The HMGA1-IGF-I/IGFBP system: a novel pathway for modulating glucose uptake(690 views) Iiritano S, Chiefari E, Ventura V, Arcidiacono B, Possidente K, Nocera A, Nevolo MT, Fedele M, Greco A, Greco M, Brunetti G, Fusco A, Foti D, Brunetti A
Keywords: Fluorodeoxyglucose F 18, Glucose Transporter 4, High Mobility Group A1a Protein, Somatomedin Binding Protein 1, Adaptation, Animal Cell, Animal Experiment, Article, Biological Activity, Chromatin Immunoprecipitation, Controlled Study, Gene Activation, Genetic Transcription, Glucose Clamp Technique, Human, Human Cell, Hyperglycemia, In Vivo Study, Mouse, Nonhuman, Positron Emission Tomography, Priority Journal, Protein Dna Interaction, Protein Expression, Protein Protein Interaction, Protein Transport, Regulatory Mechanism, Signal Transduction, Skeletal Muscle, Transactivation, Transcription Regulation, Wild Type, Blotting, Western, Cell Line, Tumor, Hep G2 Cells, Hmga Proteins, Insulin-Like Growth Factor Binding Protein 1, Knockout, Nih 3t3 Cells, Positron-Emission Tomography, Promoter Regions, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Metabolism,
Affiliations: *** IBB - CNR ***
Dipartimento di Scienze della Salute, Università di Catanzaro 'Magna Græcia', 88100 Catanzaro, Italy
Cattedra di Endocrinologia, Università di Catanzaro 'Magna Græcia', 88100 Catanzaro, Italy
Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro 'Magna Græcia', 88100 Catanzaro, Italy
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Università di Napoli 'Federico II', 80131 Napoli, Italy
Ceinge, Biotechnologie Avanzate, Scarl, Naples, Italy
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Baxter, R. C., Insulin-like growth factor (IGF) -binding proteins: Interactions with IGFs and intrinsic bioactivities (2000) Am J Physiol Endocrinol Metab, 278, pp. E967-E976
Clemmons, D. R., Insulin-like growth factor binding proteins and their role in controlling IGF actions (1997) Cytokine Growth Factor Rev, 8, pp. 45-62
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Myers Jr, M. J., Sun, X. J., Cheatham, B., Jachna, B. R., Glasheen, E. M., Backer, J. M., White, M. F., IRS-1 is a common element in insulin and insulin-like growth factor-I signaling to the phosphatidylinosi-tol 3'-kinase (1993) Endocrinology, 132, pp. 1421-1430
Brown, G. K., Glucose transporters: Structure, function and consequences of deficiency (2000) J Inherit Metab Dis, 23, pp. 237-246
Gerich, J. E., Physiology of glucose homeostasis (2000) Diabetes Obes Metab, 2, pp. 345-350
Woods, K. A., Camacho-Hubner, C., Bergman, R. N., Barter, D., Clark, A. J., Savage, M. O., Effects of insulin-like growth factor 1 (IGF-I) therapy on body composition and insulin resistance in IGF-I gene deletion (2000) J Clin Endocrinol Metab, 85, pp. 1407-1411
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Silha, J. V., Gui, Y., Murphy, L. J., Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice (2002) Am J Physiol Endocrinol Metab, 283, pp. E937-E945
The HMGA1-IGF-I/IGFBP system: a novel pathway for modulating glucose uptake
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 F-18-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. (Molecular Endocrinology 26: 1578-1589, 2012)
The HMGA1-IGF-I/IGFBP system: a novel pathway for modulating glucose uptake