Mechanisms of FFA-Induced Hepatic Insulin Resistance

血浆游离脂肪酸水平升高与胰岛素抵抗状态有关，包括腹型肥胖和2型糖尿病。大量数据支持脂肪酸在胰岛素抵抗的发病机制中的重要作用，无论是在外周胰岛素敏感组织还是在肝脏，以及胰岛素分泌功能障碍。尽管游离脂肪酸在2型糖尿病多器官病理生理学中具有明显的潜在作用，但我们并不了解脂肪酸诱导的胰岛素抵抗的细胞和分子机制。鉴于肝脏胰岛素作用和葡萄糖代谢在维持葡萄糖稳态中的重要性，以及2型糖尿病肝脏葡萄糖生成增加的特点，我们的研究集中在饱和脂肪酸诱导肝脏胰岛素抵抗的机制上。初步数据表明，棕榈酸酯暴露抑制了PI3-激酶依赖途径的胰岛素信号转导，并以一种β-氧化依赖的方式抑制胰岛素受体蛋白和基因的表达。这些研究与K08的长期目标是一致的，即进一步确定胰岛素作用的营养调节机制。因此，通过R03补充资金机制寻求支持，以解决K08资金最后一年的以下具体目标：1.确定棕榈酸酯或其氧化产物(S)下调培养细胞中胰岛素受体基因表达和信号转导的离散代谢和/或信号转导途径。2.探讨饱和脂肪酸对大鼠肝脏胰岛素信号转导及基因表达的影响。这些研究的长期目标是了解脂肪酸诱导的胰岛素抵抗的病理生理学机制，并开发新的药物靶点来改善肝脏胰岛素抵抗和2型糖尿病。

Increased plasma levels of free fatty acids are associated with insulin resistant states, including abdominal obesity and type 2 diabetes mellitus. Abundant data support a important role for fatty acids in the pathogenesis of insulin resistance, both in peripheral insulin-sensitive tissues and in the liver, and insulin secretory dysfunction. Despite the clear potential role for free fatty acids as key to the multi-organ patho- physiology of type 2 diabetes, we do not understand the cellular and molecular mechanisms underlying fatty acid-induced insulin resistance. Given the importance of hepatic insulin action and glucose metabolism in maintenance of glucose homeostasis and the increased hepatic glucose production characteristic of type 2 diabetes, our investigation has focused on mechanisms for the induction of hepatic insulin resistance by saturated fatty acids. Preliminary data indicate that palmitate exposure inhibits insulin signaling to PI 3-kinasedependent pathways and inhibits insulin receptor protein and gene expression in a beta-oxidation- dependent manner. These studies are consistent with the long-term objective of the K08, namely to further define mechanisms of nutrient modulation of insulin action. Support is therefore sought through the R03 mechanism for supplemental funding to address the following specific aims during the final year of K08 funding: 1. To determine the discrete metabolic and/or signal transduction pathways by which palmitate or its oxidation product(s) downregulates insulin receptor gene expression and signaling in cultured cells. 2. To determine the effects of saturated fatty acids on insulin signal transduction and gene expression in the perfused rat liver. The long-term goal of these studies is to understand the pathophysiology of fatty acid-induced insulin resistance and to develop novel drug targets to ameliorate hepatic insulin resistance and type 2 diabetes.