The Role of Glucose Mediated Glucose Uptake in the pathogenesis of IFG and IGT

描述（由申请方提供）：空腹血糖受损受试者进展为T2 DM的风险增加。在非糖尿病范围内，对导致FPG升高的代谢缺陷的研究很少。更清楚地了解这些缺陷的机制将有助于制定更好的策略来治疗和预防T2 DM。我们以前已经表明，基础葡萄糖清除率降低IFG的主题。由于基础组织葡萄糖清除通过葡萄糖介导的葡萄糖摄取（GMGU）机制发生，我们假设受损的GMGU是导致非糖尿病范围内FPG浓度升高和IFG发展的主要缺陷。在这项资助计划中，我们将：（i）用阶梯式高血糖钳夹和生长抑素输注定量全身GMGU，用阶梯式正常血糖胰岛素钳夹定量胰岛素介导的葡萄糖摄取（IMGU），（ii）胰岛素依赖性葡萄糖代谢产物的蛋白质含量。（GLUT 4/GLUT 12）和葡萄糖介导的葡萄糖转运蛋白IFG、IGT和NGT受试者骨骼肌中GLUT 1/GLUT 3/GLUT 11和基因表达;（三）转录因子和mRNA结合蛋白的水平及其与GLUT 1基因启动子和GLUT 1 mRNA的结合及其与GLUT 1水平，和（iv）在基础状态期间和葡萄糖摄入后定量内脏葡萄糖摄取（SGU），以检查SGU降低对IFG受试者中GMGU降低和血浆葡萄糖浓度过度早期升高的贡献。我们相信，这些研究的结果将有助于确定负责IFG的发展的分子/生物化学/生理缺陷，并有助于阐明有效的策略，以纠正这些缺陷和恢复IFG NGT。 公共卫生相关性：空腹血糖受损（IFG）受试者未来发生2型糖尿病（T2 DM）的风险增加。在这项资助计划中，我们将研究在非糖尿病范围和IFG发展过程中导致空腹血糖浓度升高的分子、代谢和生理缺陷。因此，本研究的结果将提高对葡萄糖稳态调节的理解，并将有助于确定新的干预靶点，以防止IFG进展为T2 DM，并将IFG恢复为NGT。

DESCRIPTION (provided by applicant): Subjects with impaired fasting glucose have increased risk of progression to T2DM. The metabolic defects responsible for the increase in FPG within the nondiabetic range have been poorly studied. A clearer understanding of the mechanisms of these defects will help to develop improved strategies to treat and prevent T2DM. We previously have shown that basal glucose clearance is decreased in IFG subjects. Since basal tissue glucose clearance takes place via glucose-mediated glucose uptake (GMGU) mechanisms, we hypothesize that impaired GMGU is the primary defect responsible for the rise in the FPG concentration in the non-diabetic range and development of IFG. In this grant proposal we will: (i) quantitate whole body GMGU with the stepped hyperglycemic clamp and somatostatin infusion, and insulin-mediated glucose uptake (IMGU) with the stepped euglycemic insulin clamp, (ii) the protein content of insulin dependent (GLUT4/GLUT12) and glucose-mediated glucose transporters (GLUT1/GLUT3/GLUT11) and gene expression in skeletal muscle in subjects with IFG, IGT and NGT; (iii) the level of transcription factors and mRNA binding proteins and their binding to GLUT1 gene promoter and GLUT1 mRNA and their relationship to GLUT1 level, and (iv) quantitate splanchnic glucose uptake (SGU) during basal state and following glucose ingestion to examine the contribution of decreased SGU to the decreased GMGU and excessive early rise in plasma glucose concentration in IFG subjects. We believe that the results of these studies will help define the molecular/biochemical/physiologic defects responsible for the development of IFG and help to elucidate effective strategies to correct these defects and revert IFG to NGT. PUBLIC HEALTH RELEVANCE: Subjects with impaired fasting glucose (IFG) have increased future risk for type 2 diabetes (T2DM). In this grant proposal, we will study the molecular, metabolic and physiologic defects responsible for the increase in the fasting plasma glucose concentration during the non-diabetic range and development of IFG. Thus, the results of the present studies will improve the understanding of the regulation of glucose homeostasis and will help identify novel targets for intervention to prevent the progression of IFG to T2DM and revert IFG to NGT.