BIOCHEMICAL MECHANISMS OF IN VIVO INSULIN RESISTANCE

在这个项目中，我们建议继续研究“胰岛素抵抗”获得的生化和分子机制。我们长期关注的是营养过剩和胰岛素作用受损之间的潜在联系。在这方面，我们最近表明，增加的营养（如碳水化合物和脂质）可用性导致胰岛素抵抗和通过增加碳通量进入己糖胺生物合成途径增加瘦素基因表达。我们在此提出，在营养物质及其代谢结果之间通常存在闭环反馈调节。因此，营养过剩通过己糖胺生物合成途径被感知，并产生导致胰岛素对葡萄糖摄取作用降低和瘦素基因表达增加的信号。它们还通过增加丙二酰辅酶a和长链辅酶a的组织水平来增加脂质储存，最终增加肥胖和体重增加。然而，伴随而来的瘦素表达的诱导试图通过拮抗营养物质对丙二酰辅酶a和甘油三酯储存的影响、对己糖胺途径的影响以及可能通过对胰岛素信号的直接影响来抵消这种驱动。这种生理反应的任何破坏（由于营养物质对瘦素表达的刺激受损或瘦素作用于目标组织的有效性降低）都可能导致肥胖增加和胰岛素抵抗加剧。根据初步结果和这一总体假设，我们希望实现以下具体目标：营养物质如何调节胰岛素的作用？我们将重点关注脂质可用性增加与骨骼肌胰岛素信号传导和作用之间的相互作用。我们假设，对过度营养暴露产生胰岛素抵抗的易感性是由骨骼肌在糖酵解途径中利用果糖-6-磷酸的能力调节的。2. 瘦素如何调节肝脏和肌肉的糖/脂代谢和胰岛素作用？我们将研究瘦素的特定下丘脑靶点是否在调节其复杂的代谢作用中发挥不同的作用。3. 瘦素的合成和/或作用是否在长时间刺激后被调节？我们将建立相对高瘦素血症的短期模型，并将验证如果瘦素信号/转导系统长期过度刺激，瘦素对营养过剩的“保护”作用减弱的假设。

In this project, we propose to continue our investigation of the biochemical and molecular mechanism(s) by which "insulin resistance" is acquired. Our long-term focus has been on the potential link between nutrient excess and impairment of insulin action. In this regard, we have recently shown that increased nutrient (eg, carbohydrate and lipid) availability results in insulin resistance and in increased leptin gene expression via increased flux of carbons into the hexosamine biosynthetic pathway. We propose herein that a close loop feed-back regulation is normally operating between nutrients and their metabolic outcomes. Thus, nutrient excess is sensed via the hexosamine biosynthetic pathway and generates signals leading to decreased insulin action on glucose uptake and to increased leptin gene expression. They also favor increased storage into lipid via increased tissue levels of Malonyl-CoA and Long Chain-CoA and ultimately increased adiposity and weight gain. However, the concomitant induction of leptin expression attempts to counteract this drive by antagonizing the effects of nutrients on Malonyl-CoA and triglyceride storage, on the hexosamine pathway and perhaps via direct effects on insulin signaling. Any disruption of this physiological response (due to either impaired stimulation of leptin expression by nutrients or to decreased effectiveness of leptin action on target tissues) is likely to lead to increased adiposity and more insulin resistance. Based on preliminary results and on this overall hypothesis we wish to pursue the following specific aims: 1. How do nutrients regulate insulin action? We will focus on the interaction between increased lipid availability and skeletal muscle insulin signaling and action. We hypothesize that the susceptibility to develop insulin resistance in response to excessive nutrient exposure is modulated by the skeletal muscle ability to utilize fructose-6-phosphate in the glycolytic pathway. 2. How does leptin modulate hepatic and muscle glucose/lipid metabolism and insulin action? We will examine whether specific hypothalamic targets of leptin play distinct roles in mediating its complex metabolic effects. 3. Is leptin synthesis and/or action modulated following prolonged stimulation? We will generate short-term models of relative hyperleptinemia and will test the hypothesis that the "protective" effect of leptin against nutrient excess wanes if the leptin signal/transduction system is chronically over-stimulated.