New Treatment for Diabetes
At the age of 14, Robert Teskey was diagnosed with type 1 DIABETES (better known as juvenile diabetes), a condition which normally comes with an automatic life sentence of insulin therapy. For nearly four decades, Teskey's days and nights revolved around regularly testing his blood-sugar levels and injecting INSULIN. The 55-year-old Edmonton lawyer reckons he gave himself more than 40,000 injections, while carefully monitoring what he ate and never missing a meal in an attempt to keep his blood-sugar levels stable. For Teskey, the challenge always was to live as normal a life as possible. "Diabetes management," he says, "is having a bunch of different balls in the air and trying to keep them there, 24 hours a day, seven days a week, 365 days a year. You always know that, at some point, the balls can come crashing down."
Teskey's own juggling act began to falter in the mid-1990s. Like many long-term diabetics, he had become hypoglycemic insensitive, meaning he was often unaware when his blood-sugar levels deteriorated. As a result, he would pass out, sometimes when meeting with clients, sometimes in his sleep. Teskey struggled for nearly five years before becoming part of a groundbreaking medical research program at the University of Alberta. In 1999, he was one of seven severe diabetics to undergo a trial procedure known as the Edmonton Protocol. Doctors injected insulin-secreting cells, known as islets of Langerhans, from donated human pancreases into the patients through the portal vein leading into the liver. The results were spectacular. All the recipients were able to give up insulin injections. And all were freed from the wild blood-sugar swings and temporary comas that had threatened their livelihoods - in some cases their lives.
The Edmonton Protocol caused an international stir when the New England Journal of Medicine documented the research results in June, 2000. Islet cell transplants had been performed at medical centres around the world for years, but with dismal results. Of nearly 300 transplants done in the 1990s, only eight per cent of the patients remained free of insulin for more than a year. No surprise, then, that Edmonton's success was seen as a major breakthrough. In Washington, then-president Bill Clinton announced funding to help replicate the Edmonton results at 10 centres throughout North America and Europe. A further boost came last fall when the New York-based Juvenile Diabetes Research Foundation committed $24 million to the cause.
Overseeing the international trials is James Shapiro, a 39-year-old surgeon who is also director of the clinical islet transplant program at the University of Alberta. Shapiro says 124 transplants have been conducted so far, 34 of them in Edmonton - where about 85 per cent of the patients remained insulin-free for a year or more after the transplant. Another 75 centres are gearing up to implement the procedure independently. There is a long way to go before the treatment can be applied to the estimated five million who suffer from juvenile diabetes worldwide. (Another 145 million have type 2, or adult-onset diabetes, which does not usually require insulin injections.) Still, Shapiro believes the Edmonton Protocol, and related research, are "providing robust hope that we will, once and for all, find a cure for diabetes."
So how did the Edmonton team succeed where so many before them failed? Shapiro says it began with a careful review of the record. They found that a majority of the earlier islet transplants involved patients who had already undergone a kidney transplant after suffering kidney failure, a common long-term side effect of type 1 diabetes. To prevent rejection of the new kidneys, patients received high doses of steroids and cyclosporine - drugs which, when combined, can actually induce diabetes. Through his own research, Shapiro came up with a new "cocktail" of safer anti-rejection drugs. He then set about writing what became the Edmonton Protocol.
To start with, islet transplants would not be done on patients who had prior kidney transplants. Instead, patients were selected who experienced severe swings in blood-sugar levels that can put them at risk of kidney failure, blindness or even death. Secondly, it was determined that as many islet cells as possible should be transplanted in each case - and the procedure must commence as soon as possible after a donor pancreas became available. In this regard, Shapiro was greatly assisted by Jonathan Lakey, director of the University of Alberta's islet isolation laboratory, who has perfected methods for extracting and purifying islet cells from donated organs.
The actual transplant procedure requires no surgery and can take as little as 30 minutes to complete. A needle containing the islet cells is placed through the right side of the abdomen and, using X-ray technology, is guided into the liver's portal vein. Most patients are able to leave the hospital within 24 hours of the cells being injected.
The most obvious obstacle to implementing the Edmonton Protocol on a broad scale is the lack of cadaver pancreases. Fewer than 800 of the organs were donated in Canada last year, while more than 12,000 patients were referred to Shapiro's program as potential candidates. Intensive research is underway at several centres into alternative sources of insulin-secreting cells. These include the possible use of cells from live donors; extracting adult stem cells and growing them in the laboratory into new islet cells; or finding ways of tricking other cells, such as those in the intestine, into producing insulin.
Shapiro says it is impossible to tell when these various research projects will pave the way for widespread islet transplants. But he delights in the progress already made. "In talking to the people who have gone through this procedure you see how it has transformed their lives," says Shapiro. "That is very moving and very gratifying."
Patients like Teskey are also grateful. Dispensing with insulin shots is a relief, he says, but more significant is being rid of the extreme low blood-sugar episodes. They "leave you feeling like you've been assaulted," and it sometimes took him days to recover. Most of all, Teskey is thankful for getting a crack at a normal life. "It feels," he says, "like nothing less than a miracle."
Prompting New Cells to Produce Insulin
The Edmonton Protocol has sparked a flurry of research worldwide, much of it aimed at providing alternative sources of the insulin-secreting cells needed to cure juvenile diabetes. One of the more promising discoveries, documented in the May issue of the U.S. medical journal Diabetes, is the result of research conducted at the University of Calgary and Shiga University in Japan. It began with the understanding that pancreatic cells, which routinely produce insulin, and intestinal cells, which do not, share a common origin in the embryo. The question: could an intestinal cell be tricked into performing like a pancreatic cell? The answer: yes, at least judging by experiments conducted in rats.
The scientists began by exposing the intestinal cells of rats to a protein called Pdx-1, known to regulate insulin production. When the cells were subsequently exposed to a growth factor called Betacellulin, they started producing insulin - lots of it. While human trials are at least five years away, the implications are enormous. One of the researchers, the University of Calgary's Norman Wong, points out that the Edmonton Protocol now relies on rare donated pancreases from cadavers. But if this research proves successful, he says, it presents the possibility of extracting intestinal cells from a diabetic, turning them into pancreatic cells and replacing them in the patient through a vein of the liver - the transplant procedure prescribed by the Edmonton Protocol. "What this could be," says Wong, "is a whole new frontier for fighting diabetes."
Maclean's June 10, 2002