Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give a brief introduction to type 1 diabetes? How does it differ from type 2 diabetes?
Type 1 diabetes is an attack by the immune system of the islet of Langerhans within the pancreas. Basically, the islet of Langerhans harbor beta cells, which produce insulin and when the islets are attacked, the beta cells destruct and there is no more insulin. When the insulin level goes low, blood glucose levels go high and that creates a problem.
Type 2 diabetes, for a long time has been defined as a resistance to insulin. I think the thought is still there, but at the end stage of type 2 diabetes, it evolves to resemble type 1 diabetes and there is destruction of beta cells.
So, that’s as close as we can get now as far as finding the similarities and differences between type 1 and type 2 diabetes.
What was previously known about the causes of type 1 diabetes?
There are predisposition genes that are required in order for type 1 diabetes to develop, but, it is not sufficient. There are other factors that play a role.
Ultimately, it is the immune system that turns against the islets and destroys the beta cells. So, as far as what triggers the immune system to attack the islets, that etiology remains undefined. Type 1 diabetes is an autoimmune mediated disease, which means it is the immune system that causes type 1 diabetes.
Your recent research revealed that the immune system causes more damage to the insulin-producing cells than previously thought. How extensive was the damage you discovered?
Well, what we discovered is that the immune system causes a severe attack of the beta cells and it has always been thought that, if you stopped the immune system from attacking the beta cells, we cure type 1 diabetes.
What the findings are demonstrating is that stopping the immune system from attacking the beta cells is not enough to cure type 1 diabetes. The damage was so severe that it wasn’t only an attack on the beta cells; there was collateral damage to the tiny blood vessels that connect the islet to the rest of the pancreas and the blood. That damage has caused malfunction of these vessels.
So, the beta cells cannot receive nutrients in the blood and cannot send insulin in the blood and therefore, they can neither divide nor send their insulin in those blood vessels.
The exact finding is really an advanced concept. You need to fix the blood vessels that vascularize the islet, not just remove the immune system from the islet. So that’s the essence of the findings.
Why had this extensive damage never been revealed by previous research?
Well, that’s why we do research: to make progress and find the unknown. We happen to have a model that we were working on that allowed us to discover this. Most of the other studies, especially the clinical trials, were done with drugs that remove the immune system regardless, while our drugs remove specifically the bad cells of the immune system that attack the islets.
It took us a long, long, long time to remove those. And so, we were watching while removing and we did an experiment to increase the beta cell production.
The findings told us that the experiment worked, but it’s not what you thought was going on. When we looked closely and used reagents that allow us to trace the bone marrow cells and the drug we gave the mice we found out that yes, the beta cells are coming back, but they don’t originate from the transferred bone marrow cells we gave, but just from the mouse’s own cells.
What our bone marrow transfer did was give rise to endothelial cells and that’s how we figured out that it is those stem cells that come from the transfer of the bone marrow cells that are helping the blood vessels around the islet to be functional. Ultimately, the blood vessels assist the mouse’s beta cells to regenerate and thrive.
Does this discovery highlight a potential cure for type 1 diabetes?
It does, but it is not there yet. What the discovery does is reorient the research and the clinical trials towards a new concept. Fixing the blood vessels around the islets facilitate renewal and the beta cells will thrive.
So it is really good progress, and a change of concept, and the right direction, I believe.
How did the idea of combining a drug with adult stem cells originate?
We did not think of endothelial cells. What we did was, since the drug did not work when the disease was severe, we thought, maybe we don’t have enough left over beta cells to induce their proliferation. So, we said, “Let’s add some bone marrow cells so we can increase the precursors for the beta cells and hopefully that will help.”
It did help, but when we looked at what really came out of the stem cells we gave, it was the endothelial cells not the beta cells we thought we were waiting for.
It was not a planned discovery; it was an analysis of the data discovery.
How successful has the combination been in treating type 1 diabetes?
In mice it was successful. Most of the animals had been cured and remember, we treated mice that have been advanced far along with the disease. So it was really successful.
We monitored the mice for 70 days after diagnosis. The diagnosis was made when the mice are about 60 days; so all together, the mice are around 1 year old, so that’s very good.
So far your work has been carried out in mice. Do you think it will translate to humans?
Hopefully. That is the purpose of the research. We need to produce the human version of the drug and then collect stem cells from adult people and then try the combination.
We have to produce the human version and we have to carry out the clinical trial. That is what probably will be the focus of the next 5 years.
What further research do you have planned?
Well, we need to test how we can fix the blood vessels - that’s the direction I want the research to go.
In terms of clinics, I think we want to produce the human version of the drug and find support and get approval to carry out the clinical trial.
Do you think restoring blood vessels in combination with a drug could be used to treat other autoimmune diseases?
I hope so. I think whenever there is an attack by the immune system, the findings are helping us understand that it is not just the target organ or the target cells - there are collateral damages.
Those collateral damages probably differ from disease to disease or organ to organ.
It’s like a war where you drop a bomb. When you drop a bomb, you kill the target but you also have collateral damage.
For type 1 diabetes, we think you need to fix the collateral damage before you can rebuild. You need to build roads around the building you’ve destroyed in order to rebuild the building.
The Director of Research at Diabetes UK has recently said that a vaccine for type 1 diabetes is potentially on the horizon. Do you think this is a realistic prospect?
A vaccine for the future, I think, will probably be worth it. But, what we are focused on here is to treat people that already have the disease.
Preventive measures are good for type 1 diabetes and it will be good for the future. What we are targeting now is to reverse the established disease.
Where can readers find more information?
Our findings were published in the journal of American Diabetes Association called Diabetes: http://diabetes.diabetesjournals.org/content/early/2013/04/17/db12-1281.abstract?sid=d6e3c320-694b-4389-b7e1-27851c0974ff
About Dr. Habib Zaghouani
Habib Zaghouani, Ph.D., is the J. Lavenia Edwards Chair in Pediatrics in the Departments of Molecular Microbiology and Immunology, Child Health, and Neurology at the University of Missouri School of Medicine in Columbia, Missouri.
He earned his Ph.D. in immunology from the University of Paris and Pasteur Institute in Paris, France, in 1987.
Dr. Zaghouani’s current research projects focus on the biology of T lymphocytes and their role in immunity and autoimmunity and include investigations about autoimmune encephalomyelitis, autoimmune diabetes, neonatal immunity and the development of immune memory.
His research is being supported by the National Institute of Health (NIH) with previous grant awards from the National Multiple Sclerosis Society and NIH.
Dr. Zaghouani has 80 peer-reviewed publications in journals including Diabetes, the Journal of Immunology, The Journal of Experimental Medicine, Proceedings of the National Academy of Sciences, and Science.
His recent findings about type 1 diabetes published in Diabetes, the American Diabetes Association’s flagship research publication, received national attention for its potential to lead to a cure for the disease.
Dr. Zaghouni is also currently a section editor for The Journal of Immunology and is an editorial board member of Open Journal of Autoimmunity.