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


Anonymous says, “You recommend high-glycemic
carbs to help tryptophan get into the brain. What is the maximum level that your blood
glucose can spike to after a meal without causing any damage? Some say 140 is the limit. Is there any evidence to support this?” Anonymous, what the evidence is, is that people
who, in a controlled test have their blood glucose spike over 140, are at a higher risk
of developing diabetes. That’s really what the evidence is. Now, does it cause damage? It’s tough to say. I’ll come out and say it. I don’t believe that hyperglycemia is harmful
because it is hyperglycemia. I will clarify that there are levels of hyperglycemia
that can kill you. That’s definitely true. But what I mean is that outside the context
of someone with diabetic ketoacidosis or hyperglycemia that is causing osmotic stress to the level
that can kill the person that winds them up in the emergency room, even in diabetes, I
think that it’s not really about the glucose. Let’s start with diabetes as the model where
we really have the evidence of what is causing harm. The harm of actually damaging your tissues
and actually producing the cardiovascular and retinal, eye and other neurological complications
of diabetes, that’s caused primarily by advanced glycation end products. Advanced glycation end products are partly
caused by glucose reacting with proteins, but they are mainly caused by methylglyoxal
reacting with proteins. 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 high glucose is an influence, but it’s
a minor influence compared to the effect of insulin. Besides this, insulin stops ketogenesis and
suppresses the generation of methylglyoxal from ketogenesis. Insulin also stops the generation of methylglyoxal
from threonine, which is an amino acid found in protein. Insulin also makes you make more glutathione,
and glutathione is what detoxifies methylglyoxal. Insulin also stimulates the enzymes that use
glutathione to clear out methylglyoxal. Insulin is way more important to the formation
of advanced glycation end products than glucose is. Specifically, the problem is not too much
insulin. The problem is not enough insulin signaling. Even in type 2 diabetes where insulin levels
are high, you don’t have enough insulin to normalize the protective pathways because
you’re resistant to that function of insulin. A great example, totally irrelevant to how
you treat diabetes, but a great mechanistic demonstration of this is a study where they— First of all, type 2 diabetics have bad glutathione
status. If you put them in a normoglycemic hyperinsulinemic
clamp, which is a situation where you pump them full of glucose and you pump them full
of insulin, and you try to pump them with as much insulin as you want, but you pump
them with enough glucose to prevent that insulin from dropping their blood sugar. It’s a way to mechanistically intervene by
raising insulin levels and keeping glucose levels normal. In type 2 diabetics who have high insulin
levels already, as long as you keep their blood sugar normal, raising their insulin
levels even further will take their bad glutathione status and make it the glutathione status
of a normal healthy person. Real world practical implications, nothing. In other words, I’m not saying that the treatment
for diabetes is that people inject you continuously with glucose and insulin. What I am saying is that this is proof of
principle that the problem in diabetes, especially with respect to advanced glycation end products,
is low insulin signaling. It isn’t high glucose. High glucose plays a role but a very minor
role compared to low insulin signaling. 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. With that said, at some point, your blood
glucose spiking will spill glucose into what’s called the polyol pathway. The polyol pathway is a way of metabolizing
glucose that you can’t put into the normal pathways. When that happens, you start sucking up NADPH,
and NADPH happens to be very important for glutathione recycling. Glutathione recycling is very important for
getting rid of methylglyoxal. Here is a way that a normal spike in blood
glucose, maybe to 140, depending on your metabolism, could zap your glutathione status and contribute
to advanced glycation end products. There’s a way to test for that. There is a test called 1,5-anhydroglucitol
I think is what it’s called. Let me look that up to make sure. This test is called the GlycoMark. I’ll put a link to it in the show notes, but
it’s 1,5-anhydroglucitol. This is a marker
of whether your glucose spikes are on average generating consumption of glucose in the polyol
pathway. I think the best thing to do is to individualize
the question of what’s too high of a glucose spike. Too high of a glucose spike is whatever gives
you a bad mark on the GlycoMark test. That I think is the real true answer to your
question. Now, if you want to use a rule of thumb that
is not individually tailored to you, then the answer that is not a long rant is yeah,
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. All right. Thanks, Anonymous, for your question.

7 comments

  1. Explanations are fine, but not one single mention of a solution?, ——-> flawed insulin signaling<———-………ok, now, what to DO about it?

  2. Very provocative presentation. I am a 63 year old female Type 1 DM diagnosed at age 20. As per 23 and me I have 53% reduced methylation function. In an effort to obtain better blood glucose control I have been following low carb, healthy fat diet for past 2 years and have been able to lower insulin levels by 1/3 and HgbA1c levels have improved to almost normal levels (which had eluded me for decades. I have been fortunate to avoid any vascular complications thus far other than some background retinopathy that has not required treatment.
    My questions are:
    1) Would my decreased methylation function be beneficial to keep methylglyoxal levels low?
    2) Should I avoid even low level nutritional ketosis in order to suppress methylglyoxal generation from ketosis?
    3) Should I limit protein intake in order to suppress methylglyoxal generation?
    Would love to hear your expert opinion on these questions and realize it is just theoretical as likely no studies.
    Thank you !

  3. I believe that it is better for people to consider "deficient insulin signaling" as "deficient insulin receptors" or "insulin resistance" first and foremost.

  4. Very interesting. I’ll be getting the Glycomark test! Here are some other views and studies on high glucose and organ damage. Lots of information to sift through.
    https://www.bloodsugar101.com/organ-damage-and-blood-sugar-level

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