Heart failure is associated with generalized insulin resistance. Moreover, insulin resistant states such as type 2 diabetes and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes alters the systemic and neurohumoral milieu leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead (FOXO) transcriptional signaling or glucose transport which may also impair cardiac metabolism, structure and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed.

Abstract-Impaired insulin signaling via phosphatidylinositol 3-kinase/Akt to endothelial nitric oxide synthase (eNOS) in the vasculature has been postulated to lead to arterial dysfunction and hypertension in obesity and other insulin resistant states. To investigate this, we compared insulin signaling in the vasculature, endothelial function, and systemic blood pressure in mice fed a high-fat (HF) diet to mice with genetic ablation of insulin receptors in all vascular tissues (TTr-IR Ϫ/Ϫ ) or mice with genetic ablation of Akt1 (Akt1Ϫ/Ϫ). HF mice developed obesity, impaired glucose tolerance, and elevated free fatty acids that was associated with endothelial dysfunction and hypertension. Basal and insulin-mediated phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in the vasculature was preserved, but basal and insulin-stimulated eNOS phosphorylation was abolished in vessels from HF versus lean mice. In contrast, basal vascular eNOS phosphorylation, endothelial function, and blood pressure were normal despite absent insulinmediated eNOS phosphorylation in TTr-IR Ϫ/Ϫ mice and absent insulin-mediated eNOS phosphorylation via Akt1 in Akt1Ϫ/Ϫ mice. In cultured endothelial cells, 6 hours of incubation with palmitate attenuated basal and insulinstimulated eNOS phosphorylation and NO production despite normal activation of extracellular signal-regulated kinase 1/2 and Akt. Moreover, incubation of isolated arteries with palmitate impaired endothelium-dependent but not vascular smooth muscle function. Collectively, these results indicate that lower arterial eNOS phosphorylation, hypertension, and vascular dysfunction following HF feeding do not result from defective upstream signaling via Akt, but from free fatty acid-mediated impairment of eNOS phosphorylation. Key Words: arterial insulin signaling Ⅲ hypertension Ⅲ endothelial dysfunction Ⅲ mice Ⅲ diabetes S timulation of insulin receptors in the vasculature leads to increased activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the mitogen-activated protein (MAP) kinase (eg, extracellular signaling-regulated kinase [ERK]1/2) pathway. [1][2][3][4] Insulin receptor (IR)-mediated stimulation of PI3K/Akt leads to endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and vasorelaxation. 4 -7 Insulin-mediated activation of ERK1/2 leads to endothelin (ET)-1 production, inhibition of eNOS phosphorylation, and subsequent vasocontraction. 1,4,8 Evidence from several experimental models of insulin resistance reveals impaired insulin-mediated PI3K/Aktdependent signaling in the vasculature, whereas ERK1/2 pathways are preserved or even augmented. 2,8,9 Collectively, these observations have led to the hypothesis that an imbalance in vascular insulin-mediated signaling can precipitate cardiovascular complications including endothelial dysfunction and hypertension. 1,4 Recently, it was shown that insulinmediated Akt phosphorylation was preserved, but NOmediated vasorelaxation was blunted, in arteries from obese, glucose ...

OBJECTIVETo elucidate the molecular basis for mitochondrial dysfunction, which has been implicated in the pathogenesis of diabetes complications.RESEARCH DESIGN AND METHODSMitochondrial matrix and membrane fractions were generated from liver, brain, heart, and kidney of wild-type and type 1 diabetic Akita mice. Comparative proteomics was performed using label-free proteome expression analysis. Mitochondrial state 3 respirations and ATP synthesis were measured, and mitochondrial morphology was evaluated by electron microscopy. Expression of genes that regulate mitochondrial biogenesis, substrate utilization, and oxidative phosphorylation (OXPHOS) were determined.RESULTSIn diabetic mice, fatty acid oxidation (FAO) proteins were less abundant in liver mitochondria, whereas FAO protein content was induced in mitochondria from all other tissues. Kidney mitochondria showed coordinate induction of tricarboxylic acid (TCA) cycle enzymes, whereas TCA cycle proteins were repressed in cardiac mitochondria. Levels of OXPHOS subunits were coordinately increased in liver mitochondria, whereas mitochondria of other tissues were unaffected. Mitochondrial respiration, ATP synthesis, and morphology were unaffected in liver and kidney mitochondria. In contrast, state 3 respirations, ATP synthesis, and mitochondrial cristae density were decreased in cardiac mitochondria and were accompanied by coordinate repression of OXPHOS and peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC)-1α transcripts.CONCLUSIONSType 1 diabetes causes tissue-specific remodeling of the mitochondrial proteome. Preservation of mitochondrial function in kidney, brain, and liver, versus mitochondrial dysfunction in the heart, supports a central role for mitochondrial dysfunction in diabetic cardiomyopathy.

Heart disease is a major cause of death worldwide with increasing prevalence, which urges the development of new therapeutic strategies. Over the last few decades, numerous small animal models have been generated to mimic various pathomechanisms contributing to heart failure (HF). Despite some limitations, these animal models have greatly advanced our understanding of the pathogenesis of the different aetiologies of HF and paved the way to understanding the underlying mechanisms and development of successful treatments. These models utilize surgical techniques, genetic modifications, and pharmacological approaches. The present review discusses the strengths and limitations of commonly used small animal HF models, which continue to provide crucial insight and facilitate the development of new treatment strategies for patients with HF.

Rationale Pressure overload cardiac hypertrophy, a risk factor for heart failure, is associated with reduced mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) proteins that correlate in rodents with reduced PGC-1α expression. Objective To determine the role of PGC-1β in maintaining mitochondrial energy metabolism and contractile function in pressure overload hypertrophy. Methods and Results PGC-1β deficient (KO) mice and wildtype controls (WT) were subjected to transverse aortic constriction (TAC). Although LV function was modestly reduced in young KO hearts, there was no further decline with age so that LV function was similar between KO and WT when TAC was performed. WT – TAC mice developed relatively compensated LVH, despite reduced mitochondrial function and repression of OXPHOS and FAO genes. In non-stressed KO hearts, OXPHOS gene expression and palmitoyl-carnitine supported mitochondrial function were reduced to the same extent as banded WT, but FAO gene expression was normal. Following TAC, KO mice progressed more rapidly to heart failure and developed more severe mitochondrial dysfunction, despite a similar overall pattern of repression of OXPHOS and FAO genes as WT – TAC. However, relative to WT TAC, PGC-1β deficient mice exhibited greater degrees of oxidative stress, decreased cardiac efficiency, lower rates of glucose metabolism and repression of hexokinase II protein. Conclusions PGC-1β plays an important role in maintaining baseline mitochondrial function and cardiac contractile function following pressure overload hypertrophy by preserving glucose metabolism and preventing oxidative stress.

Diabetes mellitus increases the risk of heart failure independent of co-existing hypertension and coronary artery disease. Although several molecular mechanisms for the development of diabetic cardiomyopathy have been identified, they are incompletely understood. The pathomechanisms are multifactorial and as a consequence, no causative treatment exists at this time to modulate or reverse the molecular changes contributing to accelerated cardiac dysfunction in diabetic patients. Numerous animal models have been generated, which serve as powerful tools to study the impact of type 1 and type 2 diabetes on the heart. Despite specific limitations of the models generated, they mimic various perturbations observed in the diabetic myocardium and continue to provide important mechanistic insight into the pathogenesis underlying diabetic cardiomyopathy. This article reviews recent studies in both diabetic patients and in these animal models, and discusses novel hypotheses to delineate the increased incidence of heart failure in diabetic patients.

Insulin and adrenergic stimulation are two divergent regulatory systems that may interact under certain pathophysiological circumstances. Here, we characterized a complex consisting of insulin receptor (IR) and β2-adrenergic receptor (β2AR) in the heart. The IR/β2AR complex undergoes dynamic dissociation under diverse conditions such as Langendorff perfusions of hearts with insulin or after euglycemic-hyperinsulinemic clamps in vivo. Activation of IR with insulin induces protein kinase A (PKA) and G-protein receptor kinase 2 (GRK2) phosphorylation of the β2AR, which promotes β2AR coupling to the inhibitory G-protein, Gi. The insulin-induced phosphorylation of β2AR is dependent on IRS1 and IRS2. After insulin pretreatment, the activated β2AR-Gi signaling effectively attenuates cAMP/PKA activity after β-adrenergic stimulation in cardiomyocytes and consequently inhibits PKA phosphorylation of phospholamban and contractile responses in myocytes in vitro and in Langendorff perfused hearts. These data indicate that increased IR signaling, as occurs in hyperinsulinemic states, may directly impair βAR-regulated cardiac contractility. This β2AR-dependent IR and βAR signaling cross-talk offers a molecular basis for the broad interaction between these signaling cascades in the heart and other tissues or organs that may contribute to the pathophysiology of metabolic and cardiovascular dysfunction in insulin-resistant states.

Insulin and insulin-like growth factor 1 (IGF-1) receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrate 1 (IRS1) and IRS2, which also differentially regulate resting cardiac mass. To determine the role of IRS isoforms in mediating the hypertrophic and metabolic adaptations of the heart to exercise training, we subjected mice with cardiomyocyte-specific deletion of either IRS1 (CIRS1 knockout [CIRS1KO] mice) or IRS2 (CIRS2KO mice) to swim training. CIRS1KO hearts were reduced in size under basal conditions, whereas CIRS2KO hearts exhibited hypertrophy. Following exercise swim training in CIRS1KO and CIRS2KO hearts, the hypertrophic response was equivalently attenuated, phosphoinositol 3-kinase (PI3K) activation was blunted, and prohypertrophic signaling intermediates, such as Akt and glycogen synthase kinase 3␤ (GSK3␤), were dephosphorylated potentially on the basis of reduced Janus kinase-mediated inhibition of protein phosphatase 2a (PP2A). Exercise training increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1␣) protein content, mitochondrial capacity, fatty acid oxidation, and glycogen synthesis in wild-type (WT) controls but not in IRS1-and IRS2-deficient hearts. PGC-1␣ protein content remained unchanged in CIRS1KO but decreased in CIRS2KO hearts. These results indicate that although IRS isoforms play divergent roles in the developmental regulation of cardiac size, these isoforms exhibit nonredundant roles in mediating the hypertrophic and metabolic response of the heart to exercise. C ardiac hypertrophy is the growth response of the heart to increased workload and has been categorized as physiological or pathological hypertrophy. Cardiac hypertrophy is considered pathological if contractile dysfunction occurs after an initial phase of compensation, which ultimately results in heart failure. Common causes for pathological hypertrophy are valvular disease and hypertension. In contrast, physiological hypertrophy is characterized by adaptive myocyte growth with a new steady state and preserved contractile function, as exemplified by the response to chronic exercise training, also known as "athlete's heart" (1). The differences between physiological and pathological cardiac hypertrophy have been attributed in part to differences in intracellular signaling pathways. For example, insulin receptor-and insulinlike growth factor 1 (IGF-1) receptor-mediated signaling to phosphatidylinositol 3-kinase (PI3K) and Akt1 have been implicated in physiological cardiac hypertrophy, whereas activation of G protein-coupled pathways, such as angiotensin II and adrenergic signaling, has been associated with pathological hypertrophy (2, 3).We previously reported that cardiomyocyte-selective deletion of the insulin receptor (CIRKO) reduced heart size by 20 to 30% (4), whereas under basal conditions IGF-1 receptor deletion was without effect (5). CIRKO hearts exhibit increased ...