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Rethinking the State of the Art for Type 1 Diabetes

Nov 9, 2004

A large percentage of human type 1 diabetes is known to be associated with altered forms of the major histocompatibilty complex (MHC), a group of proteins made by immune cells that regulate many of the functions of the immune system. Evan David Rosen, M.D brings us up to date on research focused on therapy for MHC.

Patients with Type 1 diabetes make up about 10% of all cases of diabetes.  Unlike Type 2 diabetes, its more common cousin, Type 1 diabetes (formerly called juvenile-onset diabetes or insulin-dependent diabetes) tends to occur in patients who are younger and thinner. These people have mounted an autoimmune attack against their own insulin-producing beta cells, leaving them deficient in this crucial hormone. Before the discovery of insulin, Type 1 diabetes was almost uniformly fatal.


There are very few therapeutic options in type 1 diabetes, because insulin sensitizers like metformin and thiazolidinediones are irrelevant, and insulin secretagogues like sulfonylureas and meglitinides can’t squeeze any additional hormone out of the battered beta cells. Insulin is the only drug with any significant value, and lifelong therapy with multiple injections per day has been the lot of these folks since the early 1920’s.

This frustrating situation has caused an enormous amount of energy to be expended on the development of cutting edge approaches, ranging from whole pancreas transplantation to islet transplants to stem cell therapy to gene therapy. At one time or another, each of these strategies has been trumpeted as the next big thing for Type 1 diabetes, and organizations like the Juvenile Diabetes Research Foundation, the American Diabetes Association, and the National Institutes of Health have poured hundreds of millions of dollars into these efforts. To date, the payoff has been disappointing. Certainly, whole pancreas transplantation has allowed some Type 1 diabetics to come off insulin injections, but it is an extremely costly procedure that requires lifelong immunosuppression. There are even some indications that patients with such transplants might not live as long as those still waiting for them, although this is a contentious issue yet to be resolved. For sure, there are not enough organs to go around, even if the procedure were shown to be fully safe.

Islet transplantation suffers from many of the same problems as whole pancreas transplantation, including issues of availability, immunosuppression, and safety. Even successful islet transplants tend to peter out with time, and most patients are back on insulin again after a year or two, even in the best cases.

Stem cells have shown promise, but the technology is still in its infancy. Political obstacles have slowed critical research in this area, although we’ve seen positive movement lately as private institutions and industrial labs rise to the challenge of identifying funding that doesn’t rely on the U.S. government. In previous Viewpoints, I have noted that I see embryonic stem cell therapy as the most likely solution for Type 1 diabetes in the intermediate term, and I still feel that way.

Gene therapy has also been proposed as a way to combat Type 1 diabetes, but this technology is even less advanced than stem cell approaches. Nonetheless, there are certain advantages to gene therapy that are tantalizing. For one, the contentious ethical and political issues surrounding embryonic stem cells could be sidestepped, a major plus in a society polarized by this issue. Additionally, gene therapy offers opportunities to cut off the autoimmune process at its roots, thus eliminating the need for immunosuppressants, which would still be necessary with stem cells.

This is, in fact, just what a group from Harvard Medical School reported in a recent issue of the Journal of Clinical Investigation. These investigators used a popular animal model of Type 1 diabetes called the NOD (non-obese diabetic) mouse. A large percentage of human type 1 diabetes is associated with altered forms of the major histocompatibilty complex (MHC), a group of proteins made by immune cells that regulate many of the functions of the immune system. One of tasks performed by MHC proteins is to identify cells (usually T cells) that are “auto-reactive,” which can go on to attack normal tissues like beta cells. People born with specific forms of certain MHC proteins are genetically susceptible to Type 1 diabetes, while others born with a different form of the same proteins are protected against diabetes. The NOD mouse carries a “bad” form of an MHC protein, and about 75% of these animals will develop diabetes over a five- or six-month period—making these mice a useful model in which to study the disease.

In the current study, the investigators harvested bone marrow (which contains the cells that form the immune system) from NOD mice. Next, they added the protective or “good” form of the MHC protein to the bone marrow cells in a laboratory dish, using a virus to carry the new genes. They then put the genetically altered bone marrow cells back into NOD mice that had been irradiated to destroy their own, normal bone marrow.  Amazingly, the transplanted marrow with the “good” form of the MHC protein seemed to re-educate the immune system of the recipient mice, leading to the destruction of the unwanted auto-reactive T cells. The net result was that not one of the transplanted mice developed diabetes, even when challenged with a drug that normally triggers almost all NOD mice to become diabetic.

If this approach could be translated to humans, it might benefit those at risk for Type 1 diabetes as well as those in the earliest stages of the disease. It is known that many people still have a fair amount of functional beta cells when they first present with symptoms of Type 1 diabetes. In the future, with gene therapy these folks might undergo a bone marrow harvest, the protective form of the MHC protein would be introduced to those cells in a dish, and the altered marrow would be given back to the patient. Because the patient would be getting their own bone marrow back, there is no risk of rejection and thus no need for dangerous immunosuppressive therapy.  Furthermore, if these results translate to the human, the altered marrow would re-educate the immune system and halt the autoimmune process, thus protecting the remaining islets. Perhaps the surviving beta cells will even reproduce (as we now know they can) and make up for those lost in the early stages of the disease.

Pie in the sky?  Perhaps.  But the success of this study will certainly spur other people to replicate the results, and to extend the findings to other models of diabetes and even to other autoimmune diseases such as rheumatoid arthritis and lupus. Despite the long road ahead, results like this keep the field buzzing and striving for improvement. It won’t happen tomorrow, but I predict that one day we will see successful gene therapy for Type 1 diabetes. It can’t come soon enough.


Chaorui Tian, Jessamyn Bagley, Nathalie Cretin, Nilufer Seth, Kai W. Wucherpfennig, and John Iacomini. Prevention of type 1 diabetes by gene therapy.  Journal of Clinical Investigation. 2004 114:969-978

This information was last reviewed November 5, 2004.

Viewpoint is an editorial column that expresses the opinion of the specific Medical Director, who is solely responsible for its content. Viewpoint does not represent the views or opinions of Veritas Medicine and does not reflect the opinions of other physicians and researchers.