The Heart Of Diabetes Part 9

diabetes medicine







We left off talking about lipotoxicity, or poisoning by fat, as being the primary cause of type 2 diabetes.  I think that primary cause isn't strong enough, I'd that proximate cause would be better, although there are causes of course for the lipotoxicity, this is the smoking gun though.

Resuming our discussion of the video, Dr. Unger now goes into a discussion of the factors that come into play here when we go from fat to fat poisoning of our islet cells.  In the case of beta cells, he has been able to show that palmitate derived ceramide is the culprit.  Palminate is found in many foods but more notably is the fat that is produced by lipogenesis, in the liver under the influence of insulin.

So this leads to lipoapotosis of the beta cells, in other words, death by fat poisoning, and he shows a slide in his presentation of a beta cell which has been subject to this and it is indeed devoid of its normal cellular structure and is rendered non functional.

So where the glucagon secreting alpha cells are concerned, ceramide does not kill them, and it might be better for diabetics if we did get some alpha cell death actually.  Instead it makes the cells much less sensitive to insulin signaling and this results in an inappropriate level of glucagon being secreted, a much higher level per unit of insulin.

So in spite of what a lot of people believe, it isn't the alpha cells resisting the insulin directly, it's the increased fat that excess insulin causes which does the dirty work in the alpha cells, through increasing levels of ceramide.  We aren't guessing at this, as Dr. Unger has produced this in experiments.

He next looks at the paracrinology of the pancreas, which means the way that pancreatic hormones interact with each other in the pancreas itself.  We first look at the normal, non diabetic response to glucose, where insulin and blood sugar both rise and glucagon decreases significantly.

This is the way it's supposed to work, the glucose stimulates insulin release and the insulin suppresses glucagon, because there is no need for the extra glucose that glucagon promotes when there is glucose in the blood already.  The system works beautifully, as it should.

He shows that insulin spikes within a short period of time, 15 minutes after ingestion, and that spike corresponds to a spike downward in glucagon.  He explains that this very brief spike in insulin is of such a short duration that it is metabolically insignificant, but it is significant in the pancreas itself as its effects upon glucagon are dramatic.

Dr. Unger also references the insulin to glucagon ratio which is used by the liver as a signal to store glycogen, and in this case the ratio was found to be 7.4, which is in the range where glycogen storage would occur.

Now here comes the interesting part, and for those who aren't familiar with the diabetic glucagon response you may be in for a surprise.  Now, what happens is that glucagon isn't suppressed at all by insulin, it actually rises with insulin, and in lock step with it, as seen in the slide with Dr. Unger's data on the measurements of these hormones in response to glucose.

This is actually behind why type 2 diabetics tend to have such high blood sugar in response to glucose, just about everyone thinks it was the glucose, and if they are aware of liver dumping, in other words the effects of excess glucagon, they will assume this just goes on when you don't eat, and when you eat well that's the glucose alone putting you up.

As it turns out though, glucagon is at its highest in the presence of glucose, after a meal in other words, and if this spells trouble when you don't eat, from being too high, it spells even more trouble when it goes up even more.

I've been aware of this for quite a while and have had discussions with people who don't believe it, I'm not even sure why they don't, people tend to come up with a lot of their own ideas about why blood sugar goes up and everyone knows that you go up from a meal from the meal, and that's part of it but glucagon is a big part of it as well when you look at the levels it's measured at here.

Another noteworthy observation in these experiments has to do with the insulin to glucagon ratio, and compared to being in the 7's with non diabetic subjects, it tends to be much lower, and in this experiment came in at 0.4.  In this case, insulin levels are much higher than in non diabetics, but in spite of that, glucagon levels are much, much higher, so insulin isn't now 7 times higher, it's only a tad higher, and this confuses the hell out of the liver.

Actually, the signaling here is pretty clear, the liver is told by this not to store incoming glucose, but instead continue making it, and in fact step up the production.  So both of these are going to cause our blood sugar to go even higher, and this contributes very markedly to post prandial hyperglycemia.

So as Dr. Unger puts it, the liver thinks that we are starving, even though we may have eaten a big meal, and now the glucose from the liver not only doesn't put the glucose from the meal away as it is supposed to, it piles on even more glucose.

So we move on to another of his experiments where he compared glucagon receptor knockout mice to normal mice and fed both both a high fat diet.  The normal mouse got obese, the glucagon receptor mouse did not.

So to look for an explanation, he looked at the insulin levels of the two mice, and found that the normal mouse got hyperinsulinemic while the glucagon knockout mouse did not.  So we know what insulin does as far as fat storage goes so that does explain it well.

The knockout mouse actually only gained a bit of body fat on the high fat diet while the normal mouse with glucagon producing capability gained a lot of fat, a huge amount in fact, and when you look at both the graph of body fat and the photos of the two mice this is quite dramatic.

As well, the wild mice also experience mild hyperglycemia, while the knockout mice maintain normal blood sugar.  Now we already know from past experiments we've discussed that without glucagon you can't even get hyperglycemic so that part isn't a surprise but the fact that the normal mice did raises our eyebrows.

Stay tuned in part 10 where we'll look further into this.

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