Researchers Use Gene to End High Blood Sugars

Delivering a gene called neurogenin3 into the livers of diabetic mice activates adult stem cells that promote steady insulin production, say researchers. 

More than five years ago, Dr. Lawrence C.B. Chan and colleagues in his Baylor College of Medicine laboratory cured mice with Type 1 diabetes by using a gene to induce liver cells to make insulin.

“Now we know how it works,” said Chan, director of the federally designed Diabetes and Endocrinology Research Center at BCM and chief of the division of endocrinology in BCM’s department of medicine. “The answer is adult stem cells.”

The mice had Type 1 diabetes. Within a week after the gene was delivered using a disarmed virus, the researchers said, the rodents’ blood sugar levels returned to normal and remained that way for the rest of their lives.

The gene triggers a two-step response. First, neurogenin3 goes into the mature liver cells and causes them to make small quantities of insulin, enough to reduce blood sugar levels to normal.

“This is a transient effect. Liver cells lose the capacity to make insulin after about six weeks,” Dr. Vijay Yechoor, assistant professor of medicine-endocrinology at Baylor and the study’s first author, said in a news release from the college.

However, they found that other cells that made larger quantities of insulin showed up later, clustered around the portal veins (blood vessels that carry blood from the intestines and abdominal organs to the liver).

“They look similar to normal pancreatic islet cells (that make insulin normally),” said Yechoor.

They found that these “islet” cells came from a small population of adult stem cells usually found near the portal vein. Only a few are needed usually because they serve as a safety net in case of liver injury. When that occurs, they quickly activate to form mature liver cells or bile duct cells.

However, neurogenin3 changes their fates, directing them down a path to becoming insulin-producing islet cells located in the liver. The mature liver cell cannot make this change because its fate appears to be fixed before exposure to neurogenin3.
The islet cells in the liver look similar to those made by pancreas after an injury, said Yechoor.

“If we didn’t use neurogenin3, none of this would happen,” he said. “Neurogenin3 is necessary and sufficient to produce these changes.”

Chan cautioned that much more work is needed before similar results could be seen in humans. The gene therapy they undertook in the animals used a disarmed viral vector that could still have substantial toxic effects in humans.

“The concept is important because we can induce normal adult stem cells to acquire a new cell fate. It might even be applicable to regenerating other organs or tissues using a different gene from other types of adult stem cells,” he said.

Finding a way to use the treatment in humans sounds easier than it is, he said. The environment in which cells grow appears to be an important part of the cell fate determination.

However, he and Yechoor plan to continue their work with the eventual goal of providing a workable treatment for people with diabetes.

Developmental Cell, March 2009