Potential of Regeneration of Insulin Producing Cells to Reverse Type 1 Diabetes
Interesting new evidence suggests that not all beta cells may have been destroyed in people with long-standing type 1 diabetes, and they may even continue to regenerate their own insulin producing cells.
Research has shown that the pancreas is not a static organ, like the brain. Rather, the failure to produce insulin results from continuous destruction of the beta cells. Though this is not a new concept, scientists now have the technology to begin to understand this process.
Dr. Peter Butler and collaborators have recently discovered live beta cells in the ducts of the pancreas. One 42-year-old patient who had diabetes for 23 years, for example, tested positive for insulin in the pancreatic ducts. However, the ongoing attempt of the beta cells to regenerate is counteracted by ongoing autoimmunity.
Researchers are investigating various methods to restore insulin production, among them turning stem cells into functional beta cells, and transdifferentiation, the turning of one cell type into another. They’re also exploring the possibilities of regeneration. According to Dr. Nadler, it is likely that two approaches will be needed for successful beta cell regeneration in people with long-standing type 1 diabetes. The first is to stop the autoimmune destruction, and the second is to enhance the regeneration.
Dr. Nadler addressed a study from investigators at Harvard that was widely publicized in the media, which reported success involving the transdifferentiation of spleen cells into beta cells. Three research teams from three different institutions tried to reproduce the study, and their results were published in the journal Science. Each team’s findings pointed to the fact that transdifferentiation of the spleen cells into beta cells was unlikely, but that blockade of the autoimmune process was necessary to see reversal of type 1 diabetes in the mouse model.
The question scientists are now trying to answer is if you stop the autoimmune process, could the cells regenerate?
The immune system continues to sense the beta cells as foreign. The factor triggering the immune system is not fully clear, but it appears that once a cell produces insulin, it becomes a target for attack.
Some approaches to stop autoimmunity and enhance regeneration involve:
1. A vaccine – probably would be more effective in newly-diagnosed patients
2. Block the T-cell response that kills the beta cells – current agents shut down the total immune system and thus, may have limited use.
3. Use of immunomodulators – these selectively block the attacking cells. Drugs that block certain proteins, such as Interleukin 12, may be examples.
Researchers are also looking at ways to increase the growth of the beta cells, and these methods include:
1. Use of GLP1 receptor, Exendin 4 (Exenatide), to increase growth and differentiation
2. Increase the body’s own GLP1 production to biologically increase growth of beta cells
3. Use of growth factors
Dr. Nadler and his team conducted a study in NOD mice (non-obese diabetic mice), which looked at the Interleukin 12 - STAT4 pathway. They wanted to determine what would happen if the STAT4 gene was eliminated in NOD mice. They discovered that none of the mice without the STAT4 gene developed diabetes, and concluded this was an important pathway for type 1 diabetes.
They went on to test a new agent, Lisofylline (LSF), for its ability to stop the activation of the STAT4 pathway and prevent diabetes in the mouse model. LSF is a new, experimental medication being developed to reduce the Interleukin 12 – STAT4 pathway and more selectively reduce autoimmune damage to beta cells. In a recent study, only 2 of the 19 recipients developed diabetes compared to a much higher percentage of NOD mice that developed diabetes when given a placebo
The researchers also looked at administering the drugs, Exenatide and LSF, alone and in combination to mice already having type 1 diabetes. They already had evidence that the placebo didn’t work. The use of Exendin alone did not induce the growth of the beta cells. They also tested the use of LSF alone and found that it did indeed block the autoimmune response, but when the drug was stopped, the disease returned.
When the researchers tested the combination of LSF and Exendin, they observed that diabetes was reversed in almost all of the animals, and it prevented recurrence of the disease in 75 – 80% of the test group. Additionally, the study group that received the combination treatment showed a normal glucose tolerance test
Dr. Nadler also shared some very recent data performed in collaboration with Dr. Raghu Mirmira that suggests the drug combination is leading to regeneration of insulin producing cells in the pancreatic ducts. There was presence of a specific gene switch for a beta cell marker in the ducts of NOD mice.
He concluded that:
>> The body continues to regenerate beta cells even in long-standing diabetes
>>Ongoing autoimmunity is a major factor preventing successful regeneration
Lisofylline (LSF), being supplied by Diakine Therapeutics, Inc., will be used in a phase 2 clinical trial at the Diabetes Research Institute as part of the Islet Cell Transplant Consortium funded by the NIH. DRI is the only site testing LSF in this clinical trial.
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Jerry Nadler, M.D.
Crispell Professor of Medicine; Division Chief of Endocrinology and Metabolism, University of Virginia; Director, Diabetes and Hormone Center of Excellence; Associate Director of the NIH-funded Diabetes and Endocrinology Research Center
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