Curing Diabetes Using Implanted Glucose Responsive Beta Cells

I wish there was a way to do so but I just can’t conscionably sugarcoat it. Diabetes has become an epidemic that has crept its way into almost every American family. Now, I personally know and it’s likely that you do too, family and friends that have diabetes, and they are just some of the 37.3 million Americans who currently live with this disease. And that doesn’t even account for the over 96 million others who have pre-diabetes.

Now, type one diabetes is the cause of 5% to 10% of all diagnoses, and is the most commonly diagnosed form of diabetes in children. It is caused by the body not making enough insulin. And currently, there is no cure for type one diabetes, but it can be managed with multiple daily injections of insulin. That being said, what if there was a way to cure type one diabetes?

Hi folks! My name is Cole and I have a Master’s of immunology. Today on Investigate Explore Discover, we’re going to be talking about implanted glucose responsive beta cells. So hang around with me throughout this whole video to get all of the relevant background information so we can dive into some exciting experimental results. But before we can dive into diabetes, we need to know a bit about how our body works.

When we eat food, it provides us nutrients so that we can continue to live our daily lives. Some of these nutrients are sugars like glucose, which spike in the blood shortly after they are consumed. Now our bodies normally secrete insulin to absorb glucose into our cells for energy within about an hour of eating. Insulin itself is derived from proinsulin, which is cleaved apart to yield one insulin and one C peptide molecule. C peptide is clinically measured as a proxy for insulin due to their one-to-one ratio and because it is not used up by the body in the same fashion. This will be important for later. Type one diabetics do not produce enough insulin in their bodies. Thus, glucose builds up in their blood.

Now too much sugar in the blood causes a whole host of problems. Some of the more noticeable symptoms include going to the toilet more, being thirsty, tired and getting rapidly thinner. Now, long term diabetes can also have many complications throughout the body, such as damage to the kidney, brain, heart and eyes. And these complications lead to type one diabetics having to pay more than double the cost for American healthcare for something they have no control over. Not to mention the criminal cost of insulin itself, but that is a whole other discussion.

The reason why type one diabetics do not produce insulin is because the immune system went rogue and attacked and killed islet cells in the pancreas, particularly the beta cells which produce insulin. In 2000, there was a scientific breakthrough in Edmonton, Canada, which is actually where I did my schooling. Edmonton was where the first successful transplantation of pancreatic islet cells occurred, freeing the first seven people from having to take daily insulin and normalizing other diabetic physiological parameters. Since then, over 1500 others have had this procedure which is a three year success rate of just under 45%. Now despite these encouraging findings, widespread adoption of this procedure remains limited, particularly because there remains a scarcity of pancreatic islet cells from deceased donors because all possible donors are definitely being used for more important reasons. This is why there’s a need for an alternative abundant supply of pancreatic islet cells.
Luckily, we have a few other avenues for tackling the cure for type one diabetes. Now, based on current estimates, this problem should be solved by about the mid 2030s. But these solutions aim to deliver a near normal lifestyle for people living with established type one diabetes. Some of these options include the cyborg approach, where we can create an advanced artificial pancreas. Or you could take a more biological route and transplant new cells, which would then secrete insulin in response to glucose. This is what we’re talking about today.

Normally, the pancreas develops just like every other organ over the course of nine months. And as the cells mature from endoderm cells to endocrine cells, to mature insulin secreting beta cells, they express multiple different expression markers. Currently, scientists are actively trying to cut that time down to a matter of weeks using human pluripotent stem cells. This process is being verified by looking at expression markers and functions that correlate to beta cell development. Previously, pancreatic endoderm cells (PECs) have been successfully used to implant into animals, where they then differentiate into beta cells in the body. The scientists at ViaCyte have used these endoderm cells by putting them into small, thin semi-permeable devices that do not allow for direct vascularization, all to try and cure diabetes. They called this product PEC-Encap.

However, through their first study, cell survival was inconsistent, and there was no measurable insulin being secreted. In an effort to fix this, a new approach was tested called PEC-Direct. This approach utilizes vascularization of the implanted devices, which allows for more direct access of the stem cells to the blood supply and all the signals that come with it. However, this is a double-edged sword because being in contact with the blood also means being in contact with the immune system. And of the multitudes of cells that make up our immune system, today we’re going to focus on just the T cells.

Now, T cells are a critical part of our adaptive immune system, which is long lasting and specific, and also doesn’t like foreign invaders of any kind. Cytotoxic CD8 T cells and helper CD4 T cells mediate foreign body clearance, which includes implants, transplants, and foreign medical devices. However, there are also T regulatory cells, which suppress these other T cells to help induce tolerance.

Now, I want to take a moment and really highlight why research on curing type one diabetes is so important. For starters, diabetes does not just affect America. This chronic disease affects over 460 million people around the world. And as it stands, there is currently no readily available or easily administrable cure, leaving people to just manage the symptoms. A cure for diabetes would alleviate people and especially kids from needing to inject insulin daily and prevent chronic diabetes complications.

This brings us to the paper that we’re focusing on today. This paper is called Implanted Pluripotent Stem-cell-derived Pancreatic Endoderm Cells Secrete Glucose-responsive C-peptide in Patients with Type 1 Diabetes by Ramzy et al. from the University of British Columbia, Vancouver, Canada. And in this paper, the authors investigated the safety and efficacy of ViaCyte’s attempt at a diabetes cure in one site of their multi-site clinical trial. In this study, the authors implanted PEC-Direct products, which are macro-encapsulated stem cell derived pancreatic progenitor cells in people with type one diabetes and allowed them to vascularize. To ensure that this occurred, immunosuppressive drugs were also administered.

Based on the enrollment criteria, the authors enrolled 15 patients for this study. The participants were diagnosed with diabetes for 10 to 54 years, were aged 34 to 56, were predominantly white, and had varying degrees of chronic complications from diabetes. Throughout the course of this study, two of the 15 participants withdrew to serious adverse reactions to the immunosuppressive medications, and five other participants were recommended to withdraw because of failed risk benefit assessment, particularly revolving around a lack of clinical outcomes, leaving them with eight patients at the end of their study.

Now, all of the data collected during the first year of patient enrollment and prior to final patient withdrawal have been included. Throughout the course of this study, the participants had many bodily metrics tested. Over time, there was improved low blood sugar awareness and a reduction in insulin requirements post transplant. It was even noted that one patient had over 50% reduction in insulin requirements, though no patients were able to achieve insulin independence. However, they did have improved glucose regulation, spending more time in the target blood glucose range, and significantly less time with too much sugar in their blood.

Now during this study from weeks 1 through 39, the authors measured the fasting C peptide and blood glucose serum levels. They found no change in blood glucose levels over time, but there was a significant increase in C peptide, which is equivalent to insulin levels. It is important to point out here that most of these patients only had increases of a few picomolars at max. Nevertheless, it indicated that the devices were having some positive effect.

When assessing multiple factors that could also affect C peptide levels, one of the statistical models used, identified that older patients and those that used insulin pumps had greater increases in C peptide. But since we cannot survive without eating, it was also important to look at the levels of C peptide in the blood after a meal. Notably, there was high heterogeneity within and between participants over time. But when looking at the blood serum one hour post eating, which assessed the rapid insulin response to meals, the authors found no significant change in C peptide levels over time. However, when looking at the meal response over four hours or weeks 0, 26 and 52, it was found that C peptide secretion increased at week 26. And it was found that there was no difference in meal responsiveness from weeks 26 to 52.

Now because immune activity is crucial to monitor when giving patients transplants of any sort, and to see how well they’re being immunosuppressed from the medication, the authors also investigated T cell activity. They looked at the absolute numbers and proportions of T cell subsets in the peripheral blood through the duration of the study. These will let the authors know if immune related rejection was the cause of non clinically relevant C peptide secretion. As expected when using immunosuppressive drugs, the participants had reduced numbers of T cells. This also included a decreased ratio of CD4 to CD8 T cells, and an increased ratio of the T regulatory cells alongside a generally increased proportion of effector T memory cells, indicating that these implants were being tolerated by the patients.

Given that the implantation of these devices caused slight development of meal responsive C peptide secretion, the question then became, were the implanted cell filled devices directly responsible for the observed C peptide increase? In two patients tested for this, it was observed that removing the implanted devices caused C peptide levels to fall to pre-implantation ranges.

To further get a better understanding of how the cells in the devices were functioning, the authors wanted to determine what the phenotype of the implanted cells looked like. So they took three slices from each implant and got a certified pathologist to assess the tissues using immunohistochemistry. These tissues were stained for various markers that indicated whether the cells were differentiating into beta cells, and whether there was cancer forming around the devices. As time progressed, the cells of the devices looked more and more similar to cells found in the human pancreas, then to initially implanted precursor cells. They were also able to successfully secrete insulin, which is exactly what the authors were hoping to see. Additionally, they found that there was no cancer formation around the devices and no large presence of infiltrating immune cells, indicating that the implants were not being rejected or causing any funny business.

Now, to quickly summarize everything from this paper altogether, the authors looked at a small sample population at one of ViaCyte’s trial sites for the safety and efficacy of its PEC-Direct product, which needs immunosuppression to maintain. They found that by using these devices, some of the patients were able to lessen the burden of diabetic disease, because the stem cells in the devices matured over time from pancreatic endoderm cells to insulin producing beta cells. Specifically, after a year of observation, the authors found that the devices were well tolerated, produced C peptide in response to meals, and the surviving cells had a mature insulin producing phenotype. Though, it is very important to note that the changes seen were typically very tiny and very few patients actually had surviving cells.

Now, not only do I think that these findings are exciting to investigate and learn about, they are also significant in a broader context. This information is significant because it shows that implanted stem cells can successfully differentiate into insulin producing beta cells in patients. And this data provides a proof of concept that stem cell products can be used as a mass producible alternative to cadaveric islet cells for treating diabetes. This data also provides valuable primary evidence that can be used to further refine the process. All science is basically a stepping stone for new knowledge. And these steps are driven by questions. And I had a few questions myself after reviewing this information.

My first question revolves around the effectiveness of these cells. From these experiments, they were not very effective at producing insulin. So can this somehow be increased, maybe through more differentiation? Another approach to the problem of low insulin production might be increasing the number of micro-devices but how many would be feasible or tolerable to achieve insulin independence? My third question revolves around using immunosuppressants. Now, being immunosuppressed comes with its own set of problems. So, is the trade off of curing diabetes worth another condition? What steps can be made to not use immunosuppression when treating diabetes?

As always, my final question revolves around you. What sort of ideas or questions popped into your head when hearing about this information? I would love to hear about them in the comment section below. Also, let me know if there are any topics that you’d like to hear about in the future. Ultimately, I hope that you learned something. But more importantly, I hope that you enjoyed your time doing so. So if you did, give this video a like and subscribe for more in the future. Well, that’s everything for today. Thank you for watching, and I’ll see you next time.

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