虾青素对脓毒症胰岛素抵抗的作用及其机制研究

Stress hyperglycemia (SHG) is an independent risk factor of sepsis mortality. Recent randomized clinical trials have found no decrease in sepsis hospital mortality under the main treatment for SHG -intensive insulin therapy (IIT), moreover, IIT could increase their risk of hypoglycaemia and its complications. It is of great importance to look for a safe and effective alternative medicine for insulin treatment. Astaxanthin (Asta), a non-toxic red carotenoids derivative, has a widespread source in natural food. We have identified, for the first time, that Asta intervention could increase the plasma level of adiponectin (APN) in rats with sepsis significantly; improve insulin resistance (IR) and reduce the morbidity of SHG, protect multiple organ function and eventually improve survival rate of septic rats. Reports in the literature show plasma APN levels are independently related to insulin sensitivity; APN interacts with its receptor (AdipoRs, AdipoR1 and AdipoR2) and then mediates AMPK and PPAR α pathways, thus improving IR. This research is aimed to discuss whether Asta intervention could improve IR and reduce SHG of septic rats and what the mechanism is. We will further discuss whether Asta could affect the expression of APN and AdipoRs, and then mediates AMPK and PPAR α pathways under the whole animal, organization, cell and molecular level. The research is expected to reveal the fact that Asta could improve IR and reduce SHG of sepsis and to elucidate its mechanism, it also provide the experiment foundation and new idea for developing safe and effective medicine for SHG of sepsis treatment.

应激性高血糖（SHG）是脓毒症患者死亡的独立危险因素；近来随机临床试验观察到其主要治疗手段强化胰岛素治疗并不能降低病死率，反而增加低血糖和其并发症的危险性；寻找胰岛素治疗的替代药物具有重要意义。虾青素（Asta）是一种安全且来源丰富的类胡萝卜素衍生物。申请者首次发现，Asta干预脓毒症大鼠可增加其血浆脂联素（APN）水平，改善胰岛素抵抗（IR）、降低SHG，保护多器官功能及提高存活率。文献显示血浆APN与胰岛素敏感性独立相关；它通过与其受体（AdipoRs）结合后相互作用影响AMPK 及PPARα 通路，改善IR。本项目拟进一步从整体动物、组织、细胞及分子水平探讨Asta是否通过对APN及AdipoRs表达的调节影响AMPK 及PPARα 通路发挥改善IR、降低SHG的作用。开展本研究，可望揭示Asta对脓毒症IR及SHG的作用及机制，为开发新的安全有效的抗脓毒症SHG药物提供实验基础。

应激性高血糖（stress hyperglycemia, SHG）是脓毒症患者死亡的独立危险因素之一；近年来多项大规模的随机临床试验观察到其主要治疗手段胰岛素强化治疗非但不能降低病死率，反而增加低血糖和其并发症的危险性；寻找和开发胰岛素治疗的安全有效的替代药物具有非常重要的意义。虾青素（Astaxanthin）是一种安全无毒且来源丰富的红色类胡萝卜素的含氧衍生物，它具有很强的抗氧化能力，又称“超级维生素E”。近年来研究发现其可通过抗炎、抗凝及抗氧化的作用保护内皮细胞及胰岛β细胞的功能，可用于糖尿病及并发症的治疗。虾青素对高蔗糖饮食大鼠有降血压及胰岛素增敏效应，但其作用机制并不清楚。另外，临床研究发现口服虾青素可使高脂血症患者血清脂联素（adiponectin, APN）水平显著升高。大量文献报道显示血浆APN水平与胰岛素敏感性独立相关，认为其对胰岛素增敏作用的主要机制是通过与其受体结合后影响AMPK 及PPARα 通路，改善胰岛素抵抗（insulin resistance, IR）。但是虾青素能否改善IR，从而降低脓毒症SHG，国内外目前尚无报道。因此，本研究拟先在整体动物水平观察虾青素对脓毒症大鼠IR及SHG、多器官损伤及死亡率的影响，并探讨该影响作用是否与其对APN及其受体的表达调节有关；并在此基础上采用小鼠脂肪细胞系3T3-L1细胞模型，观察内毒素和高糖刺激下APN及其受体表达的变化；通过抗体中和及RNA干扰技术阻断脂联素及其受体。探讨虾青素是否通过对脂联素及其受体表达的调节影响AMPK 及PPARα通路改善IR，从而降低SHG。结果发现，虾青素可提高APN及其受体的表达，降低脓毒症大鼠所致SHG、改善IR，抑制脓毒症大鼠全身炎症反应及氧化应激、减轻脓毒症大鼠多器官损伤，提高7天存活率；虾青素通过对炎症和高糖应激条件下成熟脂肪细胞内脂联素及其受体AdipoR1表达的调节影响下游AMPK 及PPARα 信号通路而改善IR。本研究提示虾青素可成为脓毒症SHG胰岛素治疗的潜在替代药物之一。