Diabetes: Will It Ever Be Cured?

While the end to diabetes is still in the distant future, strides in genetic research are showing promise.

Immunology and beta cell function have long been two core areas of research in the hunt for a cure for diabetes. But in recent years, scientists have made discoveries that could lead to genetic therapies that allow the body’s own cells to combat and even rid itself of the disease. Researchers are learning to turn gut cells into insulin-producing cells, replenish beta cells once thought decimated beyond hope, and use viral vectors to deliver genes into beta cells that may protect them from attack by the immune system.

And that’s just for type 1.

For type 2 diabetes, researchers have found evidence that beta cells do not burn out and die as previously thought, but instead revert to more primitive cells or ones with altered function, leading some scientists to believe that if they can prevent this dedifferentiation or somehow push dedifferentiated cells to turn back into beta cells, they could prevent or cure type 2.

“Findings like these represent a shift in our thinking,” says Richard J. Santen, MD, president of the Endocrine Society and professor of medicine, endocrinology, and metabolism at the University of Virginia School of Medicine in Charlottesville. “We are learning much more about the biology of diabetes, and it is beginning to pay major dividends. As time goes on, our increased understanding will play a key role in altering 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 several discoveries about FOXO1, a protein that controls when genes are switched on or off.

In research published in the March 11, 2012, Nature Genetics, the team found that deactivating FOXO1 in progenitor cells in the small intestines of newborn mice resulted in the cells becoming insulin-producing cells. In follow-up research published in the June 30, 2014, Nature Communications, Accili’s team conducted similar experiments in human intestinal cells derived from stem cells. Within seven days of FOXO1 deactivation, the cells began to produce insulin in response to glucose.

The gut was a logical place to look for cells that could be manipulated into becoming insulinproducing cells, says Accili. “There is enough kinship between insulin-producing cells in the pancreas and hormone-producing cells in the gut that this is not that big of a leap to make. It’s not like we’re asking a gut cell to become a neuron or muscle fiber.”

Using gut cells may be particularly advantageous over using cells from other parts of the body, Accili adds. “In type 1, the main issue is destruction of insulin-producing cells by the immune system, but the gut has immune privilege. It is always exposed to foreign antigens in food, and it has a different immune response that may be more permissive and might give the cells a break.”

The lifespan of gut cells may also give them an advantage, Accili says. “Cells in the gut turn over very fast, every seven to 10 days, so even if the cells are attacked, they might be able to withstand it long enough for newer cells to take over.”

In separate research published in the September 14, 2012, Cell, Accili’s team found evidence that FOXO1 plays a role in the release of insulin by beta cells. In a mouse study, the team saw that when a beta cell is stressed, such as when it is bathed in glucose, FOXO1 moves from the cell’s cytoplasm into its nucleus, and the cell produces insulin. However, if the cell remains stressed for too long, FOXO1 degrades and the cell stops producing insulin. What’s more, once the cell stops producing insulin, it reverts back to a more basic, undifferentiated type of cell.

These findings challenge the prevailing thought about the development of type 2, which is that beta cells die from overwork caused by insulin resistance.

“In terms of type 2, FOXO1 is a marker of a process we are trying to prevent, dedifferentiation,” Accili says. “In the pancreas, we would look at protecting differentiation, or maybe finding a way to force redifferentiation.”

Researchers at Joslin Diabetes Center and Harvard Medical School in Boston have taken another approach: beta cell regeneration in the pancreas. Their work is inspired in part by the Joslin 50-Year Medalist Study, in which researchers found that the pancreases of 66% of participants were still producing small amounts of insulin even after 50 years of diabetes.

“That means there are residual beta cells, and there is something to work with,” says George L. King, MD, the center’s research director and chief scientific officer. “We are looking for ways of helping the body regenerate those cells. We believe that several growth factors and beta cell regeneration factors can play a part.”

One team, led by Douglas Melton, PhD, adjunct investigator at Joslin and co-director of the Harvard Stem Cell Institute, published a paper in the May 2013, Cell describing how betatrophin, a hormone primarily expressed in liver and fat, is associated with the growth of beta cells in mice.

Another team, led by Rohit N. Kulkarni, MD, PhD, principal investigator at Joslin and associate professor of medicine at Harvard Medical School, published a paper in the January 2014, Diabetes in which they identified immune cells in mice that had minimal effects on destroying beta cells in type 1 and instead actually promoted their growth.

King says that this research could be just as important for type 2 as type 1. “Even if we can’t get rid of the insulin resistance in type 2, we might be able to generate enough beta cells to overcome the insulin resistance and get rid of diabetes,” he says.

Protect and Defend

Altering or turning off the body’s attack on beta cells has been a major hurdle in the race for a cure for type 1. A team led by Thomas Serwold, PhD, investigator in Joslin’s Section on Immunobiology, is studying the role of the thymus in the autoimmunity that destroys beta cells. Normally other cells in the thymus train T cells not to attack the body’s own cells, and most of the T cells that fail the training are destroyed before they can leave the thymus. However, some of the faulty T cells do get out into the body, and those that target beta cells in the pancreas cause type 1 diabetes.

“Dr. Serwold is looking at how we might target how the thymus programs these cells,” says King. “Th e thymus is a master organ for immune tolerance, and redeveloping or reprogramming it could be an exciting approach to decreasing autoimmunity in type 1.”

At the University of North Carolina at Chapel Hill, Roland Tisch, PhD, professor of microbiology and immunology, and his team are investigating the use of viral vectors to transfer genes into the beta cells as a way of helping the beta cells avoid attack. Th e vectors come from the adenoassociated virus (AAV), a benign virus that infects humans but generally does not cause any harm. These AAV vectors are popular among cell biologists because of their track record for safety.

“The guts of the virus, the DNA, have been used over many years to transfer genes to different cell types and tissues in animals, but are now also being used in the clinic for genetic disorders such as hemophilia and various eye disorders,” Tisch says.

In Tisch’s lab, researchers are using these vectors to transfer genes that encode certain cytokines (proteins important to cell signaling). These cytokines have anti-inflammatory properties known to disrupt T cells should the T cells attack.

“The gist is that we are trying to indirectly tweak T cells, which will help protect the beta cells from destruction,” Tisch says. “Different cytokines can affect different T cells, so the catch is figuring out which ones are the most effective.”

Although widespread genetic therapies that could cure diabetes are still years away, such innovative research offers hope for the 382 million people across the globe with diabetes.

“It’s this kind of highly innovative, basic research that will inform how efforts go forward,” says Santen. “As our knowledge expands, we will be able to pursue ways not only of curing diabetes, but ultimately of preventing it.

— D’Arrigo is a health and science writer based in Holbrook, N.Y., and a regular contributor to
Endocrine News. She wrote about depression and diabetes in the August issue

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