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Molecular and Cellular Biology, June 2004, p. 5005-5015, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.5005-5015.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Giovanni Vigliotta,1,2,{dagger},{ddagger} Claudia Miele,1,2,{dagger} Stefania Santopietro,1,2 Giuseppe Portella,1,2 Anna Perfetti,1,2 Maria Alessandra Maitan,1,2 Angela Cassese,1,2 Francesco Oriente,1,2 Alessandra Trencia,1,2 Francesca Fiory,1,2 Chiara Romano,1,2 Cecilia Tiveron,3 Laura Tatangelo,3 Giancarlo Troncone,4 Pietro Formisano,1,2 and Francesco Beguinot1,2*

Dipartimento di Biologia e Patologia Cellulare e Molecolare,1 Dipartimento di Scienze Biomorfologiche e Funzionali, Federico II University of Naples, and,4 Istituto di Endocrinologia ed Oncologia Sperimentale del CNR Naples,2 Transgenic Mouse Service Center, Istituto Regina Elena, Rome, Italy3

Received 14 November 2003/ Returned for modification 24 January 2004/ Accepted 7 March 2004

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{alpha} activation and block of insulin induction of protein kinase C{zeta}. 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{alpha} 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.

* Corresponding author. Mailing address: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via Sergio Pansini, 5, Naples 80131, Italy. Phone: 39081 7463248. Fax: 39081 7463235. E-mail: beguino{at}unina.it.

{dagger} G.V. and C.M. contributed equally to this work.

{ddagger} Present address: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Lecce, Lecce, Italy.

Molecular and Cellular Biology, June 2004, p. 5005-5015, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.5005-5015.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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