Islet Cell Regeneration and the gene INGAP, Part 6
Date: November 15, 2000
Moderator: Melissa Davis
Subject: Islet Cell Regeneration Update, Part VI
Guest: Dr. Aaron I. Vinik, Director of Research, Strelitz Diabetes Institutes
Appearing on www.diabetesstation.com
Moderator:
Dr. Vinik, Director of Research at the Strelitz Diabetes Institutes, is often described as the man who could cure diabetes, and with good cause. Dr. Vinik is approaching the problem of how to put an end to diabetes by working to regenerate, rather than to transplant islets.
The main difference between islet regeneration and islet transplantation is that regeneration will allow the regrowth of islets from your own cells so there may be no need to take the anti-rejection drugs that are required when foreign cells are transplanted. Most importantly, islet regeneration is not limited by the scarcity of pancreas organs.
Welcome Dr. Vinik. That was the first two paragraphs of an article that Deb Butterfield wrote for the Summer 2000 edition of Insulin Free Times. It was a very interesting and simple to understand article. How are you regenerating the islet cells Dr. Vinik?
Jerry:
Dr. Vinik, have you gotten any further with INGAP, it is to me what I would refer to as the cure of the near future. How is the ilotropin inserted, or injected, in the body?
Dr. Vinik:
Yes, we have gotten a long way since our last chat. We do not have to insert the Ilotropin into the pancreas.Ilotropin was the original crude extract of regenerating pancreases that we gave to animals and showed that it could reverse diabetes. Since then, we have cloned and sequenced the gene for INGAP that we now know is the major constituent of Ilotropin and is capable of doing the same thing. We give it by injection, very much the same way we give insulin, and it hones in on the pancreas where it does its thing.
Jerry, it is possible that what sent you on the road to diabetes can recur, but the good news is that after you have had diabetes for many years, the autoimmune process tends to die down. It seems that the body has to see foreign material to keep the autoimmune flames alive. When there is sufficient destruction of islets that have been damaged by the process, then the body no longer recognizes these as foreign and loses interest in further destruction.
Ruth:
Dr. Vinik, that is fascinating. Are you saying that the destruction stops? Yet, I remain confused if this is true then, why do we need immunosuppresion drugs for islet transplants?
Dr. Vinik:
You need immunosuppression drugs for islet transplants because the islets you receive have been put through a purification process that itself causes damage and leakage of proteins that are recognized as foreign, and the islets come from another individual, or more than one, or from another species and therefore are indeed foreign.
Lisa Marie:
Dr. Vinik, this is the most exciting thing that I have heard in the field of “advancing” toward a cure for diabetes. Has this “theory” been around all these years? Because 20 years ago in nursing school the thought of this was really NOT in the picture of what we learned. Have you ever tried it on a human?
Dr. Vinik:
When we started this work back in 1983, nobody believed that it was possible to cause a stem cell to grow into a new islet. In fact, it was heretical to believe that there were stem cells in the pancreas that retained the capacity to regrow.This certainly did not appear in the textbooks let alone some of the journals. With years of painstaking work and confirmation of our studies by other laboratories, it is now the accepted norm. We have a team working on the problem and making very good progress.
Moderator:
Can you tell us exactly what the difference is between Ilotropin and INGAP? How is INGAP better?
Dr. Vinik:
The key differences between Ilotropin and INGAP are that the former was a crude extract from regenerating pancreases that contained at least 100 proteins. When Banting and Best first administered insulin to Leonard Thompson back in 1922, the insulin was a similar crude extract but fortunately contained enough insulin to lower the blood glucose. INGAP, on the other hand, derives from the DNA of a gene found in the regenerating pancreas and encodes a single pure protein.
Bertie:
Dr. Vinik, tell us about your current application of INGAP in testing. Are you currently injecting large diabetic animals in your research?
Dr. Vinik:
We are starting large animals work within the next few weeks.
Tami:
If you were a diabetic with peripheral and autonomic neuropathy, hypoglycemic unawareness, retinopathy, but no kidney damage, would you go for a pancreas transplant, wait on the islet cell, or wait on this?
Dr. Vinik:
If I were diabetic with somatic and autonomic neuropathy and retinopathy, but no nephropathy, I would consider waiting because the results of transplantation are so much better if the pancreas and kidney are done simultaneously. There are other questions with regard to the stability of the other complications and how they are being managed which could color this decision.
Gregg:
Will the FDA allow testing soon?
Dr. Vinik:
We are working closely with two people who are former members of the FDA to be sure that we do the right things en route to developing this as a treatment for humans. We are planning a set of experiments in preparation for an FDA meeting to be sure that we are on the right wavelength with the FDA.
Lisa Marie:
Jerry, it certainly makes you want to be a large animal! I guess it is just too premature to ask if we can apply to your study?
Dr. Vinik:
It is too early to apply for the program right now, but we are following a very aggressive course to make this available as early as possible. We are planning to at least do the safety studies in humans in the near future.
Angellady:
Dr. Vinik, thank you for coming. I just have one question – what does this all mean for Type 2 diabetics?
Dr. Vinik:
Angellady, this means a whole lot for the person with Type 2 diabetes. In times gone by, people believed that the person with Type 2 diabetes had resistance to the action of insulin and that the treatment had to be sensitization of the body to insulin. We now know that one does not develop Type 2 diabetes without a reduction in the beta cells of the pancreas’ capacity to make insulin. Therefore, if we restore this capacity towards normal, then we anticipate that we will reverse the diabetes even in patients with Type 2 diabetes.
Bertie:
From your studies so far, are the INGAP injections required on an ongoing basis? Are they given periodically? i.e. once a day, once a week, once a month or a one time only injection?
Dr. Vinik:
Boy, what a wonderful inquisitive group you are and what questions! In the hamster studies we have done, we have given several injections over a short period and then had complete recovery without the need for further treatments. We have just completed a study in mice and done exactly the same thing. After a course of treatment, all the mice recovered, and we did not have to go back to retreat. We do not know now that this will be the case in all instances. But what would be so bad if every now and then one needed a shot to fill up the tank again?
Lisa Marie:
Do you have any indication that once the INGAP is used to stimulate the stem cells to transform into insulin producing ones, how long they will last?
Dr. Vinik:
Does INGAP work alone or is it necessary to have other factors around? You are absolutely right in surmising that there may be other factors around that are either necessary or sufficient to allow INGAP to do its things. It is, however, like pushing a stone to the edge of the cliff, once over the edge, it keeps on rolling and gathers the moss it needs. INGAP seems to be able to do just that, initiate the process and whatever other factors are required in a permissive manner are there to facilitate its action. That does not mean that we are not actively engaged in research to learn about these factors and how INGAP works to enhance its capability.
Moderator:
How will you produce enough INGAP to go around?
Dr. Vinik:
The fortunate thing about INGAP is that we can produce gallons if we have to. Our most recent discovery is that one does not need the whole molecule to stimulate islet growth. We now know that a small peptide, just 15 amino acids, part of the INGAP protein sequence from amino acids 104-118 is all that is required for this action. We have just had hundreds of grams synthesized in the test tube and can make lots by recombinant technology using bacteria. This is a whole lot better than the acute limitations of islet transplant methods.
Bertie:
E-coli?
Dr. Vinik:
Yes, E-coli, similar to the process now used for insulin and a number of other peptides.
Jen:
Dr. Vinik, would there be any problems for someone that had an islet transplant to go for INGAP? If so, what? Thank you.
Dr. Vinik:
There will be no contraindication for somebody who has had an islet transplant since the pancreas is not removed and retains those stem cells that can then be reawakened. What may be necessary is continued immunosuppressive therapy while the transplanted islets are still present and create a reservoir of foreign material that the body needs to eliminate.
LisaMarie:
So, perhaps just the mere fact that the INGAP initiates the process makes it smart enough to overcome the “other factors” – Are you saying that things like C-peptide will come along after the insulin is again produced by the body? What is an example of the “other factors?”
Dr. Vinik:
Lisa Marie, when the islets regenerate, they produce insulin in a normal manner, and the precursor proinsulin and its derivative C-peptide are part of the process. What is more exciting to us now is that the reconstituted islet develops all the other hormones produced by the islet including glucagon. What happens to people with intensive glycemic control or organ transplantation is that they lose the ability to counter-regulate their blood glucoses and are prone to hypoglycemia. With the ability to make glucagon, one of the body’s primary defense mechanisms, this ability to combat hypoglycemia is restored.
LisaMarie:
Dr. Vinik, I hope that you will soon become the Edmonton of the U.S.-- having many other doctors come and learn your procedures and get it out to us. How do you know how much is too much Ilotropin?
Daver:
Dr. Vinik, in regard to Jen’s earlier point – are any stem cells transplanted as part of an islet transplant, and if so, would they not be subject to regrowth in their new (liver) home?
Dr. Vinik:
With islet transplants, the objective has always been to use islets that have been very, very purified, free of any contaminating cells, which, in essence, removes the coexisting stem cells. What is of interest is that some groups have now come to realize that they may inadvertently removed the INGAP producing cells, thereby shooting themselves in the foot. We are exploring this possibility.
Ruth:
Dr. Vinik, presumably this treatment would then only work with “established” diabetics – who have T-cells that have not had anything to attach for a reasonably long time, hence less chance of immediate rejection?
Dr. Vinik:
Ruth, your question on would it only work with established diabetics, those in whom the T-cells were no longer active, is clearly a nice window of opportunity for INGAP, but even if you have an active ongoing immune defense mechanism, it requires at least a double hit, a foreign protein plus other antigens to alert the body to the presence of foreign tissue. While we may not be able to eliminate one of these, the introduction of new islets that are recognized as self eliminates one of the hits, and it becomes likely that newly diagnosed people with diabetes would also benefit.
Bertie:
What large animal will you be using for the next part of your research?
Dr. Vinik:
The large animals planned for the next phase are dogs. We will also be doing mice. We are abiding by the FDA requirements for toxicity studies. We are also in the planning phase of efficacy studies in dogs.
Lisa Marie:
What a thought – so no matter how many “pooled islets” there are, the INGAP is gone, so therefore – they are too “sterile?”
Dr. Vinik:
Lisa Marie, what a nice way of expressing the notion that islets deprived of their INGAP are too sterile to procreate.The sterility, however, is in the islet but not in the stem cell, it can procreate, but needs the right stimulus.
Gregg:
Will the FDA allow you, after safety tests, to begin human clinical studies in perhaps late 2001?
Dr. Vinik:
Gregg, we plan to meet with the FDA early in 2001 to be sure that we do everything by the book, so to speak, so that there is no obstruction to pursuing a rapid course to the human studies. We also have an advisory board selected from the most prominent diabetes experts and researchers from all over the world to fine tune our progress in this direction.
Moderator:
Thank you so much for your time Dr. Vinik. I hope you will return soon and update us on how the dogs are doing!
Dr. Vinik:
My parting thoughts are the delight that I have in sharing our excitement and enthusiasm with you and the probing questions you ask. Each time I have chatted with you, I have returned to the bench to make sure that we have not overlooked the issues raised. Thanks to you all for your wonderful input and insights. Take care.
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