Abstract
Influx of excess fatty acids and the resultant accumulation of intracellular triglycerides are linked to impaired insulin secretion and action in the pathogenesis of type 2 diabetes. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls cellular synthesis of fatty acids and triglycerides. SREBP-1c is highly expressed in high-energy and insulin-resistant states. To investigate effects of this synthetic lipid regulator on insulin secretion, we generated transgenic mice overexpressing nuclear SREBP-1c under the insulin promoter. beta-Cell-specific expression of SREBP-1c caused reduction in islet mass and impaired glucose-stimulated insulin secretion and was associated with accumulation of triglycerides, suppression of pancreas duodenal homeobox-1, and upregulation of uncoupling protein 2 gene expression. The mice presented with impaired glucose tolerance that was exacerbated by a high-energy diet. Taken together with enhanced insulin secretion from SREBP-1-null islets, these data suggest that SREBP-1c and endogenous lipogenesis could be involved in beta-cell dysfunction and diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Base Sequence
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CCAAT-Enhancer-Binding Proteins / genetics*
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CCAAT-Enhancer-Binding Proteins / physiology
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Cell Nucleus / physiology*
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DNA Primers
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DNA, Complementary / genetics
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / physiology
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Diet
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Energy Metabolism
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Gene Expression Regulation
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Glucose Intolerance / genetics*
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Helix-Loop-Helix Motifs
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Homeodomain Proteins / genetics
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Humans
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Hyperinsulinism / prevention & control
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Insulin / genetics
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Insulin / metabolism
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Insulin Secretion
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Ion Channels
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Islets of Langerhans / metabolism
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Islets of Langerhans / physiology*
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Membrane Transport Proteins / genetics
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Mice
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Mice, Transgenic
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Mitochondrial Proteins / genetics
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Promoter Regions, Genetic
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Rats
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Sterol Regulatory Element Binding Protein 1
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Trans-Activators / genetics
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Transcription Factors / genetics*
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Transcription Factors / physiology
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Uncoupling Protein 2
Substances
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CCAAT-Enhancer-Binding Proteins
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DNA Primers
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DNA, Complementary
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DNA-Binding Proteins
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Homeodomain Proteins
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Insulin
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Ion Channels
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Membrane Transport Proteins
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Mitochondrial Proteins
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SREBF1 protein, human
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Srebf1 protein, mouse
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Srebf1 protein, rat
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Sterol Regulatory Element Binding Protein 1
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Trans-Activators
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Transcription Factors
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UCP2 protein, human
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Ucp2 protein, mouse
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Ucp2 protein, rat
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Uncoupling Protein 2
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pancreatic and duodenal homeobox 1 protein