We'll now continue our look and discussion of Dr. Unger's video lecture called "A New Biology for Diabetes" that we've been reviewing over the past few articles.
So Dr. Unger has proven with his experiments that hyperglycemia cannot occur without glucagon action, and hyperglycemia is caused by glucagon action in fact, not an absence of insulin. If you remove all insulin, blood sugar will be normal unless glucagon is elevated.
The islets of the pancreas, the part that secretes hormones, consists of a collection of both beta and alpha cells. In type 2 diabetics, the beta cells are of course destroyed, but the alpha cells remain intact, and the two types of cells are comingled in the pancreas, in proximity to one another, to allow for direct communication between them and to allow each type to regulate the other.
So without the beta cells in place, the glucagon secreting alpha cells are unchecked, and therefore excrete very large amounts of glucagon, and this is in fact what causes the extreme hyperglycemia in uncontrolled type 1 diabetes, and this has nothing in fact to do with their ability to take this glucose in. The same is true with type 2 diabetics although the glucagon secretion in uncontrolled type 2 diabetes is less severe, but it is nonetheless persistent.
Dr. Unger feels that the juxtapositioning of the alpha and beta cells in the islets of the pancreas do serve a function and a vital function, and we know this to be the case not only because they are alongside of each other, but due to the signaling that is involved, as insulin signaling, insulin sensitivity in other words, of the alpha cells directly controls glucagon secretion.
So this is how injected insulin is a life saver in type 1 diabetics, glucagon is going wild and when you inject insulin in high enough amounts, some of it will be detected by the alpha cells and glucagon secretion will be reduced, although it is worth pointing out that this is a far cry from having insulin right next door in the next cell over.
Dr. Unger ran an experiment back in 1974 which showed the effects of insulin on glucagon secretion, where he first measured the glucagon secretion of the alpha cells of rats, and then administering an agent which neutralized insulin, and saw a dramatic rise in glucagon secretion, where it rose several times higher than normal, way more than enough to tell us that this wasn't a random event but was caused by the lack of effect of insulin on glucagon suppression.
Once the anti insulin serum was stopped, glucagon levels returned to normal. So this clearly establishes the role of insulin as an important mediator of glucagon and this has since come to be widely accepted, but it was Dr. Unger who discovered this well before scientists had even begun to look at glucagon, and they still don't look at it very much even after all the years of research and insights that Dr. Unger has fashioned as the pioneer of the science here.
We've also discovered that insulin not only blocks glucagon secretion, but also limits its expression in alpha cells, meaning that not only is less secreted, less is created in the first place in the presence of what we could call normal insulin signaling in the alpha cells.
I want to point out here that this is how it is supposed to work with healthy pancreatic cells, and the two types of cells, when working properly, work together to regulate blood sugar, and it's the level of glucagon secretion that matters here, not the level of insulin secretion, and in cases where insulin sensitivity is diminished in alpha cells, more insulin does not mean more insulin action.
If it were indeed that simple than our approaches to treating type 2 diabetes by increasing insulin would actually work, however there's a big wrench thrown into the thing and that wrench is insulin resistance, and where insulin resistance is concerned, it is the insulin resistance of alpha cells which is the type that really matter the most, by far, since this is the hormone that elevates blood sugar, period.
In the next study, they compared the glucose tolerance of glucagon knockout mice before and after beta cell destruction, to address the belief that insulin is required for peripheral glucose uptake and glucose tolerance.
So in the first instance where the mice had normal insulin secretion, we see a normal graph of insulin and glucose levels after the ingestion of glucose. In the second graph, after the beta cells in these mice were destroyed, the same glucose tolerance test was performed and the results were normal as well there was little difference in all between the two.
To be sure of this, they checked the insulin levels before and after the beta cell destruction was performed, and indeed, insulin levels were normal prior to the administration of the agent, and the agent did successfully kill off most of the beta cells, resulting in a very low level of insulin secretion.
So this really shows, strikingly, that our beliefs about the critical nature of insulin for maintaining glucose tolerance are false. This has some very big implications in our approach to diabetes, we tend to believe that our bodies need this insulin to take in enough glucose in our periphery and when our blood sugar is elevated, this means that not enough is being taken in from a lack of insulin, so we look to elevate insulin levels with no regard to where they may be already, in other words no regard to looking to balance this hormone.
So as it turns out, the role of insulin in glucose regulation has been proven to be its effects upon glucagon action, and that is a different matter altogether, and particularly since lack of insulin sensitivity, not lack of insulin, is behind the hyperglycemic effects of our alpha cells, and behind hyperglycemia itself.
One may think that this doesn't seem to be an important distinction, as it shouldn't matter whether or not we're battling insulin resistance at the peripheral level or at the level of the pancreas, and in a sense that's true, but only because looking to treat insulin resistance by making it worse with higher levels of insulin is the wrong approach at all levels.
However, the real confusion here lies in the fact that we tend to neglect or not be aware of the fact that high blood sugar does not mean insufficient glucose uptake, and in fact it is a result of blood sugar being elevated beyond normal physiological capacity, there's just simply too much sugar being put into our blood in the first place, instead of a normal amount being there but not enough making it into our cells.
We'll pick this up in Part 5.