The Heart Of Diabetes Part 2

diabetes experiments

 

 

 

 

 

 

In Part 1 we left off talking about how Dr. Unger has demonstrated that, in spite of the beliefs that insulin is necessary for proper glucose metabolism, this isn't the case at all, as if we prevent glucagon from going too high, normal blood sugar can be maintained even in the total absence of insulin.

We do know that insulin does inhibit glucagon though and this is a big reason why we can see blood sugar improvements when we increase insulin, however when we increase it beyond normal levels, what happens is that the alpha cells which secrete glucagon and which sense insulin levels as a limiting factor become more and more resistant to this signaling, therefore requiring higher and higher levels of insulin to elicit the same reduction.

These higher levels of insulin also produce other negative effects in the body, most notably increasing lipogenesis, the making of fat in our liver, and these higher levels of lipids increase the lipotoxicity in our cells, including pancreatic cells, and including the alpha cells that secrete glucagon.  So they become even more deaf to insulin and their glucagon secretion becomes even more pronounced.

This is the pathology of type 2 diabetes in a nutshell, and it's not hard to see how conventional approaches to it, ignoring glucagon, ignoring insulin resistance, ignoring hyperinsulinemia, and ignoring lipotoxity, is such a bad idea, but that's how it's done, and that's why the outcomes are so grim.

So now back to the lecture.  In his next experiment, he destroyed the beta cells of glucagon receptor knockout mice.  In normal mice, this results in extreme hyperglycemia, ketoacidosis, and death.  With the glucagon knockout mice, they maintained normoglycemia in spite of their beta cells being destroyed.

So this turns conventional thinking about glucose metabolism on its head, which is preoccupied with things like glucose uptake by the cells being the main modulator of blood sugar, and Dr. Unger has clearly demonstrated that this isn't even a relevant factor in blood sugar regulation, it all comes down to managing glucagon levels.

So type 2 diabetes is indeed a hormonal disturbance but we pay way too much attention to the wrong hormone here, it's all about hyperglucagonemia, and insulin does play a role here, but with type 2 diabetes it's too much insulin leading to increased levels of glucagon which does us in.

With type 1 diabetics though, it is not enough insulin that causes the hyperglucagonemia that results in their higher blood sugar, and they go the same way that the lab animals do when we destroy their beta cells, but it is not lack of insulin per se that kills them, it's too much glucagon.  Insulin in proper amounts does control glucagon secretion, or rather, it's one of the ways that glucagon is kept in check, but once again we need to be looking at the right tree here with type 1 as well, or at least look at both trees.

So what makes glucagon receptor mice unique isn't that they can't produce glucagon, it's the receptor for glucagon in their liver that is lacking, so no matter how high their glucagon levels go, and they go high enough to kill them normally in the absence of insulin, the liver does not churn out deadly levels of glucose like it normally does.

The liver is actually the pointy end of this stick, glucagon is actually just the messenger, so it's not just glucagon levels we want to pay attention to here, and far from it, as signaling in the liver plays a huge role in this story, something that Dr. Unger doesn't go into but this is something we already know from the way that our livers influence our blood sugar.

So in a nutshell, glucagon tells our livers to make more glucose, and this extra glucose that is made is at the heart of diabetes, it's not just one of the factors, it's the factor itself, and Dr. Unger's research clearly shows this, even though he's really only looking at one of the messengers here, although one of paramount importance in the gluconeogenesis gone haywire that we see in type 2 diabetics.

I do want to throw in here that other signaling mechanisms such as AMPK, which we've talked about already to some extent, also play a role in this, and the simplest way to think of all this is that our livers produce too much glucose and we need to look at all of the things that influence this, and glucagon is but one influencer, although it is a very major one, to the extent that if we simply control glucagon we've cured diabetes completely, and that's something that is not in doubt at all from looking at Dr. Unger's research.

So I want you to keep this connection in mind as we explore the issue of liver dumping even further, and the point of all this here is to show that liver dumping isn't just a big factor in hyperglycemia, it's the only factor, and without excessive liver dumping, our body will maintain normoglycemia even in an absolute insulin deficiency.

So going back to this particular experiment by Dr. Unger, after seeing that destroying the beta cells in the glucagon receptor mice had no effect on raising blood sugar, he injected them with the glucagon receptor, and blood sugar spiked dramatically while under the influence of this agent, returning to normal after its effects had worn off.

Dr. Unger then concluded that it wasn't a lack of insulin per se that causes the symptoms of type 1 diabetes, it was the lack of glucagon action as he puts it.  So in other words, it wasn't that insulin was too low or absent, it was that glucagon was allowed to be raised to very high levels, and it is these high levels of glucagon that produce the extreme hyperglycemia that is present in untreated type 1 diabetes.

So you don't hear about the role of glucagon in type 1 diabetics much, other than the fact that we know that when we test them even on insulin therapy, it tends to be too high, but this may be a product of the effects of the inefficiencies in injected insulin, where a state of hyperinsulinemia must be maintained to achieve adequate glucagon suppression, requiring serum levels several times higher than normal.

This also produces excess lipolysis of course, as this is just what too much insulin does, and this goes back to the problem of lipotoxicity, which is always a problem when you are hyperinsulinemic, and type 1 diabetics are definitely hyperinsulinemic because the effective dosage of exogenous insulin guarantees this will be the case, as much higher than normal amounts of insulin are required.

We'll pick this up in Part 3.

Please follow and like us: