Stomaching diabetes

SAN DIEGO — If your pancreas fails you, go with your gut.

Inserting a gene into gut cells in mice enabled those cells to take over the pancreas’s job, producing insulin after meals, according to unpublished research announced June 18 in San Diego at the Biotechnology Industry Organization International Convention. The work may offer a novel way to treat diabetes.

“This is the first time that we’ve engineered a tissue that is not the pancreas to manufacture insulin” in animals, says researcher Anthony Cheung, a molecular biologist and cofounder of enGene, a biotechnology company based in Vancouver, British Columbia.

“It’s going to be very beneficial to patients,” comments Christopher Rhodes, research director of the KovlerDiabetesCenter at the University of Chicago, who enGene asked to critique the research. “It’s a very promising approach.” Cheung says that he and his colleagues hope to begin safety trials in people by 2010.

People with diabetes don’t produce enough insulin to properly control their blood sugar. Often, the pancreatic cells that produce the insulin have become damaged, either from attack by the immune system or from chronic overtaxing because of poor diet.

Existing treatments include frequent intravenous injections of insulin and transplant of pancreas cells from cadavers into diabetes patients. Scientists have also proposed using stem cells to make fresh pancreas cells for transplant. The new research presents the possibility of recruiting cells at the junction between the stomach and small intestines to make insulin instead.

“It’s a lot simpler than transplanting beta cells,” the insulin-producing cells of the pancreas, Cheung says. The new approach could potentially treat both juvenile and late-onset diabetes, Rhodes adds.

New gene, new job

The gut cells, called K cells, sit at the surfaces of tiny, fingerlike projections in the gut lining. These cells normally release a hormone called glucose-dependent insulinotropic polypeptide, or GIP, into the bloodstream after meals. This hormone helps prepare the pancreas to make insulin to respond to the post-meal surge of blood sugar, so the K cells are roughly synchronized with the pancreas.

Cheung’s team created tiny rings of DNA containing the gene for insulin. To coax the cells into releasing insulin at the right time, they also included a snippet of DNA on the rings that normally activates GIP after a meal. But because the snippet was linked to insulin instead of GIP, once the rings were inserted into K cells, the cells that produced GIP also produced insulin when the body needed it.

Using viruses to deliver DNA into cells is a common technique in gene therapy, but it risks triggering cancerous mutations. Instead, the researchers developed a new gene-delivery method that bundles the ring of DNA inside microscopic spheres made of a material called chitosan, which is extracted from shrimp shells.

These spheres, each about 100 nanometers across, also contain a second ring of DNA encoding a gene that controls where along the animals’ chromosomes the insulin gene gets inserted. Previous research by Michèle Pamela Calos of StanfordUniversity and her colleagues showed that none of the 370 possible insertion points trigger cancer.

Rather than injecting a dose of these microscopic spheres into the bloodstream, Cheung’s team sprayed the spheres directly onto the gut lining using a modified endoscope, a tube-shaped tool that doctors use to look down a person’s throat at their intestines. That way, the spheres only get absorbed by cells of the gut lining.

Cheung says that it might also be possible for patients to ingest the spheres in a drink or a pill.

In the experiments, the genetically altered K cells responded when the animals ate sugar by producing insulin with the same timing as a healthy pancreas. The K cells performed the new task for about five months. Because cells of the gut lining are constantly replaced, the treatment would have to be reapplied periodically, Cheung says.

Previous work by Cheung and his colleagues showed that mice engineered to have the altered K cells from birth remained alive and healthy after the insulin-producing beta cells of the pancreas had been destroyed. In separate experiments using mice with a juvenile diabetes–like condition in which beta cells are attacked by the animals’ immune systems, K cells were not attacked even when altered to produce insulin.

The team has begun testing the technique on pigs, whose intestines are very similar to human intestines.