Document Detail

Sterol regulatory element-binding protein-1c and pancreatic beta-cell dysfunction.
MedLine Citation:
PMID:  17919187     Owner:  NLM     Status:  MEDLINE    
It has long been known that excess intracellular fatty acids cause impaired insulin secretion, referred to as beta-cell lipotoxicity. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls hepatic fatty acid synthesis. Activation of SREBP-1c by overnutrition also inhibits insulin receptor substrate-2 (IRS-2) and induces insulin resistance in the liver. As SREBP-1c is also expressed in beta cells, we hypothesized that activation of SREBP-1c could be a part of the mechanism by which saturated fatty acids induce beta-cell lipotoxicity. We found that nuclear SREBP-1c has a negative impact on both glucose- and potassium-stimulated insulin secretion as determined in islets from beta-cell-specific SREBP-1c transgenic mice as well as SREBP-1c knockout mice. This effect of SREBP-1c involves multiple functional pathways required for insulin secretion from beta cells: (i) decreased ATP caused by energy consumption through lipogenesis and uncoupling protein-2 (UCP-2) activation; (ii) repressed IRS-2 and pancreas duodenum homeobox 1 (PDX1) expression, leading to impaired beta-cell mass; and (iii) impaired post-ATP membrane voltage-dependent steps of the insulin secretion pathway caused by upregulated granuphilin and other ion channel proteins. Saturated fatty acids, such as palmitic acid (PA), impair insulin secretion through SREBP-1c activation, whereas polyunsaturated fatty acids including eicosapentaenoic acid (EPA) restore PA-suppressed insulin secretion through suppression of SREBP-1c. These data implicate a therapeutic potential of EPA against insulin secretion defects caused by lipotoxicity.
H Shimano; M Amemiya-Kudo; A Takahashi; T Kato; M Ishikawa; N Yamada
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Diabetes, obesity & metabolism     Volume:  9 Suppl 2     ISSN:  1462-8902     ISO Abbreviation:  Diabetes Obes Metab     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2007-10-08     Completed Date:  2008-03-31     Revised Date:  2009-11-03    
Medline Journal Info:
Nlm Unique ID:  100883645     Medline TA:  Diabetes Obes Metab     Country:  England    
Other Details:
Languages:  eng     Pagination:  133-9     Citation Subset:  IM    
Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
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MeSH Terms
Fatty Acids / pharmacology*
Glucose / metabolism
Insulin / secretion
Insulin Receptor Substrate Proteins
Insulin-Secreting Cells / physiology*
Intracellular Signaling Peptides and Proteins / metabolism*
Mice, Transgenic
Phosphoproteins / metabolism*
Sterol Regulatory Element Binding Protein 1 / metabolism*
Reg. No./Substance:
0/Fatty Acids; 0/Insulin Receptor Substrate Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/Irs2 protein, mouse; 0/Phosphoproteins; 0/Sterol Regulatory Element Binding Protein 1; 11061-68-0/Insulin; 50-99-7/Glucose

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