The HMGA1-IGF-I/IGFBP system: A novel pathway for modulating glucose uptake

Stefania Iiritano, Eusebio Chiefari, Valeria Ventura, Biagio Arcidiacono, Katiuscia Possidente, Aurora Nocera, Maria T. Nevolo, Monica Fedele, Adelaide Greco, Manfredi Greco, Giuseppe Brunetti, Alfredo Fusco, Daniela Foti, Antonio Brunetti

Research output: Contribution to journalArticle

Abstract

We previously showed that loss of the high mobility group A1 (HMGA1) protein expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major target tissues of insulin action, causing a type 2-like diabetic phenotype, in which, however, glucose intolerance was paradoxically associated with increased peripheral insulin sensitivity. Insulin hypersensitivity despite impairment of insulin action supports the existence of molecular adaptation mechanisms promoting glucose disposal via insulin-independent processes. Herein, we provide support for these compensatory pathways/circuits of glucose uptake in vivo, the activation of which under certain adverse metabolic conditions may protect against hyperglycemia. Using chromatin immunoprecipitation combined with protein-protein interaction studies of nuclear proteins in vivo, and transient transcription assays in living cells, we show that HMGA1 is required for gene activation of the IGF-binding proteins 1 (IGFBP1) and 3 (IGFBP3), two major members of the IGF-binding protein superfamily. Furthermore, by using positron emission tomography with 18F-labeled 2-fluoro-2-deoxy-D-glucose, in combination with the euglycemic clamp with IGF-I, we demonstrated that IGF-I's bioactivity was increased in Hmga1-knockout mice, in which both skeletal muscle Glut4 protein expression and glucose uptake were enhanced compared with wild-type littermates. We propose that, by affecting the expression of both IGFBP protein species, HMGA1 can serve as a modulator of IGF-I activity, thus representing an important novel mediator of glucose disposal.

Original languageEnglish
Pages (from-to)1578-1589
Number of pages12
JournalMolecular Endocrinology
Volume26
Issue number9
DOIs
Publication statusPublished - Sep 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Iiritano, S., Chiefari, E., Ventura, V., Arcidiacono, B., Possidente, K., Nocera, A., Nevolo, M. T., Fedele, M., Greco, A., Greco, M., Brunetti, G., Fusco, A., Foti, D., & Brunetti, A. (2012). The HMGA1-IGF-I/IGFBP system: A novel pathway for modulating glucose uptake. Molecular Endocrinology, 26(9), 1578-1589. https://doi.org/10.1210/me.2011-1379