November 27, 2003
Insulin Production May Resume If Auto-Immune Attack Halted

Many researchers have been pursuing what they have believed two separate parts of the solution to type I diabetes: A) stop the auto-immune response that kills pancreatic isle of Langerhan cells and B) either replace the lost cells or deliver gene therapy to instruct other cells to take their place as insulin releasers. Well, the good news is that while pursuing these problems researchers may have discovered that there are adult precursor stem cells in the spleen that have the ability to take over the function of the lost pancreatic insulin-making islet cells.

Cells from an unexpected source, the spleen, appear to develop into insulin-producing pancreatic islet cells in adult animals. This surprising finding from Massachusetts General Hospital (MGH) researchers, published in the Nov. 14 issue of Science, is a followup to the same team's 2001 report of a treatment that cures advanced type 1 diabetes in mice. In discovering the biological mechanism behind that accomplishment, the researchers also have opened a potential new approach to replacing diseased organs and tissues using adult precursor cells.

"We have found that it is possible to rapidly regrow islets from adult precursor cells, something that many thought could not be done," says Denise Faustman, MD, PhD, director of the MGH Immunobiology Laboratory and principal investigator of the study. "By accomplishing effective, robust and durable islet regeneration, this discovery opens up an entirely new approach to diabetes treatment."

David M. Nathan, MD, director of the MGH Diabetes Center, notes, "These exciting findings in a mouse model of Type 1 diabetes suggest that patients who are developing this disease could be rescued from further destruction of their insulin-producing cells. In addition, patients with fully established diabetes possibly could have their diabetes reversed." Nathan has developed a protocol to test this approach in patients, but additional grant support is needed before a clinical trial can begin. Type 1 diabetes develops when the body's immune cells mistakenly attack the insulin-producing islet cells of the pancreas. As islet cells die, insulin production ceases, and blood sugar levels rise, damaging organs throughout the body. In their earlier study, Faustman's team directly attacked this process by retraining the immune system not to attack islet cells. They first used a naturally occurring protein, TNF-alpha, to destroy the mistargeted cells. Then they injected the mice with donor spleen cells from nondiabetic mice. A protein complex on these cells plays a key role in teaching new immune cells to recognize the body's own tissues, a process that goes awry in diabetes and other autoimmune disorders.

The earlier study's results are also quite important because it is essential to develop the ability to selectively knock out immune cells that are causing an auto-immune response in order to cure diabetes, rheumatoid arthritis, lupus, multiple sclerosis, and other auto-immune disorders.

The researchers expected to follow that process, which eliminated the autoimmune basis of the animals' diabetes, with transplants of donor islet cells. However, they were surprised to find that most of the mice did not subsequently need the transplant: Their bodies were producing normal islet cells that were secreting insulin.

"The unanswered question from that study was whether this was an example of rescuing a few remaining islet cells in the diabetic mice or of regeneration of the insulin-secreting islets from another source," says Faustman. "We've found that islet regeneration was occurring and that cells were growing from both the recipient's own cells and from the donor cells." An associate professor of Medicine at Harvard Medical School, Faustman notes that it has been generally believed that most adult organs cannot regenerate and that adult stem cells or cellular precursors would not be powerful enough to reconstitute functioning insulin-secreting islets.

In order to determine whether or not the new islets had developed from the donated spleen cells, the researchers carried out the same treatment using spleen cells from healthy male donors to re-educate the immune cells of female diabetic mice. In those diabetic mice that achieved long-term normal glucose metabolism, the researchers found that all of the new functioning islets had significant numbers of cells with Y chromosomes, indicating they had come from the male donors. In another experiment, donor spleen cells were marked with a fluorescent green protein, and again donor cells were found throughout the newly developed islets.

Here comes the especially interesting part: if the auto-immune response can be halted in human diabetes sufferers then it is likely that over a period of months the body will slowly develop the ability to secrete enough insulin to control blood sugar without insulin shots.

A separate experiment, however, indicated that islets also could grow from remaining precursor cells in the diabetic mice and resume insulin secretion once the autoimmune process had been halted. Such regrowth from the animal's own cells was slightly slower than regeneration from donor cells – taking about 120 days – but the eventual regeneration of islets was just as complete. The result suggests that, given time, regrowth of islets can occur in animals who have immune system re-education to eradicate their diabetes but do not receive the donor islet cell precursors.

The researchers then separated spleen cells into those with a surface molecule called CD45, which indicates the cell is destined to become an immune cell, and those without CD45. They injected labeled spleen cells with or without CD45 – or unseparated cells – into young mice in which autoimmunity had begun but full-blown diabetes had not yet developed. After the immune system re-education therapy, all of the mice maintained normal glucose control, while their untreated littermates soon became diabetic. However, close examination of pancreatic tissue from the treated mice revealed markers from the donor cells only in the islets of those who had received spleen cells without CD45.

"It's the cells without CD45 that are the precursors for pancreatic islets. They have a distinct function that has not previously been identified for the spleen," Faustman says.

Any time a new source of cells are found in the body that are capable of turning into other cell types that alone is a small reason to celebrate. Each type of stem cell that is identified is another useful piece in the puzzle and helps with the development of future stem cell treatments. But this report is also great news because it indicates that cell therapy to replace islet cells may not even be necessary in order to cure type I diabetes.

Share |      Randall Parker, 2003 November 27 07:24 PM  Biotech Organ Replacement


Comments
Ellen said at December 4, 2003 6:41 PM:

When will this treatment be offered to the diabetic community? My son had been "D" for 21 of his 23 years. The cure is long overdue. Please do not tell me another FIVE years!!!!!

Chas said at February 24, 2004 12:25 PM:

Why isn't the JDRF funding this research??
WHERE IS THE JDRF??
They have been promising us a cure for decades!!!!!!!!!
Shit or get off the pot JDRF, we need a cure and we need it NOW!

Ed Cesar said at May 25, 2004 10:56 PM:

I'll bet your report about using spleen cells to reverse diabetes is generating a LOT of comments. I am hoping you will read what I am sending you. I am a research analyst who worked at RAND for many years, although I am not an MD/. I also have diabetes, so I have more than a casual interest in a cure during my lifetime.

Towards a General Theory of Diabetes Reversal

This think piece was instigated by the report in
Injected Spleen Cells Reverse Type 1 in Mice

I have had Type 1 diabetes for more than 30 years, and for the past 28 years I have been using an insulin infusion pump.
From time to time, my BGs go out of kilter and I have to go through a rather intensive process of skipping meals for days with frequent testing to readjust my basal rates. By “going out of kilter,” I mean, my basal rate settings are first, too high and I a couple of months later I experience a lot of below normal lows. After getting the rates adjusted to where I want them, a gradual process takes place which requires me to adjust the rates back up again.

Having gone through this many times, I have begun to realize that something may be happening that I, and perhaps you and others who are doing research on diabetes, may not yet understand very well, but if my experience is confirmed, what I have to say may be very useful to you and could possibly help lead to developing a therapy for diabetes reversal.
This experience may also help you with your work with mice.

I can’t tell you how joyful being able to reverse diabetes would make me! Those of us who are forced to live with diabetes know only too well how this disease controls our lives and affects every organ in our bodies negatively.

Beginning with just the presumption that reversal is possible let’s hypothesize some of the conditions that would have to be met:
1. One’s auto-immune system must restored as fully as possible or any rejuvenated cells in the pancreas may be destroyed.
2. Demands for insulin that may be produced by the body are kept at a strict minimum during the early stages of reversal. I am assuming that any insulin that is produced will be used up before any externally administered insulin is used because one’s own insulin will always be preferred. This may suggest eating very few carbohydrates, just enough to make work for the insulin-producing cells, but not enough to exhaust their production.
3. The islet cell replication rate is important, so the auto-immune environment must be intact and essential nutrition for reproduction must be provided. Perhaps these components have already been determined. If so, they could contribute importantly here.

The human islet cell life is probably only a few days, so if the number of new cells are too few to meet demands for insulin they may die sooner than normal because of stress. This assumes a constant rate of replication. However, the ages of the injected cells must be taken into account. If it were possible to produce the majority injected, all with the same birthday, most would die normally at the end of their expected lifespan. However, the cells would be under a great deal of stress, so an impatient researcher may inadvertently test them to the max which could account for their early demise. Have autopsies been performed on dead injected islet cells? If so, what were the results? The reason that many attempts have been made to inject islet cells in the pancreas with a lack of success may be due to a lack of attention to these details rather than the belief that organ rejection or attacks by a virus are the sole reasons. In other words, injecting islet cells may yet be successful if performed differently. The report of successfully injecting spleen cells may be repeated with pancreas islet cells using the same conditions. Quoting from the referenced report, “The spleen cells were then turned into insulin-producing islets…” The report doesn’t say how this was done. Perhaps the spleen cells simply adapted to produce insulin because they were injected in the pancreas where demands for insulin were made. Since all cells contain the characteristics of all the other cells, it shouldn’t matter whether spleen cells or islet cells are used.

Continuing from above, the next proposition is that it would not be necessary to inject spleen cells if the pancreas can be stimulated to produce and activate its own islet cells. Since the body is inherently capable of producing and reproducing any cell, seeding it with spleen cells shouldn’t be necessary, only restoring the proper conditions for the survival and maturation of islet cells is all that is required because the pancreas’ capability to reproduce islet cells already exists. Transplantation isn’t necessary, just restoring the process and nurturing it should be all that is required.

4. However, this process doesn’t happen by itself. If it did, we would read about many Type 1 diabetes reversal cases which we don’t. Perhaps there have been some cases, if so their reports should be interesting. The next step is to consider the necessary conditions to cause whatever cells exist in the pancreas of a person with Type 1 diabetes (assuming his/her pancreas is otherwise intact) to reproduce themselves. Just as all other cells do, the entire pancreas replicates itself, one cell at a time, according to some probably known interval. The task is to help make the cells regenerate active, insulin-producing cells, plus (Peptide 1 and other ).
5. Logically, placing immediate, large demands for insulin on new cells would be counterproductive. I suspect this is what happens when my BG test results over a period of time drift low, then after awhile go up again. My self-restoring pancreas doesn’t get a chance to fully rejuvenate because of the continual demands. Injecting insulin doesn’t solve this because as I said earlier, my body will always use up all the human insulin I produce before accepting any that is externally produced, whether it is Humalog or another copied form. Perhaps placing the pancreas in some kind of nurturing and protective environment until it is ready would be a solution. But I suspect that a rejuvenating pancreas won’t fully recover unless there are some demands placed on it. The question is how much? One possible solution may be to use my own DNA to manufacturer my own personalized form of insulin. That would enable the externally injected insulin to be accepted equally as well and quickly as insulin produced by my recovering pancreas, both while not placing it under great stress, yet exercising it sufficiently. This also suggests careful timing sequence of external insulin delivery and food intake, a matter to attend to later.
6. Summing up at this point, the work reported by Denise Faustman, MD, PhD, of the Massachusetts General Hospital may have a profound
influence on research to eventually reverse Type 1 diabetes in humans, and her work should be commended. Further research along the lines suggested above are indicated, especially finding ways to protect and nuture the pancreas to help it self-rejuvenate, and to produce personalized insulin from one’s own DNA. More work needs to be done to overcome staid opinions with out-of-the box thinking about why Type 1 pancreas’ doesn’t respond to cell islet transplantation and consider that transplantation isn’t really necessary, rejuvenating existing cells may be a more productive way.

If this works, the nay-sayers will exclaim that it would be too expensive to produce insulin from personalized DNA, all those who don't have diabetes, that is. But if that is the way to do it, then a way will be found to produce it.

I would appreciate, but not expect a reply. If you use anything I wrote here just a credit would be ample.

Aloha,

Ed Cesar


Ed Cesar said at May 28, 2004 2:00 PM:


Towards a General Theory of Diabetes Reversal

This think piece was inspired by your report about
Injected Spleen Cells Reverse Type 1 in Mice

I have had Type 1 diabetes for more than 30 years, and for the past 28 years I have been using an insulin infusion pump.
From time to time, my BGs go out of kilter and I have to go through a rather intensive process of skipping meals for days with frequent testing to readjust my basal rates. By “going out of kilter,” I mean, my basal rate settings are first, too high and a couple of months later, I experience a lot of below normal lows. After getting the rates adjusted to where I want them, a gradual process takes place which requires me to adjust the rates back up again. I eat nearly the same food items and quantites at each meal and I stay well-regulated.

Having gone through this many times, I have begun to realize that something may be happening that I, and perhaps you and others who are doing research on diabetes, may not yet understand very well, but if my experience is confirmed, what I have to say may be very useful to you and could possibly help lead to developing a therapy for diabetes reversal.
This experience may also help you with your work with mice.

I can’t tell you how joyful being able to reverse diabetes would make me! Those of us who are forced to live with diabetes know only too well how this disease controls our lives and affects every organ in our bodies negatively.

Beginning with just the presumption that reversal is possible let’s hypothesize some of the conditions that would have to be met:
1. One’s auto-immune system must restored as fully as possible or any rejuvenated cells in the pancreas may be destroyed.
2. Demands for insulin that may be produced by the body are kept at a strict minimum during the early stages of reversal. I am assuming that any insulin that is produced will be used up before any externally administered insulin is used because one’s own insulin will always be preferred. This may suggest eating very few carbohydrates, just enough to make work for the insulin-producing cells, but not enough to exhaust their production.
3. The islet cell replication rate is important, so the auto-immune environment must be intact and essential nutrition for reproduction must be provided. Perhaps these components have already been determined. If so, they could contribute importantly here.

The human islet cell life is probably only a few days, so if the number of new cells are too few to meet demands for insulin they may die sooner than normal because of stress. This assumes a constant rate of replication. However, the ages of the injected cells must be taken into account. If it were possible to produce the majority injected, all with the same birthday, most would die normally at the end of their expected lifespan. However, the cells would be under a great deal of stress, so an impatient researcher may inadvertently test them to the max which could account for their early demise. Have autopsies been performed on dead injected islet cells? If so, what were the results? The reason that many attempts have been made to inject islet cells in the pancreas with a lack of success may be due to a lack of attention to these details rather than the belief that organ rejection or attacks by a virus are the sole reasons. In other words, injecting islet cells may yet be successful if performed differently. The report of successfully injecting spleen cells may be repeated with pancreas islet cells using the same conditions. Quoting from the referenced report, “The spleen cells were then turned into insulin-producing islets…” The report doesn’t say how this was done. Perhaps the spleen cells simply adapted to produce insulin because they were injected in the pancreas where demands for insulin were made. Since all cells contain the characteristics of all the other cells, it shouldn’t matter whether spleen cells or islet cells are used.

Continuing from above, the next proposition is that it would not be necessary to inject spleen cells if the pancreas can be stimulated to produce and activate its own islet cells. Since the body is inherently capable of producing and reproducing any cell, seeding it with spleen cells shouldn’t be necessary, only restoring the proper conditions for the survival and rejuvenation of islet cells is all that is required because the pancreas’ capability to reproduce and utilize insulin and other secretions from the islet cells already exists. Transplantation isn’t necessary, just restoring/reactivating the process and nurturing it should be all that is required.

However, this process doesn’t happen by itself. If it did, we would read about many Type 1 diabetes reversal cases which we don’t. Perhaps there have been some cases, if so their reports should be interesting. The next step is to consider the necessary conditions to cause whatever cells exist in the pancreas of a person with Type 1 diabetes (assuming his/her pancreas is otherwise intact) to reproduce/rejuvenate themselves. Actually, this process may actually be occuring from time to time and health care professionals and those with diabetes aren't able to recognize it. That may be happening to me when my basal rates go awry for no explained reason.

Just as all other cells do, the entire pancreas replicates itself, one cell at a time, according to some probably known interval. The task is to help make the cells regenerate active, insulin-producing cells, plus (Peptide 1 and other viutal secretions to prevent neuropathy and other diseases).

4. Logically, placing immediate, large demands for insulin on new cells would be counterproductive. I suspect this is what happens when my BG test results over a period of time drift low, then after awhile go up again. My self-restoring pancreas doesn’t get a chance to fully rejuvenate because of the continual demands. Injecting insulin doesn’t solve this because as I said earlier, my body will always use up all the human insulin I produce before accepting any that is externally produced, whether it is Humalog or another copied form. Perhaps placing the pancreas in some kind of nurturing and protective environment until it is ready would be a solution. But I suspect that a rejuvenating pancreas won’t fully recover unless there are some demands placed on it. The question is how much? One possible solution may be to use my own DNA to manufacturer my own personalized form of insulin. That would enable the externally injected insulin to be accepted equally as well and quickly as insulin produced by my recovering pancreas, both while not placing it under great stress, yet exercising it sufficiently. This also suggests careful timing sequence of external insulin delivery and food intake, a matter to attend to later. Concerns about the high cost of producing one's own persona;ized DNA form of insulin should be deferred until it is determined if this will work.

5. Summing up at this point, the work reported by Denise Faustman, MD, PhD, of the Massachusetts General Hospital may have a profound
influence on research to eventually reverse Type 1 diabetes in humans, and her work should be commended. Further research along the lines suggested above are indicated, especially finding ways to protect and nuture the pancreas to help it self-rejuvenate, and to produce personalized insulin from one’s own DNA. More work needs to be done to overcome staid opinions with out-of-the box thinking about why Type 1 pancreas’ doesn’t respond to cell islet transplantation and consider that transplantation isn’t really necessary if rejuvenating existing islet cells is a more productive way.

If this works, the nay-sayers will exclaim that it would be too expensive to produce insulin from personalized DNA, all those who don't have diabetes, that is. But if that is the way to do it, then a way will be found to produce it.

I would appreciate, but not expect a reply. If you use anything I wrote here just a credit would be ample.

BTW, I think your offering a way for lay people to send comments is great. Researchers need more/better sources of information from disease-sufferers experinces, IMHO.
How may I view postings from others?

Aloha,

Ed Cesar
cesar@lava.net

Rebecca said at December 15, 2004 3:10 PM:

When will this be offered? My son is 13 and has had diabetes for 12 years. Please consider the CHILDREN in this clinical trial. When will the clinical trial be offered, or if it is now where.

Hugh said at December 29, 2004 6:04 PM:

Please go to www.joinleenow.org if you want to read the latest info about Dr. Faustman's work and,or join the study. They seek donations to help fund the studies. JDRF is apparently minimally involved. I've been diabetic for 30 years too...the cure is at hand. If only the politics and turf wars could be overcome....

If we want diabetes cured quick, we're going to have to fund the cure ourselves. Pretty amazing hunh? Write the JDRF and our politicians.

Hugh

Dr. Rashid said at January 24, 2005 5:09 AM:

my dad is a diabetic and i would be very interested to know when u r starting a clinical trial as he has heard about this new breakand is very excited about it. pls keep me posted
thank you

mohamad ahmad said at May 29, 2005 6:27 PM:

Hello how are you? This is mohamad ahmad. I am 15 years old and i was diagnosed with type 1 diabetes about 5 months ago. I am taking a product that has been shown to regenerate islet or beta cells in the pancreas. But i am afraid that if the islets were regenerated would the immune system just attack them again? Also for being recently diagnosed what do you recommend that i do? Please answer me and i appreciate it. Thanks a lot. Email me @ moahmad@sbcglobal.net

Erik Green said at June 8, 2005 2:33 PM:

I have been Diabetic since the age of five. I have had for 19 years. My father, grandmother and a whole bunch of cousins have the disorder. I tend to call it a disorder because it seems to fit the name better. I am hoping the cure will be found very soon. I have gone to the Joslin Camp as a youth to learn more about diabetes as well as managing it. At first I felt wierd....you know like "why me" but as time went on and I got older I realized that there are a lot more people out there than us with the disorder. At least we are able to do the same everyday activities as everyone else.

My father is having a lot of complications with his diabetes. His body is not releasing insulin slowly like it should. It is taking the insulin...holding it and then releasing it all at once causing my father to have some really nasty insulin reactions. He has been hospitalized Sunday and then again this Tuesday. I am getting worried. My grandmother said that he also has low white blood cells and the doctors have to inject plasma in him. I don't know what the disorder is called but whatever the case is I am concerned.

pgy said at February 28, 2010 10:58 PM:

LDN holds the promise of stopping the immune system attack. The theory is it doesn't stop it permanently put stops the attack going forward.

I have been told that where it is being used by people with Thyroid disease they need to reduce their Thyroid medication as the Thyroid starts to produce more normally. The question remains would the pancreas crank back to life if the immune attack is under control.

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