title: The HMGA1-IGF-I/IGFBP system: a novel pathway for modulating glucose uptake.
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 (18)F-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.
authors: Dipartimento di Scienze della Salute, Università di Catanzaro Magna Græcia, 88100 Catanzaro, Italy.
authors: Stefania
authors: S
authors: Iiritano
authors: Eusebio
authors: E
authors: Chiefari
authors: Valeria
authors: V
authors: Ventura
authors: Biagio
authors: B
authors: Arcidiacono
authors: Katiuscia
authors: K
authors: Possidente
authors: Aurora
authors: A
authors: Nocera
authors: Maria T
authors: MT
authors: Nevolo
authors: Monica
authors: M
authors: Fedele
authors: Adelaide
authors: A
authors: Greco
authors: Manfredi
authors: M
authors: Greco
authors: Giuseppe
authors: G
authors: Brunetti
authors: Alfredo
authors: A
authors: Fusco
authors: Daniela
authors: D
authors: Foti
authors: Antonio
authors: A
authors: Brunetti
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005947:Glucose; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D047468:Immunoprecipitation; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D049268:Positron-Emission Tomography; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024003:HMGA Proteins; C032231:IGFBP1 protein, human; C515497:IGFBP3 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D005947:Glucose