2001
DOI: 10.2337/diabetes.50.2007.s118
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Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover.

Abstract: A recently identified function of leptin is to protect nonadipose tissues from the nonoxidative metabolic products of long-chain fatty acids (FAs) during periods of overnutrition by increasing the ␤-oxidative metabolism of surplus FAs and reducing lipogenesis. When this protective system fails, harmful products of nonoxidative metabolism such as ceramide increase in nonadipose tissues, including the pancreatic islets and heart, and cause nitric oxide-mediated lipotoxicity and lipoapoptosis. The triacylglycerol… Show more

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Cited by 433 publications
(349 citation statements)
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“…NF-κB activation represents a crucial event in cytokine-regulation of expression of several chemokines and cytokines [8], Fas expression [9], iNOS and COX-2 expression [10,11], which are all regarded as essential factors for causing dysfunction and destruction of insulin-producing cells thus leading to the development of insulin-dependent diabetes. Importantly, a ceramide-dependent NF-κB-mediated up-regulation of iNOS expression was recently shown in response to palmitic acid, indicating a potential involvement of this transcription factor also in the regulation of beta-cell lipotoxicity and pathogenesis of Type 2 diabetes [6].…”
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confidence: 98%
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“…NF-κB activation represents a crucial event in cytokine-regulation of expression of several chemokines and cytokines [8], Fas expression [9], iNOS and COX-2 expression [10,11], which are all regarded as essential factors for causing dysfunction and destruction of insulin-producing cells thus leading to the development of insulin-dependent diabetes. Importantly, a ceramide-dependent NF-κB-mediated up-regulation of iNOS expression was recently shown in response to palmitic acid, indicating a potential involvement of this transcription factor also in the regulation of beta-cell lipotoxicity and pathogenesis of Type 2 diabetes [6].…”
mentioning
confidence: 98%
“…In the case of Type 2 diabetes, which is associated with peripheral insulin resistance and beta-cell dysfunction, recent evidence suggests a reduced beta-cell mass as a contributor to the pathogenesis of this chronic disease [4]. Moreover, fatty acid-induced apoptosis of pancreatic beta cells has been regarded as a critical determinant in switching from obesity and insulin resistance to Type 2 diabetes [5,6].…”
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confidence: 99%
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“…Whether this damage occurs by autoimmune mechanisms, as in Type I (insulin-dependent) diabetes mellitus [1], or by other less defined phenomena (e.g., glucose toxicity [2], lipotoxicity [3], prolonged excessive insulin secretion [4]), as in Type II (non-insulin-dependent) diabetes mellitus [5], the final result is impaired insulin secretion [6]. A number of autoantibodies (aAbs) marking the immune-mediated destruction of the beta cell typical of Type I diabetes have been described since the identification of islet cell antibodies (ICA) [7].…”
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confidence: 99%