title: 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 Calpha activation and block of insulin induction of protein kinase Czeta. 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 Calpha 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.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Via Sergio Pansini, 5, Naples 80131, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vigliotta
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.forename: Stefania
authors.initials: S
authors.lastname: Santopietro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Portella
authors.forename: Anna
authors.initials: A
authors.lastname: Perfetti
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Maitan
authors.forename: Angela
authors.initials: A
authors.lastname: Cassese
authors.forename: Francesco
authors.initials: F
authors.lastname: Oriente
authors.forename: Alessandra
authors.initials: A
authors.lastname: Trencia
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiory
authors.forename: Chiara
authors.initials: C
authors.lastname: Romano
authors.forename: Cecilia
authors.initials: C
authors.lastname: Tiveron
authors.forename: Laura
authors.initials: L
authors.lastname: Tatangelo
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Troncone
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; D015395:Histocompatibility Antigens Class I; D007328:Insulin; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; C032907:Q surface antigens; D005947:Glucose