BIOCHEMICAL MECHANISMS OF IN VIVO INSULIN RESISTANCE

在这个项目中，我们建议继续我们对“胰岛素抵抗”形成的生化和分子机制的研究(S)。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，我们最近发现，营养(如碳水化合物和脂肪)供应的增加会导致胰岛素抵抗，并通过增加碳水化合物进入氨基己糖生物合成途径而增加瘦素基因的表达。我们在此提出，正常情况下，营养物质及其代谢结果之间存在一个闭环反馈调节机制。因此，营养过剩是通过己糖胺生物合成途径感受到的，并产生信号，导致胰岛素对葡萄糖摄取的作用减少，并增加瘦素基因的表达。他们还倾向于通过增加组织中丙二酰辅酶A和长链辅酶A的水平来增加脂肪的储存，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对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一驱动。这种生理反应的任何干扰(由于营养物质对瘦素表达的抑制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更多的胰岛素抵抗。根据初步结果和这一总体假设，我们希望追求以下具体目标：1.营养物质如何调节胰岛素的作用？我们将重点讨论脂肪供应增加和骨骼肌胰岛素信号和作用之间的相互作用。我们假设，骨骼肌在糖酵解途径中利用果糖-6-磷酸的能力调节了对过度营养暴露导致的胰岛素抵抗的敏感性。2.瘦素是如何调节肝脏和肌肉的糖脂代谢和胰岛素作用的？我们将研究特定的下丘脑瘦素靶点是否在调节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？我们将建立相对高瘦素血症的短期模型，并将检验假设，即如果瘦素信号/转导系统长期过度刺激，瘦素对营养过剩的“保护”作用减弱。

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.