International Circulation: There are a number of mechanisms by which HDL may influence type 2 diabetes. Could you outline those?
　　《国际循环》：HDL影响2型糖尿病的可能机制有很多，您能否简单列举一下？
　　Prof Rye: There are two points to consider. Firstly， you are likely to improve beta-cell function so that there is more insulin secreted. We know this happens in cultured cells but the question is whether it happens in people whose HDL levels are raised. The other point is that in people with diabetes， their insulin doesn’t work very well so they end up with insulin resistance. What should happen is that a lot of the glucose in circulation should be taken up by skeletal muscle cells， by the liver， by adipose tissue， and that is not happening. The beta-cells keep pumping out more and more insulin until they are exhausted and disappear. That is the point where someone goes from being insulin resistant to having diabetes. This is still a new area of study and we don’t know too much about it yet. One point of action of HDL is at the level of the pancreas and insulin secretion; and the other is uptake of glucose into skeletal muscle. There was a study that was done probably four years ago by an Australian group where they infused reconstituted HDL into diabetes sufferers and they saw increased insulin levels and also improvement in insulin resistance. The numbers again were small but it looked promising.
　　Prof Rye: 应考虑2点。首先，我们希望改善β细胞功能以分泌更多的胰岛素。在培养细胞中我们证实这是可行的，但问题是在HDL水平升高的人体内是否如此。另一点是，在糖尿病患者中胰岛素作用减弱，存在胰岛素抵抗。正常情况下循环中大量的葡萄糖应被骨骼肌细胞、肝脏和脂肪组织所摄取，但在胰岛素抵抗情况下这一切没有发生。β细胞持续泵出更多的胰岛素，直至其功能衰竭和消失。这就是一些患者从胰岛素抵抗进展为糖尿病的关键点。这仍是一个有待研究的崭新领域，我们还有许多未解之谜。总之，HDL一方面在胰腺和胰岛素分泌的水平发挥作用；另一方面在骨骼肌对葡萄糖的摄取水平发挥作用。大概4年前一个澳大利亚研究组进行了一项试验，他们对糖尿病患者注入重组HDL，观察到胰岛素水平上升以及胰岛素抵抗的改善。然而这项研究规模仍然很小，但似乎显示了光明的前景。
　　International Circulation: Exactly how does HDL help the beta-cells?
　　《国际循环》：那么HDL到底是如何对β细胞产生有利影响的？
　　Prof Rye: This is what we are looking at at the moment. We haven’t got a clear answer yet and we are conducting a range of studies. One of my colleague’s interests is intracellular signaling and we are trying to figure out the pathways by which you get increased insulin secretion from beta-cells by HDL but we have not got there yet. The mechanism， at present， is not known. There is one study showing that beta-cell apoptosis is reduced by HDL. HDL has profound anti-inflammatory effects. Whether that is a mechanism by which they improve beta-cell function， we don’t know as no one has looked directly at that. From an in vitro study from a few years back， we have seen that if you remove cholesterol from beta-cells using HDL， you increase insulin secretion. So there are lots of small bits and pieces but no big picture yet. There is a classical inflammatory pathway in cells and we know that HDL inhibits that pathway. We also know there are many other pathways， equally important but quite different， which are inhibited by HDL in a range of cells like endothelial cells and macrophages. I believe there are multiple mechanisms by which HDL inhibits inflammation. Coming back to inflammasomes; no one has actually done too much in terms of looking at inflammasomes and HDL. It is something I would really like to do and I have talked with Eicke Latz about this. One of the issues is that when doing animal studies， when you look at inflammasomes， any samples you collect by any current techniques such as microscopy or sectioning， melts the cholesterol crystals， which creates somewhat of a problem. We haven’t found a way around this yet.
　　Prof Rye: 这正是我们当前正在研究的。目前还不能明确回答，我们正在实施多项研究。我们的同仁感兴趣的一点是细胞内信号传导，我们正在努力阐明HDL使β细胞分泌胰岛素增加的旁路机制，但尚未达到目标。目前尚不清楚其作用机制。有一项研究显示HDL使β细胞凋亡减少。HDL有很强的抗炎作用。我们还不清楚这是否HDL改善β细胞功能的机制，因为还没有人直接观察这一点。多年前一项体外研究显示，使用HDL移除β细胞内的胆固醇，可增加胰岛素分泌。因此，可以说，我们得到了大量的片段，但尚未构成完整的拼图。我们知道HDL可抑制细胞内的经典炎症旁路；我们还知道存在许多其他同样重要但完全不同的旁路，HDL同样可抑制内皮细胞和单核细胞等多种细胞内的这些旁路。我相信HDL通过多重机制抑制炎症反应。回到炎症组学，还没有人对炎症组和HDL进行充分的研究，我非常希望进行这方面的研究，并同Eicke Latz进行了交谈。这当中存在的一个问题是，实施动物实验观察炎症组，在利用当前任何技术如显微镜或切片收集样本时，会导致胆固醇结晶的溶解。我们还没有找到解决这一问题的理想方法。
　　International Circulation: Do you think the HDL-raising drugs such as CETP inhibitors are going to be used in the future for the prevention or treatment of type 2 diabetes?
　　《国际循环》：您认为升HDL药物如CETP抑制剂未来会用于2型糖尿病的预防或治疗吗？
　　Prof Rye: That’s a crystal ball gazing question. First of all， CETP inhibitors have to be shown to improve hard endpoints. Without that they are going to fall by the wayside. Everything is pointing to that happening. If and when that happens that we have large scale outcomes trials where there is a reduction in deaths and cardiovascular disease， people are then going to start scrambling to look at the subgroups in these cohorts –those with inflammatory disorders， those with diabetes and so on – and there will be absolute goldmines of information come out of such studies. At the moment， we have a little bit of evidence that is really tantalizing and it looks really good but I think we have to wait and see.
　　Prof Rye: 这是一个如水晶球预测未来的问题。首先，必须有证据证实CETP抑制剂能够改善硬终点，否则他们只能走向终结。任何事物均是如此。一旦我们从大型终点试验中得出死亡和心血管疾病发生率降低的证据，我们就可以观察其研究队列中的亚组——炎症紊乱的患者、糖尿病患者，等等——由此可从这些研究中得到如金矿般的宝贵信息。就目前而言，我们只有很少的证据，这是一些看起来非常好、非常诱人的数据，但我们还必须等待，继续观察。