A disordered thermostat pg. 7
Viral vectors as Trojan horses
One of the new tools in the researchers’ armamentarium is the recombinant adenovirus, a common respiratory virus that has been genetically engineered so that it is relatively harmless.
In 2003, researchers at Baylor College of Medicine in Houston and Shiga University in Otsu, Japan, reported they had used this tool to completely reverse diabetes in mice that had high blood glucose because of non-functioning beta cells.
The researchers inserted genes for beta cell growth and transcription factors into the genetic material of the adenovirus. After injection into the bloodstream, the viral “vector” traveled to the liver. There, the imported genes, also called “transgenes,” expressed factors that seemed to stimulate formation of new, insulin-secreting beta cells and reversed the hyperglycemia.
While more study of these “transgenic” mice is needed before the technique can be attempted in humans, this finding, reported in the journal Nature Medicine, raises hopes for a gene therapy that could reverse type 1 diabetes in humans.
Adenovirus vectors also have proven useful in exploring the relationship between obesity and insulin resistance.
For example, Newgard and his colleagues recently tested an adenovirus vector that contained the gene for malonyl-CoA decarboxylase, an enzyme that essentially can “melt fat” out of tissue. The vector was used to carry extra copies of the gene into the livers of rats that had become insulin resistant after being fed a high-fat diet.
The researchers found that when the enzyme was over-expressed and specifically melted fat out of the liver, insulin sensitivity in the muscles improved.
“Somehow melting the fat out of the liver is a signal to restore insulin action in the muscle,” Newgard says. “So there’s tissue networking going on (messages sent between organs and tissues) that we are only at the threshold of understanding.”
Another important research tool pioneered by Magnuson and his colleagues at Vanderbilt involves the use of “tissue-specific knock-out” mice – animals in which a gene has been inactivated in a specific tissue like the liver or pancreas by an enzyme called Cre recombinase.
In 1999, for example, Magnuson, C. Ronald Kahn, M.D., former president of the Joslin Diabetes Center in Boston, and their colleagues discovered that beta cells have their own functional insulin receptors. When these receptors are “knocked out,” the beta cells don’t secrete insulin normally in response to a rise in blood glucose.
This finding suggests that insulin can regulate its own secretion and that impaired regulation may contribute to inadequate insulin secretion that is a hallmark of type 2 diabetes.
“There is nothing that we’ve found that is so precise, so accurate and so useful as that (Cre) enzyme,” says Magnuson, who also directs the Vanderbilt Center for Stem Cell Biology. “It is like a cruise missile for manipulating the mouse genome.”