Nov. 22, 2000 -- Using a new form of gene therapy, researchers in South Korea and Canada have tricked the liver into producing a substance like insulin to replace the insulin the pancreas can't produce, resulting in long-term control of blood sugar in animals with a form of type 1 diabetes. If successful in humans, the technique, described in the Nov. 23 issue of the journal Nature,could enhance or perhaps replace the need for insulin injections.
Type 1 diabetes, in the past referred to as juvenile-onset or insulin-dependent diabetes, for the majority of people is caused when the body turns on itself and directs the immune system to attack and destroy cells in the pancreas that produce insulin. The cells, called beta-islet cells, produce insulin, a hormone that is necessary for the regulation of glucose, the primary blood sugar used by the body for energy. Because their bodies can no longer produce the insulin they need, people with type 1 diabetes must inject themselves with insulin to keep blood sugar under control.
The experimental therapy uses a specially modified virus to carry into liver cells a gene that senses glucose levels in the blood, coupled with a gene that will cause the liver cells to produce a modified form of insulin that the body can readily use.
When the gene package was injected into the livers of rats with a chemically induced type of diabetes and into mice with a hereditary form of the disease, blood glucose levels returned to normal within two weeks of treatment, and have remained normal for more than five months in mice and more than eight months in rats. The treated animals have shown no apparent side effects from the treatment, report Ji-Won Yoon, PhD, and associates at the University of Calgary in Alberta, and at Yonsei University Medical School in Seoul.
"One of the significant findings of our study is that the liver cells producing [the modified insulin] now take over the function of insulin-producing beta cells, which have been completely destroyed by the autoimmune attack in the mice," Yoon comments in a written statement. But because the new insulin-producing cells are different from beta cells, they are apparently protected from immune system attacks, Yoon says.
Several research teams in Asia, Europe, and North America are working on gene therapy strategies for promoting long-term insulin production in the liver to treat type 1 diabetes. One of the barriers to this form of therapy, however, is that once you've turned on production of insulin, you have to find a way to turn it off to avoid the problems associated with hypoglycemia, a condition caused by extremely low blood sugar levels, which can cause loss of consciousness, diabetic comas, and in extreme cases, death.
"Unlike other areas of gene therapy where you're missing some gene and it doesn't make a difference how much of the protein it makes, with insulin it's a double-edged sword: You not only have to make ... [enough] insulin ... you have to stop making the insulin when you don't need it," says Alvin Powers, MD, associate professor of medicine at Vanderbilt University and a physician in the Department of Veterans Affairs Medical Center in Nashville, Tenn., who reviewed the study for WebMD.
To do an end-run around the problem of maintaining proper glucose levels, the researchers added to their gene package a portion of a liver gene that is activated in response to changes in glucose levels.
"The new twist here is that they have engineered the cells so that not only do they make 'insulin,' but they also are regulated in their level of 'insulin,' and that the blood sugar and the 'insulin' level and the amount of 'insulin' that's put out or secreted by the liver cells is related," Powers says.
"But rodents are quite different from humans, with respect to maintaining glucose levels, and extending these results to human physiology may prove a challenge," writes Jerrold Olefsky, MD, from the University of California at San Diego, in an editorial accompanying the study. He notes that mice and rat livers produce glucose at much higher rates than human livers do, "so small effects of insulin on the liver may be able to control post-eating glucose levels in rodents, but may be less effective in humans."
In addition, both standard insulin injections and experimental gene therapies are capable of controlling glucose fluctuations that occur over a span of hours, but glucose levels in the body are normally regulated minute by minute, Powers points out. "It's much easier to cure diabetes in rodents than it is in people," he tells WebMD, "and the field is littered with things that have worked in rodents but wind up not working in humans. This study is more in the proof of principle area."