An End to an Epidemic

by Jessica Hanewinckel | June 2011 | 1 Comment »

By Jessica Hanewinckel

As one of the fastest growing diseases in the world today, diabetes has not left one corner of the earth untouched. In fact, according to the Centers for Disease Control and Prevention, 25.8 million people in the U.S. (8.3 percent of the population) currently live with the disease, with 7 million of those people not yet diagnosed. Another 79 million have prediabetes. It’s the seventh leading cause of death in the U.S., and it’s closely associated with heart disease, stroke, kidney disease (it’s the leading cause) and hypertension — the first, third, ninth and 13th leading causes of death in the U.S., respectively. The World Health Organization calls it a global epidemic. Even 318,800 Israelis had been diagnosed as of 2010, reports the International Diabetes Federation. Measured in both lives and economics, diabetes is dangerous to society, and in nearly every country across the world, predictions are that prevalence of the disease will increase two-fold, if not more, by 2030.

Since its discovery centuries ago, diabetes, in all its forms, has gone without a cure or even a surefire, no-fail technique for at least managing the disease.

Now, a team of researchers at Ben-Gurion University of the Negev, in Be’er Sheva, Israel, is working in conjunction with researchers at Harvard and at the University of Colorado Health Sciences Center on a new technique that might just become the be-all and the end-all to treatment of and a cure for diabetes.

First, though, it’s important to understand some of the science behind diabetes. The pancreas, an abdominal organ, produces insulin and enzymes, which help the body process and use food. Within the pancreas are cell clusters called islets. Inside these islets are beta cells, which actually produce the insulin themselves. Insulin helps the body process glucose for energy. Diagnosis of diabetes occurs when the body no longer produces enough insulin to process the glucose, is unable to use insulin properly, or both, causing a dangerous buildup of glucose in the blood.

One form of therapy for type 1 diabetes patients has been to transplant the pieces of pancreas containing those insulin-producing islets from donor pancreases into diabetic patients. Theoretically, these new, healthy islets should begin producing sufficient insulin, reducing or eliminating the need for insulin injection.

But this therapy has been found to be less helpful than once thought. Studies have shown that in patients who received the therapy, the transplanted islets took effect and made a positive difference in the patients’ lives — for no more than five years. After that, the patients had to return to their regular insulin injections because their bodies had attacked the grafted tissue, rendering it useless.

So what’s causing this therapy to fail? According to Dr. Eli Lewis, director of the Clinical Islet Laboratory of the Department of Clinical Biochemistry at BGU, it has to do with inflammation.

“[My team and I] started studying transplant rejection — not so much diabetes — seeking a therapy that protects grafts but doesn’t render the recipient susceptible to opportunistic infections,” says Dr. Lewis, whose work with Professor Charles Dinarello at UCHSC initiated this research that could possibly lead to a cure. “Inflammation was the key word, and we advanced greatly on that arm of the study, just when reports on pancreatic islet transplants surfaced and revealed a very grim situation — that the sensitive grafts expire in the patients despite the afforded immune suppression.”

Though Dr. Lewis’s initial studies (conducted while working on his post-doctoral fellowship in immunology in Colorado before returning to Israel and BGU to serve on the faculty and continue research there) were not in diabetes, what he was studying was closely linked to a possible solution to the failed islet transplants.

“Our studies were closely related to diabetes,” says Dr. Lewis, who was in San Diego March 14 and 15 to present his findings to the community. “The immune response against the individual with the disease executes a series of processes similar to an acute graft rejection upon transplantation…Once we established the role of inflammation in these processes, it seemed logical that we could try to capture the same platform of events in recently diagnosed type 1 autoimmune juvenile diabetes.”

The problem, Dr. Lewis explains, is that the immune system of the diabetes patient brings about inflammation to the transplanted pancreatic islets, destroying them. Enter alpha-1-antitrypsin (AAT), a drug that’s been in use for about 20 years to treat an unrelated rare condition, that’s already FDA approved, and that’s already naturally produced in the liver to fight inflammation. An extra boost of AAT can reduce the inflammation caused by islet transplantation, and, as ongoing studies have shown, the effects are long-term, meaning the patient eventually shows no symptoms and no longer requires insulin injections. (Though the liver produces AAT naturally, it doesn’t produce the elevated levels necessary to protect islet grafts upon transplant, hence the necessity of additional AAT given through therapy.)

According to Dr. Lewis, AAT therapy doesn’t affect the body’s ability to trigger inflammation when it actually needs to, since, he says, the body is never ‘not inflamed,’ but is dampening inflammation constantly, whether from dying cells or external pathogens. It’s constant in human blood, he says, and it naturally maintains a homeostatic balance that allows some reactions to take place while also preventing inflammatory flares from spreading uncontrolled to other areas. Because AAT is a tissue protector, when it rises as the body struggles with a larger inflammatory event like the flu, tissues that would otherwise succumb to inflammation actually remain intact. Because of this, AAT therapy protects transplanted islets from inflammation while allowing for other inflammatory processes in the body to still occur. Additionally, Dr. Lewis reports, the effects of the therapy appear to be permanent, though nothing is certain yet.

“From what we learned in animals, the immune system is constantly being educated in a dynamic manner to destroy the foreign damaged tissue,” he says. “During these weeks of acute phase response and higher AAT levels, this process of self-recognition is compromised, and the cells gradually recognize our tissues, as well as the grafted tissue, as a non-authentic threat that should be protected…we find the body in a risky junction whereby its immune system is excited, yet should be prevented from accidentally attacking its own cells. AAT, in this environment, prevents such recognition and re-educates the system to prefer protection over destruction. Specifically, we found that a population of protective regulatory T cells emerged in the graft.”

In mice, the changes toook effect after 21 days. Before that point, they were not permanent.

“We started injecting patients [as part of clinical trials] in October 2010,” Dr. Lewis says. “September 2011 is year one out of two, at which point we will probably report findings [thus far]. Once our results come out, I can’t imagine that anyone will refuse a diabetic individual AAT therapy. However, the material is factory-lined for a rare condition, and scaling up for such a common condition as diabetes will be difficult. That said, there is tremendous effort today to find ways to produce the material in larger quantities…scientists have been trying to make AAT out of almost anything possible…from transgenic sheep to transgenic rice.”

The first patient to receive AAT therapy under the study (run out of the Barbara Davis Center for Childhood Diabetes at the University of Colorado) was a young Jewish boy in San Diego, back in 2008. Though Dr. Lewis won’t divulge the patient’s identity, he does describe the boy’s life before and after therapy.

“At the beginning of the trial, we gave the boy eight injections, one a week,” he says. “Each one took an hour and a half by drip. Yesterday, I saw the mother, father and child. [The boy] was playing the piano, playing on the playground. We had dinner, and he ate more than I did. His mother said that when he was diagnosed, they cut down on carbs and fed him a ‘diabetic’ diet, and even then he was taking more than 10 mm of insulin per meal. After the course of injections, that went down to one…Today, his glucose is controlled, and so far, the child has improved, and his body tolerated the therapy very well.”

But the cost of injections is not cheap. According to Dr. Lewis, the series of eight ranges from $5,000-$6,000 (or a series of 12 in a new Israeli study probably beginning next month). He adds, though, that this is just a starting point, and the choice to perform eight (or 12) therapy sessions is based on sessions with mice.

“There is some assumption that we might require more prolonged injections to overturn the immune system at such an established point — months after diagnosis of type 1 diabetes,” he says. “Since we really don’t know how long we might need to continue the injections, we simply decided that if we find the treatment to fail, we can always resume injections.”

But type I diabetics aren’t the only ones who can benefit from Dr. Lewis’s team’s research.

“Type 2 diabetes has been shown to heavily lean on an inflammatory axis,” he says. “Approaches that blunt inflammation show promise in [type 2] patients. Also, 50 percent of type 2 diabetic individuals have recently been shown to have deficiency in AAT. The normal rate of deficiency should be one in every 3,000-5,000, so this means the association is probably not accidental. Most notably, recent progress has shown that islets are actually targets of disease in type 2 diabetes, so again we place AAT as their protector and hope it can diminish the disease below clinical symptoms. Out lab at BGU has found that when we subject islets to fatty acids, they are severely injured unless AAT is added. We find, again, that giving AAT when the body fails to realize it needs to may be of great benefit.”

Only time will tell how effective AAT therapy really is. But even if it’s not permanent, and patients have to undergo another eight-week series of AAT injections every several years, it’s not such a bad trade-off to return to a normal life free from severe symptoms of diabetes. At its best, AAT therapy could be the long-awaited cure for diabetes. But even at its worst, it’s not a bad way for diabetics to live much more normal, much less restricted lives.

For more information on Dr. Lewis and the Clinical Islet Laboratory within BGU’s Department of Clinical Biochemistry, visit www.aabgu.org or call (212) 687-7721.

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