Stem cells may hold key to reversing diabetes

American Association of Clinical Endocrinologists 20th Annual Meeting

SAN DIEGO — Stem cells and pancreatic precursor cells may someday help researchers make beta-cell replacement therapy a reality for patients with diabetes, Gordon C. Weir, MD, said here.

Weir, senior investigator at Joslin Diabetes Center and professor of medicine at Harvard Medical School, provided an update on the latest in pancreatic islet stem cell research.

“I don’t know when we will find a cure for diabetes, but we know the direction we have to head in,” Weir said during a presentation. “The science is breathtaking.”

Currently, researchers can isolate islets from the pancreas. The favored transplant site now is the liver, he said.

“This is a really important proof of principle. You can have a patient with type 1 diabetes undergo a painless radiological procedure and leave the hospital 1 or 2 days later without diabetes,” he said.

Unfortunately, it remains an imperfect treatment, Weir said. Patients do not achieve perfect glucose tolerance; insulin independence is generally lost after about 2 years; the procedure is expensive; and toxic immunosuppressive medications are required to protect the islet cells from transplant rejection and autoimmunity. Further, more than one pancreas is usually needed to yield an adequate amount of beta cells. Nevertheless, Weir said he remains hopeful.

“It is important that this work continues in various centers because when we have a better source of beta cells and better ways to prevent immunosuppression, we will benefit from these important lessons,” he said.

Stem cell benefits, drawbacks

Despite advances in research, an insufficient supply of beta cells presents a major barrier to achieving successful results. Weir said embryonic stem cells may help researchers overcome this hurdle, citing a study in which mature beta cells were created from embryonic stem cells in vivo. However, the presence of teratoma-like structures and the inability to create beta cells in vitro are concerns.

“If we could just understand these final stages [of beta cell maturation], then maybe we could have it happen in vitro,” Weir said. “This has practical implications because if we’re going to have cell manufacturing facilities, we can envision an industrial plant that would be able to characterize these cells with flow cytometry or other techniques. You could make sure you have a mature cell, screen for teratomas and be able to create a stable and safe product.”

Encapsulation may also be a way to approach the problem of teratomas, but transplantation of encapsulated islet cells has not yet been shown to work as well in humans as it does in mice. Packing the cells in a device that can easily be retrieved in the event of an adverse reaction would be ideal, but research has not yet reached this point, Weir said.

Potential for human iPs cells

Induced pluripotent stem (iPs) cells are another option for producing beta cells, according to Weir. Research suggests that iPs cells may be similar, if not indistinguishable, from embryonic stem cells and, therefore, may be directed to become beta cells.

However, the landmark research demonstrating iPs cells’ potential by Yamanaka and colleagues was concerning because lentiviruses were used to re-program mouse fibroblasts to iPs cells. Therefore, physicians may be hesitant to use viral vectors to treat humans. Since the initial study, however, researchers have been able to produce iPs cells using synthetic modified mRNA instead of viruses.

Although autoimmunity may complicate the use of beta cells created from iPs cells in patients with type 1 diabetes, patients with type 2 diabetes may particularly benefit from these cells because autoimmunity and transplant rejection are not concerns, Weir said.

These cells may also aid researchers in discovering more about the pathogenesis of diabetes, according to Weir.

“We can get people with type 1 diabetes to give fibroblasts and, at some point, generate beta cells to understand why they’re such a target for autoimmunity or make different kinds of T-cells, endothelial cells and more. We can also learn more about the complications of diabetes,” he said.

Promise of beta-cell regeneration

Beta-cell replication is also an area of interest, Weir said, because if researchers found a way to stimulate replication, physicians may be able to expand on whatever amount of beta cells that a patient with diabetes has.

To explore this process, colleagues at Harvard and Weir use high throughput screening with rodent islets to find compounds that will selectively stimulate replication of beta cells. Recent results indicate that inhibition of adenosine kinase can stimulate replication. Currently, this information does not have clinical implications, but the discovery may lead to future breakthroughs, Weir said.

Understanding the process of neogenesis is important as well, according to Weir. Currently, researchers know that pancreatic precursor cells have the ability to create new islets. He cited a study conducted by Bonner-Weir and colleagues using tissue culture in which new budding islets were found associated with duct cells taken from human pancreas.

“This, in my mind, is pretty clear evidence that these are real islets being formed in vitro,” Weir said. “If this is true, why haven’t we cured diabetes? The answer is we can’t get enough of them.”

Glucagon-like peptide 1 agonists, gastrin, epidermal growth factor and islet neogenesis-associated protein (INGAP) are thought to stimulate neogenesis in rodents, but researchers have yet to find evidence of similar regeneration in humans, Weir said. However, researchers are hindered in this assessment because they are unable to directly measure beta-cell mass in patients. Therefore, future advances are possible.

Other opportunities

Although embryonic stem cells receive a great deal of attention, studies also suggest that, similar to iPs cells, acinar cells can be reprogrammed into beta cells by injecting them with several transcription factors, according to Weir.

Mesenchymal stem cells also warrant further research, he said. These cells are already being extensively studied for treatment of cardiovascular disease and other conditions, and they have the potential to modulate the immune system. These cells may also have the potential to enhance islet regeneration. However, researchers are finding it difficult to define different kinds of mesenchymal stem cells and their actions, according to Weir.

Although optimal methods for beta-cell replacement therapy are not yet available, current studies that include multiple approaches are encouraging.

“We are going to keep making beta cells from stem-precursor cells, keep working on regeneration and push immunologists to find better immunosuppressive treatments,” Weir said. “Someday, it will happen.” – by Melissa Foster

For more information:

• Weir GC. General session: The latest on pancreatic islet stem cells. Presented at: American Association of Clinical Endocrinologists 20th Annual Meeting; April 13-17, 2011; San Diego.

Disclosure: Dr. Weir reports involvement with Beta O2 and is a speaker for Merck.

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