We left off Part 9 looking at how glucagon contributes to weight gain, and the effects are dramatic. Now we are already well familiar with how insulin does this so it might come as a surprise that if we knock out glucagon receptors in mice they don't really gain weight on a high fat diet, where normal mice do.
Glucagon itself doesn't directly cause weight gain of course and if we look at what happens to their insulin levels on this diet, this does cause them to be hyperinsulinemic, whereas we don't find this in the glucagon knockout mice. So we know the role of insulin in at least trying to restrain excess glucagon and if it doesn't have to deal with that, then it does make sense that insulin levels will be lower on the exact same diet, and less fat will be stored as a result.
The plasma insulin levels of the normal mice were way higher than in the knockout mice, and what's particularly interesting about the graph that Dr. Unger presents is that this is not an acute effect at all, and it takes several weeks on the high fat diet for insulin to really start rising, and then it continues to keep going up.
The knockout mice though maintain normal insulin levels throughout the 12 weeks of the study, and there is no reason to suspect that their insulin levels will ever be put up by this diet given the flat line we see here.
Going back to looking at changes in body fat, not surprisingly, the normal mice gained a lot of weight from all this extra insulin, whereas the knockout mice did gain a bit of weight but not much and nowhere near as much. The normal mice also experienced hyperglycemia where the knockout mice did not.
So Dr. Unger concludes from this that the hyperinsulinemia caused the mice to get fat, but the loss of glucagon action prevented this, which is extremely interesting. So to show this further, he gave the knockout mice exogenous insulin to bring their levels up, and sure enough, they got just as fat as the normal mice, showing that it was indeed the insulin levels on a high fat diet that produced the gain.
This was rather surprising back then, and now that we understand more about how insulin does regulate weight gain, even though much of the world is still pretty much in the dark about this, this is another debt that we owe Dr. Unger, and it's worth reminding you that we're listening to a true pioneer in the field of diabetes research, and was discovering things 40 years ago that the world of diabetes research is only now beginning to appreciate.
This study though does leave us with a bigger question, which is, why does the lack of glucagon action prevent the high insulin levels that we see in normal mice with normal glucagon action? These weren't diabetic mice or even lab mice, these were mice straight out of the wild, in their natural state.
So why do normal mice become hyperinsulinemic and what role does glucagon play? Well we know that hyperinsulinemia is caused by insulin resistance, and there is an interplay between glucagon and insulin resistance, as well as a high fat diet being well known to cause it, perhaps not as well known as it should be though.
So if we just look at the glucose levels of the normal mice on this diet we see that they are elevated, and insulin is very elevated, that's insulin resistance all right.
Next he compares wild mice with db/db mice which are bred for diabetes, and in the normal state of these db/db mice they are diabetic, so he compared the insulin and glucose levels of both and of course the normal mice were normal and the diabetic mice had very elevated glucose and insulin.
So then he cross bred the db/db mice with glucagon knockout mice, and in spite of these mice being diabetic naturally, the lack of glucagon receptors permitted them to have normal blood sugar and be diabetes free, with normal levels of insulin as well, and they lived out their lives in this normal state.
He then took these mice and increased their glucagon by giving them an agent which brought up glucagon levels, and they not only returned to their diabetic state, their diabetes became even worse than regular db/db mice.
Dr. Unger then concludes that glucagon action is central to diabetes, and given what we know about the role of both insulin and glucagon in diabetes, and that treating insulin resistant type 2 diabetes with more insulin is not only not beneficial, it is harmful.
I would add that it's not just harmful, it's actually directly and significantly worsening the disease of insulin resistant type 2 diabetes, and it's actually easy to figure out how it does this, and in fact there really isn't another outcome that is possible given that high insulin is what drives insulin resistance. You would have to show that one would be better off with more insulin resistance, but all we have to do is increase insulin resistance experimentally, or even observe this in patients, to see that this view is horribly mistaken.
So this brings us to Dr. Unger's main proposal on how we should be treating type 2 diabetes, and it cashes out to the same recommendations he has for type 1's, which is to reduce glucagon action. He uses the word block but I think that's a bit strong and ambitious and we couldn't really block it if we wanted to, but we could certainly reduce it from excessive levels to normal ones.
So he mentions two approaches to doing this, which are glucagon suppressors and an antibody to glucagon receptors and both have shown to resolve diabetes all by themselves. I'm skeptical about using an antibody in humans though and I also think that this is an area that we need to tread carefully with due to not wanting to overshoot normal ranges, but the idea of reducing glucagon is certainly the one we want to pay a lot more attention to.
Dr. Unger then looks to wrap up his presentation by giving a summary which we will pick up in Part 11.