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

描述(由申请人提供)：空腹血糖受损的受试者进展为T2 DM的风险增加。在非糖尿病范围内导致空腹血糖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改进的治疗和预防T2 DM的策略。我们先前已经证明，IFG受试者的基础葡萄糖清除率降低。由于基础组织的葡萄糖清除是通过葡萄糖介导的葡萄糖摄取(GMGU)机制进行的，我们假设GMGU受损是导致非糖尿病范围内空腹血糖浓度升高和IFG发生的主要原因。在这项拨款提案中，我们将：(I)用阶梯式高血糖钳夹和生长抑素输注来定量全身GMGU，用阶梯式正糖胰岛素钳夹来定量胰岛素介导的葡萄糖摄取(IMGU)，(Ii)胰岛素依赖性(GLUT4/GLUT12)和葡萄糖介导的葡萄糖转运蛋白(GLUT1/GLUT3/GLUT11)的蛋白质含量以及IFG、IGT和NGT受试者骨骼肌中的基因表达；(Iii)转录因子和mRNA结合蛋白水平及其与GLUT1基因启动子和GLUT1 mRNA的结合水平及其与GLUT1水平的关系；(Iv)定量测定基础状态和糖摄取后内脏葡萄糖摄取量(SGU)，以探讨SGU减少对IFG患者GMGU降低和血糖浓度过早升高的作用。我们相信，这些研究的结果将有助于确定导致IFG发生的分子/生化/生理缺陷，并有助于阐明纠正这些缺陷并将IFG恢复为NGT的有效策略。

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.