structure and function. These insights afford the opportunity to design therapeutic approaches targeted at specific pathogenic mechanisms including suppression of lipolysis, maturation of adipocytes, and restoration of cellular insulin action, in addition to the traditional target of maintaining euglycemia.

View larger version (37K): [in this window] [in a new window]   Figure 4. Schematic illustration of a unifying hypothesis that links NEFAs, hyperinsulinemia, and hyperglycemia to the structural and functional phenotypes in diabetic cardiomyopathy.

	Acknowledgments

 
This work has been supported in part by US Public Health Service grants NIH R01-HL75836 and R01-AG 023125. I.G.P. is the recipient of a Beginning Grant in Aid from the Pennsylvania Delaware Affiliate of the American Heart Association (AHA-0465484U), and P.P. is the recipient of a Post-Doctoral Fellowship Grant from the Pennsylvania Delaware Affiliate of the American Heart Association (AHA-0525596U).

	Footnotes

 
Original received May 11, 2005; resubmission received October 27, 2005; revised resubmission received December 27, 2005; accepted January 18, 2006.

	References

Top Abstract Introduction Cellular Mechanisms Predisposing... Increased NEFAs Hyperinsulinemia Hyperglycemia Cardiac Phenotypes in... Models of Hyperglycemia Without... Models of Hyperinsulinemia With... Models of Increased... Cardiovascular Manifestations in... Unifying Hypothesis References

 
1. Francis GS. Diabetic cardiomyopathy: fact or fiction? Heart. 2001; 85: 247–248.[Free Full Text]

2. Picano E. Diabetic cardiomyopathy. The importance of being earliest. J Am Coll Cardiol. 2003; 42: 454–457.[Free Full Text]

3. Avogaro A, Vigili dKS, Negut C, Tiengo A, Scognamiglio R. Diabetic cardiomyopathy: a metabolic perspective. Am J Cardiol. 2004; 93: 13A–16A.[Medline] [Order article via Infotrieve]

4. Adeghate E. Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell Biochem. 2004; 261: 187–191.[CrossRef][Medline] [Order article via Infotrieve]

5. Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol. 1993; 22: 6A–13A.[Medline] [Order article via Infotrieve]

6. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974; 34: 29–34.[CrossRef][Medline] [Order article via Infotrieve]

7. Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R, Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL; Cardiovascular Health Study Research Group. Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol. 2001; 87: 413–419.[CrossRef][Medline] [Order article via Infotrieve]

8. McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart. 2000; 83: 596–602.[Free Full Text]

9. Bertoni AG, Tsai A, Kasper EK, Brancati FL. Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care. 2003; 26: 2791–2795.[Abstract/Free Full Text]

10. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000; 106: 171–176.[Medline] [Order article via Infotrieve]

11. Birnbaum MJ. Turning down insulin signaling. J Clin Invest. 2001; 108: 655–659.[CrossRef][Medline] [Order article via Infotrieve]

12. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001; 108: 437–446.[CrossRef][Medline] [Order article via Infotrieve]

13. Brazil DP, Hemmings BA. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci. 2001; 26: 657–664.[CrossRef][Medline] [Order article via Infotrieve]

14. Lawlor MA, Alessi DR. PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci. 2001; 114: 2903–2910.[Medline] [Order article via Infotrieve]

15. Morisco C, Zebrowski D, Condorelli G, Tsichlis P, Vatner SF, Sadoshima J. The Akt-glycogen synthase kinase 3beta pathway regulates transcription of atrial natriuretic factor induced by beta-adrenergic receptor stimulation in cardiac myocytes. J Biol Chem. 2000; 275: 14466–14475.[Abstract/Free Full Text]

16. Schwartzbauer G, Robbins J. The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chem. 2001; 276: 35786–35793.[Abstract/Free Full Text]

17. Unger RH, Orci L. Lipotoxic diseases of nonadipose tissues in obesity. Int J Obes Relat Metab Disord. 2000; 24 (suppl 4): S28–S32.[CrossRef]

18. Liu GX, Hanley PJ, Ray J, Daut J. Long-chain acyl-coenzyme A esters and fatty acids directly link metabolism to K(ATP) channels in the heart. Circ Res. 2001; 88: 918–924.[Abstract/Free Full Text]

19. Halse R, Pearson SL, McCormack JG, Yeaman SJ, Taylor R. Effects of tumor necrosis factor-alpha on insulin action in cultured human muscle cells. Diabetes. 2001; 50: 1102–1109.[Abstract/Free Full Text]

20. Zhang DX, Fryer RM, Hsu AK, Zou AP, Gross GJ, Campbell WB, Li PL. Production and metabolism of ceramide in normal and ischemic-reperfused myocardium of rats. Basic Res Cardiol. 2001; 96: 267–274.[CrossRef][Medline] [Order article via Infotrieve]

21. Ilercil A, Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Lee ET, Welty TK, Fabsitz RR, Howard BV. Associations of insulin levels with left ventricular structure and function in Am Indians: the strong heart study. Diabetes. 2002; 51: 1543–1547.[Abstract/Free Full Text]

22. Iacobellis G, Ribaudo MC, Zappaterreno A, Vecci E, Tiberti C, Di Mario U, Leonetti F. Relationship of insulin sensitivity and left ventricular mass in uncomplicated obesity. Obes Res. 2003; 11: 518–524.[Medline] [Order article via Infotrieve]

23. McNulty PH. Insulin resistance and cardiac mass: the end of the beginning? Obes Res. 2003; 11: 507–508.[Medline] [Order article via Infotrieve]

24. Ueno M, Carvalheira JB, Tambascia RC, Bezerra RM, Amaral ME, Carneiro EM, Folli F, Franchini KG, Saad MJ. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia. 2005; 4: 506–518.

25. O’Neill BT, Abel ED. Akt1 in the cardiovascular system: friend or foe? J Clin Invest. 2005; 115: 2059–2064.[CrossRef][Medline] [Order article via Infotrieve]

26. Morisco C, Condorelli G, Trimarco V, Bellis A, Marrone C, Condorelli G, Sadoshima J, Trimarco B. Akt mediates the cross-talk between beta-adrenergic and insulin receptors in neonatal cardiomyocytes. Circ Res. 2005; 96: 180–188.[Abstract/Free Full Text]

27. Khamzina L, Veilleux A, Bergeron S, Marette A. Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology. 2005; 146: 1473–1481.[Abstract/Free Full Text]

28. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol. 2004; 167: 399–403.[Abstract/Free Full Text]

29. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol. 2004; 14: 1650–1656.[CrossRef][Medline] [Order article via Infotrieve]

30. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem. 2001; 276: 38052–38060.[Abstract/Free Full Text]

31. Kern W, Peters A, Born J, Fehm HL, Schultes B. Changes in blood pressure and plasma catecholamine levels during prolonged hyperinsulinemia. Metabolism. 2005; 54: 391–396.[CrossRef][Medline] [Order article via Infotrieve]

32. Grassi G. Counteracting the sympathetic nervous system in essential hypertension. Curr Opin Nephrol Hypertens. 2004; 13: 513–519.[CrossRef][Medline] [Order article via Infotrieve]

33. Yosefy C, Magen E, Kiselevich A, Priluk R, London D, Volchek L, Viskoper RJ Jr. Rosiglitazone improves, while Glibenclamide worsens blood pressure control in treated hypertensive diabetic and dyslipidemic subjects via modulation of insulin resistance and sympathetic activity. J Cardiovasc Pharmacol. 2004; 44: 215–222.[CrossRef][Medline] [Order article via Infotrieve]

34. Wang CC, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes. 2004; 53: 2735–2740.[Abstract/Free Full Text]

35. Naito Z, Takashi E, Xu G, Ishiwata T, Teduka K, Yokoyama M, Yamada N, Sugisaki Y, Asano G. Different influences of hyperglycemic duration on phosphorylated extracellular signal-regulated kinase 1/2 in rat heart. Exp Mol Pathol. 2003; 74: 23–32.[Medline] [Order article via Infotrieve]

36. Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C, Brownlee M. Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003; 112: 1049–1057.[CrossRef][Medline] [Order article via Infotrieve]

37. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000; 404: 787–790.[CrossRef][Medline] [Order article via Infotrieve]

38. Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl. 2000; 77: S26–S30.[CrossRef][Medline] [Order article via Infotrieve]

39. Cai L, Kang YJ. Oxidative stress and diabetic cardiomyopathy: a brief review. Cardiovasc Toxicol. 2001; 1: 181–193.[CrossRef][Medline] [Order article via Infotrieve]

40. Farhangkhoee H, Khan ZA, Mukherjee S, Cukiernik M, Barbin YP, Karmazyn M Chakrabarti S. Heme oxygenase in diabetes-induced oxidative stress in the heart. J Mol Cell Cardiol. 2003; 35: 1439–1448.[CrossRef][Medline] [Order article via Infotrieve]

41. Bidasee KR, Nallani K, Yu Y, Cocklin RR, Zhang Y, Wang M, Dincer UD, Besch HR Jr. Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels. Diabetes. 2003; 52: 1825–1836.[Abstract/Free Full Text]

42. Candido R, Forbes JM, Thomas MC, Thallas V, Dean RG, Burns WC, Tikellis C, Ritchie RH, Twigg SM, Cooper ME, Burrell LM. A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes. Circ Res. 2003; 92: 785–792.[Abstract/Free Full Text]

43. Cooper ME Importance of advanced glycation end products in diabetes-associated cardiovascular and renal disease. Am J Hypertens. 2004; 17: 31S–38S.[CrossRef][Medline] [Order article via Infotrieve]

44. Herrmann KL, McCulloch AD, Omens JH. Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy. Am J Physiol Heart Circ Physiol. 2003; 284: H1277–H1284.[Abstract/Free Full Text]

45. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, Dillmann WH. Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem. 2003; 278: 44230–44237.[Abstract/Free Full Text]

46. Wu-Wong JR, Berg CE, Dayton BD. Endothelin-stimulated glucose uptake: effects of intracellular Ca (2+), cAMP and glucosamine. Clin Sci (Lond). 2002; 103 (suppl 48): 418S–423S.[Medline] [Order article via Infotrieve]

47. Galvez AS, Ulloa JA, Chiong M, Criollo A, Eisner V, Barros LF, Lavandero S. Aldose reductase induced by hyperosmotic stress mediates cardiomyocyte apoptosis: differential effects of sorbitol and mannitol. J Biol Chem. 2003; 278: 38484–38494.[Abstract/Free Full Text]

48. Ramasamy R. Aldose reductase: a novel target for cardioprotective interventions. Curr Drug Targets. 2003; 4: 625–632.[CrossRef][Medline] [Order article via Infotrieve]

49. Guo M, Wu MH, Korompai F, Yuan SY. Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes. Physiol Genomics. 2003; 12: 139–146.[Abstract/Free Full Text]

50. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998; 47: 859–866.[Abstract]

51. Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD, Walsh RA, King GL. Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci U S A. 1997; 94: 9320–9325.[Abstract/Free Full Text]

52. Tahiliani AG, McNeill JH. Diabetes-induced abnormalities in the myocardium. Life Sci. 1986; 38: 959–974.[CrossRef][Medline] [Order article via Infotrieve]

53. Fang ZY, Prins JB, Marwick TH. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev. 2004; 25: 543–567.[Abstract/Free Full Text]

54. Depre C, Young ME, Ying J, Ahuja HS, Han Q, Garza N, Davies PJ, Taegtmeyer H. Streptozotocin-induced changes in cardiac gene expression in the absence of severe contractile dysfunction. J Mol Cell Cardiol. 2000; 32: 985–996.[CrossRef][Medline] [Order article via Infotrieve]

55. Dhalla NS, Pierce GN, Innes IR, Beamish RE. Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol. 1985; 1: 263–281.[Medline] [Order article via Infotrieve]

56. Jackson CV, McGrath GM, Tahiliani AG, Vadlamudi RV, McNeill JH. A functional and ultrastructural analysis of experimental diabetic rat myocardium. Manifestation of a cardiomyopathy. Diabetes. 1985; 34: 876–883.[Abstract]

57. Hu P, Zhang D, Swenson L, Chakrabarti G, Abel ED, Litwin SE. Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload. Am J Physiol Heart Circ Physiol. 2003; 285: H1261–H1269.[Abstract/Free Full Text]

58. Scognamiglio R, Avogaro A, Negut C, Piccolotto R, Vigili dK, Tiengo A. Early myocardial dysfunction in the diabetic heart: current research and clinical applications. Am J Cardiol. 2004; 93: 17A–20A.[Medline] [Order article via Infotrieve]

59. Rodrigues B, Cam MC, McNeill JH. Myocardial substrate metabolism: implications for diabetic cardiomyopathy. J Mol Cell Cardiol. 1995; 27: 169–179.[Medline] [Order article via Infotrieve]

60. Vadlamudi RV, Rodgers RL, McNeill JH. The effect of chronic alloxan- and streptozotocin-induced diabetes on isolated rat heart performance. Can J Physiol Pharmacol. 1982; 60: 902–911.[Medline] [Order article via Infotrieve]

61. Fein FS, Strobeck JE, Malhotra A, Scheuer J, Sonnenblick EH. Reversibility of diabetic cardiomyopathy with insulin in rats. Circ Res. 1981; 49: 1251–1261.[Abstract/Free Full Text]

62. Malhotra A, Penpargkul S, Fein FS, Sonnenblick EH, Scheuer J. The effect of streptozotocin-induced diabetes in rats on cardiac contractile proteins. Circ Res. 1981; 49: 1243–1250.[Abstract/Free Full Text]

63. Rajapurohitam V, Gan XT, Kirshenbaum LA, Karmazyn M. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res. 2003; 93: 277–279.[Abstract/Free Full Text]

64. Purdham DM, Zou MX, Rajapurohitam V, Karmazyn M. Rat heart is a site of leptin production and action. Am J Physiol Heart Circ Physiol. 2004; 287: H2877–H2884.[Abstract/Free Full Text]

65. Atkinson LL, Fischer MA, Lopaschuk GD. Leptin activates cardiac fatty acid oxidation independent of changes in the AMP-activated protein kinase-acetyl-CoA carboxylase-malonyl-CoA axis. J Biol Chem. 2002; 277: 29424–29430.[Abstract/Free Full Text]

66. Tajmir P, Ceddia RB, Li RK, Coe IR, Sweeney G. Leptin increases cardiomyocyte hyperplasia via extracellular signal-regulated kinase- and phosphatidylinositol 3-kinase-dependent signaling pathways. Endocrinology. 2004; 145: 1550–1555.[Abstract/Free Full Text]

67. Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A, Carella C, de Divitiis O, Varricchio M. Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men. Hypertension. 1999; 34: 1047–1052.[Abstract/Free Full Text]

68. Mazumder PK, O’Neill BT, Roberts MW, Buchanan J, Yun UJ, Cooksey RC, Boudina S, Abel ED. Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes. 2004; 53: 2366–2374.[Abstract/Free Full Text]

69. Barouch LA, Berkowitz DE, Harrison RW, O’Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation. 2003; 108: 754–759.[Abstract/Free Full Text]

70. McDonagh PF, Hokama JY. Microvascular perfusion and transport in the diabetic heart. Microcirculation. 2000; 7: 163–181.[CrossRef][Medline] [Order article via Infotrieve]

71. Raev DC. Left ventricular function and specific diabetic complications in other target organs in young insulin-dependent diabetics: an echocardiographic study. Heart Vessels. 1994; 9: 121–128.[CrossRef][Medline] [Order article via Infotrieve]

72. Belke DD, Larsen TS, Gibbs EM, Severson DL. Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab. 2000; 279: E1104–E1113.[Abstract/Free Full Text]

73. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, Youker KA, Taegtmeyer H. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes. 2002; 51: 2587–2595.[Abstract/Free Full Text]

74. Paradise NF, Pilati CF, Payne WR, Finkelstein JA. Left ventricular function of the isolated, genetically obese rat’s heart. Am J Physiol. 1985; 248: H438–H444.[Medline] [Order article via Infotrieve]

75. Ren J, Sowers JR, Walsh MF, Brown RA. Reduced contractile response to insulin and IGF-I in ventricular myocytes from genetically obese Zucker rats. Am J Physiol Heart Circ Physiol. 2000; 279: H1708–H1714.[Abstract/Free Full Text]

76. Conti M, Renaud IM, Poirier B, Michel O, Belair MF, Mandet C, Bruneval P, Myara I, Chevalier J. High levels of myocardial antioxidant defense in aging nondiabetic normotensive Zucker obese rats. Am J Physiol Regul Integr Comp Physiol. 2004; 286: R793–R800.[Abstract/Free Full Text]

77. Rosen P, Herberg L, Reinauer H. Different types of postinsulin receptor defects contribute to insulin resistance in hearts of obese Zucker rats. Endocrinology. 1986; 119: 1285–1291.[Abstract/Free Full Text]

78. Sidell RJ, Cole MA, Draper NJ, Desrois M, Buckingham RE, Clarke K. Thiazolidinedione treatment normalizes insulin resistance and ischemic injury in the zucker Fatty rat heart. Diabetes. 2002; 51: 1110–1117.[Abstract/Free Full Text]

79. Wang P, Lloyd SG, Zeng H, Bonen A, Chatham JC. Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats. Am J Physiol Heart Circ Physiol. 2005; 288: H2102–H2110.[Abstract/Free Full Text]

80. Chatham JC, Seymour AM. Cardiac carbohydrate metabolism in Zucker diabetic fatty rats. Cardiovasc Res. 2002; 55: 104–112.[Abstract/Free Full Text]

81. Huisamen B, van Zyl M, Keyser A, Lochner A. The effects of insulin and beta-adrenergic stimulation on glucose transport, glut 4 and PKB activation in the myocardium of lean and obese noninsulin dependent diabetes mellitus rats. Mol Cell Biochem. 2001; 223: 15–25.[CrossRef][Medline] [Order article via Infotrieve]

82. Golfman LS, Wilson CR, Sharma S, Burgmaier M, Young ME, Guthrie PH, Van Arsdall M, Adrogue JV, Brown KK, Taegtmeyer H. Activation of PPAR{gamma} enhances myocardial glucose oxidation and improves contractile function in isolated working hearts of ZDF rats. Am J Physiol Endocrinol Metab. 2005; 289: E328–E336.[Abstract/Free Full Text]

83. Fredersdorf S, Thumann C, Ulucan C, Griese DP, Luchner A, Riegger GA, Kromer EP, Weil J. Myocardial hypertrophy and enhanced left ventricular contractility in Zucker diabetic fatty rats. Cardiovasc Pathol. 2004; 13: 11–19.[Medline] [Order article via Infotrieve]

84. Yu Y, Ohmori K, Kondo I, Yao L, Noma T, Tsuji T, Mizushige K, Kohno M. Correlation of functional and structural alterations of the coronary arterioles during development of type II diabetes mellitus in rats. Cardiovasc Res. 2002; 56: 303–311.[Abstract/Free Full Text]

85. Abe T, Ohga Y, Tabayashi N, Kobayashi S, Sakata S, Misawa H, Tsuji T, Kohzuki H, Suga H, Taniguchi S, Takaki M. Left ventricular diastolic dysfunction in type 2 diabetes mellitus model rats. Am J Physiol Heart Circ Physiol. 2002; 282: H138–H148.[Abstract/Free Full Text]

86. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002; 109: 121–130.[CrossRef][Medline] [Order article via Infotrieve]

87. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest. 2005; 115: 547–555.[CrossRef][Medline] [Order article via Infotrieve]

88. Chiu HC, Kovacs A, Blanton RM, Han X, Courtois M, Weinheimer CJ, Yamada KA, Brunet S, Xu H, Nerbonne JM, Welch MJ, Fettig NM, Sharp TL, Sambandam N, Olson KM, Ory DS, Schaffer JE. Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res. 2005; 96: 225–233.[Abstract/Free Full Text]

89. Rutter MK, Parise H, Benjamin EJ, Levy D, Larson MG, Meigs JB, Nesto RW, Wilson PW, Vasan RS. Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study. Circulation. 2003; 107: 448–454.[Abstract/Free Full Text]

90. Tenenbaum A, Fisman EZ, Schwammenthal E, Adler Y, Benderly M, Motro M, Shemesh J. Increased prevalence of left ventricular hypertrophy in hypertensive women with type 2 diabetes mellitus. Cardiovasc Diabetol. 2003; 2: 14.[CrossRef][Medline] [Order article via Infotrieve]

91. Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KDR, Schaefer E, Kajstura J, Anversa P, Sussman MA. Myocardial Akt activation and gender. Increased nuclear activity in females versus males. Circ Res. 2001; 88: 1020–1027.[Abstract/Free Full Text]

92. Sugden PH, Clerk A. Akt like a women. Gender differences in susceptibility to cardiovascular disease. Circ Res. 2001; 88: 975–977.[Free Full Text]

93. Dagres N, Saller B, Haude M, Husing J, von Birgelen C, Schmermund A, Sack S, Baumgart D, Mann K, Erbel R. Insulin sensitivity and coronary vasoreactivity: insulin sensitivity relates to adenosine-stimulated coronary flow response in human subjects. Clin Endocrinol (Oxf). 2004; 61: 724–731.[CrossRef][Medline] [Order article via Infotrieve]

94. Dietz U, Tries HP, Merkle W, Jaursch-Hancke C, Lambertz H. Coronary artery flow reserve in diabetics with erectile dysfunction using sildenafil. Cardiovasc Diabetol. 2003; 2: 8.[Medline] [Order article via Infotrieve]

95. Pop-Busui R, Kirkwood I, Schmid H, Marinescu V, Schroeder J, Larkin D, Yamada E, Raffel DM, Stevens MJ. Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol. 2004; 44: 2368–2374.[Abstract/Free Full Text]

96. Yokoyama I, Yonekura K, Ohtake T, Yang W, Shin WS, Yamada N, Ohtomo K, Nagai R. Coronary microangiopathy in type 2 diabetic patients: relation to glycemic control, sex, and microvascular angina rather than to coronary artery disease. J Nucl Med. 2000; 41: 978–985.[Abstract/Free Full Text]

97. Sasso FC, Carbonara O, Cozzolino D, Rambaldi P, Mansi L, Torella D, Gentile S, Turco S, Torella R, Salvatore T. Effects of insulin-glucose infusion on left ventricular function at rest and during dynamic exercise in healthy subjects and noninsulin dependent diabetic patients: a radionuclide ventriculographic study. J Am Coll Cardiol. 2000; 36: 219–226.[Abstract/Free Full Text]

98. Huikuri HV, Airaksinen JK, Lilja M, Takkunen JT. Echocardiographic evaluation of left ventricular response to isometric exercise in young insulin-dependent diabetics. Acta Diabetol Lat. 1986; 23: 193–200.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				A. Van den Bergh, P. Vangheluwe, A. Vanderper, P. Carmeliet, F. Wuytack, S. Janssens, W. Flameng, P. Holvoet, and P. Herijgers Food-restriction in obese dyslipidaemic diabetic mice partially restores basal contractility but not contractile reserve Eur J Heart Fail, December 1, 2009; 11(12): 1118 - 1125. [Abstract] [Full Text] [PDF]

				C. Whee Park, H. Wook Kim, J. Hee Lim, K. Dong Yoo, S. Chung, S. Joon Shin, H. Wha Chung, S. Ju Lee, C.-B. Chae, Y.-S. Kim, et al. Vascular Endothelial Growth Factor Inhibition by dRK6 Causes Endothelial Apoptosis, Fibrosis, and Inflammation in the Heart via the Akt/eNOS Axis in db/db Mice Diabetes, November 1, 2009; 58(11): 2666 - 2676. [Abstract] [Full Text] [PDF]

				E. Shen, Y. Li, Y. Li, L. Shan, H. Zhu, Q. Feng, J. M. O. Arnold, and T. Peng Rac1 Is Required for Cardiomyocyte Apoptosis During Hyperglycemia Diabetes, October 1, 2009; 58(10): 2386 - 2395. [Abstract] [Full Text] [PDF]

				D.-F. Yeih, H.-I Yeh, H.-T. Hsin, L.-Y. Lin, F.-T. Chiang, C.-D. Tseng, S.-H. Chu, and Y.-Z. Tseng Dimethylthiourea normalizes velocity-dependent, but not force-dependent, index of ventricular performance in diabetic rats: role of myosin heavy chain isozyme Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1411 - H1420. [Abstract] [Full Text] [PDF]

				Y. Li, Y. Li, Q. Feng, M. Arnold, and T. Peng Calpain activation contributes to hyperglycaemia-induced apoptosis in cardiomyocytes Cardiovasc Res, October 1, 2009; 84(1): 100 - 110. [Abstract] [Full Text] [PDF]

				R. W. Gross and X. Han Shotgun lipidomics of neutral lipids as an enabling technology for elucidation of lipid-related diseases Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E297 - E303. [Abstract] [Full Text] [PDF]

				S. Messaoudi, P. Milliez, J.-L. Samuel, and C. Delcayre Cardiac aldosterone overexpression prevents harmful effects of diabetes in the mouse heart by preserving capillary density FASEB J, July 1, 2009; 23(7): 2176 - 2185. [Abstract] [Full Text] [PDF]

				S. Matsushima, S. Kinugawa, T. Yokota, N. Inoue, Y. Ohta, S. Hamaguchi, and H. Tsutsui Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H409 - H416. [Abstract] [Full Text] [PDF]

				D. Westermann, T. Walther, K. Savvatis, F. Escher, M. Sobirey, A. Riad, M. Bader, H.-P. Schultheiss, and C. Tschope Gene Deletion of the Kinin Receptor B1 Attenuates Cardiac Inflammation and Fibrosis During the Development of Experimental Diabetic Cardiomyopathy Diabetes, June 1, 2009; 58(6): 1373 - 1381. [Abstract] [Full Text] [PDF]

				Y. Wang, W. Feng, W. Xue, Y. Tan, D. W. Hein, X.-K. Li, and L. Cai Inactivation of GSK-3{beta} by Metallothionein Prevents Diabetes-Related Changes in Cardiac Energy Metabolism, Inflammation, Nitrosative Damage, and Remodeling Diabetes, June 1, 2009; 58(6): 1391 - 1402. [Abstract] [Full Text] [PDF]

				L. van Heerebeek and W. J. Paulus The dialogue between diabetes and diastole Eur J Heart Fail, January 1, 2009; 11(1): 3 - 5. [Full Text] [PDF]

				B. Laczy, B. G. Hill, K. Wang, A. J. Paterson, C. R. White, D. Xing, Y.-F. Chen, V. Darley-Usmar, S. Oparil, and J. C. Chatham Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H13 - H28. [Abstract] [Full Text] [PDF]

				L. J. Rijzewijk, R. W. van der Meer, J. W.A. Smit, M. Diamant, J. J. Bax, S. Hammer, J. A. Romijn, A. de Roos, and H. J. Lamb Myocardial Steatosis Is an Independent Predictor of Diastolic Dysfunction in Type 2 Diabetes Mellitus. J. Am. Coll. Cardiol., November 25, 2008; 52(22): 1793 - 1799. [Abstract] [Full Text] [PDF]

				L. S.M. Wong, R. A. de Boer, N. J. Samani, D. J. van Veldhuisen, and P. van der Harst Telomere biology in heart failure Eur J Heart Fail, November 1, 2008; 10(11): 1049 - 1056. [Abstract] [Full Text] [PDF]

				B.-C. Yu, C.-K. Chang, H.-Y. Ou, K.-C. Cheng, and J.-T. Cheng Decrease of peroxisome proliferator-activated receptor delta expression in cardiomyopathy of streptozotocin-induced diabetic rats Cardiovasc Res, October 1, 2008; 80(1): 78 - 87. [Abstract] [Full Text] [PDF]

				L. Bertrand, S. Horman, C. Beauloye, and J.-L. Vanoverschelde Insulin signalling in the heart Cardiovasc Res, July 15, 2008; 79(2): 238 - 248. [Abstract] [Full Text] [PDF]

				M. R. MacDonald, M. C. Petrie, F. Varyani, J. Ostergren, E. L. Michelson, J. B. Young, S. D. Solomon, C. B. Granger, K. Swedberg, S. Yusuf, et al. Impact of diabetes on outcomes in patients with low and preserved ejection fraction heart failure: An analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme Eur. Heart J., June 1, 2008; 29(11): 1377 - 1385. [Abstract] [Full Text] [PDF]

				M. Kindermann and M. Bohm Sweet hearts die earlier--lessons from CHARM Eur. Heart J., June 1, 2008; 29(11): 1342 - 1343. [Full Text] [PDF]

				M. Ueno, J. Suzuki, Y. Zenimaru, S. Takahashi, T. Koizumi, S. Noriki, O. Yamaguchi, K. Otsu, W.-J. Shen, F. B. Kraemer, et al. Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1109 - E1118. [Abstract] [Full Text] [PDF]

				K. Venkatachalam, S. Mummidi, D. M. Cortez, S. D. Prabhu, A. J. Valente, and B. Chandrasekar Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2078 - H2087. [Abstract] [Full Text] [PDF]

				S. Van Linthout, F. Spillmann, A. Riad, C. Trimpert, J. Lievens, M. Meloni, F. Escher, E. Filenberg, O. Demir, J. Li, et al. Human Apolipoprotein A-I Gene Transfer Reduces the Development of Experimental Diabetic Cardiomyopathy Circulation, March 25, 2008; 117(12): 1563 - 1573. [Abstract] [Full Text] [PDF]

				D.-F. Yeih, L.-Y. Lin, H.-I Yeh, Y.-J. Lai, F.-T. Chiang, C.-D. Tseng, S.-H. Chu, and Y.-Z. Tseng Temporal changes in cardiac force- and flow-generation capacity, loading conditions, and mechanical efficiency in streptozotocin-induced diabetic rats Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H867 - H874. [Abstract] [Full Text] [PDF]

				L. van Heerebeek, N. Hamdani, M. L. Handoko, I. Falcao-Pires, R. J. Musters, K. Kupreishvili, A. J.J. Ijsselmuiden, C. G. Schalkwijk, J. G.F. Bronzwaer, M. Diamant, et al. Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension Circulation, January 1, 2008; 117(1): 43 - 51. [Abstract] [Full Text] [PDF]

				Y. G. Ni, N. Wang, D. J. Cao, N. Sachan, D. J. Morris, R. D. Gerard, M. Kuro-o, B. A. Rothermel, and J. A. Hill FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases PNAS, December 18, 2007; 104(51): 20517 - 20522. [Abstract] [Full Text] [PDF]

				Z. Lu, Y.-P. Jiang, X.-H. Xu, L. M. Ballou, I. S. Cohen, and R. Z. Lin Decreased L-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling Diabetes, November 1, 2007; 56(11): 2780 - 2789. [Abstract] [Full Text] [PDF]

				K.A. Connelly, D.J. Kelly, Y. Zhang, D.L. Prior, J. Martin, A.J. Cox, K. Thai, M.P. Feneley, J. Tsoporis, K.E. White, et al. Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat Cardiovasc Res, November 1, 2007; 76(2): 280 - 291. [Abstract] [Full Text] [PDF]

				F. L. Ruberg Myocardial Lipid Accumulation in the Diabetic Heart Circulation, September 4, 2007; 116(10): 1110 - 1112. [Full Text] [PDF]

				S. Belmadani, J. Bernal, C.-C. Wei, M. A. Pallero, L. Dell'Italia, J. E. Murphy-Ullrich, and K. H. Berecek A Thrombospondin-1 Antagonist of Transforming Growth Factor-{beta} Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II Am. J. Pathol., September 1, 2007; 171(3): 777 - 789. [Abstract] [Full Text] [PDF]

				R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]

				S. Kobayashi, K. Mao, H. Zheng, X. Wang, C. Patterson, T. D. O'Connell, and Q. Liang Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury J. Biol. Chem., July 27, 2007; 282(30): 21945 - 21952. [Abstract] [Full Text] [PDF]

				H. Ashrafian, M. P. Frenneaux, and L. H. Opie Metabolic Mechanisms in Heart Failure Circulation, July 24, 2007; 116(4): 434 - 448. [Abstract] [Full Text] [PDF]

				S. M. Davidson and M. R. Duchen Endothelial Mitochondria: Contributing to Vascular Function and Disease Circ. Res., April 27, 2007; 100(8): 1128 - 1141. [Abstract] [Full Text] [PDF]

				P. G. Laustsen, S. J. Russell, L. Cui, A. Entingh-Pearsall, M. Holzenberger, R. Liao, and C. R. Kahn Essential Role of Insulin and Insulin-Like Growth Factor 1 Receptor Signaling in Cardiac Development and Function Mol. Cell. Biol., March 1, 2007; 27(5): 1649 - 1664. [Abstract] [Full Text] [PDF]

				D. Qi and B. Rodrigues Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E654 - E667. [Abstract] [Full Text] [PDF]

				R. Loganathan, M. Bilgen, B. Al-Hafez, S. V. Zhero, M. D. Alenezy, and I. V. Smirnova Exercise training improves cardiac performance in diabetes: in vivo demonstration with quantitative cine-MRI analyses J Appl Physiol, February 1, 2007; 102(2): 665 - 672. [Abstract] [Full Text] [PDF]

				N. Fulop, R. B. Marchase, and J. C. Chatham Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system Cardiovasc Res, January 15, 2007; 73(2): 288 - 297. [Abstract] [Full Text] [PDF]

				M. Aragno, R. Mastrocola, C. Medana, M. G. Catalano, I. Vercellinatto, O. Danni, and G. Boccuzzi Oxidative Stress-Dependent Impairment of Cardiac-Specific Transcription Factors in Experimental Diabetes Endocrinology, December 1, 2006; 147(12): 5967 - 5974. [Abstract] [Full Text] [PDF]

				D. An and B. Rodrigues Role of changes in cardiac metabolism in development of diabetic cardiomyopathy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1489 - H1506. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Poornima, I. G. Articles by Shannon, R. P. Search for Related Content PubMed PubMed Citation Articles by Poornima, I. G. Articles by Shannon, R. P. Related Collections Congestive Myocardial cardiomyopathy disease Type 1 diabetes Type 2 diabetes