Islet Cell Regeneration and the gene INGAP, Part 1

Edited Chat on www.virtualnurse.com/Chat/Diabetes.htm (no longer available)
Date: December 3, 1998, 10:00 PM EST
Melissa Davis, moderator.
Subject: Islet Cell Regeneration and INGAP
Guest: Dr. Aaron I. Vinik, Research Director, Leonard R. Strelitz Diabetes Institutes Eastern Virginia Medical School, Norfolk, VA

75 Active Participants, 8600 Hits on Site

Melissa
Hi everyone!! :-)
Lets discuss what INGAP is! A lot of people have never heard of it!

Dr. Aaron Vinik
The big scheme of things is that we are all trying to find the cure for diabetes or, at least certain forms of diabetes. At present the major hopes have been pinned on pancreatic transplantation or islet( the organ that makes insulin) transplantation but this is still fraught with many obstacles that need to be overcome.

Our notion is that we ought to be able to recapture normal fetal development and induce the pancreas to regrow from stem cells that are present in the pancreas even after many years of diabetes. The name INGAP is islet neogenesis associated peptide, and it is capable of stimulating these stem cells to grow and transform into cells that can make insulin.

Our islet regeneration program is going on gangbusters. We have been successful in curing a significant number of animals with diabetes by giving them Ilotropin which was the forerunner of INGAP and more recently we have been able to achieve similar results with INGAP again in diabetic hamsters.

Melissa
Lets start with INGAP and how it works, shall we?

Dr. Aaron Vinik
These stem cells that develop into new islets could be attacked by the immune system but there are several reasons to suspect that this will not happen.

Firstly, the treatment could be given when antibodies have already disappeared form the persons system.

Secondly, these new cells might not be subject to damage by viral infections or any of the agents that trigger damage to the islets releasing their proteins that set up the immune reaction.

Thirdly, we could stimulate enough growth of islets that would outstrip the rate of destruction by the immune system so that we would not have to worry.

Fourthly, it is likely that we will have good immunosuppressive drugs to suppress any immune reaction when the islets have grown.

Alan F. Bachrach, M.D.
But, don't a lot of diabetics continue to manifest ICA's (islet cell antibodies) throughout most of their lives?

Dorothy
How long does it take for antibodies to disappear -- I thought they never did! I also have always thought that immunosuppressive drugs taken for the rest of one's life is a very poor trade-off even if it might mean a cure

Ellen
You said "Firstly the treatment could be given when antibodies have already disappeared form the persons system" When does this happen?

Sandy Donchess
Dr. Vinik, has INGAP been used yet on animals other than hamsters or mice?

Tomokazu Ise
Dr. Vinik, Have you tested human Ilotropin?

Dr. Aaron Vinik
No, we have not tested human Ilotropin, but we have done a nice series of studies to find out if INGAP exists in humans. The good news is that we have made an antibody to INGAP that cross reacts with the protein in all species including the monkey and humans. Using this antibody we have been able to show that INGAP in the human is very similar to that in hamsters, and it is present in the human pancreas. Interestingly we have had the chance to examine a pancreas from a 65 year old patient who had diabetes since youth, and INGAP was present in the pancreas.

Melissa
Wow! I never knew antibodies could just disappear....

Dorothy
Wow! that's very interesting information Dr. Vinik, that INGAP could be present in a pancreas of a person having diabetes 50-odd years.

Butterfly26
Was the patient the 65 year old...alive or deceased when you examined pancreas?

Sandy Donchess
Dr. Vinik, if INGAP is still present in the pancreas of a person who's had diabetes (Type 1, I assume) for 50+ years, why would administration of INGAP help that person?

Alan F. Bachrach, M.D.
What's the significance of the presence of INGAP in a 65 year old with DM? Obviously new islets were not being produced??

Dr. Aaron Vinik
The interesting thing about antibodies is that at the onset of diabetes, when it first starts, about 95% of patients have antibodies to islets present in their blood. Each year as diabetes goes along fewer and fewer patients have antibodies so that when diabetes has been present for 20 years only about 5% of people have antibodies to islets. Thus the window of opportunity is large. Also to answer another question, it is clear that this form of treatment will not only apply to newly diagnosed diabetics.

Sandy Donchess
Dr. Vinik, would the islet cell antibodies somehow destroy or render ineffective INGAP? If so, your basically saying that it takes time for the antibodies to "go away," that would mean that INGAP administration would not "work." Am I missing something?

Dr. Aaron Vinik
The importance of finding INGAP in the pancreas of someone who has had diabetes for 50 years is that it is telling us that the body is using this mechanism to try to fight the disease. This patient’s pancreas had islet neogenesis( growth of new islets) but did not have enough to beat the disease. Its like needing insulin in type 2 diabetes. These people often make a lot of insulin but not enough for their body's demands.

Jay Watson
Dr. Vinik, If the body "looses" most of the original islet antibodies, why won't they regenerate if new islets are transplanted? Isn't the same immune system malfunction still present?

Alan
Dr. Vinik, does Dr. Candace McDaniel’s research have any validity and if so can it be applied to yours?

Dr. Aaron Vinik
Several questions relate to the problem of whether or not the antibodies would destroy INGAP. We have not yet tested humans to find out if antibodies to INGAP occur, like antibodies to insulin or to islets. This may be the case and it will be important to find out if this is true. One of the things we are doing is developing an assay to measure antibodies, and we will then be able to address that question.

Jackie from Alaska
This is giving me some HOPE!!!! *SMILE*

Tomokazu Ise
I've heard that some Japanese doctors are studying same islet regeneration in Tohoku University. Do you know that, Dr. Vinik?

Dr. Aaron Vinik
Yes, I am aware of the work in Tohuku and also the parallel studies in Kobe and Kyoto. They are working with a cell line that derives from the tissue in the pancreas that is not the islet and have shown that with treatment with a bunch of substances the cells will grow and make insulin. We and others have tried to work with this cell line and have not been able to achieve the same success. It will be important to learn why there are these differences.

Cyndee Fena RDH MT
Always interesting to hear someone new ask the question of a cure in 15-20 years...You might want to think about how to keep him in good control during the time if/and /when there is a cure. What happens when a cure is developed to fix all the complications developed by patients in the waiting period??

Dr. Aaron Vinik
I think it is very important that we do everything possible to prevent the complications while we are waiting for a cure. The single best thing one can do right now is control the diabetes as well as possible, We will have the chance to chat about this in a later session right?

Cyndee Fena RDH MT
Having Chat rooms like this with important people interested in letting us know things and letting us give them our input, that helps all of us keep in good control...Thanks Dr. and Melissa!!!

Dorothy
Are these scientists in Tohuku and Kobe and Kyoto working with the same animals Dr. Vinik? Or are they even at the testing with animals stage?

Donna
Doctor, are you aware of the work being done in Houston that Diane just spoke about? I would like your input. Thank you

Dr. Aaron Vinik
The work in Texas is directed at trying to engineer cells genetically to make insulin. They start with tumor cells and by genetic manipulation fool them into making insulin. The problem so far is that these cells are not regulated in the way a normal pancreas is so that it turns on when the blood sugar is high, and turns off when the sugar is low. The learning curve for what happened with islet transplantation has been a somewhat long and slow one. We hope that we will have learned a great deal from those failures, and successes and that this information will be applicable to our direction. Other animals that have shown expression of INGAP include dogs, mice, rats and monkeys. We are working with people all over the world to try to bring this close to use in the human. The Japanese researchers have not applied their finding to intact animals as far as I am aware.

Ellen
Dr. Vinik, this is off subject and I apologize, but do you believe Nicotinamide can thwart the onset of diabetes in someone who tests positive for ICA but negative for GADab, ICA512, and IAA? Also does not show presence of protective gene.

Dr. Aaron Vinik
The nicotinamide story is an interesting one. The notion behind this form of treatment is that it would allow repair of the genes that are damaged in the process of developing diabetes. Trials have been done in New Zealand and Australia but without great success. I personally still have concerns with this approach because of what is seen with long-term treatment of animals with nicotinamide. Ilotropin was the crude mixture we made from regenerating pancreas that when given to other animals with diabetes was able to reduce the sugars to normal. Ilotropin, like the original crude extracts of insulin contains many proteins, some of which may also be important in restoring pancreatic function.

The most important protein is INGAP. We came to this conclusion backwards. We first found the gene for INGAP and then introduced the gene into cells that were able to decode it and make the protein. When we had the protein we were able to to make an antibody and use it to learn that Ilotropin contained INGAP. It is the INGAP protein that we used to treat animals but this does not mean we will not be able to introduce the gene at some point. The Canadian and other papers did hail INGAP as being possibly as important as insulin. We hope that when this all comes to fruition it will be more important because as you all know insulin is not a cure but a panacea and we hope that one day we will get beyond that.

Diane Massey
This is a very early stage of a study. I do not think that the Doctor who is running the study particularly wants this out.... I just couldn't help myself.... Lauren was given MINUTE doses of interferon by mouth daily to preserve her honeymoon. It is clear that her dead islets were DEAD! At first she was on an inadequate does (for the first 9 months), The dose was doubled. Her pancreas started working which was confirmed by c-peptide tests on two occasions. However, by the time that her pancreas was working it was clear that she had a sick malfunctioning pancreas and control was nearly impossible because of the erratic performance of the pancreas. Her pancreas had taken too much damage before the cells were revived. There were 5 in the study. 3 others maintained a constant controllable honeymoon beyond a year + no complete revivals, everyone on reduced insulin as in a regular honeymoon. 27 + new patients in study... results not in. But it seems clear that the interferon has an arresting affect on the autoimmune process!

Alan
Dr. Vinik should we as parents try to prolong the honeymoon period as long as possible ?

Tomokazu Ise
I agree with Alan.

Dr. Aaron Vinik
We should all try to prolong the honeymoon period for as long as possible provided we do not ignore high blood sugars and think they will go away. There have been trials on prolonging the honeymoon period and this has been achieve for up to two years with immunosuppressive drugs but when these were stopped the diabetes came back. Nobody can say right now if a long honeymoon period is better in the long run but while it is there it can be enjoyed. Ilotropin and INGAP do do the same thing. The problem with Ilotropin is that it contains so many different proteins that these may ultimately cause trouble. In the earlier years we used insulin that had lots of other proteins and it came from animals. This led the body to make antibodies to insulin and these other proteins and this caused difficulties in managing the diabetes and led to some of the side effects. Now that we use mostly human insulin we almost never see any of these effects.

Sandy Donchess
Dr. Vinik, it sounds to me that INGAP/Ilotropin research is still in a very basic stage. Have any animals been cured of diabetes? How was the INGAP/Ilotropin administered, and how often?

Melissa
How much more research do you need to do on animals before you progress to humans? I just want to make sure I understand this correctly... Ilotropin is the forerunner of INGAP? So basically they do the same thing?

Dr. Aaron Vinik
INGAP research is at a basic stage. We have now treated many animals and about 30-40% respond. We are trying to learn how to make that 100%, but we are excited that we have at least this chance!

Dorothy
is a 30-40% response from animals being tested a good rate of response Dr. Vinik? It sounds pretty promising to me...

Kelly Ellis
of the 30-40% success rate in animals were there any down regulation issues experienced?

Steve
Dorothy.. the animal model of human diabetes is NOD mice or autoimmune destroyed ilets in the mice strain.

Dr. Vinik... Dr. Peck of Ixion report in vitro regeneration of islets from stem cells. When these islets are autograf transplanted in autoimmune mice the islets are not attacked by the immune system. Will your process be similar?

Dr. Aaron Vinik
We hope that these new islets will be free of immune attack since they come from the person's own body. In Dr Peck's case giving transformed stem cells to animals that are immunosupressed or deficient still dose not address the issue of what would transpire if stem cells from a foreign species or person would be given to a human. Our approach is to get the individual to make his own stem cells turn on. We think that 30-40% is excellent !!!

Steve
Dr. Vinik In Dr. Peck's work the islets were transplanted back to the original stem cell donor and as such were not immunosupressed.

Dr. Aaron Vinik
Thanks for the comment about Dr. Peck's experiments. It would be nice if we could harvest stem cells from the individual and then convert these into islet cells and then give them back to the same individual. This is an approach but a little more circuitous than directly stimulating the individuals stem cells that we now know are there. Even if antibodies are present to islets we think that giving INGAP can stimulate the growth of new islets that will survive. We have used the NOD mouse, which destroys its islets by an immune process and are able to beat the destruction by having more regeneration. Hope that you all want to volunteer when we are at the stage of giving INGAP to humans.

Dorothy
Yes, it certainly sounds like an excellent percentage Dr. Vinik! and once more ad nauseum (smile) when do you think we could offer our bodies to test this on humans?

Anomali
EXACTLY, Dorothy... When can WE participate in these studies...

Tina
So, if research continues uninterruptedly on animals, how long (approximately of course) before trials with humans could occur?

Dr. Aaron Vinik
Thanks for the comment about Dr. Peck's experiments. It would be nice if we could harvest stem cells from the individual and then convert these into islet cells and then give them back to the same individual. This is an approach but a little more circuitous than directly stimulating the individuals stem cells that we now know are there. Even if antibodies are present to islets, we think that giving INGAP can stimulate the growth of new islets that will survive. We have used the NOD mouse, which destroys its islets by an immune process and are able to beat the destruction by having more regeneration. Hope that you all want to volunteer when we are at the stage of giving INGAP to humans.

There are some people in the world who have shown that islets themselves can proliferate, but this accounts for less than 12% of the pancreas capacity to do so and also requires a whole different set of hormones. It is the process that occurs during pregnancy for example.

Janet
Dr, do you know what triggers the INGAP gene?

Dr. Aaron Vinik
A very interesting question is what triggers the INGAP gene because if we knew that, then possibly we would be able to use this approach rather than to give the protein. We are working on that as we speak. The exciting thing for us is that the normal human pancreas does not make INGAP but, when we examine pancreas that are undergoing regeneration of new islets for a variety of reasons INGAP is always expressed. In animal models in which we induce new islet formation the gene is also always turned on. We will have more of that soon.

Alan F. Bachrach, M.D.
Dr. Vinik. Would you please give us some assurance that Lilly is actively working on using this discovery to produce a cure.

MAR
I've been in awe of your quest since reading a spring 1997 article hailing you as "The Man Who Would Cure Diabetes". I certainly hope so and look forward to your responses to the outstanding questions.

Melissa
I want to thank you all for sticking to the topic and now I think we're ready to move on to the topic of Lilly! I know you all have many questions about that! Dr. Vinik, for those who don't know, can you first tell us how Lilly became involved with INGAP?

Dr. Aaron Vinik
You all raise a bunch of important questions. Yes, we have licensed INGAP to Lilly and we are working with their scientists to further this approach to the cure. There are hurdles to overcome, and they have been very helpful in sorting out many of these, not the least of which has been the production of the full length protein. There are other moral and ethical issues you raise but these have not entered into our discussions with the scientists at Lilly who have been totally supportive of the work. Indeed, we are working with them now to enlist the help of international scientists to help speed up the process and bring it closer to reality sooner.

Sandy Donchess
Dr. Vinik, I spoke with a VP of research at Lilly who indicated that years of "basic research" must be done on INGAP. I was told that islet cell transplants will be forthcoming much, much sooner.

Dr. Aaron Vinik
Islet transplants are being done now, but there are still a host of problems. Even if these are overcome the mathematics precludes all or even a significant proportion of people with diabetes receiving sufficient numbers of islets to allow a cure. Yes it will take some time but we have been working with islet transplantation for about 30 years and INGAP is still in its infancy and already made great strides.

Dorothy
That information sounds very familiar, Dr. Vinik...that it would be impossible to provide all the islet cells that the diabetic population would need...wasn't it hard enough to just provide a low percentage of the realistically necessary islet cells in the first few "test" patients?

It is a continuing and nagging disappointment to us diabetics the amount of times we are told "a cure within 10 years" throughout the term of our chronic disease...REALISTICALLY what do you think the potential time frame is on this being disseminated to the general public if it works on human subjects?

Marina
We have been working with islet transplantation for about 30 years, but there was never a concerted, focused effort with islet transplants nor adequate funding from the NIH and other organizations. I don't believe all avenues have adequately been explored.

Melissa
What does it mean to License INGAP to Lilly? Some folks think Lilly is in sole control or have ulterior motives!

Dr. Aaron Vinik
Licensing INGAP to Lilly does not mean that we have stopped work on the subject. Indeed it has meant that we have intensified our efforts. Some of the scientists mentioned this evening are collaborators.

Ellen
Is Diabetes Research Institute in Miami Florida collaborating with you?

Dr. Aaron Vinik
Yes, we are collaborating with scientists at the Miami Diabetes Institutes and yes if Lilly does not move forward with the project it will revert to us. This decision can of course be made bilaterally and this was the protection we sought when entering into the agreement so that what some of what you fear would not transpire.

Melissa
Dr. Vinik, what was the motivation behind involving Lilly? Was it that you didn't have the resources to continue developing it yourself?

Dr. Aaron Vinik
We needed a big company's resources to bring INGAP into the therapeutic arena. Those of you who follow scientific developments closely as it seems you all do know that when you are trying to make a drug it costs huge amounts and one needs deep pockets to do this. Cord blood stem cells may be an approach. So far attempts at islet expansion have met with limited success and not all the factors that are needed have been worked out.

Melissa
Yes INGAP sounds a lot more logical to me! and it's a REAL cure, isn't it! No booster shots!!

Alan F. Bachrach, M.D.
My understanding is that we don't need to provide ANY islets. We need to provide a protein (INGAP) which (I presume) can be mass produced through genetic engineering and this protein could theoretically stimulate the differentiation of all the islets a patient would ever need? This is the point, right?

Sandy Donchess
I disagree that islet transplantation would be fettered because of an insufficient supply of islets. Xenotransplantation would be the answer there.

Al Gordon
Dr. Vinik, you are right about the limited supply of human islets. That is why there is so much work being done with pig islets (pig islets have the same glucose set point as human islets and pig insulin has worked well for diabetics for 77 years). Recent studies by CDC have demonstrated the safety of pig islets. The advantage of INGAP, of course, is that the insulin produced is 100% human and there is no need for immunoprotection (encapsulation).

Judith
My impression was that sufficient amounts of islets could be produced from cord blood stem cells.

Muralist
There is a lot of talk on the immune antibody problem. Is it a math problem with efficient numbers concerning Microencapsulation for protection or is that a viable answer for protection?

Dr. Aaron Vinik
Sure, the first islet transplants required islets from pancreases of up to 12 people to even achieve a temporary relief of the diabetes and there are not many people out there who have had transplants and in whom the islets are functioning. I would like to give you more information on specifics about who is doing what but that would require a longer chat. I do believe we will have several opportunities to do this and look forward to answering more of your questions next time Take Care and Have a good night.

Cyndee Fena RDH MT
Thank you Dr. Vinik!!

Melissa
Goodnight to those who are leaving! Be sure to check the archives tomorrow.... Diabetes Hyper Link

Alan F. Bachrach, M.D.
Dr. Vinik, Thanks so much for joining us. It is not very often that we have the opportunity to interact with a researcher such as yourself online. Good night until next week.

Ellen
Thank you.

Sharon
Thank you Dr. Vinik for all your hard work towards a cure for this unfortunate disease. I look forward to cure one day soon and thank you Melissa I will see you next week.

Dorothy
Dr. Vinik I have to say I truly, truly appreciate your taking the time to chat with us...

Al Gordon
Thanks, Dr Vinik. Good night!

Darlene (Rikki's mom)
Thank you!!!! I can't say how much this has encouraged me.

Ellen
And thank you Melissa.

Faith
Thank you both.

Beth
Looks like I'll have to settle for the archives.

Therese
Thank you Melissa and Dr. Vinik. Goodnight everyone!

Melissa
Thank you so much for joining us Dr.Vinik! I have a lot of hope for the future! I look forward to chatting with you again next week! I'll be in touch!

Lori
May God give you the wisdom to find a cure!

Aaron Vinik
Thanks Melissa for the opportunity to chat and thank you all for your wonderful questions. We scientists are always delighted to share with people our good news and hope that this brings . Good Night.