Beating diabetes

Susan Williamson spoke with eminent scientist Len Harrison about his views for the future of diabetes research.

WILLIAMSON: How do you envision the future for diabetes research, and what do you think will be the main factors that drive things forward in this area?

HARRISON: In public health terms, the most important aspect is the rising incidence of both forms of diabetes, particularly type 2, and the relationship of this to environmental factors and lifestyle. Diabetes is a major public health problem that impacts on other areas of public health, particularly cardiovascular disease.

The thing that connects both type 1 (insulin dependent) diabetes and type 2 (insulin resistant) diabetes to vascular complications is inflammation. Inflammation is an underlying mechanism for insulin resistance and its associated vascular complications. There's increasing evidence that the insulin resistance in type 2 diabetes reflects a low-grade inflammatory process that involves cells of the innate immune system such as macrophages. And insulin resistance is not unique to type 2 diabetes -- it is a common ground for both type 1 and type 2.

In type 1 diabetes, there is activation of the innate immune system, as in type 2 diabetes, but this then extends to the adaptive immune system where you have specific receptors on T cells and B lymphocytes, and antibodies, that are involved in targeting pancreatic beta cells in an antigen-specific manner.

So, in terms of research, my prediction would be that a greater understanding of inflammatory mechanisms and the realisation that there is a relationship between inflammation and metabolic pathways and pathways leading to atherosclerosis, will lead to many new targets for preventing both insulin resistance and the vascular complications associated with insulin resistance. This will have enormous ramifications for public health.

Are you suggesting that a vaccine could be developed?

I'm suggesting that there are many targets in inflammatory pathways for therapeutic agents, from small molecule drugs to even perhaps vaccines that, for example, could influence how innate immune cells function. It is possible, for example, to vaccinate and generate a specific type of immune response to endogenous targets other than to bacteria or viruses. There are experimental animal models of vaccines to treat conditions like Alzheimer's disease and stroke, based on the fact that these conditions are associated with inflammation that can be modulated through vaccination.

Do you see that there will be a way of preventing diabetes in the future?

Yes, and we are proceeding along that route. The 'holy grail' is antigen-specific immunotherapy, where autoantigens or self-antigens that are the targets of the destructive or pathogenic immune response are used, paradoxically, as therapeutic tools. We think that proinsulin, the major product of the beta cell, as well as being the target and the driver of the autoimmune response, is also such a tool.

The NOD mouse is a model of spontaneous type 1 diabetes. When we vaccinate the NOD mouse with proinsulin via what we call tolerogenic routes, like the mucosal immune system, or tolerogenic cells, such as stem cells or resting [inactive] dendritic cells, we can shut down the development of diabetes. This proof of -concept in an animal model of spontaneous type 1 diabetes forms the basis of trials that we have started and are continuing to do with intranasal insulin, and in the near future, proinsulin peptide in humans.

We are past the stage of wondering if we can identify people at risk of diabetes and predict that risk -- we can. So it now is really a matter of ploughing on with clinical trials to try and come up with the best single or combination agent approach to prevention. It's not only by vaccination with proinsulin. It may be that other approaches will be complementary, particularly those that reduce insulin resistance.

What about diet and lifestyle issues? Can managing the disease be as simple as managing these?

For some people with type 2 diabetes it can be as simple as that, but not for the majority. The expression of type 2 diabetes is accelerated by lifestyle factors like obesity and physical inactivity, but the disease is still genetically pre-determined. If you reduce your calorie intake you will lose weight, but even before you lose much weight your insulin resistance and your diabetes will improve.

It is a lifestyle disease that can be forestalled through knowledge, a proper diet and an active life. The big problem is fat, especially the high fat content of fast food. I think that a high intake of fat stimulates the innate immune system, especially the macrophages, and that this leads to insulin resistance. Thankfully, people are starting to wake up to this. There is a big push in the United States to do something about the galloping obesity that is evident in kids even before they start school.

Do you think stem cells will have a place in the future of this area of research?

Definitely. Stem cells are important on a number of levels. It is clear that in the long term, one way to cure type 1 diabetes is to replace the insulin-producing beta cells with the diabetic person's own cells if possible. There is convincing evidence that stem progenitor cells are present in the adult pancreas and that they respond to demands for more insulin under physiological conditions, for example during pregnancy. Regeneration of the insulin-producing beta cells has also been seen in animals after pancreatic injury, for example if part of the pancreas has been surgically removed or is chemically destroyed.

The key is to be able to reproduce this and work out how to grow beta cells in the lab and then apply this knowledge. Individuals with diabetes could then regenerate their own beta cells, at the same time as they are given treatment to suppress the immune response that destroyed their beta cells in the first place.

At present we are going through a renaissance in islet transplantation for people with poorly controlled or complicated type 1 diabetes, with a better protocol developed in Edmonton, Canada. This protocol avoids steroids and uses a drug called rapamycin. It also incorporates other modifications, mainly giving a lot more islets. The outcomes are better -- more patients off insulin injections after one or two years -- but they still need to take anti-rejection drugs and how they will fare in the longer-term remains to be seen. A problem is that you need two or three donors to get enough islets for one patient. Although this is an important advance, islet transplantation is really just a temporary solution -- there are not enough donors and you need heavy anti-rejection drugs to keep the islets. It is clearly not the final solution to 'cure' type 1 diabetes. That's where stem cells will come into their own.

Stem cells might be delivered locally through the pancreatic duct, which is accessible via endoscopic means. Stem cells will also be important as agents for inducing immune tolerance. If you engineer stem cells to express proinsulin at the stage that their progeny are developing into resting dendritic cells, this stops T cells that can cause diabetes from being activated. It is a much more refined form of bone marrow transplantation.

We take bone marrow cells from an individual, expand the stem cells, introduce the gene for proinsulin into them, then give them back to the individual. We've shown that this works in young NOD mice. But will it work in humans? I think the induction of tolerance to autoantigens like proinsulin will work in humans, but humans are outbred. We therefore have to be asking who responds and who doesn't, and why. This will open up the field of pharmacogenetics.

Prof Len Harrison is divisional head of the Automimmunity and Transplantation unit of The Walter and Eliza Hall Institute of Medical Research in Melbourne.