The HMGA1-IGF-I/IGFBP System: A Novel Pathway for Modulating Glucose Uptake
The HMGA1-IGF-I/IGFBP System: A Novel Pathway for Modulating Glucose Uptake
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DOI：
10.1210/me.2011-1379
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发表时间：
2012-09-01
影响因子：
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通讯作者：
Brunetti, Antonio
中科院分区：
文献类型：
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作者：
Iiritano, Stefania;Chiefari, Eusebio;Brunetti, Antonio
我们以前表明，高迁移率族A1（HMGA 1）蛋白表达的损失，诱导小鼠通过破坏Hmga 1基因，大大降低胰岛素作用的主要靶组织中的胰岛素受体表达，导致2型糖尿病表型，其中，然而，葡萄糖耐受不良与外周胰岛素敏感性增加矛盾。尽管胰岛素作用受损，但胰岛素超敏反应支持通过胰岛素非依赖性过程促进葡萄糖处置的分子适应机制的存在。在此，我们为体内葡萄糖摄取的这些代偿途径/回路提供了支持，在某些不利的代谢条件下激活这些途径/回路可以防止高血糖症。使用染色质免疫沉淀结合蛋白质-蛋白质相互作用的核蛋白在体内的研究，并在活细胞中的瞬时转录测定，我们表明，HMGA 1是所需的基因激活的IGF结合蛋白1（IGFBP 1）和3（IGFBP 3），两个主要成员的IGF结合蛋白超家族。此外，通过使用F-18标记的2-氟-2-脱氧-D-葡萄糖的正电子发射断层扫描，结合IGF-I的正葡萄糖钳夹，我们证明了IGF-I的生物活性在Hmga 1基因敲除小鼠中增加，其中骨骼肌Glut 4蛋白表达和葡萄糖摄取与野生型同窝小鼠相比均增强。我们建议，通过影响两种IGFBP蛋白质的表达，HMGA 1可以作为IGF-I活性的调节剂，从而代表葡萄糖处置的重要新介质。（分子内分泌学26：1578-1589，2012）
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)