Glucolipotoxicity of the pancreatic β-cell: myth or reality?

Poitout, Vincent

doi:10.1042/bst0360901

Cited by 72 publications

(66 citation statements)

References 30 publications

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“…Excessive amounts of glucose and FAs cause a functional decline and apoptosis of β cells, leading to metabolic disorders such as diabetes (Poitout et al 2010). Our data are related to the glucolipotoxicity model at the organismal level because SFAs cause rapid death in animals fed a high glucose diet.…”

Section: Glucose-responsive Lipid Metabolism By Srebp and Foxomentioning

confidence: 69%

“…Association of fat and glucose metabolism by SREBPs in pathology and aging models Glucolipotoxicity underlies the deleterious effects of chronically high levels of glucose and FAs in pancreatic β cells (Poitout et al 2010). Excessive amounts of glucose and FAs cause a functional decline and apoptosis of β cells, leading to metabolic disorders such as diabetes (Poitout et al 2010).…”

Section: Glucose-responsive Lipid Metabolism By Srebp and Foxomentioning

confidence: 99%

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SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat

et al. 2015

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Glucose-rich diets shorten the life spans of various organisms. However, the metabolic processes involved in this phenomenon remain unknown. Here, we show that sterol regulatory element-binding protein (SREBP) and mediator-15 (MDT-15) prevent the life-shortening effects of a glucose-rich diet by regulating fat-converting processes in Caenorhabditis elegans. Up-regulation of the SREBP/MDT-15 transcription factor complex was necessary and sufficient for alleviating the life-shortening effect of a glucose-rich diet. Glucose feeding induced key enzymes that convert saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), which are regulated by SREBP and MDT-15. Furthermore, SREBP/MDT-15 reduced the levels of SFAs and moderated glucose toxicity on life span. Our study may help to develop strategies against elevated blood glucose and free fatty acids, which cause glucolipotoxicity in diabetic patients.

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Section: Glucose-responsive Lipid Metabolism By Srebp and Foxomentioning

confidence: 69%

Section: Glucose-responsive Lipid Metabolism By Srebp and Foxomentioning

confidence: 99%

SREBP and MDT-15 protect C. elegans from glucose-induced accelerated aging by preventing accumulation of saturated fat

et al. 2015

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“…Although lipid accumulation in skeletal muscle is more difficult to quantify accurately, several studies do suggest that lipids in skeletal muscle contribute to the development of peripheral insulin resistance and type 2 diabetes (Petersen and Shulman, 2002). Intriguingly, lipid accumulation in the pancreas (either in  cells themselves or in adipocytes within the pancreas) may impair pancreatic islet function, thereby also contributing to the pathogenesis of type 2 diabetes (Poitout, 2008). These metabolic problems are compounded by absolute or relative leptin and adiponectin deficiencies, both of which reflect the adipose tissue deficiency.…”

Section: What Is Lipodystrophy and Why Is It Of Interest?mentioning

confidence: 99%

Mouse models of inherited lipodystrophy

Savage

2009

Disease Models &Amp; Mechanisms

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Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and underpins the strong association between obesity and diabetes. Paradoxically, the metabolic consequences of having ‘too much’ fat (obesity) are remarkably similar to those of having ‘too little’ fat (lipodystrophy): a finding that has generated considerable interest in a rare disease. In both cases, excess energy accumulates as lipid in ectopic sites such as the liver (fatty liver) and skeletal muscle, where it plays a central role in the pathogenesis of insulin resistance, dyslipidemia and type 2 diabetes. Human lipodystrophies are characterised by a total or partial deficiency of body fat, and may be inherited or acquired in origin. Genetically engineered mice with generalised lipodystrophy manifest many of the features of the human disorder, including hyperphagia, fatty liver, hypertriglyceridaemia, insulin resistance and type 2 diabetes, providing a useful tractable model of the human disorder. Partial lipodystrophy, which causes similar, albeit milder, metabolic problems in humans has been more difficult to mimic in the mouse. This review discusses key translational studies in mice with generalised lipodystrophy, including fat transplantation and the use of recombinant leptin replacement therapy. These studies have been instrumental in advancing our understanding of the underlying molecular pathogenesis of ectopic lipid accumulation and insulin resistance, and have prompted the initiation and subsequent adoption of leptin replacement therapy in human lipodystrophies. This review also considers the possible reasons for the apparent difficulties in generating mouse models of partial lipodystrophy, such as interspecies differences in the distribution of fat depots and the apparent lack of sexual dimorphism in fat mass and distribution in mice compared with the dramatic differences present in adult humans.

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“…Several studies have provided evidence that prolonged exposure to increased concentrations of fatty acids is associated with reduction of glucose induced insulin secretion [27], impairment of insulin gene expression [28,29] and induction of -cells death [30,31]. Importantly, lipoapoptosis only occurs in the presence of concomitant elevation in insulin secretion [32,33].…”

Section: Pathophysiology Of T2dmmentioning

confidence: 99%