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Exploring Why the Immune System May Attack Insulin-Producing Beta Cells

Insulin-producing beta cells are essential for effective blood sugar control. However, in individuals with type 1 diabetes, these cells are mistakenly destroyed by the immune system. That means exogenous insulin must be used instead to manage blood sugar. For years, scientists have been researching ways to replace or reproduce these islet cells. Two of the most common challenges faced, however, have been the need for long-term immunosuppression to protect transplanted cells from rejection, and limited availability of donor cells.

A recent study found that an improved source of encapsulation may protect islet cells from an immune response without decreasing their ability to secrete insulin. By using a conformal coating that is only a few tens of micrometers thick (as opposed to hundreds of micrometers thick), not only could insulin flow more freely through the encapsulation, so could oxygen, nutrients, and glucose as well. Yet larger immune cells were still unable to penetrate the barrier. In addition, the thinner coating allowed for more cells to be contained in a smaller space, and the capsule could be implanted in a wider range of locations so long as there was strong vascular function.

The encapsulated cells were implanted in NOD-scid mice and compared with non-coated stem cells as well as human islets. There were no statistically significant differences in performance of the cells and their ability to regulate glucose levels. The mice all showed a reversal in diabetes with the transplanted cells and returned to hyperglycemia once the cells were explanted.

The use of a microencapsulation method allows for more variability in placement of transplanted cells and helps protects against hypoxia-induced islet death and cell rejection. Furthermore, the thinner coating enabled islets to obtain better oxygenation because they are closer to blood vessels. It also allowed insulin to be secreted more quickly because it flowed more freely through the barrier.

One drawback that researchers noted was that encapsulated islets are unable to shed dead cells because they are contained within the capsule and have a lower absolute quantity of insulin secretion when compared to non-coated stem cell-derived islets.

Through this study, the researchers concluded that, “CC (conformal-coated) mouse islets can reverse diabetes long-term in a fully MHC-mismatched model.” While additional research is necessary to explore the effectiveness of this process in humans, it is a step in the right direction toward one day potentially curing type 1 diabetes.

Though not involved with this study, Diabetes Research Connection (DRC) stays abreast of the latest advancements in the field and provides critical funding to early career scientists pursuing novel research studies for type 1 diabetes. It is through these types of projects that researchers are able to improve quality of life for individuals living with the disease and move closer to finding a cure. To learn more about current DRC-funded projects or support these efforts, visit https://diabetesresearchconnection.org.

 

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Understanding the Impact of GABA on Insulin Secretion and Regulation

In order to manage blood glucose levels, pancreatic beta cells release insulin in pulses. These bursts of insulin help the body to regulate and stabilize blood sugar. In individuals with type 1 diabetes, however, the pancreatic beta cells that normally secrete insulin are mistakenly destroyed by the body. This leaves the body unable to effectively regulate blood sugar on its own. Understanding the interaction between insulin-producing beta cells and other processes in the body may help researchers improve treatment and prevention options when it comes to diabetes.

A recent study examined the different roles gamma amino-butyric acid (GABA) plays in cell activity. In the brain, GABA is released from nerve cell vesicles each time a nerve impulse occurs. The GABA prepares cells for subsequent impulses by working as a calming agent. Researchers previously believed that this process worked in much the same way in the pancreas.

However, in the pancreas, GABA is evenly distributed throughout the beta cells rather than contained within small vesicles, and it is transported via the volume regulatory anion channel. This is the same channel that helps stabilize pressure inside and outside of cells so that they maintain their shape. Furthermore, research showed that GABA is released in a similar pattern and frequency as pulsatile in vivo insulin secretion. Just like in the brain, GABA plays an integral role in preparing and calming cells to make them more receptive to subsequent insulin pulses.

Scientists are interested in learning more about how GABA signaling can support the regulation of insulin secretion and potentially protect cells from autoimmune activity. This opens new doors for biomedical research that has the ability to impact diabetes care.

It is encouraging to see different types of researchers all coming together and learning from and building upon one another’s work in order to advance understanding, prevention, and treatment of various diseases, including diabetes.

Diabetes Research Connection stays abreast of the latest discoveries in the field and supports early career scientists in contributing to this body of work by providing critical funding for their projects. It is essential that scientists have the resources to pursue novel research in order to develop improved prevention, treatment, and management options for type 1 diabetes. Learn more and support current projects by visiting https://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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ETH Researchers T1D

New Weapon Against Diabetes

Original article published by ETH Zurich on December 1, 2016. Click here to read the original article.

Researchers have used the simplest approach yet to produce artificial beta cells from human kidney cells. Like their natural model, the artificial cells act as both sugar sensors and insulin producers.

Researchers led by ETH Professor Martin Fussenegger at the Department of Biosystems Science and Engineering (D-BSSE) in Basel have produced artificial beta cells using a straightforward engineering approach. These pancreatic cells can do everything that natural ones do: they measure the glucose concentration in the blood and produce enough insulin to effectively lower the blood sugar level. The ETH researchers presented their development in the latest edition of the journal Science.

Previous approaches were based on stem cells, which the scientists allowed to mature into beta cells either by adding growth factors or by incorporating complex genetic networks.

For their new approach, the ETH researchers used a cell line based on human kidney cells, HEK cells. The researchers used the natural glucose transport proteins and potassium channels in the membrane of the HEK cells. They enhanced these with a voltage-dependent calcium channel and a gene for the production of insulin and GLP-1, a hormone involved in the regulation of the blood sugar level.

Voltage switch causes insulin production

In the artificial beta cells, the HEK cells’ natural glucose transport protein carries glucose from the bloodstream into the cell’s interior. When the blood sugar level exceeds a certain threshold, the potassium channels close. This flips the voltage distribution at the membrane, causing the calcium channels to open. As calcium flows in, it triggers the HEK cells’ built-in signalling cascade, leading to the production and secretion of insulin or GLP-1.

The initial tests of the artificial beta cells in diabetic mice revealed the cells to be extremely effective: “They worked better and for longer than any solution achieved anywhere in the world so far,” says Fussenegger. When implanted into diabetic mice, the modified HEK cells worked reliably for three weeks, producing sufficient quantities of the messengers that regulate blood sugar level.

Helpful modelling

In developing the artificial cells, the researchers had the help of a computer model created by researchers working under Jörg Stelling, another professor in ETH Zurich’s Department of Biosystems Science and Engineering (D-BSSE). The model allows predictions to be made of cell behaviour, which can be verified experimentally. “The data from the experiments and the values calculated using the models were almost identical,” says Fussenegger.

He and his group have been working on biotechnology-based solutions for diabetes therapy for a long time. Several months ago, they unveiled beta cells that had been grown from stem cells from a person’s fatty tissue. This technique is expensive, however, since the beta cells have to be produced individually for each patient. The new solution would be cheaper, as the system is suitable for all diabetics.

Market-readiness is a long way off

It remains uncertain, though, when these artificial beta cells will reach the market. They first have to undergo various clinical trials before they can be used in humans. Trials of this kind are expensive and often last several years. “If our cells clear all the hurdles, they could reach the market in 10 years,” the ETH professor estimates.

Diabetes is becoming the modern-day scourge of humanity. The International Diabetes Federation estimates that more than 640 million people worldwide will suffer from diabetes by 2040. Half a million people are affected in Switzerland today, with 40,000 of them suffering from type 1 diabetes, the form in which the body’s immune system completely destroys the insulin-producing beta cells.
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diabetes research

Economic 3D-Printing Approach for Transplantation of Human Stem Cell-Derived β-Like Cells

Original article published by IOP Science on December 1, 2016. Click here to read the original article.

Abstract

Transplantation of human pluripotent stem cells (hPSC) differentiated into insulin-producing βcells is a regenerative medicine approach being investigated for diabetes cell replacement therapy. This report presents a multifaceted transplantation strategy that combines differentiation into stem cell-derived β (SC-β) cells with 3D printing. By modulating the parameters of a low-cost 3D printer, we created a macroporous device composed of polylactic acid (PLA) that houses SC-β cell clusters within a degradable fibrin gel. Using finite element modeling of cellular oxygen diffusion-consumption and an in vitro culture system that allows for culture of devices at physiological oxygen levels, we identified cluster sizes that avoid severe hypoxia within 3D-printed devices and developed a microwell-based technique for resizing clusters within this range. Upon transplantation into mice, SC-β cell-embedded 3D-printed devices function for 12 weeks, are retrievable, and maintain structural integrity. Here, we demonstrate a novel 3D-printing approach that advances the use of differentiated hPSC for regenerative medicine applications and serves as a platform for future transplantation strategies.

[su_button url=”http://iopscience.iop.org/article/10.1088/1758-5090/9/1/015002/meta?elqTrackId=96062d779f46499eb7cc18d9ab30d665&elq=3d599e01edda49df92afa531a8a717ae&elqaid=17717&elqat=1&elqCampaignId=10609″ target=”blank” style=”flat” background=”#64b243″ size=”6″ center=”yes” radius=”5″ icon=”icon: angle-right”]Continue Reading[/su_button]

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Research suggests that diabetes could be due to failure of beta cell ‘hubs’

Original article published by University of Birmingham on July 21, 2016. Click here to read the original article.

The significant role of beta cell ‘hubs’ in the pancreas has been demonstrated for the first time, suggesting that diabetes may due to the failure of a privileged few cells, rather than the behaviour of all cells.

Researchers used optogenetic and photopharmacological targeting to precisely map the role of the cells required for the secretion of insulin.

The team believe that the findings, published in Cell Metabolism, could pave the way for therapies that target the ‘hubs’.

Dr David Hodson, from the University of Birmingham, explained, “It has long been suspected that ‘not all cells are equal’ when it comes to insulin secretion. These findings provide a revised blueprint for how our pancreatic islets function, whereby these hubs dictate the behaviour of other cells in response to glucose.”

According to the NHS, there are currently 3.9 million people living with diabetes in the UK, with 90% of those affected having type 2 diabetes.

Type 2 diabetes occurs when the pancreas fails to produce enough insulin to function properly, meaning that glucose stays in the blood rather than being converted into energy.

Beta cells (β cells) make up around 65-80% of the cells in the islets of the pancreas. Their primary function is to store and release insulin and, when functioning correctly, can respond quickly to fluctuations in blood glucose concentrations by secreting some of their stored insulin.

These findings show that just 1-10% of beta cells control islet responses to glucose.

Dr Hodson, who is supported by Diabetes UK RD Lawrence and EFSD/Novo Nordisk Rising Star Fellowships, continued, “These specialised beta cells appear to serve as pacemakers for insulin secretion. We found that when their activity was silenced, islets were no longer able to properly respond to glucose. “

Prof Guy Rutter, who co-led the study at Imperial College London, added “This study is interesting as it suggests that failure of a handful of cells may lead to diabetes”.

Studies were conducted on islet samples from both murine and human models.

The team noted that, though the findings present a significant step forward in understanding the cell mechanisms, the experiments therefore may not be reflected in vivo, where blood flow direction and other molecule dynamics may influence the role of the hubs and insulin secretion.

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Kristin-Mussar in a labcoat

Type 1 Diabetes Research Updates

We’re so grateful for everyone who donates to individual projects and our General Fund – it allows us to accomplish our vision of supporting innovative scientific inquiry until type 1 diabetes is eliminated.

To show our gratitude, it’s important to us that we keep our donors updated on the research they’ve helped fund. Scientific research can at times be an arduous process, which is why we sometimes go months without any updates. However, our researchers are constantly working to complete their research projects and are dedicated to spending every day finding innovative new ways to treat and cure diabetes.

Update: Creating New Insulin-Producing Cells To Repair Damaged Pancreas

Kristin Mussar provided the following update to her research at the end of April:

In our last update we identified a population of macrophages residing in the pancreas of newborns that was necessary for islet cells to expand in number as well as to mature into functional insulin-producing cells. Recently, we found that a functionally similar population capable of boosting islet proliferation exists in the bone marrow of adult individuals, which suggests that there might be potential for islet repair in adults. We are currently investigating whether this bone marrow population can be used as a cell therapy to enhance the repair process of islet cells in adult mouse models of injury. Additionally, we are still working to characterize the molecular signals underlying the effects that this cell population has on islet cell expansion and maturation. Thank you again for donating and making this research possible!

Visit her project page to learn more about this study.

Once again, thanks for your support in helping our mission to prevent, treat and cure type 1 diabetes. It may sound cliché, but we truly couldn’t do it without you. Stay tuned for more updates later this summer. We’re expecting to hear from Dr. Subhadra Gunawardana and Wendy Yang, in particular!

To support more innovative research project like this, click here.

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Halting Diabetes: UCSF Researchers Publish Study

UCSF DC Bhushan HebrokWritten by Kathleen Jay on June 23, 2015, via Diabetes Center at UCSF. Click here to read original article.

This week, novel findings by UCSF researchers Anil Bhushan, PhD, and Matthias Hebrok, PhD, for developing therapeutic strategies to combat diabetes were published in the Journal of Clinical Investigation.

The study, entitled “DNA methylation directs functional maturation of pancreatic beta cells,” analyzes how pancreatic beta cells become fully functional after birth.

“Pancreatic beta cells respond to glucose increases after a meal by secreting insulin. On the other end of the spectrum, the cells react to fasting conditions by preventing insulin production,” said Bhushan, a professor at the Diabetes Center at UCSF. “These cells only acquire the ability to secrete insulin in response to changing glucose levels post-natally, indicating that epigenetic mechanisms direct beta cell maturation after birth.”

External or environmental processes can affect how genes are expressed through a process known as epigenetics. If the DNA code for genes are the words in a book, epigenetics are like bookmarks that direct how and if the words are read. External factors can lead to epigenetic alterations, with molecular changes such as DNA methylation,that affect gene expression, without altering the underlying DNA sequence. Thus, epigenetic modifications provide an additional layer of control of how genes are expressed and impact whether a gene is turned “on” (expressed) or “off” (inhibited).

“Our results highlight a novel epigenetic mechanism that governs how beta cells functionally mature during neonatal life and provide new insights into impaired beta cell function in diabetes,” Bhushan said.

To develop these findings, Sangeeta Dhawan, PhD (now an independent scientist at UCLA) in the Bhushan team worked collaboratively with the Hebrok lab, which performed human beta cell analysis for this study.

“Because diseases, such as diabetes, are characterized by beta cell dysfunction which may involve epigenetic changes, we are trying to counteract these modifications with therapeutic, epigenetic treatments,” Bhushan said. “Unlike DNA sequence mutations, epigenetic changes – by nature – appear to be reversible.”

“With Anil’s arrival to UCSF this year, we have elevated beta cell work to new heights,” Hebrok, the director of the Diabetes Center at UCSF said. “This type of research will be highly useful in predicting diseases, such as type 1 diabetes, as well as improving the overall effectiveness of therapeutics to both reduce beta cell destruction and to promote beta cell regeneration.”

For more information, visit http://diabetes.ucsf.edu.

 

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Stem Cell

Type 1 Diabetes Discovery: Stem Cells Make Millions of Human Insulin Cells

As we are all aware, type 1 diabetes is an autoimmune disease where the body destroys insulin-producing beta cells in the pancreas. Without insulin, the body cannot control glucose, which can lead to high levels of blood sugar that eventually damage tissues and organs. A new study exposes how scientists successfully created billions of insulin-producing pancreatic beta cells from embryonic stem cells.(1)

The Harvard stem cell researchers report how they transplanted the stem cell-derived beta cells into the kidney of a diabetic mouse that showed no signs of the disease after two weeks. The study is a huge advance for patients with type 1 diabetes, and some with type 2 diabetes, many who require daily injections of insulin.

For their new technique to work in people with type 1 diabetes, the researchers must create a mechanism that halts a recipient’s immune system from attacking and destroying the 150 million or so beta cells they would receive. The team is currently collaborating with colleagues at the Massachusetts Institute of Technology (MIT) to develop an implant that protects the stem cell-derived beta cells from immune attack.

Stem Cells Diagram

With human embryonic stem cells as a starting point, the scientists were able to produce, in the massive quantities needed for cell transplantation and pharmaceutical purposes, human insulin-producing beta cells that are equivalent in almost every way to normally functioning beta cells.(3) This is the first time this has been done.

The stem-cell-derived beta cells are currently undergoing trials in animal models, including non-human primates. Researchers have attempted to generate human pancreatic beta cells that could be cultured under conditions where they produce insulin. Cell transplantation as a treatment for diabetes is still experimental, using cells from cadavers, requiring the use of powerful immunosuppressive drugs, and having been available to only a small number of patients.

Richard A. Insel, chief scientific officer of JDRF, formerly known as the Juvenile Diabetes Research Foundation, said, “JDRF is thrilled with this advancement toward large-scale production of mature, functional human beta cells by Dr. Melton and his team. This significant accomplishment has the potential to serve as a cell source for islet replacement in people with type 1 diabetes, and may provide a resource for discovery of beta-cell therapies that promote survival or regeneration of beta cells and development of screening biomarkers to monitor beta cell health and survival to guide therapeutic strategies for all stages of the disease.”(4)

The work was funded by the Juvenile Diabetes Research Foundation, the Harvard Stem Cell Institute, the National Institutes of Health, the JPB Foundation, and Mike and Amy Barry.(4)

Screening for abnormal blood glucose and diabetes

Stem Cell

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