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City MD closes on cure for diabetes

Montreal Gazette

Monday, February 11, 2002

A discovery Dr. Lawrence Rosenberg stumbled upon 20 years ago at McGill University might prove to be more than just an effective treatment for diabetes - it could very well be a cure.

After the effects of diabetes were reversed in hamsters, mice and, most recently, dogs, human trials have begun on Rosenberg's special insulin producing protein.

"We're not claiming that it's a cure because it sounds too far-fetched at this point to say that, but certainly in our animal studies we've cured animals for the last couple of years," Rosenberg said. "I mean, really cured."

The concept behind Rosenberg's research is ingenious, if not deceptively simple. Rather than treat the symptoms of diabetes, Rosenberg and co-researchers at the Eastern Virginia Medical School have decided to tackle the root causes of the disease.

Diabetes occurs when the pancreas fails to produce enough of the hormone insulin to break down sugar in the blood. When that happens, an excess of blood sugar can cause heart problems, kidney failure and blindness, and require amputations.

There are about 500,000 diabetics in Quebec, a number that's expected to double by 2025. And doctors suspect that 40 per cent of diabetics are unaware of their condition.

To date, the most common treatment for diabetes has been synthetic insulin injections. There are also glucose sensitizers that make the use of insulin more effective in the body, and chemicals that release what little insulin exists in diabetics.

"What we're doing is stimulating the body to do what it normally does, but we've sort of ramped up the process," Rosenberg explained in his cluttered ninth-floor lab at the Montreal General Hospital.

"We're accelerating the development of new insulin-producing cells, which are normal cells."

It was while Rosenberg was studying pancreatic cancer at McGill in the early 1980s that he serendipitously discovered a protein that triggers the creation of insulin-producing cells, or islets. Later on, Dr. Aaron Vinik, of the Eastern Virginia Medical School, found a way of refining the protein, called Islet Neogenesis Gene Associate Protein (INGAP).

The researchers first tested a cruder form of INGAP on hamsters, and found that 60 per cent were cured. This past year, Rosenberg tested a purer form of the protein on lab mice - with a 100-per-cent cure rate.

A U.S. biotech company that has licensed the protein tested it on about 48 diabetic dogs, with similarly great results.

"Certainly, in the animals we've got evidence that you can give this treatment for a period of time and then stop it," Rosenberg said of the injectable solution.

What that means is that the lab animals regained the ability to naturally regulate insulin and no longer required the INGAP medication.

"If everything goes well, it is quite conceivable that there would be a therapy on the market within five years," he said.

There are two forms of diabetes: juvenile, or Type I, and adult-onset, or Type II. For reasons that are still not understood, the immune systems of Type I diabetics recognize the insulin-producing cells as foreign and destroy them. Type II diabetes mainly affects people older than 45, usually as a result of obesity. In their case, the insulin-producing cells malfunction - partly because they are damaged by an excess of fat in the bloodstream.

Diabetics must be constantly vigilant about the amount of sugar in their blood. They must also be careful not to administer too much insulin for fear of losing consciousness. The standard therapies are far from a cure; half of all diabetics inevitably develop complications despite their medication.

"Our hope is that with our treatment - if we can restore a normal state of affairs with the body regulating itself again with its own insulin - those secondary complications won't develop," Rosenberg said. "Or else we can temper those complications somewhat so that they're not severe."

The INGAP therapy would also eliminate the need for blood-sugar tests and insulin injections. The clinical trials now under way in three U.S. cities are focusing on both types of diabetes.

Mark Lipsett, a graduate student working with Rosenberg, said the merit of the research is that it doesn't concentrate on the "tail end" of the disease.

"It's almost like a magic bullet because the body would build new insulin-producing cells," he said.

"I myself am a Type I diabetic, so finding a way to cure diabetes is very exciting from a personal context."

At the Montreal General last Friday, Lipsett and Rosenberg isolated islets from a cadaveric pancreas donated by Transplant Quebec. The idea behind that work is to collect enough of the cells to transplant them in the livers of diabetics.

In that regard, Rosenberg said his INGAP research is simply a more advanced form of the islet transplants. Rather than transplant islets, Rosenberg's treatment allows the body to naturally regenerate islets.

How the INGAP molecule triggers the creation of insulin-producing cells is still a mystery.

One leading theory is that the molecule binds to a receptor in stem cells of the pancreas and turns them into insulin-producing cells.

In the laboratory, Rosenberg and his colleagues synthesize INGAP by "stringing together a certain number of amino acids." However, they've discovered that a similar protein is found in the pancreas.

"This is the culmination of 22 years of work," Rosenberg said. "It's nice to know that you haven't wasted 22 years of your life doing something.

"In the larger scheme of things, diabetes is a huge health-care problem that affects millions of people. To think that we have a therapy that could significantly impact the lives of these people is just incredible to contemplate."

� Montreal Diabetes Research Center 2006
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