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Paul R Robertson - One of the best experts on this subject based on the ideXlab platform.
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glucoLipotoxicity fuel excess and β cell dysfunction
Endocrine Reviews, 2008Co-Authors: Vincent Poitout, Paul R RobertsonAbstract:Glucotoxicity, Lipotoxicity, and glucoLipotoxicity are secondary phenomena that are proposed to play a role in all forms of type 2 diabetes. The underlying concept is that once the primary pathogenesis of diabetes is established, probably involving both genetic and environmental forces, hyperglycemia and very commonly hyperlipidemia ensue and thereafter exert additional damaging or toxic effects on the β-cell. In addition to their contribution to the deterioration of β-cell function after the onset of the disease, elevations of plasma fatty acid levels that often accompany insulin resistance may, as glucose levels begin to rise outside of the normal range, also play a pathogenic role in the early stages of the disease. Because hyperglycemia is a prerequisite for Lipotoxicity to occur, the term glucoLipotoxicity, rather than Lipotoxicity, is more appropriate to describe deleterious effects of lipids on β-cell function. In vitro and in vivo evidence supporting the concept of glucotoxicity is presented first, as well as a description of the underlying mechanisms with an emphasis on the role of oxidative stress. Second, we discuss the functional manifestations of glucoLipotoxicity on insulin secretion, insulin gene expression, and β-cell death, and the role of glucose in the mechanisms of glucoLipotoxicity. Finally, we attempt to define the role of these phenomena in the natural history of β-cell compensation, decompensation, and failure during the course of type 2 diabetes.
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β cell glucose toxicity Lipotoxicity and chronic oxidative stress in type 2 diabetes
Diabetes, 2004Co-Authors: Paul R Robertson, Jamie S Harmon, Phuong Oanh T Tran, Vincent PoitoutAbstract:The relentless decline in β-cell function frequently observed in type 2 diabetic patients, despite optimal drug management, has variously been attributed to glucose toxicity and Lipotoxicity. The former theory posits hyperglycemia, an outcome of the disease, as a secondary force that further damages β-cells. The latter theory suggests that the often-associated defect of hyperlipidemia is a primary cause of β-cell dysfunction. We review evidence that patients with type 2 diabetes continually undergo oxidative stress, that elevated glucose concentrations increase levels of reactive oxygen species in β-cells, that islets have intrinsically low antioxidant enzyme defenses, that antioxidant drugs and overexpression of antioxidant enzymes protect β-cells from glucose toxicity, and that Lipotoxicity, to the extent it can be attributable to hyperlipidemia, occurs only in the context of preexisting hyperglycemia, whereas glucose toxicity can occur in the absence of hyperlipidemia.
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minireview secondary β cell failure in type 2 diabetes a convergence of glucotoxicity and Lipotoxicity
Endocrinology, 2002Co-Authors: Vincent Poitout, Paul R RobertsonAbstract:Chronic hyperglycemia and hyperlipidemia can exert deleterious effects on -cell function, respectively referred to as glucotoxicity and Lipotoxicity. Over time, both contribute to the progressive deterioration of glucose homeostasis characteristic of type 2 diabetes. The mechanisms of glucotoxicity involve several transcription factors and are, at least in part, mediated by generation of chronic oxidative stress. Lipotoxicity is probably mediated by accumulation of a cytosolic signal derived from the fatty acid esterification pathway. Our view that hyperglycemia is a prerequisite for Lipotoxicity is supported by several recent studies performed in our laboratories. First, prolonged in vitro exposure of isolated islets to fatty acids decreases insulin gene expression in the presence of high glucose concentrations only, and glucose is ratelimiting for the incorporation of fatty acids into neutral lipids. Second, normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, whereas normalization of plasma lipid levels is without effect. Third, high-fat feeding in Goto-Kakizaki rats significantly impairs glucoseinduced insulin secretion in vitro, whereas a similar diet has no effect in normoglycemic animals. We propose that chronic hyperglycemia, independent of hyperlipidemia, is toxic for -cell function, whereas chronic hyperlipidemia is deleterious only in the context of concomitant hyperglycemia. (Endocrinology 143: 339 –342, 2002)
Vincent Poitout - One of the best experts on this subject based on the ideXlab platform.
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glucoLipotoxicity fuel excess and β cell dysfunction
Endocrine Reviews, 2008Co-Authors: Vincent Poitout, Paul R RobertsonAbstract:Glucotoxicity, Lipotoxicity, and glucoLipotoxicity are secondary phenomena that are proposed to play a role in all forms of type 2 diabetes. The underlying concept is that once the primary pathogenesis of diabetes is established, probably involving both genetic and environmental forces, hyperglycemia and very commonly hyperlipidemia ensue and thereafter exert additional damaging or toxic effects on the β-cell. In addition to their contribution to the deterioration of β-cell function after the onset of the disease, elevations of plasma fatty acid levels that often accompany insulin resistance may, as glucose levels begin to rise outside of the normal range, also play a pathogenic role in the early stages of the disease. Because hyperglycemia is a prerequisite for Lipotoxicity to occur, the term glucoLipotoxicity, rather than Lipotoxicity, is more appropriate to describe deleterious effects of lipids on β-cell function. In vitro and in vivo evidence supporting the concept of glucotoxicity is presented first, as well as a description of the underlying mechanisms with an emphasis on the role of oxidative stress. Second, we discuss the functional manifestations of glucoLipotoxicity on insulin secretion, insulin gene expression, and β-cell death, and the role of glucose in the mechanisms of glucoLipotoxicity. Finally, we attempt to define the role of these phenomena in the natural history of β-cell compensation, decompensation, and failure during the course of type 2 diabetes.
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β cell glucose toxicity Lipotoxicity and chronic oxidative stress in type 2 diabetes
Diabetes, 2004Co-Authors: Paul R Robertson, Jamie S Harmon, Phuong Oanh T Tran, Vincent PoitoutAbstract:The relentless decline in β-cell function frequently observed in type 2 diabetic patients, despite optimal drug management, has variously been attributed to glucose toxicity and Lipotoxicity. The former theory posits hyperglycemia, an outcome of the disease, as a secondary force that further damages β-cells. The latter theory suggests that the often-associated defect of hyperlipidemia is a primary cause of β-cell dysfunction. We review evidence that patients with type 2 diabetes continually undergo oxidative stress, that elevated glucose concentrations increase levels of reactive oxygen species in β-cells, that islets have intrinsically low antioxidant enzyme defenses, that antioxidant drugs and overexpression of antioxidant enzymes protect β-cells from glucose toxicity, and that Lipotoxicity, to the extent it can be attributable to hyperlipidemia, occurs only in the context of preexisting hyperglycemia, whereas glucose toxicity can occur in the absence of hyperlipidemia.
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minireview secondary β cell failure in type 2 diabetes a convergence of glucotoxicity and Lipotoxicity
Endocrinology, 2002Co-Authors: Vincent Poitout, Paul R RobertsonAbstract:Chronic hyperglycemia and hyperlipidemia can exert deleterious effects on -cell function, respectively referred to as glucotoxicity and Lipotoxicity. Over time, both contribute to the progressive deterioration of glucose homeostasis characteristic of type 2 diabetes. The mechanisms of glucotoxicity involve several transcription factors and are, at least in part, mediated by generation of chronic oxidative stress. Lipotoxicity is probably mediated by accumulation of a cytosolic signal derived from the fatty acid esterification pathway. Our view that hyperglycemia is a prerequisite for Lipotoxicity is supported by several recent studies performed in our laboratories. First, prolonged in vitro exposure of isolated islets to fatty acids decreases insulin gene expression in the presence of high glucose concentrations only, and glucose is ratelimiting for the incorporation of fatty acids into neutral lipids. Second, normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, whereas normalization of plasma lipid levels is without effect. Third, high-fat feeding in Goto-Kakizaki rats significantly impairs glucoseinduced insulin secretion in vitro, whereas a similar diet has no effect in normoglycemic animals. We propose that chronic hyperglycemia, independent of hyperlipidemia, is toxic for -cell function, whereas chronic hyperlipidemia is deleterious only in the context of concomitant hyperglycemia. (Endocrinology 143: 339 –342, 2002)
Patrick Schrauwen - One of the best experts on this subject based on the ideXlab platform.
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Exercise counteracts Lipotoxicity by improving lipid turnover and lipid droplet quality.
Journal of Internal Medicine, 2018Co-Authors: E. Zacharewicz, Matthijs K. C. Hesselink, Patrick SchrauwenAbstract:The incidence of obesity and metabolic disease, such as type 2 diabetes mellitus (T2D), is rising globally. Dietary lipid over supply leads to lipid accumulation at ectopic sites, such as skeletal muscle. Ectopic lipid storage is highly correlated with insulin resistance and T2D, likely due to a loss of metabolic flexibility - the capacity to switch between fat and glucose oxidation upon insulin stimulation - and cellular dysfunction because of Lipotoxicity. However, muscle lipid levels are also elevated in endurance-trained athletes, presenting a paradoxical phenotype of increased intramuscular lipids along with high insulin sensitivity - the 'athletes' paradox'. This review focuses on recent human data to characterize intramuscular lipid species in order to elucidate some of the underlying mechanisms driving skeletal muscle Lipotoxicity. There is evidence that Lipotoxicity is characterized by an increase in bioactive lipid species, such as ceramide. The athletes' paradox supports the notion that regular physical exercise has health benefits that might originate from the alleviation of Lipotoxicity. Indeed, exercise training alleviates intramuscular ceramide content in obese individuals without a necessary decrease in ectopic lipid storage. Furthermore, evidence shows that exercise training elevates markers of lipid droplet dynamics such as the PLIN proteins, and triglyceride lipases ATGL and HSL, as well as mitochondrial efficiency, potentially explaining the improved lipid turnover and a reduction in the accumulation of lipotoxic intermediates observed with the athelets' paradox.
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Lipotoxicity in type 2 diabetic cardiomyopathy
Cardiovascular Research, 2011Co-Authors: Tineke Van De Weijer, Vera B Schrauwenhinderling, Patrick SchrauwenAbstract:As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed Lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to Lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.
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mitochondrial dysfunction and Lipotoxicity
Biochimica et Biophysica Acta, 2010Co-Authors: Patrick Schrauwen, Vera B Schrauwenhinderling, Joris Hoeks, Matthijs K. C. HesselinkAbstract:Abstract Mitochondrial dysfunction in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus. Reduced mitochondrial capacity will contribute to the accumulation of lipid intermediates, desensitizing insulin signaling and leading to insulin resistance. Why mitochondrial function is reduced in the (pre-)diabetic state is, however, so far unknown. Although it is tempting to suggest that skeletal muscle insulin resistance may result from an inherited or acquired reduction in mitochondrial function in the pre-diabetic state, it cannot be excluded that mitochondrial dysfunction may in fact be the consequence of the insulin-resistant/diabetic state. Lipotoxicity, the deleterious effects of accumulating fatty acids in skeletal muscle cells, may lie at the basis of mitochondrial dysfunction: next to producing energy, mitochondria are also the major source of reactive oxygen species (ROS). Fatty acids accumulating in the vicinity of mitochondria are vulnerable to ROS-induced lipid peroxidation. Subsequently, these lipid peroxides could have lipotoxic effects on mtDNA, RNA and proteins of the mitochondrial machinery, leading to mitochondrial dysfunction. Indeed, increased lipid peroxidation has been reported in insulin resistant skeletal muscle and the mitochondrial uncoupling protein-3, which has been suggested to prevent lipid-induced mitochondrial damage, is reduced in subjects with an impaired glucose tolerance and in type 2 diabetic patients. These findings support the hypothesis that fat accumulation in skeletal muscle may precede the reduction in mitochondrial function that is observed in type 2 diabetes mellitus.
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UCP3 in muscle wasting, a role in modulating Lipotoxicity?
FEBS Letters, 2006Co-Authors: Ronnie Minnaard, Patrick Schrauwen, Gert Schaart, Matthijs K. C. HesselinkAbstract:UCP3 has been postulated to function in the defense against lipid-induced oxidative muscle damage (Lipotoxicity). We explored this hypothesis during cachexia in rats (zymosan-induced sepsis), a condition characterized by increased oxidative stress and supply of fatty acids to the muscle. Muscle UCP3 protein content was increased 2, 6 and 11 days after zymosan injection. Plasma FFA levels were increased at day 2, but dropped below control levels on days 6 and 11. Muscular levels of the lipid peroxidation byproduct 4-hydroxy-2-nonenal (4-HNE) were increased at days 6 and 11 in zymosan-treated rats, supporting a role for UCP3 in modulating Lipotoxicity during cachexia.
Jean E. Schaffer - One of the best experts on this subject based on the ideXlab platform.
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Manifestations and mechanisms of myocardial Lipotoxicity in obesity
Journal of Internal Medicine, 2018Co-Authors: A. C. Sletten, Linda R. Peterson, Jean E. SchafferAbstract:Environmental and socioeconomic changes over the past thirty years have contributed to a dramatic rise in the worldwide prevalence of obesity. Heart disease is amongst the most serious health risks of obesity, with increases in both atherosclerotic coronary heart disease and heart failure among obese individuals. In this review, we focus on primary myocardial alterations in obesity that include hypertrophic remodelling and diastolic dysfunction. Obesity-associated perturbations in myocardial and systemic lipid metabolism are important contributors to cardiovascular complications of obesity. Accumulation of excess lipid in nonadipose cells of the cardiovascular system can cause cell dysfunction and cell death, a process known as Lipotoxicity. Lipotoxicity has been modelled in mice using high-fat diet feeding, inbred lines with mutations in leptin receptor signalling, and in genetically engineered mice with enhanced myocardial fatty acid uptake, altered lipid droplet homoeostasis or decreased cardiac fatty acid oxidation. These studies, along with findings in cell culture model systems, indicate that the molecular pathophysiology of lipid overload involves endoplasmic reticulum stress, alterations in autophagy, de novo ceramide synthesis, oxidative stress, inflammation and changes in gene expression. We highlight recent advances that extend our understanding of the impact of obesity and altered lipid metabolism on cardiac function.
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Lipotoxicity in cardiac and skeletal muscle
Heart and metabolism, 2006Co-Authors: Jennifer L. Peura, Jean E. SchafferAbstract:Lipotoxicity is defined as the untoward consequences of the accumulation of excess lipid in non-adipose tissue. Fatty acids are an important substrate for myocyte metabolism, yet mismatch of cellular uptake and utilization results in lipid accumulation that is clearly detrimental. Within the myocyte, Lipotoxicity can lead to cellular dysfunction, resulting in defective contraction or relaxation or both, alterations in key signaling pathways, and apoptotic cell death. In this review we discuss the significance of myocyte Lipotoxicity in human disease and present insights into the pathophysiology gained from transgenic animal models of toxic lipid overload in skeletal and cardiac muscle. Heart Metab. 2006;30:00‐00.
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Lipotoxicity in the heart
Current Hypertension Reports, 2005Co-Authors: Nica M. Borradaile, Jean E. SchafferAbstract:Cardiomyopathy is associated with both rare genetic metabolic abnormalities and highly prevalent diseases characterized by elevated serum triglycerides and nonesterified fatty acids, such as obesity and type 2 diabetes. In these disorders, an imbalance between fatty acid uptake and utilization leads to the inappropriate accumulation of free fatty acids and neutral lipids within cardiomyocytes. Through the process of Lipotoxicity, this lipid overload causes cellular dysfunction, cell death, and eventual organ dysfunction. This review focuses on Lipotoxicity in the heart, with an emphasis on the contribution of this process to the pathogenesis of cardiomyopathy associated with obesity, diabetes, and the metabolic syndrome. The magnitude of the current worldwide epidemic of obesity and type 2 diabetes suggests that understanding the pathogenesis of cardiac complications associated with these diseases will contribute substantially to improvements in health care.
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Lipotoxicity when tissues overeat
Current Opinion in Lipidology, 2003Co-Authors: Jean E. SchafferAbstract:Purpose of reviewThis review will provide the reader with an update on our understanding of the adverse effects of fatty acid accumulation in non-adipose tissues, a phenomenon known as Lipotoxicity. Recent studies will be reviewed. Cellular mechanisms involved in the lipotoxic response will be discu
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triglyceride accumulation protects against fatty acid induced Lipotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Laura L Listenberger, Sarah E Lewis, Sylvaine Cases, Robert V Farese, Jean E. SchafferAbstract:Excess lipid accumulation in non-adipose tissues is associated with insulin resistance, pancreatic β-cell apoptosis and heart failure. Here, we demonstrate in cultured cells that the relative toxicity of two common dietary long chain fatty acids is related to channeling of these lipids to distinct cellular metabolic fates. Oleic acid supplementation leads to triglyceride accumulation and is well tolerated, whereas excess palmitic acid is poorly incorporated into triglyceride and causes apoptosis. Unsaturated fatty acids rescue palmitate-induced apoptosis by channeling palmitate into triglyceride pools and away from pathways leading to apoptosis. Moreover, in the setting of impaired triglyceride synthesis, oleate induces Lipotoxicity. Our findings support a model of cellular lipid metabolism in which unsaturated fatty acids serve a protective function against Lipotoxicity though promotion of triglyceride accumulation.
Katlyn R Gabriel - One of the best experts on this subject based on the ideXlab platform.
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probing the global cellular responses to Lipotoxicity caused by saturated fatty acids
Molecular Cell, 2019Co-Authors: Manuele Piccolis, Laura M Bond, Martin Kampmann, Pamela Pulimeno, Chandramohan Chitraju, Christina B K Jayson, Laura Pontano Vaites, Sebastian Boland, Katlyn R GabrielAbstract:Summary Excessive levels of saturated fatty acids are toxic to cells, although the basis for this Lipotoxicity remains incompletely understood. Here, we analyzed the transcriptome, lipidome, and genetic interactions of human leukemia cells exposed to palmitate. Palmitate treatment increased saturated glycerolipids, accompanied by a transcriptional stress response, including upregulation of the endoplasmic reticulum (ER) stress response. A comprehensive genome-wide short hairpin RNA (shRNA) screen identified >350 genes modulating Lipotoxicity. Among previously unknown genetic modifiers of Lipotoxicity, depletion of RNF213, a putative ubiquitin ligase mutated in Moyamoya vascular disease, protected cells from Lipotoxicity. On a broader level, integration of our comprehensive datasets revealed that changes in di-saturated glycerolipids, but not other lipid classes, are central to Lipotoxicity in this model. Consistent with this, inhibition of ER-localized glycerol-3-phosphate acyltransferase activity protected from all aspects of Lipotoxicity. Identification of genes modulating the response to saturated fatty acids may reveal novel therapeutic strategies for treating metabolic diseases linked to Lipotoxicity.