Information About the Latest Research Findings on Type 1 Diabetes Published in the Journal Science
Sorting Through the Science: A Commentary on Type 1 Diabetes Research Findings Reported in the March 24 issue of the journal Science
March 24, 2006 - As a person with diabetes, you, your family and friends may have questions about the many headlines and high-profile news stories in the New York Times and Wall Street Journal this past week concerning several research reports describing “cures” for type 1 diabetes in mice.
While there have been many studies of this type over the past two decades, the current debate started with a report in the journal Science in 2003 by a team from the Massachusetts General Hospital. The three latest studies appeared in the March 24, 2006, issue of the same journal and were from researchers at Joslin Diabetes Center, the University of Chicago and Washington University in St. Louis.
All four studies involved essentially the same experiments, but from what appeared in the media coverage, you may have questions about what was new and/or important about them, if they came to the same or different conclusions and what are the real implications of this work. The best and not-too-technical summary actually appeared in an article entitled “Diabetes Studies Conflict on Power of Spleen Cells” in the same issue of Science in which the latter three studies were published. We have obtained permission to link to this article for those of you who would like to read it but, for those who do not, we have attempted to summarize the history.
Let’s take a look at what we had hoped for and what we now know, and finally, where we are going.
In a nutshell, what did the first paper show?
The initial studies by Dr. Denise Faustman and her colleagues in 2003 reported some potentially very interesting findings. Using a well-known model of type 1 diabetes called the NOD mouse, the researchers demonstrated that diabetic mice could be cured by a combination of treatments involving 1) administration of an immune modulatory compound called CFA, 2) a temporary islet transplant, and 3) administration of spleen cells from other mice. It was not “new news” that CFA can reverse diabetes in NOD mice – that had been shown previously by several labs. What was most unexpected and exciting was that in the “cured” mice the insulin-secreting islet cells in the pancreas appeared to come from the transplanted spleen cells. This finding suggested that the spleen might be a source of adult cells that could “rapidly differentiate into islet...cells within the pancreas.”
What did the three more recent papers show?
In an attempt to validate and expand upon this work, three independent teams of scientists at Joslin, the University of Chicago and Washington University repeated these exact experiments. The good news was that the diabetes in some of the mice was reversed. The bad news was that the insulin-secreting cells did not come from the transplanted spleen cells, dashing the hopes raised that spleen cells could give rise to islet cells. This was disappointing news because it countered the findings previously reported by the researchers in 2003 that had generated much hope in the diabetes community. In addition, the three independent research teams found that the percentage of mice cured by this treatment was considerably lower than that previously reported. The report in Science in 2003 cited cure rates as high as 90 percent – the new studies showed a range of 16 to less than 35 percent.
How exactly the NOD mice were cured, i.e. where did the insulin-producing cells come from that reversed the diabetes, was not answered in the last three studies, but there are at least two main possibilities. One is simply that the islet cells were there all along, but the inflammatory autoimmune process had somehow dampened their ability to secrete insulin. Alternatively, it is possible that there was some element of islet cell regeneration from either existing islet cells or islet cell precursors. This would be a very exciting possibility, and is definitely being further explored. Finally, we do not really know what the temporary islet transplant is contributing to the process.
How long have scientists known that diabetes could be reversed in NOD mice? Is this a new finding?
Scientists have known since the early ‘90s that diabetes can be reversed or prevented in NOD mice. A large number of different agents have been shown to have some effect in this regard – including various antibodies, immune suppressive drugs and some chemical drugs. Also, several labs have provided evidence suggestive of regeneration of beta cells in various models of type 1 diabetes, including NOD mice, dating back 30 years. The key questions are: Where do the new islet cells come from, how can we assure that enough regrow to cure diabetes and perhaps most importantly, how can we block the immune response from destroying the islets?
So where do the insulin-producing cells come from, and can they be restored in a person with diabetes?
Researchers around the world, including at Joslin Diabetes Center – especially Drs. Susan Bonner-Weir, Gordon Weir, Rohit Kulkarni and C. Ronald Kahn – have been working for years to find ways to restore the beta cell deficiency of diabetes by regenerating islet cells in the pancreas, in other words, exploring the ability of islets to grow or regrow. Replication of preexisting beta cells was reported as early as 1981, and this is especially evident in states where more insulin is needed, such as obesity and type 2 diabetes. New islet cells also can be derived from cells lining the ducts of the pancreas, as well as perhaps from some islet cell precursors within the pancreas.
Can new islets come from cells outside the pancreas?
This remains the “$64,000 Question.” Investigators in many places, including Dr. Amy Wagers and others at Joslin, are working hard to answer this question. In addition to islets and pancreatic duct cells themselves, as described above, the most studied cells have been various types of embryonic stem cells, adult stem cells, bone marrow stem cells, and now, the spleen. While there is evidence that embryonic, and perhaps even some forms of adult stem cells can be coaxed to make small amounts of insulin, what is clear is that much research is still needed to determine how to maximize the potential of these cells to replace damaged islets in patients with type 1 diabetes. By contrast, most studies thus far have not found any potential for bone marrow stem cells (which are the best characterized of all adult stem cells) to give rise to cells that make insulin, and the three recent studies in Science indicate the same is also true of spleen cells.
But don’t we still need to find a way to stop the autoimmune attack that started diabetes in the first place? What about CFA?
Type 1 diabetes is an autoimmune disease, i.e. a disorder in which the body’s own immune system destroys the insulin-producing beta cells. Thus, blocking the autoimmune response is a key to treatment, prevention and/or cure of the disease. One potential way to stop the autoimmune attack in mice is CFA. In 1992, Rajotte and colleagues published a paper which similarly showed that CFA together with islet transplantation can stop the autoimmune process in recently diabetic NOD mice. Indeed, the 2003 Science study, as well as the more recent studies, have confirmed the fact that, under the right circumstances, CFA can cure type 1 diabetes in mice. A number of other immunomodulatory treatments also can cure diabetes in NOD mice. Unfortunately, CFA is too toxic for use in humans, and the other immunomodulators that work in NOD mice have so far shown only modest effects in humans. Some of the other immunomodulators that work in NOD mice are presently being tested in human patients and show effects that, albeit limited in time, are promising (see http://www.immunetolerance.org/public/clinical-trials/Autoimmune+Diseases). Thus, a key focus of research is to understand the nature of the autoimmune attack on islets in type 1 diabetes so that the safest and most specific approaches to blocking that attack can be found.
Some of the recent news articles have mentioned BCG. What is BCG and should the scientific community be moving forward with new clinical trials on this drug?
BCG is a vaccine used for prevention of tuberculosis in Europe and other countries, and has some of the same components and effects to modulate the immune system as CFA, suggesting that perhaps it could be used instead of CFA to treat humans. In fact, the effect of BCG on the development of diabetes has already been examined in several studies on human diabetes. An initial pilot trial on a very small number of patients offered some promise, but three larger, better controlled studies showed no effect of BCG on patients treated soon after diagnosis of type 1 diabetes. In addition, a recent study showed no evidence that BCG vaccination could prevent type 1 diabetes in children who were genetically at risk, and in fact, certain studies suggested that diabetes may even be accelerated in very young infants given BCG.
So what next?
Like many things in life, science often moves one or two steps forward, then takes a step backwards or to the side, before moving forward again. The path to the cure of a complex disease like diabetes is a difficult one, with no clear direction and few landmarks. Thus, the search for a cure is much like walking through an unfamiliar forest at night with only a small flashlight illuminating a tiny part of the pathway at a time. In research, we must often explore multiple paths before finding the correct one. In the case of type 1 diabetes, we already know that this will require the combined efforts of immunologists, islet cell biologists and many other scientists to focus on the multiple components of this disease. Working together, we will find our way through the forest and move toward conquering this disease.
Click on the links below to read the accompanying “News of the Week” article in the Science issue in which the Joslin study appeared. The article is called “Diabetes Studies Conflict on Power of Spleen Cells.”
Summary: http://www.sciencemag.org/cgi/content/summary/311/5768/1694?ijkey=n5IptXEdYTU1M&keytype=ref&siteid=sci Full Text: http://www.sciencemag.org/cgi/content/full/311/5768/1694?ijkey=n5IptXEdYTU1M&keytype=ref&siteid=sci