Adaptation and Maladaptation of the Heart in Diabetes: Part I

Taegtmeyer, Heinrich; McNulty, Patrick H.; Young, Martin E.

doi:10.1161/01.cir.0000012466.50373.e8

Cited by 478 publications

(392 citation statements)

References 115 publications

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“…29 Although the pathophysiological basis for a distinct diabetic cardiomyopathy remains controversial, 30,31 there is evidence that diabetes affects the myocardium, inducing increased left ventricular mass, diastolic dysfunction, alterations in endothelial function, and direct metabolic effects on myocytes. 30,32 Our finding that diabetes is a potent risk factor for heart failure independent of coronary disease status may support the hypothesis that diabetes operates via direct effects on the myocardium. However, all the women in this cohort had underlying coronary disease, so we cannot exclude the possibility that the adverse effects of diabetes operated via the coronary vasculature.…”

Section: Discussionsupporting

confidence: 68%

Predictors of Heart Failure Among Women With Coronary Disease

Bibbins‐Domingo

Lin²,

Vittinghoff³

et al. 2004

Circulation

152

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Background-Although heart failure is common among women with coronary disease, the risk factors for developing heart failure have not been well studied. We determined the risk factors for developing heart failure among postmenopausal women with established coronary disease. Methods and Results-This is a prospective cohort study using data from the Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled trial of 4.1 years' duration, and subsequent open-label observational follow-up for 2.7 years (HERS II), performed at 20 US clinical centers between 1993 and 2000. Of the 2763 postmenopausal women with established coronary disease in the HERS trial, we studied the 2391 women with no heart failure at baseline by self-report and physical examination. The primary outcome of this analysis was incident heart failure defined by hospital admission or death from heart failure. During the 6.3Ϯ1.4-year follow-up, 237 women (10%) developed heart failure. Nine predictors were identified: diabetes (defined as a self-reported history of diabetes on treatment), atrial fibrillation, myocardial infarction, creatinine clearance Ͻ40 mL/min, systolic blood pressure Ͼ120 mm Hg, current smoking, body mass index Ͼ35 kg/m 2 , left bundle-branch block, and left ventricular hypertrophy. Randomization to estrogen/progestin was not associated with heart failure (hazard ratioϭ1.0; 95% CI, 0.7 to 1.3). Diabetes was the strongest risk factor (adjusted hazard ratioϭ3.1; 95% CI, 2.3 to 4.2). Diabetic women with elevated body mass index or depressed creatinine clearance were at highest risk, with annual incidence rates of 7% and 13%, respectively. Among diabetic women, hyperglycemia was associated with heart failure risk (adjusted hazard ratioϭ3.0; 95% CI, 1.2 to 7.5 for fasting glucose Ͼ300 mg/dL compared with fasting glucose 80 to 150 mg/dL). Conclusions-We identified 9 predictors of heart failure in postmenopausal women with coronary disease. Diabetes was the strongest risk factor, particularly when poorly controlled or with concomitant renal insufficiency or obesity.

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Section: Discussionsupporting

confidence: 68%

Predictors of Heart Failure Among Women With Coronary Disease

Bibbins‐Domingo

Lin²,

Vittinghoff³

et al. 2004

Circulation

152

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“…Although hearts are continually contracting, increased body activity and exercise will increase the rate of heart contraction, and consequently, there will be increased demands for glucose. Insulin regulation of this activity is essential because persons with type 2 diabetes have increased risk of heart failure, and cardiovascular disease is the leading cause of death in diabetic patients (31). Impairments in glucose supply and utilization occur in heart from type 2 diabetic patients (32) and animal models of type 2 diabetes (33).…”

Section: Discussionmentioning

confidence: 99%

Insulin and Contraction Stimulate Exocytosis, but Increased AMP-activated Protein Kinase Activity Resulting from Oxidative Metabolism Stress Slows Endocytosis of GLUT4 in Cardiomyocytes

Yang

Holman

2005

Journal of Biological Chemistry

103

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Stimulations of glucose transport produced by insulin action, contraction, or through a change in cell energy status are mediated by separate signaling pathways. These are the wortmannin-sensitive phosphatidylinositol 3-kinase pathway leading to the intermediate Akt and the wortmannin-insensitive AMP-activated protein kinase (AMPK) pathway. Electrical stimulation of cardiomyocytes produced a rapid, insulin-like, wortmannin-sensitive stimulation of glucose transport activity, but this occurred without extensive activation of Akt. Although AMPK phosphorylation was increased by contraction, this response was not wortmannin-inhibitable and consequently did not correlate with the wortmannin sensitivity of the transport stimulation. Oxidative metabolism stress due to hypoxia or treatment with oligomycin led to increased AMPK activity with a corresponding increase in glucose transport activity. We show here that these separate signaling pathways converge on GLUT4 trafficking at separate steps. The rate of exocytosis of GLUT4 was rapidly stimulated by insulin, but insulin treatment did not alter the endocytosis rate. Like insulin stimulation, electrical stimulation of contraction led to a stimulation of GLUT4 exocytosis without any marked change in endocytosis. By contrast, after oxidative metabolism stress, no stimulation of GLUT4 exocytosis occurred; instead, this treatment led to a reduction in GLUT4 endocytosis.Regulation of cellular energy levels and metabolic processes are intricately dependent on the supply of glucose, and there are now known to be multiple mechanisms controlling this supply to specific tissues. Insulin stimulation of glucose transport occurs in response to raised blood glucose or when stimulated storage of glucose, in the form of glycogen and triglyceride, is necessary. A stimulation of glucose uptake is also necessary during metabolic stress such as that which occurs during hypoxia and ischemia. Recent work in this area has identified AMP-activated protein kinase (AMPK) 1 as the key regulatory intermediate of these processes. This protein functions as an energy level sensor in organisms ranging from yeast to mammals (1, 2). Increased AMPK activity is associated with increased glucose transport in cell lines (3, 4) and skeletal muscle that have been challenged by a metabolic stress stimulus or more direct activation of the kinase by the AMP analogue, ZMP, which is produced from the nucleoside AICAR (5, 6). Contraction of skeletal myocytes is also known to lead to increased levels of glucose transport. Evidence from transgenic mice expressing a dominant inhibitory form of AMPK suggest that although AMPK is involved in regulation of hypoxia-induced glucose transport, it may not be involved in the contraction response (7). Similar conclusions have been reached in studies on animal models for obesity-related type 2 diabetes (8).Electrically stimulated contraction of cardiac myocytes also leads to stimulation of glucose transport. This occurs without a marked stimulation of Akt phosphorylation. Howev...

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“…Myocardial lipid metabolism is also increased (and glucose utilisation suppressed) in diabetes (see [1,24]), so both substrate and cellular factors are likely to be important. CM-TAG from streptozotocin (STZ)-diabetic rats were apo-E deficient, and cleared from the plasma of non-diabetic rats more slowly than control CM-TAG [20]; furthermore incubation of diabetic CM with HDL increased their apo-E content and increased their uptake by heart [20].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The role of triacylglycerol in cardiac energy provision

Evans

Hui‐Kang

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity.Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through bloodborne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FA) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives.Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 3Key words:heart; triacylglycerol; very-low-density lipoprotein; VLDL; chylomicron; lipid droplet Highlights: Triacylglycerols are supplied to the myocardium within chylomicrons and VLDL  Heart assimilates triacylglycerol-rich lipoproteins by LPL and receptor-mediated routes  Exogenous triacylglycerol-derived fatty acids enter an intracellular lipid pool  Intracardiac triacylglycerol is an important source of fatty acids for oxidation  Dysregulation of triacylglycerol metabolism is associated with cardiac dysfunction

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Adaptation and Maladaptation of the Heart in Diabetes: Part I

Cited by 478 publications

References 115 publications

Predictors of Heart Failure Among Women With Coronary Disease

Predictors of Heart Failure Among Women With Coronary Disease

Insulin and Contraction Stimulate Exocytosis, but Increased AMP-activated Protein Kinase Activity Resulting from Oxidative Metabolism Stress Slows Endocytosis of GLUT4 in Cardiomyocytes

The role of triacylglycerol in cardiac energy provision

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