Abstract
We have used differential display to identify genes whose expression is altered in type 2 diabetes thus contributing to its pathogenesis. One mRNA is overexpressed in fibroblasts from type 2 diabetics compared with non-diabetic individuals, as well as in skeletal muscle and adipose tissues, two major sites of insulin resistance in type 2 diabetes. The levels of the protein encoded by this mRNA are also elevated in type 2 diabetic tissues; thus, we named it PED for phosphoprotein enriched in diabetes. PED cloning shows that it encodes a 15 kDa phosphoprotein identical to the protein kinase C (PKC) substrate PEA-15. The PED gene maps on human chromosome 1q21-22. Transfection of PED/PEA-15 in differentiating L6 skeletal muscle cells increases the content of Glut1 transporters on the plasma membrane and inhibits insulin-stimulated glucose transport and cell-surface recruitment of Glut4, the major insulin-sensitive glucose transporter. These effects of PED overexpression are reversed by blocking PKC activity. Overexpression of the PED/PEA-15 gene may contribute to insulin resistance in glucose uptake in type 2 diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Apoptosis Regulatory Proteins
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Biological Transport
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Cell Differentiation
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Cell Line
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Chromosome Mapping
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Chromosomes, Human, Pair 1 / genetics
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Cloning, Molecular
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism*
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Enzyme Inhibitors / pharmacology
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Gene Expression
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Genes / genetics
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Glucose / metabolism*
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Glucose Transporter Type 1
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Glucose Transporter Type 4
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Humans
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Insulin / pharmacology
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Intracellular Signaling Peptides and Proteins
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Molecular Sequence Data
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Monosaccharide Transport Proteins / genetics
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Monosaccharide Transport Proteins / metabolism*
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Muscle Proteins*
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Muscle, Skeletal / cytology
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Muscle, Skeletal / metabolism
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Organ Specificity
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / genetics*
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Phosphoproteins / physiology
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Protein Kinase C / antagonists & inhibitors
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Receptor, Insulin / metabolism
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Sequence Analysis, DNA
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Staurosporine / pharmacology
Substances
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Apoptosis Regulatory Proteins
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Enzyme Inhibitors
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Glucose Transporter Type 1
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Glucose Transporter Type 4
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Insulin
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Intracellular Signaling Peptides and Proteins
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Monosaccharide Transport Proteins
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Muscle Proteins
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PEA15 protein, human
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Phosphoproteins
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SLC2A1 protein, human
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SLC2A4 protein, human
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Receptor, Insulin
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Protein Kinase C
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Staurosporine
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Glucose