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

Autor: Francesco Oriente, Francesca Fiory, Francesco Beguinot, Anna Perfetti, Chiara Romano, Giovanni Vigliotta, Giancarlo Troncone, Stefania Santopietro, Giuseppe Portella, Maria Alessandra Maitan, Claudia Miele, Cecilia Tiveron, Angela Cassese, Alessandra Trencia, Pietro Formisano, Laura Tatangelo
Přispěvatelé: Vigliotta, G, Miele, C, Santopietro, S, Portella, Giuseppe, Perfetti, A, Maitan, Ma, Cassese, A, Oriente, Francesco, Trencia, A, Fiory, Francesca, Romano, C, Tiveron, C, Tatangelo, L, Troncone, Giancarlo, Formisano, Pietro, Beguinot, Francesco
Rok vydání: 2004
Předmět:
Zdroj: Molecular and cellular biology
24 (2004): 5005–5015.
info:cnr-pdr/source/autori:Vigliotta G; Miele C; Santopietro S; Portella G; Perfetti A; Maitan MA; Cassese A; Oriente F; Trencia A; Fiory F; Romano C; Tiveron C; Tatangelo L; Troncone G; Formisano P; Beguinot F./titolo:Overexpression of the ped%2Fpea-15 gene causes diabetes by impairing glucose-stimulated insulin secretion in addition to insulin action./doi:/rivista:Molecular and cellular biology (Print)/anno:2004/pagina_da:5005/pagina_a:5015/intervallo_pagine:5005–5015/volume:24
ISSN: 1098-5549
DOI: 10.1128/mcb.24.11.5005-5015.2004
Popis: Type 2 diabetes is a genetically determined disorder, affecting over 150 million people worldwide (35). The pathogenesis of type 2 diabetes is characterized both by insulin resistance in muscle, fat, and liver and by impaired insulin secretion (10, 16). Whether a single genetic defect may simultaneously cause impaired insulin action and secretion in common forms of human diabetes and by what mechanism are unknown. PED/PEA-15 is a ubiquitously expressed multifunctional protein. It controls mitogenic signaling by binding extracellular signal-regulated kinases and anchoring them to the cytoplasm (14). PED/PEA-15 also inhibits several apoptotic pathways through a number of different mechanisms and plays an important role in tumor development and sensitivity to antineoplastic agents (5, 6, 11, 15, 30, 34). Recently, PED/PEA-15 was reported to bind to and increase the cellular stability of phospholipase D, enhancing its activity in the cell (8, 35). In addition, we showed that overexpression of the ped/pea-15 gene is a common defect in type 2 diabetes (7). Overexpression of PED/PEA-15 protein impairs insulin-stimulated GLUT4 translocation and glucose transport in cultured muscle and adipose cells, suggesting that ped/pea-15 overexpression may contribute to insulin resistance in type 2 diabetics (7). Other studies have demonstrated that ped/pea-15-induced resistance to insulin action on glucose disposal is accompanied by activation of the classical protein kinase C (PKC) isoform PKCα (8). In turn, the induction of PKCα by ped/pea-15 overexpression prevents subsequent activation of atypical PKCζ/λ by insulin (8). Rescue of PKCζ/λ function in ped/pea-15-overexpressing cells restores glucose transport to its normal sensitivity to insulin. Thus, in cultured muscle and adipose cells, ped/pea-15 generates resistance to insulin action on glucose disposal by impairing normal regulation of PKCζ/λ function by PKCα. Accumulating evidence now indicates that the atypical PKCs ζ and λ are major downstream effectors activating the glucose transport machinery in response to insulin in both skeletal muscle and adipose tissues (12). Activation of atypical PKCs by insulin is defective in humans with type 2 diabetes as well as in animal models of type 2 diabetes (12, 17, 18). It therefore appears that atypical PKCs are key molecules in the pathogenesis of type 2 diabetes and may represent important drug targets as well. Defective insulin secretion in response to secretogogues also plays an important role in the pathogenesis of type 2 diabetes (24). At least in part, this further abnormality appears to be genetically determined (2, 33). However, metabolic abnormalities determined by insulin resistance also contribute to beta-cell failure in type 2 diabetes (2, 24, 33). In the present report, we show that overexpression of ped/pea-15 to levels similar to those found in many type 2 diabetics may lead to diabetes in transgenic mice. This defect is accompanied by defective insulin action on glucose transport and, additionally, by impaired glucose-stimulated insulin secretion. Thus, overexpression of the ped/pea-15 gene may cause diabetes by impairing beta-cell function in addition to insulin sensitivity.
Databáze: OpenAIRE
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