Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

Schwanke, Mary L.; Dutta, Kaushik; Podolin, Deborah A.; Davidoff, Amy J.

doi:10.1007/s00125-006-0184-9

Cited by 12 publications

(6 citation statements)

References 44 publications

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“…Experimental evidence suggested that female rats are better protected from hyperglycemic and insulin resistance–induced insult unless they are ovariectomized, consistent with the observation that estrogen alleviates diabetic complications in males (63,64). Estrogen is known to maintain normal adipose tissue biology, liver fatty acid metabolism, and suppression of hepatic glucose production.…”

Section: Gender Insulin Sensitivity Glucose and Lipid Homeostasissupporting

confidence: 77%

Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology

Ren

Kelley

2009

Obesity

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Although the classical cardiovascular risk factors (e.g., smoking and hypertension) are becoming more effectively managed, a continuous increase of the so-called "cardiometabolic risk" is noted. Starting from this century, the nomenclature "metabolic syndrome" has become more popular to identify a cluster of disorders including obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease in both genders. Interestingly, the metabolic diseases display a distinct gender disparity with an apparent "female advantage" in the premenopausal women compared with age-matched men. However, women usually lose such "sex protection" following menopause or affliction of metabolic syndrome especially insulin resistance. A controversy exists in the medical literature concerning whether metabolic syndrome is a real syndrome or simply a cluster of risk factors. Several scenarios are speculated to contribute to the gender dimorphism in the cardiovascular sequelae in patients with metabolic syndrome including sex hormones, intrinsic organ function, and the risk factor profile (e.g., hypertension, dyslipidemia, obesity, sedentary lifestyle, and atherogenic diet). With the alarming rise of obesity prevalence, heart problems in metabolic syndrome continue to rise with a distinct gender dimorphism. Although female hearts seem to better tolerate the stress insults compared with the male counterparts, the female sex hormones such as estrogen can interact with certain risk factors to precipitate myopathic changes in the hearts. This synthetic review of recent literature suggests a role of gender disparity in myopathic factors and risk attributable to each metabolic component in the different prevalence of metabolic syndrome.

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Section: Gender Insulin Sensitivity Glucose and Lipid Homeostasissupporting

confidence: 77%

Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology

Ren

Kelley

2009

Obesity

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“…Myocyte relengthening [A R /PK, TR, and maximum negative length change (Max ϪdL/dt)] was also similar in the ZDF and Lean control groups. The lack of impaired contraction and relaxation in the 6-wk ZDF group was somewhat surprising since insulin resistance (duration Ն7 wk) has been shown to adversely affect cardiomyocyte E-C coupling (29,33). However, at 22 wk of age both contraction and relaxation were significantly impaired in the hyperglycemic ZDF group compared with controls.…”

Section: Resultsmentioning

confidence: 93%

Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart

Fülöp¹,

Mason²,

Dutta³

et al. 2007

American Journal of Physiology-Cell Physiology

115

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Increased levels of O-linked attachment of N-acetylglucosamine (OGlcNAc) on nucleocytoplasmic proteins are implicated in the development of diabetic cardiomyopathy and are regulated by O-GlcNAc transferase (OGT) expression and its substrate UDP-GlcNAc. Therefore, the goal of this study was to determine whether the development of diabetes in the Zucker diabetic fatty (ZDF) rat, a model of Type 2 diabetes, results in defects in cardiomyocyte mechanical function and, if so, whether this is associated with increased levels of O-GlcNAc and increased OGT expression. Six-week-old ZDF rats were hyperinsulinemic but normoglycemic, and there were no differences in cardiomyocyte mechanical function, UDP-GlcNAc, O-GlcNAc, or OGT compared with age-matched lean control rats. Cardiomyocytes isolated from 22-wk-old hyperglycemic ZDF rats exhibited significantly impaired relaxation, compared with both age-matched lean control and 6-wk-old ZDF groups. There was also a significant increase in O-GlcNAc levels in high-molecular-mass proteins in the 22-wk-old ZDF group compared with age-matched lean control and 6-wk-old ZDF groups; this was associated with increased UDPGlcNAc levels but not increased OGT expression. Surprisingly, there was a significant decrease in overall O-GlcNAc levels between 6 and 22 wk of age in lean, ZDF, and Sprague-Dawley rats that was associated with decreased OGT expression. These results support the notion that an increase in O-GlcNAc on specific proteins may contribute to impaired cardiomyocyte function in diabetes. However, this study also indicates that in the heart the level of O-GlcNAc on proteins appears to be differentially regulated by age and diabetes. hexosamine biosynthesis; protein O-glycosylation; O-linked N-acetylglucosamine transferaseIT IS WELL ESTABLISHED that diabetes leads to a markedly increased risk for cardiovascular disease including heart failure (12). Although much of the increased risk can be attributed to an increase in atherosclerosis, there is clear clinical (11) and experimental (2, 5, 28, 32) evidence demonstrating that diabetes leads to changes at the level of the myocardium consistent with the development of a diabetic cardiomyopathy. The mechanisms underlying the development of diabetic cardiomyopathy are not well understood; however, it has been proposed that the adverse effects of hyperglycemia on cardiomyocyte function may be mediated via a number of different pathways including increased flux through the polyol pathway (2); increased advanced glycation end products (2, 26); and protein kinase activity and increased levels of O-linked N-acetylglucosamine (O-GlcNAc) on proteins (2, 7, 14, 24).There is increasing recognition that the O-GlcNAc modification of serine and threonine residues on cytosolic and nuclear proteins is an important regulatory mechanism involved in signal transduction (20,34). Unlike other glycosylation events, this reaction occurs in the cytosol and the nucleus rather than in the Golgi or the endoplasmic reticulum and is regulated by the activities ...

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“…The fructose concentration (11 mM) was chosen as an equimolar replacement of glucose to ensure controlled superfusate conditions (this fructose level would not normally be observed in vivo ). The glucose buffer composition was modeled on standard formulations used in previous in vitro studies and the glucose concentration employed is consistent with plasma glucose levels reported for rodents (generally higher than humans) [19], [20], [21]. Myocytes were superfused for 2–3 minutes to obtain steady-state, and measurements of intracellular Ca 2+ and myocyte twitch kinetics were recorded for a 2 min treatment period for each cell.…”

Section: Methodsmentioning

confidence: 99%

Fructose Modulates Cardiomyocyte Excitation-Contraction Coupling and Ca2+ Handling In Vitro

et al. 2011

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BackgroundHigh dietary fructose has structural and metabolic cardiac impact, but the potential for fructose to exert direct myocardial action is uncertain. Cardiomyocyte functional responsiveness to fructose, and capacity to transport fructose has not been previously demonstrated.ObjectiveThe aim of the present study was to seek evidence of fructose-induced modulation of cardiomyocyte excitation-contraction coupling in an acute, in vitro setting.Methods and ResultsThe functional effects of fructose on isolated adult rat cardiomyocyte contractility and Ca2+ handling were evaluated under physiological conditions (37°C, 2 mM Ca2+, HEPES buffer, 4 Hz stimulation) using video edge detection and microfluorimetry (Fura2) methods. Compared with control glucose (11 mM) superfusate, 2-deoxyglucose (2 DG, 11 mM) substitution prolonged both the contraction and relaxation phases of the twitch (by 16 and 36% respectively, p<0.05) and this effect was completely abrogated with fructose supplementation (11 mM). Similarly, fructose prevented the Ca2+ transient delay induced by exposure to 2 DG (time to peak Ca2+ transient: 2 DG: 29.0±2.1 ms vs. glucose: 23.6±1.1 ms vs. fructose +2 DG: 23.7±1.0 ms; p<0.05). The presence of the fructose transporter, GLUT5 (Slc2a5) was demonstrated in ventricular cardiomyocytes using real time RT-PCR and this was confirmed by conventional RT-PCR.ConclusionThis is the first demonstration of an acute influence of fructose on cardiomyocyte excitation-contraction coupling. The findings indicate cardiomyocyte capacity to transport and functionally utilize exogenously supplied fructose. This study provides the impetus for future research directed towards characterizing myocardial fructose metabolism and understanding how long term high fructose intake may contribute to modulating cardiac function.

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Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage

Cited by 12 publications

References 44 publications

Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology

Cardiac Health in Women With Metabolic Syndrome: Clinical Aspects and Pathophysiology

Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart

Fructose Modulates Cardiomyocyte Excitation-Contraction Coupling and Ca2+ Handling In Vitro

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