TAU Researchers Coax Liver Cells to Produce Insulin
Thursday, November 3, 2005

Adult liver cells can be redirected to produce insulin in response to glucose levels, according to a TAU study

Scientists from Tel Aviv University and Sheba Medical Center have successfully modified liver cells to produce insulin that, when transplanted into mice, brought diabetes under control. The researchers hope that one day the method will allow the use of a diabetes patient's own liver cells to treat their condition.

"This approach may overcome the shortage in tissue availability from cadaver donors and the need for lifelong immune suppression," said the director of the study, Dr. Sarah Ferber of TAU's Sackler Faculty of Medicine and Sheba's Endocrine Institute. The study was published in Proceedings of the National Academy of Sciences.

Diabetes is a potentially life-threatening condition, affecting millions of Americans, caused by the body's inability to control blood sugar levels. This is because cells in the pancreas are unable to produce the hormone insulin, either at all or in sufficient quantities.

Recent developments have made it possible to transplant donor insulin-producing cells into diabetes patients to treat the condition.

However, there is a severe shortage of donor tissue, and patients who do undergo surgery must take powerful drugs for the rest of their lives in order to prevent the new cells being rejected.

Insulin is produced by islet cells in the pancreas, but the Israeli team succeeded in persuading adult liver cells to do the same thing. Moreover, insulin production goes up in response to glucose levels, mimicking what happens in the body.

"Diabetic patients that receive insulin injections have a problem -- the injections don't result in continuous normal glycemia during the day, there are peaks of hyperglycemia and hypoglycemia. As a result, diabetes-related complications are not completely prevented," Ferber told ISRAEL21c, explaining the rationale behind the study.

"Recent clinical trials show that islet cell implantations are far more effective in controlling the diabetes. But we're restricted in the shortage of donor cells. In addition, diabetic patients need to be treated with anti-rejection therapy so the cells won't be rejected by the patient's immune system."

Ferber and colleagues investigated the possibility of using the pancreatic and duodenal homeobox gene 1 (PDX-1) to convert adult human liver cells into insulin-producing tissue.

"The rationale is that the genetic information in every somatic cell is identical. But the genetic information of the pancreas is not expressed in the liver. We thought if we know how the pancreas develops during embryogenesis in the fetus, if we express those factors into a fully differentiated adult liver, they may persuade some cells in the liver to express otherwise silent genetic information," said Ferber.

As many as half the adult and fetal liver cells infected with a recombinant adenovirus expressing PDX-1 activated the insulin promoter, Ferber reported, thereby enabling them to store and secrete insulin.

Supplementing PDX-1 treatment with the soluble factors nicotinamide and EGF increased insulin gene expression by seven orders of magnitude, the report indicates, significantly increasing insulin content and secretion.

"Our study showed that the implanted cells started to express genetic information of the pancreas, producing insulin in a regulated manner," said Ferber. "The adult liver cells also ameliorated diabetes when implanted in diabetic mice."

"Our approach represents a novel approach in tissue engineering," Ferber said. "It allows inducing a developmental redirection of adult fully differentiated tissues, allowing these tissues to acquire a new identity and function, without altering the original genetic information."

"In our application of converting liver to endocrine pancreas, it allows the diabetic patient to be also the donor of his own therapeutic tissue,"

Ferber explained. "A similar approach could be implemented in treating additional degenerative or metabolic diseases that involve other tissues."

Ferber said that she and her staff of 12 graduate students - working in conjunction with Tel Aviv University - plan more studies before clinical trials can be conducted on human patients.

"The only thing I'm doing at the Institute is converting livers to pancreas," she said with a laugh. "In the study we completed, we followed the cells for a couple months. They were still functional, but we need to show that they last longer.