PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus

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.

Microarray profiling of skeletal muscle tissues from equally obese, non-diabetic insulin-sensitive and insulin-resistant Pima Indians

“…The mRNA concentration of PED/PEA15 is increased in fibroblasts, skeletal muscle and adipose tissue of Type II diabetic subjects [45]. In line with this finding, our GeneChip analysis indicated that the PED/PEA15 was expressed marginally higher in the IR versus IS groups.…”

The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes

“…To identify tissues for which PEA15 expression can be noninvasively quantified in a large number of subjects, we first analysed lysates from PBLs by immunoblotting with specific PEA15 antibodies [4]. In samples from 21 subjects (seven with type 2 diabetes, seven euglycaemic subjects with diabetic FDR [EuF+], and seven euglycaemic subjects with no family history of diabetes [EuF−]), these assays revealed the expression of PEA15, with no significant differences between the granulocyte, lymphocyte and monocyte cells (Fig.…”

“…Proteins were separated by 15% SDS-PAGE and then transferred to 0.45-mm Immobilon-P membranes (Millipore, Bedford, MA, USA). Filters were probed with phospholipase D1 (PLD1) (BioSource International, Camarillo, CA, USA) or PEA15 antibodies [4], revealed by enhanced chemiluminescence and autoradiography, and PEA15 bands were quantitated by laser densitometry. Inter-assay variation was <15%.…”

“…Phosphoprotein enriched in astrocytes 15 (PEA15), also known as phosphoprotein enriched in diabetes (PED) is a small scaffold protein widely produced in different tissues and highly conserved among mammals [1][2][3], whose gene (PEA15) maps on human chromosome 1q21-22 [4]. Several studies in cultured cells and in rodent tissues have revealed that Pea15 regulates multiple cellular functions by binding components of major intracellular transduction pathways.…”

“…Earlier findings in humans evidenced that the PEA15 gene is overexpressed in skeletal muscle and fat tissues as well as in cultured skin fibroblasts from individuals with type 2 diabetes, and this effect occurs independently of obesity, suggesting that it may be a primary component of insulin resistance in these subjects [4]. Whether PEA15 overexpression is also detectable in more easily accessible cells, such as peripheral blood leucocytes, and whether it represents a common abnormality in type 2 diabetes is unknown.…”