PT  - JOURNAL ARTICLE
AU  - Sörhede Winzell, Maria
AU  - Svensson, Håkan
AU  - Enerbäck, Sven
AU  - Ravnskjaer, Kim
AU  - Mandrup, Susanne
AU  - Esser, Victoria
AU  - Arner, Peter
AU  - Alves-Guerra, Marie-Clotilde
AU  - Miroux, Bruno
AU  - Sundler, Frank
AU  - Ahrén, Bo
AU  - Holm, Cecilia
TI  - Pancreatic β-Cell Lipotoxicity Induced by Overexpression of Hormone-Sensitive Lipase
AID  - 10.2337/diabetes.52.8.2057
DP  - 2003 Aug 01
TA  - Diabetes
PG  - 2057--2065
VI  - 52
IP  - 8
4099  - http://diabetes.diabetesjournals.org/content/52/8/2057.short
4100  - http://diabetes.diabetesjournals.org/content/52/8/2057.full
SO  - Diabetes2003 Aug 01; 52
AB  - Lipid perturbations associated with triglyceride overstorage in β-cells impair insulin secretion, a process termed lipotoxicity. To assess the role of hormone-sensitive lipase, which is expressed and enzymatically active in β-cells, in the development of lipotoxicity, we generated transgenic mice overexpressing hormone-sensitive lipase specifically in β-cells. Transgenic mice developed glucose intolerance and severely blunted glucose-stimulated insulin secretion when challenged with a high-fat diet. As expected, both lipase activity and forskolin-stimulated lipolysis was increased in transgenic compared with wild-type islets. This was reflected in significantly lower triglycerides levels in transgenic compared with wild-type islets in mice receiving the high-fat diet, whereas no difference in islet triglycerides was found between the two genotypes under low-fat diet conditions. Our results highlight the importance of mobilization of the islet triglyceride pool in the development of β-cell lipotoxicity. We propose that hormone-sensitive lipase is involved in mediating β-cell lipotoxicity by providing ligands for peroxisome proliferator-activated receptors and other lipid-activated transcription factors, which in turn alter the expression of critical genes. One such gene might be uncoupling protein-2, which was found to be upregulated in transgenic islets, a change that was accompanied by decreased ATP levels.