Although we are still a long way from ending diabetes, advances in genetic research are promising.
Immunology and beta cell function have long been two core areas of research in the search for treatments for diabetes. But in recent years, scientists have made discoveries that could lead to gene therapies that allow the body's own cells to fight or even get rid of disease. Researchers are learning to turn gut cells into insulin-producing cells, replenish beta cells once thought to be hopelessly depleted, and use viral vectors to insert genes into beta cells to protect them from the immune system attack.
This only applies to type 1.
In type 2 diabetes, researchers have found evidence that beta cells do not deplete and die as previously thought, but instead transform into more primitive cells or cells with altered function, leading some scientists to believe they somehow ways to prevent or prevent this dedifferentiation. The cells change back to beta cells, and they can prevent or cure type 2 cells.
"Discoveries like this mean a change in our thinking," said Dr. Richard J. Santen, President of the Endocrine Society, Professor of Medicine, Endocrinology and Metabolism, University of Virginia School of Medicine, Charlottesville. "Our greater understanding of the biology of diabetes is starting to pay off. Over time, our growing understanding will play a key role in changing the course of the disease."
replace and regenerate
At Columbia University in New York, a team led by Domenico Accili, MD, professor of medicine, has made multiple discoveries about FOXO1, a protein that turns genes on or off.
In a study published March 11, 2012 in Nature Genetics, the team found that inactivating FOXO1 in intestinal progenitor cells of newborn mice caused these cells to become insulin-producing cells. In a follow-up study, published June 30, 2014, in Nature Communications, Accili's team performed a similar experiment using stem cell-derived human intestinal cells. Within seven days of inactivating FOXO1, the cells began to produce insulin in response to glucose.
The gut is a logical place to look for cells that can be manipulated to become insulin-producing cells, Achley said. "There's enough correlation between the insulin-producing cells in the pancreas and the hormone-producing cells in the gut that it's not a huge leap. It's not like we're asking gut cells to become neurons or muscle fibers."
Using cells from the gut may be particularly beneficial than using cells from other parts of the body, Achley added. "In type 1, the main problem is that the immune system destroys the insulin-producing cells, but the gut has immune privilege. It's always exposed to foreign antigens in the diet and has a different immune response, which can be more permissive and can Give the cells a break."
The longevity of gut cells may also give them an advantage, Achley said. "Gut cells change very rapidly, every seven to 10 days. So even if cells are attacked, they may be able to withstand it long enough for newer cells to take over."
In another study, published Sept. 14, 2012, in the journal Cell, Accili's team found evidence that FOXO1 plays a role in insulin release from beta cells. In a mouse study, the team found that when beta cells are stressed (such as being bathed in glucose) and the cells produce insulin, FOXO1 moves from the cell's cytoplasm to the nucleus. However, if the cells are under stress for too long, FOXO1 is broken down and the cells stop producing insulin. Furthermore, once a cell stops producing insulin, it reverts to a simpler, less differentiated cell type.
These results challenge the common notion about type 2 development that β cells die from overload caused by insulin resistance.
"For type 2, FOXO1 is a marker for a process we're trying to prevent: dedifferentiation," Accili said. "In the pancreas, we try to preserve differentiation, or maybe find a way to force redifferentiation."
Researchers at Boston's Joslin Diabetes Center and Harvard Medical School took a different approach: beta cell regeneration in the pancreas. Her work was inspired in part by Jocelyn's 50-Year Medalist Study, in which researchers found that even after 50 years of diabetes, the pancreases of 66 percent of participants continued to produce small amounts of insulin.
"That means there are residual beta cells and there's something available," said Dr. George L. King, Director of Research and Scientific Director of the Center. "We're looking for ways to help the body regenerate these cells. We believe that multiple growth factors and beta cell regeneration factors may play a role."
A team led by Dr. Douglas Melton, Joslin Associate Investigator and co-director of the Harvard Stem Cell Institute, described betatropin, a hormone found primarily in the liver and fat, in the May 2013 issue of Cell How to express with stem cells. Disease-associated growth of beta cells in mice.
Another team led by Joslin principal investigator Rohit N. Kulkarni, PhD, associate professor of medicine at Harvard Medical School, published a paper on diabetes in January 2014 in which they found minimal damage to immune cells in mice1 type beta cells, actually promoting their growth.
King said the research is just as important for type 2 diabetes as it is for type 1 diabetes. "Even if we can't eliminate insulin resistance in type 2 diabetes, it's possible that we can generate enough beta cells to overcome insulin resistance and get rid of diabetes," he said.
protect and defend
Altering or halting the body's attack on beta cells has been a major hurdle in finding a type 1 treatment. A team led by Thomas Serwold, Ph.D., a researcher in the Joslin Department of Immunobiology, is studying the role of the thymus in autoimmunity, where beta cells are destroyed. Normally, other cells in the thymus train T cells not to attack the body's own cells, and most T cells that fail the training are destroyed before leaving the thymus. However, some defective T cells enter the body, and those T cells that target beta cells in the pancreas cause type 1 diabetes.
"Dr. Serwold is studying how to program these cells through the thymus," King said. "The thymus is a key organ for immune tolerance, and engineering or reprogramming it could be an exciting way to reduce type 1 autoimmunity." ".
At UNC-Chapel Hill, Roland Tisch, Ph.D., professor of microbiology and immunology, and his team are investigating the use of viral vectors to transfer genes into beta cells to help them avoid attack. These vectors are derived from adeno-associated virus (AAV), a benign virus that infects humans but is usually harmless. These AAV vectors are popular with cell biologists for their safety records.
"The guts of viruses, or DNA, have been used for years to transfer genes into different cell types and tissues in animals, but are now also being used clinically to treat genetic diseases such as hemophilia and various eye diseases," Tisch said. "
In Tisch's lab, researchers use these vectors to transfer genes that encode specific cytokines—proteins important in cell signaling. These cytokines have anti-inflammatory properties and are known to destroy T cells when they attack.
"Most importantly, we tried to indirectly affect T cells to protect beta cells from destruction," Tisch said. "Different cytokines can affect different T cells. So our task was to find out which of these were the most effective."
While widespread gene therapy to cure diabetes is still years away, innovative research like this offers hope for the 382 million people living with diabetes worldwide.
"It's this kind of highly innovative basic research that will determine how far this work goes," Santen said. "As our knowledge expands, we will not only be able to find a cure for diabetes, but eventually a way to prevent it.
- D'Arrigo is a health and science writer based in Holbrook, NY and a regular contributor to
Endocrinology News. In the August issue she writes about depression and diabetes