PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus.
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.
Dipartimento di Biologia e Patologia Cellulare e Molecolare and Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R., Federico II University of Naples, Naples, Italy.
G
G
Condorelli
G
G
Vigliotta
C
C
Iavarone
M
M
Caruso
C G
CG
Tocchetti
F
F
Andreozzi
A
A
Cafieri
M F
MF
Tecce
P
P
Formisano
L
L
Beguinot
F
F
Beguinot
D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D001692:Biological Transport; D002454:Cell Differentiation; D002460:Cell Line; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003001:Cloning, Molecular; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D005796:Genes / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000378:metabolism; D017422:Sequence Analysis, DNA; D019311:Staurosporine / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D005947:Glucose; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011493:Protein Kinase C; D011972:Receptor, Insulin; D019311:Staurosporine; C092039:PEA15 protein, human; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human