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

Abstract

Aims/hypothesis Overexpression of the gene encoding phosphoprotein enriched in astrocytes 15 (PEA15), also known as phosphoprotein enriched in diabetes (PED), causes insulin resistance and diabetes in transgenic mice and has been observed in type 2 diabetic individuals. The aim of this study was to investigate whether PEA15 overexpression occurs in individuals at high risk of diabetes and whether it is associated with specific type 2 diabetes subphenotypes. Subjects and methods We analysed PEA15 expression in euglycaemic first-degree relatives (FDR) of type 2 diabetic subjects.Results The expression of PEA15 in peripheral blood leucocytes (PBLs) paralleled that in fat and skeletal muscle tissues. In PBLs from the FDR, PEA15 expression was two-fold higher than in euglycaemic individuals with no family history of diabetes (control subjects), both at the protein and the mRNA level (p<0.001). The expression of PEA15 was comparable in FDR and type 2 diabetic subjects and in each group close to one-third of the subjects expressed PEA15 levels more than 2 SD higher than the mean of control subjects. Subjects with IFG with at least one type 2 diabetes-affected FDR also overexpressed PEA15 (p<0.05). In all the groups analysed, PEA15 expression was independent of sex and unrelated to age, BMI, waist circumference, systolic and diastolic BP, and fasting cholesterol, triacylglycerol and glucose levels. However, in euglycaemic FDR of type 2 diabetic subjects, PEA15 expression was inversely correlated with insulin sensitivity (r=−557, p=0.01). Conclusions/interpretation We conclude that PEA15 overexpression represents a common defect in FDR of patients with type 2 diabetes and is correlated with reduced insulin sensitivity in these individuals.

Overproduction of phosphoprotein enriched in diabetes (PED) induces mesangial expansion and upregulates protein kinase C-β activity and TGF-β1 expression

“…However, in a cohort of patients with type 2 diabetes [24], we found a positive correlation between levels of PED measured in PBLs and plasma TGFβ1 levels. It could therefore be inferred that high expression levels of PED deranges renal function in a subset of diabetic individuals, thereby facilitating the onset and/or progression of diabetic nephropathy.…”

“…Correlation between individual levels of PED and plasma TGFβ in humans We had analysed plasma TGF-β1 levels and PED protein abundance in PBLs in 95 type 2 diabetic patients matched for age, BMI, waist circumference, systolic and diastolic BP, and fasting HDL-cholesterol [24]. As shown in Fig.…”

“…PBLs were separated using a 6% (vol./vol.) dextran gradient in filtered PBS, pH 7.4, as previously described [24], washed three times in PBS, counted and resuspended in 1 ml of PBS for subsequent use.…”

“…A further complicating element for understanding the molecular determinants is the lack of animal models fully representative of human diabetic nephropathy [40]. We have previously generated a transgenic mouse ubiquitously expressing high levels of PED, a gene whose expression is elevated in a large proportion of individuals with type 2 diabetes and in their first-degree relatives [21,24]. In mice, PED overproduction impairs glucose tolerance by affecting insulin action and secretion [25,41], and the animals develop overt diabetes following administration of high-fat diets [25].…”

“…PED plays an important role in mitogenic and metabolic signalling [21][22][23]. Gene profiling studies have shown that PED (also known as PEA15) is commonly overexpressed in individuals with type 2 diabetes [21,24]. In cultured muscle and adipose cells and in peripheral tissues from transgenic mice, forced production of PED impairs insulin-stimulated GLUT4 translocation and glucose transport, suggesting that PED may contribute to insulin resistance in type 2 diabetes [25].…”