Diabetes And The Danger Hypothesis

Inflammation is inextricably entwined with diabetes.  Usually, when we think inflammation we associate this with a sprained ankle or an infected cut.  We are, however, coming to realize that inflammation can be a much more expansive process that underlies virtually all pathologies.  Simply put, inflammation is the body’s response to danger. This hypothesis was put forward by Polly Matzinger in 1994. Her idea, the Danger Hypothesis was considered controversial by immunologists at the time, but has proved to be a powerful way of looking at how the body responds to stressors. Classically, immunologists only considered the case of infection. The danger signal in such a context consisted of a series of evolutionarily conserved molecules present in various bacteria, viruses, and other pathogens that could be recognized by a family of receptors found on immune cells. Matzinger expanded on this concept by proposing that the body has its own idea of what is “in balance” and what constitutes a dangerous situation.  And when the body senses danger, inflammation is the result.

The danger signal and the immune response

Let’s first consider what an immunologist would think of as a danger signal. Our immune system continuously patrols the body. Macrophages, like garbage trucks, are constantly cleaning up the dead cells that accumulate in our bodies every day. But when we get an infection, those same cells that were acting as garbage trucks become soldiers.

Pathogens have molecular signatures – things that cannot change or else change very slowly over the course of evolution. Our immune cells have evolved receptors that can bind to those molecules and when they bind our immune system recognizes that an infection has taken place. Once they realize that they are dealing with an infection they express a special protein signal on their surface. This is the danger signal. The macrophages themselves then stop engulfing dead cells and start engulfing the pathogen. They digest the pathogen and display bits of the pathogen on their surface. These bits are called antigens and we say that the macrophage is “presenting” the antigen.

Another type of immune cell called the T cell recognizes the antigens. When the T cell sees an antigen it has a range of possible responses from activating to going to sleep forever. It makes its decision on how to respond to the antigen on the basis of the presence or absence of the danger signal. If that specific molecule is present on the surface of the macrophage, the T cell decides that the antigen represents the enemy and it mobilizes a full blown immune response targeted at the pathogen. If, for example, the infection is due to a cut in your finger and you let it run its course, the tissue around the cut gets red, swollen, and painful. This is one form of inflammation. It represents a part of the immune system’s battle against the pathogen. This makes good sense and the field of Immunology was content to stop here, but Dr. Matzinger took it further. What made her idea so controversial was that she expanded the concept and applied it to virtually all diseases and conditions.

Expansion of the concept of a danger signal

Consider trauma. When we suffer trauma, the force of the blow causes cells to rupture and, like a wrecked tanker truck, spew dangerous chemicals about the local area within a tissue. These highly reactive and dangerous chemicals are often the products of cellular metabolism. Remember, the reason we breathe oxygen is that we use the energy of the oxygen atom to help power the controlled burning of glucose, storing that energy as ATP. That energy stored in the oxygen atom can cause a great deal of damage if it is not controlled. Normally, inside the cell things are well controlled. When the cell ruptures because of trauma, those fail safe controls are no longer capable of holding things back and so chemicals are spewed around the area damaging neighboring cells. The result is inflammation.

If we take a sample of the trauma damaged tissue and examine it we find exactly the same sorts of molecular signals floating around as we do in an infection. Interestingly, if we take some of those reactive oxygen containing chemicals that came out of the damaged cell and put them into a culture dish containing immune cells, we get a somewhat similar response as we do when we expose those cells to bacteria. Apparently the reactive oxygen containing compounds are serving as a danger signal.

How does this danger hypothesis relate to diabetes?

This requires a two part answer because diabetes comes as two separate diseases: type 1 and type 2. In type 1 diabetes, an autoimmune disease, T cells inappropriately recognize the islet cells of the pancreas as dangerous and directs the immune system to kill them. The onset of disease is sudden and the patient requires insulin almost immediately. Type 2 diabetes develops over decades and begins as an inability of insulin to give a strong enough signal to get things done. We call this insulin resistance. Over many years, the pancreas works harder and harder to pump out enough insulin to satisfy the body and eventually it dies of overwork. Since there is a long period wherein the pancreas is still functional, patients with type 2 diabetes are given drugs that either increase the amount of insulin that the pancreas can secrete (like Glucotrol) or that decrease the amount of glucose that needs to be processed by insulin (like Victoza).

What is the evidence that inflammation is present in type 1 diabetes and where does the danger signal come from? Sometimes it comes from a pathogen as in an infection. Indeed, a viral infection such as rubella can trigger type 1 diabetes. In a case like this, the shape of an antigen often recognized by the immune system during rubella infections is uncomfortably similar to a protein found in the pancreas. The immune system gets confused and attacks both the virus and the pancreas. The result is type 1 diabetes. Pathogens cannot explain all cases of type 1, however, and one idea is that in some people a rogue T cell arises. Like a rogue cop, this rogue T cell does not wait for “permission” to go after what it perceives to be the bad guy. It takes matters into its own hands. However, if we look carefully at this situation we find something strange. It appears that the cells of the pancreas are calling out to the T cell with signaling molecules that we associate with inflammation. Unfortunately, while we have shown the presence of inflammation (at least in animal models) we still do not yet have a good explanation for how it all begins. We have not yet identified the danger signal. It is, as we say, on the cutting edge of diabetes research.

In type 2 diabetes, obesity is a major driver and underlying obesity is, again, inflammation.  This time the danger signal comes from food; present in such excess that we cannot store it all. As we overeat, the factory of metabolism gets backed up and partially processed molecules destined for storage get pushed off the assembly line,  littering the factory floor. These molecules begin to float around and get picked up by those garbage truck cells – the macrophages, and this creates a low grade inflammatory response. What is the evidence for this? Inflammatory signaling molecules can be detected in obese (BMI > 30) people’s blood but not in a thin person (BMI < 25).

If we continue with the analogy of metabolism as a factory, insulin and glucagon are hormones that ultimately act as managers, directing the workers on the factory floor to either process energy compounds for storage as fat or for immediate use. Insulin, of course, is in control of directing the storage of food and gets glucose out of the blood where it can cause damage. Glucagon is in control of the processes by which energy is mobilized from storage to supply the body during all those times when you are not eating. It’s a beautiful system, except for one small problem: we’ve begun eating more food than the factory can handle. Since insulin is telling the factory to take in more material for storage and the factory is overloaded, the simplest response is to stop listening to insulin. What does this mean exactly?

Biochemically, we now understand this process in exquisite molecular detail. One of the intermediate proteins (IRS-1) sitting just downstream of the insulin receptor within the cell is chemically modified so that it no longer responds efficiently when the insulin receptor is bound by insulin. This, in effect, is insulin resistance. Unfortunately, the memo never gets to the islet cells in the pancreas. As far as they can tell, insulin is not doing its job because the blood is full of sugar. The result: they make more insulin. This insulin overproduction stresses the islet cells and over the course of many years of overwork, they die.

Perhaps the most amazing experiment that I have seen in the past few years that highlights the interconnection between diabetes and inflammation involves some genetically altered mice. If we feed mice a high fat diet they get fat and develop diabetes. No surprise there. However, since researchers in this case were studying the signaling pathway that drives inflammation, they genetically deleted an essential protein in that signaling pathway. When the mice grew up they tested them in a variety of ways. Just the fact that they grew up normally told the researchers that this gene was not essential for development. The gene, by the way, has the rather long and technical name “I Kappa B Kinase Epsilon” (IKKepsilon). The mice developed no disease and appeared totally normal both inside and out. If, however, they were given an infection they were unable to respond correctly. As expected the inflammation signal was not getting transmitted to the right places.

Now comes the interesting part. Someone in the group eventually thought to feed these mice a high fat diet. While the littermates that still had a functional copy of the gene got fat and developed diabetes, the mice that were missing the gene did something totally different. They did not get fat. They did not get diabetes.  This indicates that metabolism and inflammation are also inextricably entwined. This work was published in the journal, Cell.

What you have just read represents the tip of the iceberg. A search of the National Library of Medicine using the terms “diabetes” and “inflammation” pulls up over 10,000 references over 10% of which have been published in this year alone. As we increase our understanding of how inflammation interacts with metabolism new therapeutic targets will become apparent. For example, an oral inhibitor of IKKepsilon may constitute the next major diet pill.

The medical community is well aware of the problem diabetes poses to world health. All one needs to do is look at the numbers and a societal danger signal is apparent. How we respond to this signal, both as individuals and as members of our society, will determine as much and perhaps more than can be provided by new therapeutics. Meanwhile, the concept of the Danger Hypothesis continues to expand.

Robert Scheinman

Robert Scheinman received a PhD in Pharmacology in 1990 and joined the faculty of the University of Colorado Denver School of Pharmacy in 1995. Robert runs a medical research laboratory focused on the role of inflammation in various disease states including diabetes, arthritis, and cancer.

Robert Scheinman

Robert Scheinman received a PhD in Pharmacology in 1990 and joined the faculty of the University of Colorado Denver School of Pharmacy in 1995. Robert runs a medical research laboratory focused on the role of inflammation in various disease states including diabetes, arthritis, and cancer.