Islet Cell Regeneration and the gene INGAP, Part 7
Date: August 2, 2001
Moderator: Deb Butterfield
Subject: Islet Cell Regeneration Discussion – Part 7
Guest: Dr. Aaron I. Vinik, Director, Strelitz Diabetes Research Institute, EVMS
Appearing on www.diabetesstation.com
Deb
It’s nice to see so many people here to talk with Dr. Vinik, Director of Research at the Strelitz Diabetes Institutes in Norfolk, Virginia. Dr. Vinik is approaching the problem of how to put an end to diabetes by working to regenerate, rather than transplant, islets. Dr. Vinik discovered INGAP, the gene responsible for the “neogenesis” or birth of new islets.
It’s great to have you with us on Diabetes Station again Dr. Vinik! We are all very interested in your islet regeneration work and it’s potential to cure diabetes!
Dr. Vinik, would you start by giving a brief explanation of the difference between transplanting islets and regenerating them?
Dr. Vinik
The difference between transplanting islets and regenerating them is that transplanted islets retain their own identity and are recognized as foreign by the human body. Regenerating islets is a means whereby islets are regenerated from cells resident in the pancreas and are therefore recognized as self.
BBB
Hi Dr. Vinik and thanks for everything you do for us diabetics. Dr. Vinik, what’s the differences between adult and embryonic stem cells, aside from embryo vs. mature?
Alan F. Bachrach, M.D.
Hello Deb, Dr. Vinik and all. Dr. Vinik, while I am primarily interested in hearing about any progress made in the last year with regard to islet neogenesis in vivo, I would also appreciate a comment from you regarding the importance of embryonic stem cell research and possibly human cloning.
Dr. Vinik
BBB, today that is a very critical question. Embryonic cells are cells that by definition occur in the embryo and are totipotent, i.e. they can be induced to differentiate into any type of cell found in the adult body. Adult primordial cells have a limited capacity and can differentiate into a finite type of cell found in the adult, and they are therefore multi-potential and not totipotential.
BBB
I see, so adult stem cells can become certain things and embryonic stem cells can become almost anything.
Deb
What are the advantages of islet regeneration?
Steve
Hi Dr. Vinik, can you please let us know how the research is going… Any updates since the last time you talked with us?
Dr. Vinik
Well, let me try to address all these questions as well as I can. The work is going incredibly well and at a pace many of us in research are not accustomed to. There are several clear advantages of islet regeneration versus islet transplantation. There are only a limited number of pancreases that become available for islet transplants and even if all were harvested for the purposes of islet transplantation, then only a few 100 people with diabetes would benefit. In contrast, every person with diabetes has cells that can be transdifferentiated into islets, and there appears to be no limit in the capacity.
BBB
Dr. Vinik, have there been any effects on your research from the recent stem cell comments made by President Bush?
Dr. Vinik
BBB, the Presidential position on stem cells does not affect us in the least. It is critically important that we distinguish what we are doing and what the people using stem cells are doing. We encourage a cell, present in the adult body, to reiterate ‘normal fetal ontogeny,’ but since the cell is present in the normal adult pancreas, it has limited capability, and for all intents and purposes can only be induced to become one of the recognized pancreatic cells. There has been no question about this approach.
Deb
Dr. Vinik, would you say ‘normal fetal ontogeny’ in English for us?
Dr. Vinik
Deb, normal fetal ontogeny means the normal pattern of growth and sequential development of the child in its mother’s womb.
Dave
Dr. Vinik, have you done any work or plan to with Dr. Faustman (Harvard) and TNF-alpha? It’s interest that eliminating the autoimmune attack sparks some regeneration of islets naturally. Your work and hers seem to fit like a hand and glove.
Dr. Vinik
Pancreatic transplants have been successful in latter years, but of course are really intended for people with advanced diabetes and its complications. The TNF-alpha story is very interesting indeed. Nora Sorvetnick some years ago showed that in transgenic animals, over -expression of INF gamma to attempt to induce an immune-mediated destruction of the islets was not associated with diabetes. The reason for this was simply that if there was adequate regeneration, then diabetes did not ensue. The TNF alpha story is a little different. Some of the new oral hypoglycemic agents have anti-TNF alpha activity. TNF alpha is a cytokine that for the most part is proinflammatory. It seems that it may be implicated in beta cell destruction. If one neutralizes it, then beta cells seem to be able to regenerate. This would indeed be complimentary to our work.
Alan F. Bachrach, M.D.
Dr. Vinik, have you managed to induce islet neogenesis in any living animals, diabetic animal or animal with autoimmune diabetes?
Dr. Vinik
Alan, we have been able to induce islet neogenesis in normal animals, animals made diabetic with large doses of the beta cell poison, streptozotocin, and animals with a secondary autoimmune response to streptozotocin, and in all instances neogenesis has been seen to occur.
Alan F. Bachrach, M.D.
Thanks. I assume you mean that this has been accomplished by some regimen of injections (IV) of INGAP (the gene product)?
Dr. Vinik
The regimen that has worked in animals has been injections into the peritoneal cavity. We only did this because it was the route likely to ensure delivery of the compound to the pancreas. We now know that it can be delivered by other routes and will target the pancreas.
BBB
The neogenic successes you mentioned are wonderfully fantastic!! It makes me feel like there’s almost no way this won’t come to full fruition in the next few years! I’m so excited about your amazing work.
Jane
Dr. Vinik, what has transpired in the last eight months of your research?
Steve
Dr. Vinik, how are the large animal studies going?
Dr. Vinik
The studies have gone inordinately well in the last eight months. I would like to think we are all large animals, but that remains to be seen. The significant advances we have made in the last eight months or so have been in our increased awareness of the amounts we need to give and how the compound is handled in the body and so forth. All these findings have been positive and built upon a framework and infrastructure that augurs well.
Alan F. Bachrach, M.D.
Have you seen any harmful or unpleasant side effects from the administration of INGAP?
Dr. Vinik
We have never encountered any harmful effects of INGAP given in doses that far exceed the regenerating doses, and in all our studies in which we have followed animals for protracted periods, have not seen the development of unbridled cell growth.
S’Marg
Have you ever taken a Type 1 animal and caused it’s pancreas to overcome the beta cell killers, and if so, did it last?
Dr. Vinik
S’Marg, I will try to answer your question in a way that I hope will explain what transpires. When we make animals diabetic, they lose all (<2% remaining) of their islets. They are equivalent to a totally insulinless person. These animals can then be induced to start making insulin again. It does not come from a dead islet brought back to life but from a precursor cell that escapes the attention of the diabetic destructive process and then is induced to transdifferentiate into an islet cell that can make insulin.
BBB
Have there beensignificant times when cells are “activated” to become insulin-producers but haven’t become such?
Dr. Vinik
There have been times when we have attempted to induce regeneration but failed to do so. This was in the earlier days when we did not know the optimum doses to use nor the best way of delivery. We think we are smarter now and have learned a whole bunch more about what the right cocktails are.
Daver
Dr. Vinik, if you were to go to a race track and the top horse contenders were named “regeneration” and “transplant,” which horse would you bet on?
Dr. Vinik
If I were to bet on transplant versus regeneration, I would bet on islet transplant for a select few people who will be encumbered by immunosuppressive therapy for life, but in the future regeneration would be the horse to back. It has limitless capacity and the window of opportunity is infinite. It is also likely that immunosuppressive therapy would not be mandatory.
Ellen
Can you explain how a person with IA2A, ICA512,GADA65 will still be able to regenerate and not attack their own islets?
Dr. Vinik
Ellen, that is an important question. We now know that even if you have ongoing autoimmune islet destruction, as long as we can provide you with new islets at a rate that is faster than the destructive process, then you can beat the diabetes.
Alan F. Bachbrach, M.D.
Dr. Vinik, I have heard much more exciting news tonight than I had expected to hear. Particularly that “we now know that all this is necessary is for islet neogenesis to outpace islet destruction! I assume that this implies that INGAP has been tested in the setting of autoimmune destruction and that success has been achieved (in some animal model).
In those animals given INGAP, is the success uniform? That is, do all of the animals regenerate their islets? Do blood glucose values normalize?
Dr. Vinik
Alan, the blood glucoses return to normal and more important than that, the insulin secretory profile normalizes, this is not always the case in islet transplants.
BBB
Dr. Vinik, I’ve been a Type 1 for over 42 years. Do you think I have any stem cells which escaped destruction 42 years ago and can now be used to regenerate islet cells?
Dr. Vinik
We have evidence that these primordial cells are present in people over the age of 65 who have had diabetes for many years. We did this by examining pancreases of people with diabetes who had died for another reason and were fortunate enough to obtain pancreases for study. That was really a good piece of news because it meant that even late in the course of the condition, we could embark on treatment.
Steve
Dr. Vinik, congratulations, that is amazing news… What are your next steps? Are you going to do primate trials before humans? Have you begun talking with the FDA yet?
Dr. Vinik
Steve, we are doing everything to put us in position for submission.
Steve
That is great news…best of luck.
Liubov
Dr. Vinik, can you say yes or no if people already on immunosuppressants would be eligible while remaining on their current drug protocol?
Dr. Vinik
If you are already on immunosuppressives, that should not be deterrent to stimulating islet growth.
BBB
Dr. Vinik, if I still have precursor insulin producing cells, do I also have insulin producing cells and just not enough of either?
Dr. Vinik
If you have insulin -producing cells, it seems that Type 1 also have these precursors. They reside in different portions of the pancreas. While the insulin cells are constantly functioning, the primordial cells appear to become dormant and are only induced to function when reawakened.
Cheryl
Dr. Vinik, I live in Richmond, Virginia, close to you! Are there any studies or trials going on that I could participate in?
Dr. Vinik
It’s good to hear from somebody just up Interstate 64, but all the work will require meeting agency requirements.
BBB
So, I really do have insulin-producing betas? Am I to understand those cells are in me but are just dormant and so aren’t functioning properly?
Dr. Vinik
BBB, the dormant cells do not function as beta cells unless stimulated to do so.
BBB
Do non-diabetics also have as many dormant cells or is the quantity a function of diabetes?
Dr. Vinik
All people and animals seem to have these cells. They have not been quantitated as yet since there are no markers for them until they are stimulated. We can stimulate them in diabetic and normal animals so we thank they are there under all circumstances.
Alan F. Bachrach, M.D.
Deb has asked me to moderate. I’m not sure what else needs to be said. I first heard Dr. Vinik speak at the Desert Diabetes Club Day of Hope in Rancho Mirage about four years ago. It certainly sounds as if things have come a long way since then, and the possibilities of a cure for diabetes from this direction keep expanding. Thanks for sharing with us and please keep us all informed.
Dr. Vinik
Thank you all. Take care and best wishes. As usual, you have been a wonderful audience, and I look forward to our next chat.
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