Novel non-invasive assessment of de novo lipogenesis and its mechanistic role in human insulin resistance

背景自1975年以来，全球范围内的肥胖症几乎增加了两倍，世界卫生组织估计，39%的成年人口现在超重。肥胖会导致糖尿病和其他代谢紊乱，如心脏病和脂肪肝。这个过程可能是渐进的，几年后悄悄地发生在胰岛素抵抗的状态下，肌肉和肝脏的细胞对激素胰岛素反应不佳，血糖上升。因此，我们必须更好地了解胰岛素抵抗的机制，以便能够在这些疾病发生的早期阶段进行干预，在这些疾病的发展过程中，代谢变化可能仍然是可逆的。胰岛素抵抗与肝脏和骨骼肌中储存的脂肪积累密切相关。越来越多的证据表明，一种被称为新生脂肪生成(DNL)的过程与胰岛素抵抗的发展有关，在DNL中，脂肪是由过量的糖产生的。没有非侵入性的方法来测量DNL中的脂肪储存，从肝脏提取活组织样本具有很大的风险。因此，对DNL产生的脂肪的储存的研究受到了极大的限制。目的开发一种非侵入性方法来测量DNL产生的脂肪的储存，并利用该方法安全地检查这种脂肪储存与人类胰岛素抵抗的相关性。方法磁共振波谱(MRS)是一种完全非侵入性的技术，它使用MRI扫描仪从体内产生生化信息。这可以告诉我们组织的组成，例如，可以测量它含有多少脂肪。然而，正常的方法不能区分DNL产生的脂肪和其他脂肪，所以我计划在这里设计和验证一种新的特殊的MRS方法，它将能够做到这一点。使用胰岛素抵抗患者和健康人，我们将利用这一新方法来研究DNL储存的脂肪在胰岛素抵抗机制中的作用。非侵入性方法测量DNL产生的脂肪的储存将安全地使研究储存的DNL-脂肪与人类胰岛素抵抗的相关性成为可能。了解这些机制是预防包括糖尿病、心脏病和脂肪肝在内的许多代谢性疾病的关键。

BackgroundWorldwide obesity has nearly tripled since 1975 and the World Health Organisation estimates 39% of the adult population are now overweight. Obesity can lead to diabetes and other metabolic disorders such as heart and fatty liver disease. This process can be gradual, quietly occurring over a number of years by a state of insulin resistance, where cells in muscle and liver don't respond well to the hormone insulin and blood sugars rise. Therefore it is imperative that we better understand the mechanisms of insulin resistance in order to be able to intervene at an earlier stage in the development of these diseases, where metabolic changes may still be reversible.Insulin resistance is closely associated with an accumulation of fat stored in the liver and skeletal muscle. There is growing evidence to suggest a process called de novo lipogenesis (DNL), where fat is generated from excess sugars, is involved in the development of insulin resistance. There are no non-invasive ways to measure the storage of fat from DNL, and taking a biopsy sample from the liver carries substantial risk. Therefore investigations into the storage of DNL-generated fats has been significantly limited. AimTo develop a non-invasive method to measure the storage of DNL-generated fats, and to use this to safely examine the relevance of this fat storage in human insulin resistance.ApproachMagnetic Resonance Spectroscopy (MRS) is a completely non-invasive technique that uses an MRI scanner to generate biochemical information from inside the body. This can tell us about the composition of the tissue and, for example, can measure how much fat it contains. However, normal methods can not distinguish DNL-generated fat from other fat, and so here I plan to design and validate a new special MRS method that will be able to do this. Using both insulin resistant patients and healthy individuals, we shall utilise this new method to investigate the role of DNL-stored fats in the mechanisms of insulin resistance. ImportanceNon-invasive methods to measure the storage of DNL-generated fats will safely enable the investigation of the relevance of stored DNL-fats in human insulin resistance. Understanding such mechanisms is key to preventing a number of metabolic diseases including diabetes, heart and fatty liver disease.