我们目前的胰岛素抵抗模式是锁定和关键。胰岛素是一种激素，作用于细胞表面的荷尔蒙受体，以发挥作用。
这通常被称为锁和钥匙模型。锁是胰岛素受体，使门关闭的细胞。当插入正确的钥匙（胰岛素）时，门打开，使葡萄糖从细胞内的血液中释放出来。这个葡萄糖然后能够给细胞机器提供动力。
一旦你取下钥匙（胰岛素），门关闭，血液中的葡萄糖不再能进入细胞内。
在胰岛素抵抗现象中会发生什么？古典上，我们想象锁和钥匙不再适合。关键（胰岛素）能够打开锁（受体），但只能部分和不太好。结果，葡萄糖不能正常通过门。
这导致细胞内葡萄糖含量低于正常水平。被关闭的门阻塞的葡萄糖堆积在血液细胞外，我们可以检测到血糖升高，并进行2型糖尿病的临床诊断。
这也被描述为内部饥饿状态，因为细胞内部葡萄糖很少。下跪反应是为身体增加胰岛素的生产（关键）。由于每个键的工作效果都不如以前，身体过度产生键的数量，以确保足够的葡萄糖进入细胞。一个不错的理论。
问题的确在于，这种范式并不适合现实。首先，是胰岛素还是胰岛素受体？那么现在看胰岛素的结构和胰岛素抵抗患者的胰岛素受体的结构真的很容易。您只需分离胰岛素或一些细胞，并用奇特的分子工具检查其结构。很明显，胰岛素或受体没有任何问题。那么交易是什么？
唯一剩下的可能就是有什么东西在堵塞系统。某种妨碍锁和钥匙机制的阻断器。但是什么？有各种各样的理论。炎。氧化应激。晚期糖化终产物。当医生真的不知道的时候，所有常见的流行语出来了。有了这个模型，我们没有真正的想法是什么导致了胰岛素抵抗。不明白是什么原因造成的，我们没有机会处理它。
那么就存在肝脏胰岛素抵抗的中心矛盾。让我解释。胰岛素在肝脏有两个主要的作用。请记住，当你吃的时候，胰岛素会上升。它告诉身体停止在肝脏中产生葡萄糖（葡糖异生），因为有大量的葡萄糖从胃（食物）进入。这是通过FOX01途径介导的。
肝脏中的第二个主要作用是增加脂肪的生成（De Novo Lipogeneis（DNL））。这是对付葡萄糖传入的洪水，身体不能正确使用的方式。这是通过SREBP-1c途径介导的。
所以，如果肝脏变成胰岛素抵抗，那么胰岛素的这种作用就会下降。也就是说，肝脏应该继续制造葡萄糖，停止发胖。但是这仅仅是糖异生的情况。也就是说，在胰岛素抵抗期间，肝脏如预期继续产生新的葡萄糖。但是DNL（制造新的脂肪）继续增加。所以胰岛素对DNL的影响不会变钝，反而会加速！
我勒个去？
How in seven hells can this insulin resistant liver selectively be resistant to one effect of insulin yet accelerate the effect of the other? In the very same cell, in response to the very same levels of insulin, with the very same insulin receptor? That seems crazy. The same cell is insulin resistance and insulin super-sensitive at the same time!
How can we explain this paradox?
We need a new paradigm of insulin resistance that better fits the facts. In fact, we can think of insulin resistance as an overflow phenomenon, instead of a lock and key one. All we really know about insulin resistance is that it is much more difficult to move glucose into an ‘insulin resistant’ cell than a normal one.
But this does not necessarily mean that the door is jammed. Instead, perhaps the cell is already overflowing with glucose and therefore more glucose cannot go in.
Imagine the cell to be a subway car. When the door opens, the passengers on the outside (glucose in the blood) march in a nice orderly manner into the empty subway car (cell). Normally, it doesn’t really require much of a push to get this glucose into the cell (insulin gives the push).
But during insulin resistance, the problem is not that the door does not open. The problem, instead is that the subway car (cell) is already overflowing with passengers (glucose). Now the glucose outside the cell simply can’t get in and is left crowded on the platform.
Insulin tries to push the glucose into the cell like the Japanese Subway Pushers, but they simply can’t do it because it’s full. So, it looks like the cell is resistant to the effects of the insulin, but really the problem is that the cell is already overflowing. So, the knee jerk reaction is to manufacture more insulin (pushers) to help push glucose into the cell. Which works, but only for a while.
So, the cell is not in a state of ‘internal starvation’. Instead, the cell is overflowing with glucose. Glucose starts spilling out into the blood, which looks like gluconeogenesis has not been stopped which is consistent with insulin resistance. However, the Insulin and its Receptor are fine; they are simply overwhelmed by exogenous glucose ‘toxicity’.
But what happens to fat production?
In the classic model of insulin resistance, the paradox was that DNL was enhanced, not decreased which looked a lot like heightened insulin sensitivity instead of resistance. But in the overflow model, the DNL would be enhanced because the cell is trying to rid itself of the excess glucose by producing extra fat. The cell is overflowing and not in an ‘internal starvation’ mode.
为什么这非常重要？因为了解这种新的范式将导致胰岛素抵抗如何发展的答案，我们可以做些什么。问题不在于胰岛素和胰岛素受体。两者都是正常的。问题在于细胞完全充满了葡萄糖。那么，是什么造成的呢？答案似乎很明显 - 这是葡萄糖过多和胰岛素过多的问题。换句话说，是胰岛素本身导致胰岛素抵抗。我们不需要追求阴影寻找胰岛素抗性的一个神奇的起因。
一旦我们了解到过量的葡萄糖和过量的胰岛素是导致胰岛素抵抗的原因，我们现在可以设计一个合理的治疗方案。减少胰岛素和减少葡萄糖。一旦你扭转胰岛素抵抗，你治愈2型糖尿病。
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