Glucose and Palmitic Acid Induce Degeneration of Myofibrils and Modulate Apoptosis in Rat Adult Cardiomyocytes

Dyntar, Daniela; Eppenberger‐Eberhardt, Monika; Maedler, Kathrin; Pruschy, Martin; Eppenberger, Hans M.; Spinas, Giatgen A.; Donath, Marc Y.

doi:10.2337/diabetes.50.9.2105

Cited by 184 publications

(116 citation statements)

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“…In the heart, when supply of fatty acid exceeds tissue oxidative capacity, the accumulation of lipids decreases cardiolipin synthesis [36] and induces myofibrillar degeneration [10], leading to lipotoxicity and apoptosis. Given that exogenous C 2 -ceramide mimics the deleterious effects of fatty acid, and that inhibition of ceramide formation blocks these toxic effects caused by high fat, several studies have suggested that de novo ceramide formation plays an important contributory role in apoptosis [8,37,38].…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, an increase in intracardiac fatty acid concentration can overwhelm fatty acid oxidation. In this situation, fatty acids accumulate and can, either by themselves, or via their channelling towards the production of second messengers like ceramide, provoke apoptosis [9,10]. Enlargement of the intracardiac fatty acid pool during diabetes may similarly overpower the tissue capacity for utilisation, resulting in an accumulation of cardiotoxic lipid, which may be implicated in cardiac myocyte apoptosis [8,11].…”

Section: Introductionmentioning

confidence: 99%

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Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

et al. 2006

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Aims/hypothesis Metformin has been shown to increase fatty acid oxidation, an effect mediated by AMP activated protein kinase (AMPK). We hypothesised that metformin could prevent both caspase-3 activation and apoptosis when induced by palmitic acid. Materials and methods Cardiomyocytes were incubated with 1 mmol/l palmitic acid, in the absence or presence of metformin (1-5 mmol/l). Following 1 to 16 h, cell damage was evaluated by measuring lactate dehydrogenase released into the incubation medium, and Hoechst staining. To investigate the mechanism of metformin's effect on cardiomyocytes, substrate utilisation and phosphorylation of AMPK and acetyl-CoA carboxylase were measured. Intracellular mediators of apoptosis were also evaluated. Results Incubation of myocytes with palmitic acid for 16 h increased apoptosis, an effect that was partly blunted by 1 and 2 mmol/l metformin. This beneficial effect of metformin was associated with increased AMPK phosphorylation, palmitic acid oxidation and suppression of high-fat-induced increases in (1) long chain base biosynthesis protein 1 levels, (2) ceramide levels, and (3) caspase-3 activity. Unexpectedly, 5 mmol/l metformin dramatically increased apoptosis in myocytes incubated with high fat. This effect was associated with a robust increase in glycolysis, lactate accumulation, and a significant drop of pH in the myocyte incubation medium. Conclusions/interpretation Our study demonstrates that metformin reduces high-fat-induced cardiac cell death, probably through inhibition of ceramide synthesis. However, at high concentrations, metformin causes proton and lactate accumulation, leading to cell damage that is independent of caspase-3.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

et al. 2006

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“…5 . Fatty acids were dissolved at 10 mmol/l in culture medium containing 11% fatty acid-free BSA (Sigma) under N 2 -atmosphere, shaken overnight at 37°C, sonicated 15 min, and sterile-filtrated (stock solution) (15,26). For control experiments, BSA in the absence of fatty acids was prepared, as described above.…”

Section: Methodsmentioning

confidence: 99%

Monounsaturated Fatty Acids Prevent the Deleterious Effects of Palmitate and High Glucose on Human Pancreatic β-Cell Turnover and Function

Maedler¹,

et al. 2003

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Glucotoxicity and lipotoxicity contribute to the impaired ␤-cell function observed in type 2 diabetes. Here we examine the effect of saturated and monounsaturated fatty acids at different glucose concentrations on human ␤-cell turnover and secretory function. Exposure of cultured human islets to saturated fatty acid and/or to an elevated glucose concentration for 4 days increased ␤-cell DNA fragmentation and decreased ␤-cell proliferation. In contrast, the monounsaturated palmitoleic acid or oleic acid did not affect DNA fragmentation and induced ␤-cell proliferation. Moreover, each monounsaturated fatty acid prevented the deleterious effects of both palmitic acid and high glucose concentration. The cell-permeable ceramide analogue C 2 -ceramide mimicked both the palmitic acid-induced ␤-cell apoptosis and decrease in proliferation. Furthermore, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on ␤-cell turnover. In addition, palmitic acid decreased Bcl-2 expression and induced release of cytochrome c from the mitochondria into the cytosol, which was prevented by fumonisin B1 and by oleic acid. Finally, each monounsaturated fatty acid improved ␤-cell secretory function that was reduced by palmitic acid and by high glucose. Thus, in human islets, the saturated palmitic acid and elevated glucose concentration induce ␤-cell apoptosis, decrease ␤-cell proliferation, and impair ␤-cell function, which can be prevented by monounsaturated fatty acids. The deleterious effect of palmitic acid is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway, whereas Bcl-2 may contribute to the protective effect of monounsaturated fatty acids.

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“…Thus, long-term exposure to saturated fatty acids such as palmitate appear highly toxic, whereas monounsaturated fatty acids such as oleate protect against both palmitate-and glucose-induced ␤-cell apoptosis (18,31). It is of interest to note that similar toxic effects are also observed in non-␤-cells such as cardiac cells (32). Lipoproteins may affect ␤-cell survival in a similar way, whereby VLDL and LDL are pro-apoptotic and HDL is protective (33,34).…”

Section: Dyslipidemia Leptin and Inflammation: Linking Obesity To ␤mentioning

confidence: 99%

Mechanisms of β-Cell Death in Type 2 Diabetes

et al. 2005

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A decrease in the number of functional insulin-producing ␤-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in ␤-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of ␤-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K ؉ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-B, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of ␤-cell secretory function and cell turnover. Thus, the mechanisms regulating ␤-cell proliferation, apoptosis, and function are inseparable processes. Diabetes 54 (Suppl. 2):S108 -S113, 2005 F or many years, the contribution of a reduction in ␤-cell mass to the development of type 2 diabetes was heavily debated. Recently, several publications have convincingly confirmed this hypothesis (1-3), leading to a rapid overemphasis of this etiological factor. Indeed, other mechanisms contributing to the failure of the ␤-cell to produce enough insulin appear more and more neglected. While we strongly believe that ␤-cell destruction is an important etiological factor in the development and progression of type 2 diabetes, in this review, we will highlight evidence that this is not dissociable from an intrinsic secretory defect. We will show that pathways regulating ␤-cell turnover are also implicated in ␤-cell insulin secretory function. It follows that adaptive mechanisms of function and mass share common regulatory pathways and will therefore act in concert. Depending on the prevailing concentration and the intracellular pathways activated, some factors may be deleterious to ␤-cell mass while enhancing insulin secretion, protective to the ␤-cell while inhibiting function, or even protective to the ␤-cell while enhancing function. It will become apparent that the failure of the ␤-cell in type 2 diabetes is akin to a multifactorial equation, with an overall negative result.Thus, although we will review the factors and mechanisms regulating ␤-cell mass individually, only in a minority of diabetic patients does one single etiological factor underlie the failure of the ␤-cell. In addition to maturityonset diabetes of the young, another example of this is autoimmune-mediated destruction of ␤-cells in young lean individuals. However, given that the incidence of type 1 diabetes increases with obesity (4), that insulin resistance is a risk factor for the progression of this condition (5), and that ϳ50% of the general population carry the same genetic predisposition (6), this example already implicates multiple etiological factors. Recognition of ␤-cell destruction not only in type 1 but also in type 2 diabetes led us to recently propose a unif...

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Glucose and Palmitic Acid Induce Degeneration of Myofibrils and Modulate Apoptosis in Rat Adult Cardiomyocytes

Cited by 184 publications

References 38 publications

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

Metformin influences cardiomyocyte cell death by pathways that are dependent and independent of caspase-3

Monounsaturated Fatty Acids Prevent the Deleterious Effects of Palmitate and High Glucose on Human Pancreatic β-Cell Turnover and Function

Mechanisms of β-Cell Death in Type 2 Diabetes

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