Role of Fatty Acid Oxidation Defects in Insulin Sensitivity

 描述（由申请人提供）：线粒体功能障碍与动物模型和人类中胰岛素抵抗和2型糖尿病的病因学和表达有关，这些动物模型和人类处于饮食、脂肪组织内源性释放或两者兼而有之的高脂肪负荷条件下。然而，在这些条件下的胰岛素抵抗是否是由于线粒体能量利用的内在缺陷或游离脂肪酸（FFA）通量和氨基酸代谢的异常，包括积累的代谢中间体损害胰岛素信号传导的潜在作用，存在争议。为了解决这些争议，我们提出了两个目标，将正式测试的假设，即内在缺陷的线粒体功能涉及长链，但不是中链，粮农组织将防止胰岛素诱导的胰岛素抵抗，使用先进的代谢组学方法结合高胰岛素-血糖正常钳夹和分析的胰岛素信号在肌肉和脂肪活检。研究受试者将从脂肪酸氧化途径（FAO）中三种线粒体酶（包括长链脂肪酸氧化）之一存在遗传缺陷的独特患者人群中招募（极长链酰基辅酶A脱氢酶（VLCAD）或三功能蛋白（TFP），包括长链3-羟基酰基辅酶A脱氢酶（LCHAD）缺乏），以及，最后，中链脂肪酸（中链酰基辅酶A脱氢酶，或MCAD）。这些患者和年龄、性别和BMI匹配的健康对照将在单独的访视研究日期接受检测，在此期间，他们接受在先前研究中显示可诱导异位脂质蓄积和胰岛素抵抗的胰岛素联合输注，或甘油和生理盐水对照输注。与对照组相比，FAO疾病患者的这些详细研究将为我们提供一个独特的机会，以更好地了解人类脂肪酸代谢和胰岛素敏感性调节之间的界面。这些研究不仅将解决我们在这一领域的理解中存在的争议和差距，而且通过包括细胞和全身代谢组学的测量，它们还可能有助于为治疗胰岛素抵抗和2型糖尿病的潜在药物靶点的持续开发提供信息。

 DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been implicated in the etiology and expression of insulin resistance and type 2 diabetes in animal models and humans under conditions of high fat loads either from the diet, endogenous release by adipose tissue, or both. However, controversy exists as to whether insulin resistance under these conditions results from intrinsic defects in mitochondrial energy utilization or abnormalities in free fatty aid (FFA) flux and amino acid metabolism, including the potential role of accumulated metabolic intermediates to impair insulin signaling. To address these controversies, we propose two aims that will formally test the hypothesis that intrinsic defects in mitochondrial function involving long-chain, but not medium-chain, FAO will prevent intralipid-induced insulin resistance using advanced metabolomics methodology in combination with hyperinsulinemic-euglycemic clamps and analyses of insulin signaling in muscle and fat biopsies. Study subjects will be recruited from a unique population of patients with inherited defects in one of three mitochondrial enzymes in the fatty acid oxidation pathway (FAO), including oxidation of long-chain fatty acids (very long-chain acylCoA dehydrogenase (VLCAD), or trifunctional protein (TFP), including long-chain 3-hydroxy acylCoA dehydrogenase (LCHAD) deficiencies), and, finally, medium-chain fatty acids (medium-chain acyl CoA dehydrogenase, or MCAD). These patients and age, sex, and BMI-matched healthy controls will undergo testing on separate visit study dates during which they receive co-infusions of either intralipid, shown to induce ectopic lipid accumulation and insulin resistance in previous studies, or a control infusion of glycerol and saline. These detailed studies in patients with FAO disorders compared to controls will give us a unique opportunity to better understand the interface between fatty acid metabolism and regulation of insulin sensitivity in humans. Not only will these studies address current controversies and gaps in our understanding in this field, but by including measurements of both cellular and systemic metabolomics, they may also help inform on-going development of potential pharmaceutical targets for the treatment of insulin resistance and type 2 diabetes.