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A more detailed look at stem-cell therapy for diabetes

In mid-April, the popular press was full of reports on an exciting new paper published in the Journal of the American Medical Society on a stem-cell treatment for type 1 diabetes.

The phrase “stem cell research” has so many connotations that we thought it was worth taking a more detailed look at what exactly was in this widely-acclaimed paper. Published by Dr. Julio Voltarelli and colleagues from the University of Sao Paulo in Brazil, it reported the results from a small 15-patient trial that tested a method called autologous nonmyeloablative hematopoietic stem cell transplantation (AHSCT) for the treatment of new type 1 patients. The method is a complex three-step procedure that is already used to treat other autoimmune diseases like sclerosis, arthritis, Crohn’s disease, and lupus:

• In the first step, doctors collect a large number of hematopoietic stem cells (HSCs) from the patient’s blood. HSCs are the adult stem cells that normally reside in your bone marrow and that replenish both your red and white blood cells. Doctors have to collect a large number because at the end of the process, these pre-harvested HSCs will be re-infused in order to rebuild the patient’s immune system.
• In the second step, patients receive something called “immunoablative conditioning” in order to destroy their white blood cells. This is somewhat similar to the radiation therapy that leukemia patients receive when they prepare for bone marrow transplants, except that these patients receive an antibody that specifically removes their white blood cells without exposing their bodies to harmful radiation.
• In the third step, the HSCs are re-infused into the patient in order to rebuild a new immune system that (hopefully) no longer attacks their beta cells. Again, this differs from what happens in bone marrow transplants (and islet cell transplants, for that matter) in that patients are receiving their own cells, so there’s no risk of immune rejection, or any need for them to take long-term immunosuppression therapies.

In Dr. Voltarelli’s trial, 14 of the 15 type 1 patients were able to stop using insulin after they received this treatment and of these, all but one were still insulin independent at the time this paper was written, in February of 2007. Because this trial was conducted over the course of three years, at that time some of the patients had been followed for as long as 36 months and others for as little as seven.

Importantly, all of these patients had been diagnosed with type 1 diabetes within six weeks of their enrollment in this trial. There is some research that suggests that even people who have had type 1 diabetes for decades are still producing some beta cells, but the underlying autoimmune condition that is responsible for type 1 destroys these new cells as soon as they are created, perpetuating the disease. In Dr. Voltarelli’s trial, the idea was that if the autoimmune condition can be removed early in the course of disease, the remaining beta cells can be rescued and recovered, thus reversing the disease. Presumably this would be much less helpful in people with longstanding type 1 diabetes, who have few if any beta cells left and thus would not benefit from having the autoimmune condition removed.

The mechanism for how AHSCT restores beta-cell function is unknown. In an accompanying editorial to the Voltarelli paper, noted Miami endocrinologist Dr. Jay Skyler points out that while the goal of AHSCT is to eliminate autoimmune white cells and replace them with new, healthy white blood cells, this may not be the whole story. The process of AHSCT itself may somehow reset the immune system to be more tolerant of the body’s own beta cells. Alternatively, the re-infused HSCs may themselves be somehow growing into beta cells, or perhaps the treatment process mobilizes stem cells in the pancreas or bone marrow to become beta cells – this is a somewhat more controversial idea, but we simply don’t know enough about this exciting new technique to determine what exactly is happening.

Dr. Skyler identifies a few future directions of research. Ideally, doctors and scientists will want to see Dr. Voltarelli’s results replicated in a large, randomized controlled trial with a longer follow-up period to see if patients really do remain insulin independent in the long term. Having a randomized control group is particularly important because newly diagnosed type 1 patients often have a ‘honeymoon’ period during which they can stay relatively insulin independent, and it will be important to distinguish between the effects of the honeymoon period and the effects of the AHSCT procedure. Having a longer trial will also help because the honeymoon period doesn’t last very long, whereas we would hope that a “cure” for type 1 diabetes does. Finally, Dr. Skyler would like to see biological studies carried out to discover exactly how AHSCT works – whether it eliminates autoimmune cells or helps beta cells regenerate or acts through a different mechanism altogether. We agree, and we can’t wait to see more work done in this field!

Bottom line: There was a lot of hype in the press about a stem cell “cure” for diabetes in April. The study was exciting, though small and short, and it is important that more be done before we know whether this is meaningful. No embryonic stem cells were used, and no immunosuppression was required. Cells from a patient’s bone marrow were extracted, the patient underwent a sort of radiation therapy, and these cells were reintroduced. Indeed, most of the subjects of this small 15-person group did go off insulin, at least for a time.

Voltarelli JC, Couri CEB, Stracieri ABPL, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KCR, Foss-Freitas MC, Simoes BP, Foss MC, Squiers E, Burt RK. “Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation in Newly Diagnosed Type 1 Diabetes Mellitus.” JAMA 11 April 2007. 297(14):1568-76. Skyler JS. “Cellular Therapy for Type 1 Diabetes: Has the Time Come?” JAMA 11 April 2007. 297(14):1599-1600.

Two Leading Endocrinologists Debate the Merits of Inhaled Insulin

Two well-known endocrinologists debated the merits of inhaled insulin in the February edition of Diabetes Care. Dr. William Cefalu, a professor at the Pennington Biomedical Research Center at Louisiana State University, believes that the convenience of inhaled insulin will lead better adherence to doctors’ orders and to improved glucose control. But Dr. David Nathan, director of the Diabetes Center at Massachusetts General Hospital, contends that inhaled insulin causes substandard glucose control, which makes him worry that patients will further sacrifice outcomes for the sake of convenience.

Inhaled insulin’s long-term prospects are still unclear, but the first such drug – Exubera, approved in January 2006 – is off to a dismal start. Clinicians are concerned about its efficacy and its long-term safety for the lungs. Patients find the device awkward and clumsy. And for the audience who can most benefit from inhaled insulin – type 2 patients who are falling short on oral medication – insulin therapy of any kind is often shunned. Nevertheless, the majority of all diabetic patients are still not achieving target glucose levels, so some doctors remain hopeful that inhaled insulin, as currently produced or future generations, can play some role in improving outcomes. Skeptics say there is no evidence to support that hope. Thus, the debate between Dr. Cefalu and Dr. Nathan.

Dr. Cefalu believes that inhaled insulin has the potential to change the way diabetes is treated, namely, by increasing insulin use among patients who need it. There are often barriers to insulin use not only among patients, who are anxious or scared, but also on the part of physicians, some of whom are slow to change management routines, especially when patients are resistant. This “clinical inertia” helps explain why many health care providers who care for those with type 2 diabetes appear to accept less-than-optimal control for patients who are taking several oral drugs. Because inhaled insulin can help overcome these barriers to insulin use, Dr. Cefalu writes, inhaled insulin “should be considered another viable therapeutic option available to the clinician and should be used as part of a comprehensive program with other new and established agents in an attempt to improve and maintain glycemic control.”

Dr. Nathan disagrees. Though he accepts that inhaled insulin can be more convenient, he worries that the convenience comes at the price of decreased effectiveness. He compares inhaled insulin to the clinical experience of the 1930s, when twice-a-day injections of intermediate-acting insulin was convenient but was less effective in replicating the natural production of insulin and therefore resulted in diminished control. He says that clinical trials have not shown that inhaled insulin is as effective in normalizing glucose levels as injected insulin. In trials, inhaled insulin never achieved average A1c levels as low as those achieved in the Diabetes Control and Complications Trial, which showed the importance of intensive therapy. It’s possible, Dr. Nathan writes, that inhaled insulin does not absorb as well into the body. For the effect of giving five to ten units of insulin by injection, a patient would have to dose 50 to 100 units – ten times the amount of what is actually required. Moreover, Dr. Nathan says that inhaled insulin is a “distraction” for type 2 patients – they generally need basal insulin combined with oral agents, not short-acting insulin like inhaled. He agrees that it is an alternative for type 2 patients who are terrified of needles, but considers this a small group.

Bottom line: Both doctors make valid points. Ideally, patients and providers would overcome the barriers associated with multiple daily insulin, but in reality, compliance is a major barrier to success and anything that can improve compliance may improve outcomes. Injected insulin may remain the gold standard for patients who are capable of complying with the demands of multiple daily injections. But as inhaled insulin technology continues to improve in convenience and dosing, we think that many patients who are currently failing to reach their targets could benefit from this drug.

Cefalu WT. “Point: Pulmonary Inhalation of Insulin: Another ‘Brick in the Wall.’” Diabetes Care. February 2007. 30(2):439-441.

Nathan DM. “Counterpoint: No Time to Inhale: Arguments Against Inhaled Insulin in 2007.’” Diabetes Care. February 2007. 30(2):442-443.