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The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis

Eusebio Chiefari1, Francesco Paonessa1, Stefania Iiritano1, Ilaria Le Pera1, Dario Palmieri3, Giuseppe Brunetti4, Angelo Lupo56, Vittorio Colantuoni56, Daniela Foti1, Elio Gulletta1, Giovambattista De Sarro1, Alfredo Fusco3 and Antonio Brunetti12*

Author Affiliations

1 Dipartimento di Medicina Sperimentale e Clinica 'G. Salvatore', 88100 Catanzaro, Italy

2 Cattedra di Endocrinologia, Università 'Magna Græcia' di Catanzaro, 88100 Catanzaro, Italy

3 Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Università di Napoli 'Federico II', 80131 Napoli, Italy

4 Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, 20133 Milan, Italy

5 Dipartimento di Scienze Biologiche ed Ambientali, Facoltà di Scienze MM.FF.NN., Università del Sannio, 82100 Benevento, Italy

6 Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli 'Federico II', 80131 Napoli, Italy

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BMC Biology 2009, 7:24  doi:10.1186/1741-7007-7-24

Published: 21 May 2009



We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed.


We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.


These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.