The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
ER stress and SREBP-1 activation are implicated in β-cell glucolipotoxicity
Abstract
The reduction in insulin secretory capacity and β-cell mass observed in type 2 diabetes is thought to be caused by glucolipotoxicity secondary to hyperglycemia and hyperlipidemia. Our aim in this study was to elucidate the underlying molecular mechanisms. We found a strong correlation between chronic high-glucose treatment and SREBP-1c activation in INS-1 cells and rat islets. Both high-glucose treatment and SREBP-1c activation in INS-1 cells resulted in lipid accumulation, impaired glucose-stimulated insulin secretion, apoptosis, and strikingly similar gene expression patterns, including upregulation of lipogenic and pro-apoptotic genes and downregulation of IRS2, Bclxl and Pdx1. These lipotoxic effects of high glucose were largely prevented by induction of a dominant-negative mutant of SREBP-1c, suggesting SREBP-1c is a major factor responsible for β cell glucolipotoxicity. Moreover, overexpression of another lipogenic transcription factor, ChREBP, in INS-1 cells did not cause lipotoxicity. Intriguingly, chronic high glucose treatment in INS-1 cells led to pronounced induction of the ER stress marker genes, BIP and Chop10. Treatment of rat islets with both chronic high glucose and two ER stress inducers, thapsigargin and tunicamycin, enhanced SREBP-1 binding to the human IRS2 promoter. These results suggest that SREBP-1 activation caused by ER stress is implicated in β-cell glucolipotoxicity.
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Cites
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
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SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
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“Over accumulation of lipids in non-adipose tissues such as the pancreatic islets, liver and heart is often associated with type 2 diabetes and its complications (Unger, 2002; Unger and Zhou, 2001; Unger et al., 1999).”
BackgroundMethodER Stress Induces Cleavage of Membrane-Bound ATF6 by the Same Proteases that Process SREBPs
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Cited by
The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus
Eizirik, D. L., Cardozo, A. K., & Cnop, M. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0015 · Cited by 1,173
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The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients
Marchetti, P., Bugliani, M., Lupi, R., Marselli, L., Masini, M., Boggi, U., Filipponi, F., Weir, G. C., Eizirik, D. L., & Cnop, M. (2007) · Diabetologia · doi:10.1007/s00125-007-0816-8 · Cited by 413
Glucolipotoxicity of the pancreatic beta cell
Poitout, V., Amyot, J., Semache, M., Zarrouki, B., Hagman, D., & Fontés, G. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.08.006 · Cited by 382
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Metadata
- Authors
- Wang, H., Kouri, G., & Wollheim, C. B.
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2005-09-01
- Volume
- 118
- Issue
- 17
- Pages
- 3905-3915
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W2090847725
- Cited by
- 266
- References
- 14
- FWCI
- 18.82
- Type
- journal article
- Language
- en
- Open access
- closed
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