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，增加营养（如碳水化合物和脂质）的可用性导致胰岛素抵抗和增加瘦素基因表达通过增加碳流入己糖胺生物合成途径。 我们在此提出，闭环反馈调节通常在营养素和它们的代谢结果之间运行。 因此，通过己糖胺生物合成途径感知营养过剩，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。 它们还有利于通过增加丙二酰辅酶A和长链辅酶A的组织水平增加脂质储存，并最终增加肥胖和体重增加。然而，伴随的瘦素表达的诱导试图通过拮抗营养素对丙二酰辅酶A和甘油三酯储存、对己糖胺途径的影响以及可能通过对胰岛素信号传导的直接影响来抵消这种驱动。 这种生理反应的任何中断（由于营养素对瘦素表达的刺激受损或瘦素对靶组织作用的有效性降低）都可能导致肥胖增加和胰岛素抵抗增加。 基于初步结果和这一总体假设，我们希望追求以下具体目标：1。营养素如何调节胰岛素的作用？ 我们将集中在增加脂质的可用性和骨骼肌胰岛素信号和行动之间的相互作用。 我们推测，过度营养暴露引起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介导其复杂的代谢效应中发挥不同的作用。 3.长时间刺激后瘦素的合成和/或作用是否受到调节？ 我们将产生相对高瘦素血症的短期模型，并将测试的假设，“保护”的瘦素对营养过剩的效果减弱，如果瘦素信号/转导系统是长期过度刺激。

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.