Overexpression of the ped/pea-15 Gene Causes Diabetes by Impairing Glucose-Stimulated Insulin Secretion in Addition to Insulin Action

Abstract

Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. In the present work, we show that transgenic mice ubiquitously overexpressing ped/pea-15 exhibited mildly elevated random-fed blood glucose levels and decreased glucose tolerance. Treatment with a 60% fat diet led ped/pea-15 transgenic mice to develop diabetes. Consistent with insulin resistance in these mice, insulin administration reduced glucose levels by only 35% after 45 min, compared to 70% in control mice. In vivo, insulin-stimulated glucose uptake was decreased by almost 50% in fat and muscle tissues of the ped/pea-15 transgenic mice, accompanied by protein kinase C␣ activation and block of insulin induction of protein kinase C. These changes persisted in isolated adipocytes from the transgenic mice and were rescued by the protein kinase C inhibitor bisindolylmaleimide. In addition to insulin resistance, ped/pea-15 transgenic mice showed a 70% reduction in insulin response to glucose loading. Stable overexpression of ped/pea-15 in the glucose-responsive MIN6 beta-cell line also caused protein kinase C␣ activation and a marked decline in glucose-stimulated insulin secretion. Antisense block of endogenous ped/pea-15 increased glucose sensitivity by 2.5-fold in these cells. Thus, in vivo, overexpression of ped/pea-15 may lead to diabetes by impairing insulin secretion in addition to insulin action.

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

“…Linear regression analysis performed as described in the Subjects and methods section revealed a correlation between PEA15 levels in PBLs and glucose disposal (r=−0.557, p=0.01) in cells from type 2 diabetic subjects [4], this overexpression occurs at both the mRNA and protein level indicating that, as previously demonstrated in cells from type 2 diabetic subjects [4], it is caused, at least in part, by a transcriptional abnormality. Earlier studies in isolated cells and in vivo showed that PEA15 binds to and increases the cellular stability of PLD1, deregulating PKC signalling and impairing insulin-dependent glucose disposal [17,18]. We now show that enhanced PLD1 stability also appears to occur in PBLs from type 2 diabetic subjects and FDR, suggesting that it occurs in individuals who overexpress PEA15.…”

“…In transgenic mice fed high-fat diets, the overexpression of Pea15 leads to diabetes [18]. In humans, no genetic variability accounting for the differential expression of the PEA15 gene has been identified to date.…”

“…This effect deregulates protein kinase C (PKC) signalling and generates resistance to insulin action on glucose transport in muscle and adipose cells and in tissues from transgenic mice overexpressing the Pea15 gene [17,18]. Inhibited glucose-regulated insulin secretion has also been reported in these animals, contributing to their impaired glucose tolerance.…”

“…Inhibited glucose-regulated insulin secretion has also been reported in these animals, contributing to their impaired glucose tolerance. The Pea15 transgenic mice develop diabetes upon weight gain, indicating an important interaction between obesity and the Pea15 gene [18].…”

The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway

“…PEA-15/PED plays an important role in glucose metabolism and its overexpression contributes to the development of diabetes mellitus (Vigliotta et al, 2004). However, the question whether PEA-15 plays a role in glucose metabolism in cancer cells has not been addressed so far.…”