Quantitative studies of metabolic organ dynamics

正常代谢的特点是胰岛素抵抗和血浆胰岛素水平之间存在适当的关系。这种相互关系的质量由处置指数定义，处置指数被认为是衡量胰腺β细胞补偿胰岛素抵抗能力的指标。然而，最近它已经变得清楚，一个额外的补偿机制是胰岛素清除机制的改变。事实上，肝清除和肝外清除机制受到不同的调节，有证据表明，在某些高危人群中，包括非洲裔美国人和西班牙裔美国人，肝脏而非肝外胰岛素清除减少。本研究的目的是通过动物实验来阐明β细胞对胰岛素抵抗的补偿与肝脏和肝外位点的胰岛素清除水平的补偿之间的关系。我们建议研究诱导胰岛素抵抗的两种机制-高脂肪饮食和胰岛素受体拮抗剂S961的治疗。我们将探讨β细胞上调和清除率下调的相关作用和机制。此外，这种关系将在前驱糖尿病模型中进行检查，以确定补偿机制之间是否存在协调。此外，我们将研究CEACAM1反义寡核苷酸降低肝脏清除率的作用，以研究清除率降低本身是否有助于糖尿病的发病机制。最后，β细胞补偿和胰岛素清除改变的相对重要性和机制将在妊娠动物中进行研究，妊娠动物在面对极端胰岛素抵抗时可能表现出高胰岛素血症最深刻的生理表现。这些研究将确定肝脏和肝外部位胰岛素清除的变化是否可能是替代β细胞增殖以维持正常代谢功能的重要靶点，尽管存在严重的胰岛素抵抗。

Normal metabolism is characterized by an appropriate relationship between insulin resistance and plasma insulin levels. The quality of this interrelationship is defined by the Disposition Index, which has been considered a measure of the ability of the pancreatic β-cells to compensate for insulin resistance. Recently however it has become clear that an additional mechanism of compensation is alterations in insulin clearance mechanisms. In fact, liver clearance and extrahepatic clearance mechanisms are differentially regulated, revealed in evidence that hepatic but not extrahepatic insulin clearance is reduced in certain at risk populations including African Americans and Hispanic Americans. The goal of this proposal is to perform experiments in animals to elucidate the relationship between β-cell compensation for insulin resistance versus compensation at the level of insulin clearance at hepatic versus extrahepatic loci. We propose to examine two mechanisms of inducing insulin resistance – high fat diet, and treatment with the insulin receptor antagonist S961. The relative roles and mechanisms of β-cell upregulation and clearance down-regulation will be examined. Additionally, this relationship will be examined in a model of prediabetes to determine if there is coordination between compensation mechanisms. Additionally we will examine the effects of reducing liver clearance with the CEACAM1 antisense oligonucleotide to examine whether reduced clearance per se can contribute to the pathogenesis of diabetes. Finally, the relative importance and mechanisms of β-cell compensation and alteration in insulin clearance will be examined in pregnant animals which display possibly the most profound physiologic manifestation of hyperinsulinemia in the face of extreme insulin resistance. These studies will determine if changes in clearance of insulin at hepatic versus extrahepatic sites could be important targets to replace β-cell proliferation to maintain normal metabolic function despite profound insulin resistance.