It may take guts to cure diabetes

(Press-News.org) New York, NY (June 30, 2014) — By switching off a single gene, scientists at Columbia University's Naomi Berrie Diabetes Center have converted human gastrointestinal cells into insulin-producing cells, demonstrating in principle that a drug could retrain cells inside a person's GI tract to produce insulin.

The new research was reported today in the online issue of the journal Nature Communications.

"People have been talking about turning one cell into another for a long time, but until now we hadn't gotten to the point of creating a fully functional insulin-producing cell by the manipulation of a single target," said the study's senior author, Domenico Accili, MD, the Russell Berrie Foundation Professor of Diabetes (in Medicine) at Columbia University Medical Center (CUMC).

The finding raises the possibility that cells lost in type 1 diabetes may be more easily replaced through the reeducation of existing cells than through the transplantation of new cells created from embryonic or adult stem cells.

For nearly two decades, researchers have been trying to make surrogate insulin-producing cells for type 1 diabetes patients. In type 1 diabetes, the body's natural insulin-producing cells are destroyed by the immune system.

Although insulin-producing cells can now be made in the lab from stem cells, these cells do not yet have all the functions of naturally occurring pancreatic beta cells.

This has led some researchers to try instead to transform existing cells in a patient into insulin-producers. Previous work by Dr. Accili's lab had shown that mouse intestinal cells can be transformed into insulin-producing cells; the current Columbia study shows that this technique also works in human cells.

The Columbia researchers were able to teach human gut cells to make insulin in response to physiological circumstances by deactivating the cells' FOXO1 gene.

Dr. Accili and postdoctoral fellow Ryotaro Bouchi first created a tissue model of the human intestine with human pluripotent stem cells. Through genetic engineering, they then deactivated any functioning FOXO1 inside the intestinal cells. After seven days, some of the cells started releasing insulin and, equally important, only in response to glucose.

The team had used a comparable approach in its earlier, mouse study. In the mice, insulin made by gut cells was released into the bloodstream, worked like normal insulin, and was able to nearly normalize blood glucose levels in otherwise diabetic mice: http://newsroom.cumc.columbia.edu/blog/2012/03/12/new-approach-to-treating-type-i-diabetes/. That work, which was reported in 2012 in the journal Nature Genetics, has since received independent confirmation from another group.

"By showing that human cells can respond in the same way as mouse cells, we have cleared a main hurdle and can now move forward to try to make this treatment a reality," Dr. Accili said.

The key will be finding a drug that can inhibit FOXO1 in the gastrointestinal cells of people; Dr. Accili is now looking for suitable compounds.

Co-author Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, professor of pediatrics and medicine, and co-director of the Naomi Berrie Diabetes Center at CUMC, said that "this work provides a new research tool for investigating the basic biology underlying the important relationships between the gut and insulin-producing cells, as well as a clear indication of the potential clinical utility of stem cell-based approaches to diabetes."

INFORMATION: The paper is titled "FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures." The other contributors are Kylie S. Foo (CUMC and New York Stem Cell Foundation), Haiqing Hua (CUMC and New York Stem Cell Foundation), Kyoichiro Tsuchiya (Tokyo Medical and Dental University, Tokyo, Japan), Yoshiaki Ohmura (CUMC), P. Rodrigo Sandoval (CUMC), Lloyd E. Ratner (CUMC), and Dieter Egli (CUMC and New York Stem Cell Foundation).

The authors declare no financial or other conflicts of interests.

The research was supported by the NIH (grants DK58282 and DK63608); the Manpei Suzuki Diabetes Foundation, the Swedish Society for Medical Research, the Japan Society for the Promotion of Science, AstraZeneca Corporation, the JPB Foundation, and the Brehm Coalition.

The Naomi Berrie Diabetes Center at Columbia University Medical Center opened in 1998 to serve the 1.6 million people with diabetes in the New York area, by combining world-class diabetes research and education programs with family-oriented patient care. Founded with support from the Russell Berrie Foundation and other friends, the center is named in honor of the mother of the late Russell Berrie, founder of RUSS™ Toys. The Center's more than 100 faculty and students conduct basic and clinical research related to the pathogenesis and treatment of all forms of diabetes and its complications. For more information, visit http://www.nbdiabetes.org.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.