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Molecular and Cellular Biology, September 2008, p. 5634-5645, Vol. 28, No. 18
0270-7306/08/$08.00+0     doi:10.1128/MCB.00117-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism

Dipartimento di Biologia e Patologia Cellulare e Molecolare & Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Università degli Studi di Napoli Federico II, Naples, Italy,¹ Dipartimento di Scienze Biomorfologiche e Funzionali, Università degli Studi di Napoli Federico II, Naples, Italy,² IFOM (FIRC Institute of Molecular Oncology), via Adamello 16, 20134 Milan, Italy,³ Università Vita Salute San Raffaele, via Olgettina 60, 20132 Milan, Italy⁴

Received 22 January 2008/ Returned for modification 8 March 2008/ Accepted 4 July 2008

We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1^i/i) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1^i/i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1^i/i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

Published ahead of print on 21 July 2008.