Whatever Happened To Insulin Resistance?

In this entry I will discuss insulin resistance based on what I have read and thought, but not using specific web cross-references. I will rely on my more knowledgeable readers to correct me if I am off on anything here. I'm doing it this way not to absolve myself of errors, but so that I can build cohesive thoughts and do it quickly. I will also speculate. This is not an academic paper. And what you see here is not in my larger essay.

After reading many articles on the Web about diabetes, I get the feeling that the first thing doctors tell their patients when they are diagnosed with diabetes, about diabetes, is that it is a disease of insulin resistance. That is, that there's plenty of insulin around, and plenty of glucogen around, but somehow the glucogen is not being absorbed by the liver and especially by the muscles because they have become "insulin resistant." If we drill down a little deeper we see that fat cells do not develop insulin resistance, and that this is the reason diabetics find it hard to lose weight.

I have read no one who suggests that every muscle in a person's body has malfunctioned from its internal workings to produce this "insulin resistance." Everyone suggests that some external molecule or molecules cause the muscles to resist insulin, and therefore absorb glucogen slowly or not at all. Many candidate molecules are proposed. Some are even demonstrated to cause insulin resistance. But none are certified to be the sole cause, the answer. No group of them is certified to be the sole cause, the answer. The exact mechanism is never explained: how this does this to that to that to that and therefore, inexorably, causes diabetes. One reason for this is that all the candidate molecules found so far exist in healthy people who do not have diabetes.

Now, along come surgeries that resolve diabetes. Everyone's doubling down on finding molecules that are inhibited by these surgeries or stimulated by these surgeries. – Such molecules are called "hormones;" they communicate from one part of the endocrine system to another by chemical means. -- For some reason, the theories I have read concerning why weight loss surgeries resolve diabetes do not refer to "insulin resistance" by name. Instead, we hear about "incretins" and "anti-incretins." An incretin is a hormone that helps insulin do its job. An anti-incretin prevents insulin from doing its job. I am not sure if this includes actions that cause more insulin to be made, or prevent insulin from being made, or if this just relates to the action of insulin at the muscle cells themselves.

Anti-Incretins (Foregut Hypothesis)

The theory that surgical operations that resolve diabetes work because they prevent anti-incretins from entering the system is pretty straightforward. As I interpret it, that would be that anti-incretins cause diabetes and stopping their entry into the system returns the patient to normal. Of course, the issue is, "Where's the beef?" Where's the anti-incretin? But at least the proposed mechanism would be direct.

Incretins (Hindgut Hypothesis)

The theory that surgical operations that resolve diabetes work because they increase the level of incretins into the system is not, in my opinion, straightforward. That's because what the theorists seem to be saying is that something is causing diabetes/insulin resistance. The thing that causes insulin resistance is still out there, but now we've flooded the system with something that counteracts the thing that causes insulin resistance. Such a system is not at rest. One side is bound to overcome the other – too little insulin, too much insulin, or too much resistance to insulin, too much acceptance of insulin. I suppose you could say that this theory would include the idea that people who were diabetic weren't getting enough of this hormone to begin with, and now they are, but I haven't seen this proposed either. If they did propose it, they would have to eventually prove how much of any given incretin was the right amount.

Pressure Theory

The most likely candidate for pressure being the culprit in diabetes is constriction of blood flow into the pancreas, resulting in less insulin capacity in a given timeframe out of the pancreas. So let's deal with that.

If insulin resistance is due to hormones that inhibit or promote insulin usage, then the production of insulin itself cannot be the cause of diabetes. But perhaps these incretins and anti-incretins are not the whole story. It is time to drill deeper in our understanding of diabetes.

It turns out (I read it somewhere) that non-diabetics can become insulin resistant, too. This happens when their blood is supersaturated with glucogen. They differ from diabetics inasmuch as the level of glucogen required for them to be insulin resistant is greater for them than the level in diabetics. Obviously, something in the muscle cell itself senses a super abundance of glucogen in the blood and shuts down its reception to it. I would imagine that this is a good thing, that those animals in possession of muscle cells that did not behave this way did not make the evolutionary cut. I don't know what happens when muscle cells do not become insulin resistant in the presence of too much glucogen, but my guess is that they let in too much glucogen and spontaneously burst into flames or get cancer or twitch uncontrollably or something drastic like that. Another idea along these lines is that the muscle cells may be fooled by the super abundance of glucogen. Suppose the muscle cells have an internal sensor that determines when enough glucogen has entered them. Once enough glucogen is sensed, the cell shuts off its reception of glucogen, despite the presence of insulin, and is thus protected from having too much glucogen inside itself. Now suppose that too-much-glucogen sensor is tripped not by glucogen in the cell but by a super abundance of glucogen outside the cell. The cell in that scenario "thinks" it has glucogen inside, because the sensor got tripped, but it's wrong. -- Either way, when there's too much glucogen, even in the presence of insulin, the muscle cell is reluctant to let it in.

It seems to me likely that muscle cells that are exposed to too much glucogen on a regular basis learn to block out glucogen better over time. That, I speculate, is why diabetics are insulin resistant at a lower glucose level than non-diabetics. It also seems likely to me that the muscle cells in diabetics, who have undergone surgeries that resolve diabetes, return to normal over time. These muscle cells unlearn their panic at the presence of slightly increased levels of insulin (a guess, not a proven fact), or their sensors become better adept at knowing what's in and what's out (a guess, not a proven fact).

Notice that I haven't spoken of incretins or anti-incretins at all in discussing insulin resistance in this way.

There is a drug widely proscribed to diabetics that, in fact, relates directly to the lack of an insulin surge in diabetics. That drug is Metformin (glucophage). In non-diabetics, there is a huge increase in insulin shortly after eating. That huge increase "shuts down" the liver. The liver stores glucogen as glycogen. It also converts glycogen to glucogen and releases it into the blood. How terrible it would be if you ate something and your intestines not only converted the food to glucogen and released it into your system, but your liver also continued to release glucogen into your system. Why, you might have too much glucogen in your system under such circumstances! This is the case for diabetics.

For some reason, if a huge surge of insulin floods the liver, it ceases sending glucogen into the system. It then stores glucogen as glycogen. If you do not have a huge surge of insulin, as diabetics don't, then the liver doesn't know to stop putting out glucogen. So, therefore, non-diabetics get a 3 for the price of 1 with the insulin surge: they get more insulin, their muscles are exposed to less glucogen because the liver stops dumping glucogen into the blood stream, and they store more glucogen because the liver as well as the muscles and fat cells start storing it. Glucogen does not mount to intolerable levels in the blood as a result of all that.

Diabetics who take Metformin do not get more insulin, but they do inhibit the liver from continuing to release glucogen. I presume the liver goes into glycogen storage mode. Two out of three ain't bad. Again, glucogen does not rise to as high a level in the blood as it otherwise would. Therefore, if this measure is enough, the muscles do not go into insulin resistant mode.

So there you have it. Restoring the insulin surge, by restoring a healthy flow of blood to the pancreas, and thus a healthy flow of insulin out of the pancreas, could be entirely responsible for diabetes reversal. No incretins or anti-incretins need be part of the equation.

Addendum
I read somewhere that many RYGB patients have too much insulin after surgery, too little glucogen. Could it be that their diabetes is resolved by increased blood flow to the pancreas, and the extra incretins produced by their iliums and jejunems overly facilitate the affect of insulin on the muscle cells? Yes, there are plenty of questions hanging out there.