Question: Why AGEs and deficient insulin signaling are the main problem in diabetes.

The reason that methylglyoxal, which I did my doctoral dissertation on, the reason that methylglyoxal, which is quantitatively the most important form of advanced glycation end products in diabetics, the reason that it is elevated is not because of hyperglycemia. It's because of deficient insulin signaling.

That is for two reasons. One is that you can derive methylglyoxal from glycolysis. You can derive methylglyoxal from ketogenesis. You can derive methylglyoxal from protein, specifically from the amino acid threonine. Insulin prevents you from making methylglyoxal in the glycolytic pathway no matter how high the glucose level is. Insulin, what it does in glycolysis is at the step where the intermediates spill out to generate methylglyoxal, insulin stimulates that enzyme that sucks the intermediates down.

Diabetes, you have lower expression of that enzyme, and you have greater spillover out of glycolysis into forming methylglyoxal. In untreated diabetes, you can have blood glucose that goes up five times normal. That will be a factor that is influencing you to make not just five, maybe ten or far more times methylglyoxal on glycolysis. But the reason the glucose is elevated is because of deficient insulin signaling. No matter how much glucose you have or don't have, once the glucose gets into the glycolytic pathway, insulin is protecting against methylglyoxal by clearing the glucose down.

The role of methylglyoxal starts at the first instance of hyperglycemia to cause the development from an acute first ever instance of hyperglycemia through the pathway of developing diabetes. Then in diabetes, methylglyoxal is overwhelmingly responsible for causing the cardiovascular complications, the complications in the eyes, and the neurological complications of diabetes, cataracts, all of these things. And so I think it's a huge mistake to think that the spiking glucose is the thing going on rather than the deficient insulin signaling.

Now, if you want to use a rule of thumb that is not individually tailored to you, then the answer is use the 140 limit. But you follow that up with, is there evidence to support this? No, I think the evidence says that this is a mediocre approximation of how to identify whether there's a problem. But a good way to try to identify whether you're having a problem with glucose spikes is the GlycoMark test.

This Q&A can also be found as part of a much longer episode, here: https://chrismasterjohnphd.com/podcast/2019/09/06/ask-anything-nutrition-march-8-2019

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