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Pancreatic beta cell regeneration

Examining Pancreatic Beta Cell Regeneration Processes

Researchers often use cell cultures and tissue slices to study the function and processes of various cells. One of the challenges of this approach, however, is the viability of these samples. For instance, pancreatic tissue slices typically show significant cell death after less than 24 hours due to poor oxygenation. This means that only short-term studies are possible, using samples while they are most viable and representative of the integrity of the native organ.

But, researchers are looking to change that. In a recent study, scientists altered how human pancreatic slices (HPSs) are cultured and managed to preserve function for 10 days or more. This is significant when it comes to being able to conduct longer-term longitudinal studies. Studies were also conducted on tissue samples from non-transgenic mice.

Traditionally, HPSs are preserved in standard transwell dishes. In this model, tissue is placed on top of a liquid-permeable membrane and surrounded with an air-liquid medium. However, oxygenation begins to decrease within several hours, and signs of anoxia appear. A new approach uses perfluorocarbon (PFC)-based dishes. This model places tissue atop a liquid-impermeable membrane providing direct contact with oxygen. An air-liquid medium also surrounds the slice. A variety of testing shows that PFC-based cultures have improved oxygenation and lower levels of anoxia.

In turn, this allowed scientists to more effectively study pancreatic beta-cell regeneration processes. HPSs retain “near-intact cytoarchitecture” of the organ in its native state in the body. Combined with the longer-term viability of the samples in the PFC-based setting, researchers were able to focus in on how and where beta cells were regenerating. They used HPSs from non-diabetic individuals as well as those with type 2 diabetes to enhance their understanding of how to stimulate this regeneration and improve insulin production.

When samples were left to rest for 24 hours to reduce the impact of stress from slicing and then treated with Bone morphogenetic protein 7 (BMP-7) proteins, scientists found that they showed higher levels of beta-cell regeneration than controls that were not treated with BMP-7. Much of this cell development occurred in regions corresponding to pancreatic ducts. Some new cells emerged from existing beta cells, while others transitioned from alpha to beta cells.

Improved oxygenation methods are changing how scientists are able to interact with HPSs and the types of testing they are able to conduct. According to the study, “Our goal in refining the conditions for the long-term survival of HPS was to allow for the real-time detection and quantification of endocrine cell regeneration.” While more in-depth and extensive studies are needed, these findings may lead the way toward improved understanding of the pathology of pancreatic beta-cell regeneration and new treatment options for individuals with type 1 diabetes.

Diabetes Research Connection (DRC) is committed to supporting these types of advancements and efforts by providing critical funding to early-career scientists pursuing novel, peer-reviewed research related to type 1 diabetes. With adequate funding, scientists are able to bring their ideas to life and contribute to not only greater understanding of the disease, but improved methods and therapies for diagnosing, treating, managing, and eventually curing type 1 diabetes. Learn more about current projects and support these efforts by visiting https://diabetesresearchconnection.org.

 

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Targeting the Effects of Specific Drugs on Pancreatic Islets

The production of insulin and glucagon used to regulate blood sugar levels come from pancreatic islet cells. In individuals with type 1 diabetes, the immune system mistakenly attacks and destroys these cells leaving the body unable to naturally regulate blood sugar. That means that individuals must continuously monitor and manage these levels themselves.

A recent study examined the impact that specific drugs have on pancreatic islet cells and their function. Researchers were able to fine-tune single-cell transcriptomics to remove contamination from RNA molecules that could interfere with results and negatively affect reliability of the data.

Once they had created decontaminated transcriptomes, they tested three different drugs that relate to blood glucose management. They found that one drug, FOXO1, “induces dedifferentiation of both alpha and beta cells,” while the drug artemether “had been found to diminish the function of alpha cells and could induce insulin production in both in vivo and in vitro studies.” They compared these drugs in both human and mouse samples to determine if there were any differences in how the cells responded. One notable difference was that artemether did not have a significant impact on insulin expression in human cells, but in mouse cells, there was reduced insulin expression and overall beta cell identity.

Single-cell analysis of various drugs could help guide future therapeutic treatments for type 1 diabetes as researchers better understand their impact. Targeted therapies have become a greater focus of research as scientists continue to explore T1D at a cellular level.

Diabetes Research Connection (DRC) is interested to see how single-cell sequencing and the ability to decontaminate RNA sequences could affect diabetes research. The organization supports a wide array of T1D-focused studies by providing critical funding to allow early-career scientists to advance their research. To learn more and support these efforts, visit https://diabetesresearchconnection.org.

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Increasing Cell Protection Against Immune System Attacks

One of the challenges researchers have faced with using cell therapy to treat type 1 diabetes is that the body’s immune system may still attack and destroy transplanted cells. This process may be slightly delayed depending on the approach used, but it often still occurs. That means that patients may still need to rely on immune suppression medications in conjunction with cell therapy. However, immunosuppression can increase risk of infection or other complications.

A recent study found that targeting highly durable cells that have the ability to escape immune attacks and survive may be key in developing a more effective treatment for type 1 diabetes. Dr. Judith Agudo has identified stem cells with this “immune privilege” and is working to determine exactly what contributes to this level of protection and how to replicate it with beta cells. Dr. Agudo is an assistant professor in the department of immunology at Harvard Medical School and in the department of cancer immunology and virology at the Dana-Farber Cancer Institute.

If scientists can engineer insulin-producing beta cells that have the ability to avoid attacks from the immune system while still performing their intended functions, this could be a huge step forward in potentially treating type 1 diabetes. The beta cells would be able to stimulate insulin production without requiring the patient to take immune suppression medications, meaning their immune system could continue to function as normal and fend off infection.

Once Dr. Agudo is able to develop these durable beta cells, they will be tested in animal models, followed by humans a few years later. It is important to conduct thorough testing to ensure this method is both safe and effective. If it is, the goal would be to eventually make it available to anyone who requires the use of insulin.

Diabetes Research Connection (DRC) is excited to see how this study evolves and what it could mean for the future of diabetes treatment. While not involved in this study, the DRC plays an integral role in providing critical funding for early career scientists focused on research for type 1 diabetes. Scientists continue to advance understanding of the disease and potential approaches to improve diagnosis, treatment, management, and quality of life for individuals living with type 1 diabetes. Learn more about current DRC projects and how to support these efforts by visiting https://diabetesresearchconnection.org.

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Generating Pancreatic Islet Organoids to Treat Type 1 Diabetes

In individuals with type 1 diabetes, the immune system mistakenly attacks and destroys insulin-producing beta cells. Without a naturally occurring supply of insulin to manage glucose, blood-glucose levels can quickly spiral out of control leading to hypo- or hyperglycemia. If left untreated, this can become potentially fatal.

A recent study found a way to generate an abundance of pancreatic islet organoids that are glucose-responsive and insulin-secreting. As such, they can help with management and potential reversal of type 1 diabetes. Researchers identified a cluster of protein C receptor positive (Procr+) cells in the pancreas of adult mice. These cells have the ability to differentiate into alpha, beta, omega, and pancreatic polypeptide (PP) cells, with beta cells being the most abundant.

The Procr+ islet cells can then be cultured to generate a multitude of islet-like organoids. When the organoids were then be transplanted into adult diabetic mice, they were found to reverse type 1 diabetes. More research is necessary to determine if human pancreatic islets contain these same Procr+ endocrine progenitors and a similar process could be used to treat type 1 diabetes in humans.

As scientists delve deeper into the cellular impact of the disease and how different cells respond and can be manipulated, it opens new doors to potential treatments or cures for type 1 diabetes. Though not involved in this study, this is the type of cutting-edge research that the Diabetes Research Connection (DRC) is committed to supporting. Early-career scientists can receive up to $50,000 in funding through DRC for novel, peer-reviewed research aimed at preventing and curing type 1 diabetes, minimizing complications, and improving the quality of life for individuals living with the disease. To learn more and support these efforts, visit https://diabetesresearchconnection.org.

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Could Insulin-Producing Beta Cells Play a Role in Triggering Onset of Type 1 Diabetes?

Researchers know that type 1 diabetes (T1D) occurs when the immune system mistakenly attacks and destroys insulin-producing beta cells. This leaves the body unable to self-regulate blood glucose levels because it produces little or no insulin on its own. What scientists have been striving to understand is what causes the body to destroy these cells in the first place.

A recent study found that the beta cells themselves may play a role in signaling the attack. The insulin-producing cells may be sending out signals that increase M1 macrophages that cause inflammation and the resulting cell destruction. The M2 macrophages that reduce inflammation and help repair tissue are not as heavily expressed.

The researchers looked specifically at Ca2+-independent phospholipase A2beta (iPLA2beta) enzymes and the resulting iPLA2beta-derived lipids (idles) and how they are activated by beta cells.  The idols either stimulate M1 macrophages or M2 macrophages depending on the active signaling pathways.

The study involved two sets of mice – one group that had no iPLA2beta expression (knockout mice), and one group with overexpression of iPLA2beta.  Researchers found that even when M1 macrophage activation was induced, the knockout mice experienced an increase in M2 macrophages and a reduced inflammatory state. The mice that had overexpression of iPLA2beta, on the other hand, experience an increase in M1 macrophages and inflammatory eicosanoids.

According to Sasanka Ramanadham, Ph.D., research co-lead, “To our knowledge, this is the first demonstration of lipid signaling generated by beta cells having an impact on an immune cell that elicits inflammatory consequences. We think lipids generated by beta cells can cause the cells’ own death.”

As scientists continue to learn more about lipid signaling and the potential role it plays in the development of type 1 diabetes, this could lead to improved methods of delaying or preventing onset or progression of the disease. This is yet another approach that researchers are taking to understand as much as they can about how and why T1D develops and how to better manage the disease.

It is this type of research that opens doors to advancements toward preventing or curing type 1 diabetes. Diabetes Research Connection (DRC) supports early-career scientists pursuing novel, peer-reviewed research studies focused on improving diagnosis, treatment, and prevention of T1D as well as improving quality of life for individuals living with the disease and one day finding a cure. Ensuring researchers receive necessary funding for their projects is critical. To learn more about current projects and support these efforts, visit https://diabetesresearchconnection.org.

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Redifferentiating Beta Cells to Treat Type 1 Diabetes

All cells serve a specific purpose, and each one plays an integral role in the function and survival of the human body. However, in individuals with type 1 diabetes, insulin-producing beta cells are destroyed leaving the body unable to self-manage glucose levels. Scientists have been trying to determine exactly why this occurs, and how to stop, prevent, or reverse it for years. Each day they learn a little more.

A recent study out of Germany examines dedifferentiation of beta cells as a potential cause for type 1 diabetes.  Researchers believe that insulin-producing beta cells may lose their identity, which in turns causes a regression in function.  They sought to target the affected cells using diabetic mouse models to see if they could redifferentiate the beta cells back to normal function, or at least preserve existing function if regression is caught early.

To do this, they invoked diabetes in mice using streptozotocin but left some functional beta cells. Then, they administered a combination of Glucagon-like peptide-1 (GLP-1) and estrogen in conjunction with long-acting insulin.  The drug was directed to the dedifferentiated beta cells, and results showed that this combination treatment helped to “normalize glycemia, glucose tolerance, to increase pancreatic insulin content and to increase the number of beta cells.”  They also found that when GLP-1/estrogen was used together, rather than each substance on its own, human beta cells also showed improved function.

The mice in the study showed no signs of systemic toxicity even when high doses of the drug were administered.  This could help to ease the way when the treatment is ready to be used in human trials. Researchers want to further explore whether this treatment could be used as a form of regenerative therapy to redifferentiate dedifferentiated beta cells and stimulate insulin production. If type 1 diabetes was detected early on, the therapy could potentially be used to slow or stop cell regression.

This study could change the way that some researchers approach their work and inspire new studies aimed at treating or curing type 1 diabetes. Diabetes Research Connection (DRC) supports early-career scientists in pursuing this type of work by providing necessary financial resources. With proper funding, scientists can move forward with their projects and improve not only understanding of the disease, but also treatment options.  The goal is to one day discover a cure. To learn more about current projects and how to help, visit https://diabetesresearchconnection.org.

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Improving Vascularization in Pancreatic Islet Transplants

One of the approaches scientists have been exploring for the treatment of type 1 diabetes is pancreatic islet cell transplants. By introducing these cells into the body, they are often able to maintain better glycemic control and support insulin production. However, there are many challenges that come with this type of treatment. It is essential to protect transplanted islet cells from immune system attack while also promoting sustainability. Cells tend to lose function over time and poor vascularization is often a contributing factor.

In a recent study, scientists have found a way to improve vascularization and therefore function of transplanted human pancreatic islets in diabetic mice. In addition to encapsulating islet cells, they also included human umbilical cord perivascular mesenchymal stromal cells or HUCPVCs. The HUCPVCs had a positive effect on graft function and suppressed T cell responses. In both immunocompetent and immunodeficient diabetic mice, glycemic control was maintained for up to 16 weeks when cells were transplanted via a kidney capsule, and for up to six weeks or seven weeks respectively when administered via a hepatic portal route. Furthermore, with the addition of HUCPVCs to the transplanted islet mass, rejection was delayed and the graft showed some proregenerative properties.

These findings may improve the future of human islet allotransplantation as a viable option for long-term treatment of type 1 diabetes. Scientists are constantly exploring ways to reduce rejection and the need for prolonged immunosuppression while maintaining better glycemic control. This study opens doors for more advanced research on the use of HUCPVCs in islet transplantation as well as related therapies.

Diabetes Research Connection is committed to supporting research for type 1 diabetes by providing early-career scientists with essential funding to keep projects moving forward. Learn more about current studies and how to donate to these efforts by visiting https://diabetesresearchconnection.org.

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Controlling Beta Cell Proliferation and Apoptosis to Manage Type 1 Diabetes

A key indicator of type 1 diabetes is lack of insulin-producing beta cells in the pancreas. These cells are mistakenly attacked and destroyed by the immune system leaving individuals unable to naturally manage their blood sugar. With little to no production of insulin, the body cannot effectively process sugars and use them as fuel. Instead, individuals must constantly monitor their blood glucose levels and administer insulin as needed.

However, a recent study uncovered how an FDA-approved drug for treating breast cancer may also be effective in diabetes care. Neratinib is a dual inhibitor of HER2 and EGFR kinases, but researchers have also found that it is incredibly effective at blocking mammalian sterile 20-like kinase 1 (MST1) as well. MST1 plays a key role in regulating beta cell proliferation and apoptosis. By inhibiting MST1 expression, insulin-producing beta cells may be protected from this process leading to greater beta cell survival and improved function.

In addition, when mouse models and human islets were treated with neratinib, they showed a marked improvement in glucose control and maintained lower overall glucose levels. The drug also restored expression of specific transcription factors such as PDX1 that contribute to glucose metabolism and insulin production.

Neratinib is an FDA-approved cancer treatment drug currently being used for breast cancer, but its effectiveness in treating other forms of cancer is being explored as well. Now researchers are examining whether its indications could be expanded to include diabetes.  While it has been proven safe in cancer treatment, scientists are looking at ways to decrease its toxicity and improve specificity for diabetes.

In its current form, neratinib does not only target MST1 – it inhibits other kinases as well. Furthermore, there is concern that an extreme decrease in beta cell apoptosis could lead to increased expression of other cell types which could impact health. However, researchers can use this study as a foundation for exploring ways in which to refine the drug and improve beta-cell protection and function while minimizing other effects.

Diabetes Research Connection (DRC) is interested to see how this study impacts future treatment and prevention efforts in regard to type 1 diabetes. The DRC provides critical funding to early career scientists pursuing novel, peer-reviewed research projects focused on prevention, treatment, and improvement of quality of life for individuals living with the disease. This support can lead to scientific breakthroughs and have a significant impact on understanding of type 1 diabetes. To learn more about current projects and how to support these efforts, visit http://diabetesresearchconnection.org.

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Leveraging the Power of Light to Manage Type 1 Diabetes

A common problem in managing type 1 diabetes is maintaining relatively stable blood glucose levels. By the time a person realizes their blood sugar is rising or falling and begins to treat it, they may already experience spikes. This can be tough on the body and lead to over- or undertreatment in an effort to curb the highs or lows. Though technology has made it faster and easier to track blood glucose levels and more accurately administer insulin, it’s still not a perfect system.

A recent study reveals that researchers may have come up with a way to manage blood sugar without manually administering insulin. They engineered pancreatic beta cells to be responsive to exposure to blue light. By introducing a photoactivatable adenylate cyclase (PAC) enzyme into the cells, they produce a molecule that increases insulin production in response to high levels of glucose in the blood.

The molecule is turned on or off by blue light and can generate two to three times the typical amount of insulin produced by cells. However, it does not boost production when glucose levels in the blood are low. Furthermore, the cells do not require more oxygen than normal cells, which helps alleviate the common issue of oxygen starvation in transplanted cells.

The study was conducted on diabetic mice, so more research is needed to determine whether the process will be as effective in humans. If it is, this could mean that individuals with type 1 diabetes may have an option for controlling blood sugar levels without pharmacological intervention. When paired with a continuous glucose monitor (CGM) or other device as well as a source of blue light, it could create a closed loop model of managing the disease by functioning as a bioartificial pancreas.

This could be potentially life changing for individuals living with type 1 diabetes, and Diabetes Research Connection (DRC) is excited to see how the study progresses. Though not involved with this project, the DRC supports advancement of type 1 diabetes research and treatment options by providing critical funding for early career scientists pursuing novel research projects. Learn more by visiting http://diabetesresearchconnection.org.

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Improving Vascularization of Transplanted Islet Cells

One option that researchers have explored for treating type 1 diabetes is cell transplantation. By introducing new pancreatic islet cells, they aim to better control glucose levels and insulin production. However, there are still many challenges surrounding this approach including cell death due to poor vascularization.

Pancreatic islet cells are highly vascularized in order to quickly and easily transport insulin. If they are not able to establish blood vessel connections following transplantation, they cannot work as effectively and may not survive long-term. A recent study has found an improved method for promoting vascularization and enabling more effective cell transplantation.

A multidisciplinary team of researchers developed a biomimetic microvascular mesh that maintained its shape and promoted the survival of transplanted cells by stimulating revascularization. When transplanted into diabetic mouse models, they were able to maintain normoglycemia for up to three months.

The researchers created micropillars to improve anchoring of the microvascular mesh and decrease risk of shrinkage as cells matured. They had success using both human umbilical vein endothelial cells (HUVECs) and human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) in the meshes. Compared to a mesh without these cells, the mesh with the cells showed both anastomoses and vascular remodeling which are essential in vascularization during cell replacement therapy.

Though they have only been tested in mouse models, biomimetic microvascular mesh could one day be used to improve cell replacement therapy for humans with type 1 diabetes in order to improve glycemic control. This study opens doors for additional research and further refining islet transplantation methods.

Though not involved with this study, Diabetes Research Connection (DRC) supports novel research projects that strive to advance treatment for type 1 diabetes and one day find a cure. Early career scientists can receive up to $75K in funding from donations by individuals, corporations, and foundations to support their research. Learn more by visiting http://diabetesresearchconnection.org.

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