Tag: pancreas

New Biomaterial Preserves Islets in Pancreas Removal Procedure

A 3D map of the islet density routes throughout the healthy human pancreas. Source: Wikimedia CC0

Northwestern University researchers have developed a new antioxidant biomaterial that someday could provide much-needed relief to people living with chronic pancreatitis. The study was published in the journal Science Advances.

Before surgeons remove the pancreas from patients with severe, painful chronic pancreatitis, they first harvest insulin-producing tissue clusters, called islets, and transplant them into the vasculature of the liver. The goal of the transplant is to preserve a patient’s ability to control their own blood-glucose levels without insulin injections.

Unfortunately, the process inadvertently destroys 50–80% of islets, and one-third of patients become diabetic after surgery. Three years post-surgery, 70% of patients require insulin injections, which are accompanied by a list of side effects, including weight gain, hypoglycaemia and fatigue.

In the new study, researchers transplanted islets from the pancreas to the omentum – the large, flat, fatty tissue that covers the intestines – instead of the liver. And, to create a healthier microenvironment for the islets, the researchers adhered the islets to the omentum with an inherently antioxidant and anti-inflammatory biomaterial, which rapidly transforms from a liquid to a gel when exposed to body temperature.

In studies with mouse and non-human primates, the gel successfully prevented oxidative stress and inflammatory reactions, significantly improving survival and preserving function of transplanted islets. It marks the first time a synthetic antioxidant gel has been used to preserve function of transplanted islets.

“Although islet transplantation has improved over the years, long-term outcomes remain poor,” said Northwestern’s Guillermo A. Ameer, who led the study. “There is clearly a need for alternative solutions. We have engineered a cutting-edge synthetic material that provides a supportive microenvironment for islet function. When tested in animals, we were successful. It kept islet function maximised and restored normal blood sugar levels. We also report a reduction in units of insulin that animals required.”

“With this new approach, we hope that patients will no longer have to choose between living with the physical pain of chronic pancreatitis or the complications of diabetes,” added Jacqueline Burke, a research assistant professor of biomedical engineering at Northwestern and the paper’s first author.

‘Compromised quality of life’

For patients living without a pancreas, side effects such as managing blood-sugar levels can be a lifelong struggle. By secreting insulin in response to glucose, islets help the body maintain glycaemic control. Without functioning islets, people must closely monitor their blood-sugar levels and frequently inject insulin.

“Living without functional islets places a great burden on patients,” Burke said. “They must learn to count carbs, dose insulin at the appropriate time and continuously monitor blood glucose. This consumes much of their time and mental energy. Even with great care, exogeneous insulin therapy is not as effective as islets for maintaining glucose control.”

“It’s a compromised quality of life,” Ameer said. “Instead of multiple insulin injections, we would love to collect and preserve as many islets as possible.”

But, unfortunately, the current standard of care for preserving islets often leads to poor outcomes. After the surgery to remove the pancreas, surgeons isolate islets from the pancreas and transplant them to the liver through portal vein infusion. This intraportal perfusion procedure has several common complications. Islets in direct contact with blood flow undergo an inflammatory response, more than half of the islets die, and transplanted islets can cause dangerous clots in the liver. For those reasons, physicians and researchers have been searching for an alternate transplantation site.

In previous clinical studies, researchers transplanted islets to the omentum instead of the liver in order to bypass issues with clotting. To secure the islets on the omentum, physicians used plasma from the patients’ own blood to form a biologic gel. While the omentum appeared to work better than the liver as a transplantation site, several issues, including clots and inflammation, remained.

“There’s been significant interest in the research and medical communities to find an alternate islet transplantation site,” Ameer said. “The results from the omentum study were encouraging, but outcomes were varied. We believe that’s because the use of the patients’ blood and the added components required to create the biologic gel can affect reproducibility among patients.”

A citrate solution

To protect the islets and improve outcomes, Ameer turned to the citrate-based biomaterials platform with inherent antioxidant properties developed in his laboratory. Used in products approved by U.S. Food and Drug Administration for musculoskeletal surgeries, citrate-based biomaterials have demonstrated the ability to control the body’s inflammatory responses. Ameer set out to investigate whether a version of these biomaterials with biodegradable and temperature-responsive phase-changing properties would provide a superior alternative to a biologic gel obtained from blood.

In cell cultures, both mouse and human islets stored within the citrate-based gel maintained viability much longer than islets in other solutions. When exposed to glucose, the islets secreted insulin, demonstrating normal functionality. Moving beyond cell cultures, Ameer’s team tested the gel in small and large animal models. Liquid at room temperature, the material turns into a gel at body temperature, so it’s simple to apply and easily stays in place.

In the animal studies, the gel effectively secured the islets onto the omentum of the animals. Compared to the current methods, more islets survived, and, over time, the animals restored normal blood glucose levels. According to Ameer, the success is partially due to the new material’s biocompatibility and antioxidant nature.

“Islets are very sensitive to oxygen,” Ameer said. “They are affected by both too little oxygen and too much oxygen. The material’s innate antioxidant properties protect the cells. Plasma from your own blood doesn’t offer the same level of protection.”

Integrating into tissues

After about three months, the body resorbed 80-90% of the biocompatible gel. But, at that point, it was no longer needed.

“What was fascinating is that the islets regenerated blood vessels,” Ameer said. “The body generated a network of new blood vessels to reconnect the islets with the body. That is a major breakthrough because the blood vessels keep the islets alive and healthy. Meanwhile, our gel is simply resorbed into the surrounding tissue, leaving little evidence behind.”

Next, Ameer aims to test his hydrogel in animal models over a longer period of time. He said the new hydrogel also could be used for various cell replacement therapies, including stem cell-derived beta cells for treating diabetes.

Source: Northwestern University

Experimental Type 1 Diabetes Drug Shields Pancreas Cells from Immune System Attack

A 3D map of the islet density routes throughout the healthy human pancreas. Source: Wikimedia CC0

An experimental monoclonal antibody drug called mAb43 appears to prevent and reverse the onset of clinical type 1 diabetes in mice, in some cases lengthening the animals’ lifespan, report scientists at Johns Hopkins Medicine.

The drug is unique, according to the researchers, because it targets insulin-making beta cells in the pancreas directly and is designed to shield those cells from attacks by the body’s own immune system cells. The drug’s specificity for such cells may enable long-term use in humans with few side effects, say the researchers. Monoclonal antibodies are made by cloning, or making identical replicas of, an animal (including human) cell line.

The findings, published in Diabetes, raise the possibility of a new drug for type 1 diabetes, an autoimmune condition which has no cure or means of prevention. Unlike type 2 diabetes, in which the pancreas makes too little insulin, in type 1 diabetes, the pancreas makes no insulin because the immune system attacks the pancreatic cells that make it.

The lack of insulin interferes with the body’s ability to regulate blood sugar levels.

According to Dax Fu, PhD, associate professor of physiology at the Johns Hopkins University School of Medicine and leader of the research team, mAb43 binds to a small protein on the surface of beta cells, which dwell in clusters called islets. The drug was designed to provide a kind of shield or cloak to hide beta cells from immune system cells that attack them as “invaders.” The researchers used a mouse version of the monoclonal antibody, and will need to develop a humanised version for studies in people.

For the current study, the researchers gave 64 non-obese mice bred to develop type 1 diabetes a weekly dose of mAb43 via intravenous injection when they were 10 weeks old. After 35 weeks, all mice were non-diabetic. One of the mice developed diabetes for a period of time, but it recovered at 35 weeks, and that mouse had early signs of diabetes before the antibody was administered.

In five of the same type of diabetes-prone mice, the researchers held off giving weekly mAb43 doses until they were 14 weeks old, and then continued dosages and monitoring for up to 75 weeks. One of the five in the group developed diabetes, but no adverse events were found, say the researchers.

In the experiments in which mAb43 was given early on, the mice lived for the duration of the monitoring period of 75 weeks, compared with the control group of mice that did not receive the drug and lived about 18-40 weeks.

Next, the researchers, including postdoctoral fellows Devi Kasinathan and Zheng Guo, looked more closely at the mice that received mAb43 and used a biological marker called Ki67 to see if beta cells were multiplying in the pancreas. They said, after treatment with the antibody, immune cells retreated from beta cells, reducing the amount of inflammation in the area. In addition, beta cells slowly began reproducing.

“mAb43 in combination with insulin therapy may have the potential to gradually reduce insulin use while beta cells regenerate, ultimately eliminating the need to use insulin supplementation for glycaemic control,” says Kasinathan.

The research team found that mAb43 specifically bound to beta cells, which make up about 1% or 2% of pancreas cells.

Another monoclonal antibody drug, teplizumab, received US Food and Drug Administration approval in 2022. Teplizumab binds to T cells, making them less harmful to insulin-producing beta cells. The drug has been shown to delay the onset of clinical (stage 3) type 1 diabetes by about two years, giving young children who get the disease time to mature and learn to manage lifelong insulin injections and dietary restrictions.

“It’s possible that mAb43 could be used for longer than teplizumab and delay diabetes onset for a much longer time, potentially for as long as it’s administered,” says Fu.

Source: John Hopkins Medicine

T Cell Monitoring may Help Prevent Type 1 Diabetes

A 3D map of the islet density routes throughout the healthy human pancreas. Source: Wikimedia CC0

Scripps Research scientists have shown that people at risk of developing type 1 diabetes could be identified by analysis of the T cells which drive the disease. The new approach, if validated in further studies, could be used to select suitable patients for a newly FDA-approved treatment that stops the autoimmune process, thereby making type 1 diabetes a preventable condition.

In the study, which appears in Science Translational Medicine, the researchers isolated T cells from mouse and human blood samples. By analysing the T cells that can cause type 1 diabetes, they were able to distinguish the at-risk patients who had active autoimmunity from those who had no significant autoimmunity – with 100% accuracy in a small sample.

“These findings represent a big step forward because they offer the possibility of catching this autoimmune process while there is still time to prevent or greatly delay diabetes,” says study senior author Luc Teyton, MD, PhD, professor in the Department of Immunology and Microbiology at Scripps Research.

The study’s first authors were graduate student Siddhartha Sharma and research assistants Josh Boyer and Xuqian Tan, all of the Teyton lab at the time of the study.

Type 1 diabetes usually occurs in childhood or early adulthood, in an autoimmune process that destroys the pancreas’s insulin-producing islet cells. The process can last years, with multiple starts and stops. Exactly how the process begins is not well understood, though it is known to involve genetic factors and may be triggered by routine viral infections.

In 2022, the US Food & Drug Administration approved an immune-suppressing therapy that can protect islet cells and at least delay diabetes onset by months to years if given in the early stages of autoimmunity. However, doctors have not had a good method for identifying people who could benefit from such treatment. They have traditionally examined levels of anti-islet antibodies in patient blood samples, but this antibody response has not been a very accurate measure of autoimmune progression.

“Anti-islet antibody levels are poorly predictive at the individual level, and type 1 diabetes is fundamentally a T cell-driven disease,” Teyton says.

In the study, Teyton and his team constructed protein complexes to mimic the mix of immune proteins and insulin fragments that CD4 T cells normally would recognise to initiate the autoimmune reaction. They used these constructs as bait to capture anti-insulin CD4 T cells in blood samples. They then analysed the gene activity within the captured T cells, and expression of proteins on the cells, to gauge their state of activation.

In this way, they were able to develop a classification algorithm that correctly identified which at-risk patients, in a set of nine, had ongoing anti-islet autoimmunity.

Teyton now hopes to validate the CD4 T cell-based approach with a long-term study in a larger cohort of participants, comparing this approach to the traditional approach of quantifying anti-islet antibodies.

Teyton and his colleagues also are working to make the process of isolating and analysing anti-islet T cells in blood samples more affordable and convenient, so that it can be used more easily in a clinical setting.

“If we can develop this into a useful method for identifying at-risk patients and tracking their autoimmunity status, we not only would have a way of getting the right people into treatment, but also would be able to monitor their disease progress and evaluate potential new preventive therapies,” Teyton says.

Source: Scripps Research Institute

Artificial Pancreas Successfully Trialled for Type 2 Diabetes

Diabetes - person measures blood glucose
Photo by Photomix Company from Pexels

Cambridge scientists have successfully trialled an artificial pancreas for use by patients living with type 2 diabetes. They report in Nature Medicine that the device doubled the amount of time patients were in the target range for glucose compared to standard treatment and halved the time spent experiencing high glucose levels.

The artificial pancreas developed by University of Cambridge researchers combines an off-the-shelf glucose monitor and insulin pump with an app developed by the team, known as CamAPS HX. This app is run by an algorithm that predicts how much insulin is required to maintain glucose levels in the target range.

The researchers have previously shown that an artificial pancreas run by a similar algorithm is effective for patients living with type 1 diabetes, from adults through to very young children. They have also successfully trialled the device in patients with type 2 diabetes who require kidney dialysis.

Today, in Nature Medicine, the team report the first trial of the device in a wider population living with type 2 diabetes (not requiring kidney dialysis). Unlike the artificial pancreas used for type 1 diabetes, this new version is a fully closed loop system, whereas patients with type 1 diabetes need to tell their artificial pancreas that they are about to eat to allow adjustment of insulin, for example, with this version they can leave the device to function entirely automatically.

The researchers recruited 26 patients who were randomised to one of two groups – the first group would trial the artificial pancreas for eight weeks and then switch to the standard therapy of multiple daily insulin injections; the second group would take this control therapy first and then switch to the artificial pancreas after eight weeks.

The team used several measures to assess how effectively the artificial pancreas worked. The first was the proportion of time that patients spent with their glucose levels within a target range of between 3.9 and 10.0mmol/L. On average, patients using the artificial pancreas spent two-thirds (66%) of their time within the target range, compared to control (32%).

A second measure was the proportion of time spent with glucose levels above 10.0mmol/L. Over time, high glucose levels raise the risk of potentially serious complications. Patients taking the control therapy spent two-thirds (67%) of their time with high glucose levels — this was halved to 33% when using the artificial pancreas.

Average glucose levels fell from 12.6mmol/L when taking the control therapy to 9.2mmol/L while using the artificial pancreas.

The app also reduced levels of a molecule known as glycated haemoglobin, or HbA1c. Glycated haemoglobin develops when haemoglobin, a protein within red blood cells that carries oxygen throughout the body, joins with glucose in the blood, becoming ‘glycated’. By measuring HbA1c, clinicians are able to get an overall picture of what a person’s average blood sugar levels have been over a period of weeks or months. For people with diabetes, the higher the HbA1c, the greater the risk of developing diabetes-related complications. After the control therapy, average HbA1c levels were 8.7%, while after using the artificial pancreas they were 7.3%.

No patients experienced dangerously-low blood sugar levels (hypoglycaemia) during the study. One patient was admitted to hospital while using the artificial pancreas, due to an abscess at the site of the pump cannula.

Dr Charlotte Boughton from the Wellcome-MRC Institute of Metabolic Science at the University of Cambridge, who co-led the study, said: “Many people with type 2 diabetes struggle to manage their blood sugar levels using the currently available treatments, such as insulin injections. The artificial pancreas can provide a safe and effective approach to help them, and the technology is simple to use and can be implemented safely at home.”

Dr Aideen Daly, also from the Wellcome-MRC Institute of Metabolic Science, said: “One of the barriers to widespread use of insulin therapy has been concern over the risk of severe ‘hypos’ — dangerously low blood sugar levels. But we found that no patients on our trial experienced these and patients spent very little time with blood sugar levels lower than the target levels.”

Feedback from participants suggested that participants were happy to have their glucose levels controlled automatically by the system, and nine out of ten (89%) reported spending less time managing their diabetes overall. Users highlighted the elimination of the need for injections or fingerprick testing, and increased confidence in managing blood glucose as key benefits. Downsides included increased anxiety about the risk of hypoglycaemia, which the researchers say may reflect increased awareness and monitoring of glucose levels, and practical annoyances with wearing of devices.

The team now plan to carry out a much larger multicentre study to build on their findings and have submitted the device for regulatory approval with a view to making it commercially available for outpatients with type 2 diabetes.

Source: University of Cambridge

Researchers Successfully Restore Pancreatic Beta Cells in Type 1 Diabetes

Image depicting diabetes
Image by Nataliya Vaitkevich on Pexels

Scientists have successfully treated type 1 diabetes in mice using pancreatic beta-cell, target-specific, chimeric antigen-receptor (CAR) regulatory T cells (Tregs), showing the feasibility of replicating this in humans according to data presented at ENDO 2022, the Endocrine Society’s annual meeting.

The study was led by Professor Juan Carlos Jaume, MD, at the University of Toledo.

Adoptive cell transfer therapies with CAR cytotoxic T cells have proven effective for the treatment of haematologic malignancies. Prof Jaume and colleagues attempted to replicate an equally effective experimental treatment for type 1 diabetes using instead non-cytotoxic, anti-inflammatory Tregs.

“The purpose of this study was to determine if pancreatic beta-cell, target-specific, human CAR Tregs could also identify human pancreatic beta cells and home to human pancreatic islets in culture as they do in mice undergoing CAR Treg treatment for T1D,” Prof Jaume said.

The researchers drew blood one to two weeks prior to pancreas surgery, followed by a collection of a a 5cc wedge of the pancreas after the pancreas was removed for a clinically indicated reason, either cancer or pancreatitis.

The researchers isolated Tregs from the blood samples and expanded them in vitro. Those cells were genetically modified to express a beta-cell, target-specific CAR combined with a green fluorescence protein (GFP) marker.

The next step was to process the pancreas tissue for islet separation. Following this, they co-cultured the human pancreatic islets combined with the beta-cell, target-specific CAR Tregs.

Within 24 hours, confocal microscopy demonstrated the successful migration of the GFP positive, CAR Tregs onto the pancreatic islets. What’s more, the CAR Tregs significantly proliferated while in physical contact with the pancreatic islets in the subsequent 72 hours.

“Ours is the first successful, pancreatic beta-cell, target-specific CAR-Treg treatment of T1D in a humanized mouse model that closely resembles the human disease. Based on our mice and human in-vitro data, we believe treatment with pancreatic beta-cell, target-specific, CAR-Tregs will allow for recovery and reconstitution of beta cells in human T1D patients as well,” Prof Jaume said.

Source: EurekAlert!

More ACE2 Makes Pancreatic Cells a COVID Target

Source: CDC

Researchers have revealed insights into how SARS-CoV-2 attacks the insulin-producing cells of the pancreas.

There is mounting evidence of damage to the pancreas and resulting diabetes attributed to COVID, which is of great concern. The virus targets the angiotensin converting enzyme 2 (ACE2) protein on the surface of those cells, and is the subject of a special presentation at this year’s Annual Meeting of the European Association for the Study of Diabetes, given by the University of Siena’s Professor Francesco Dotta. 

“The SARS-CoV-2 virus attacks specific host tissues because of the presence of viral receptors on the surface of the target cells. As such, virus binding to ACE2 protein is the key determinant for its entry, propagation and transmissibility,” explained Prof Dotta.

“Multiple studies have shown that older adults and those with chronic medical conditions like heart and lung disease and/or diabetes are at the highest risk for complications from SARS-CoV-2 infections. Moreover, impaired blood sugar control is associated with increased risk of severe COVID, suggesting a link between COVID infection and diabetes. Several reports indicate a wide, although variable, distribution of the ACE2 protein among different tissues.”

Prof Dotta and colleagues studied the ACE2 expression pattern in pancreatic tissue samples of non-diabetic multiorgan donors to better understand the molecular link between COVID and diabetes.

In the ‘normal’ pancreas, ACE2 is highly expressed in microvasculature and in ductal cells. “Importantly, we found that ACE2 was expressed in human pancreatic islets, where it is preferentially expressed in insulin producing beta-cells. We also demonstrated that ACE2 levels were increased under pro-inflammatory conditions, thus confirming the link between inflammation and ACE2 also in pancreatic islet beta cells.”

In order to isolate the mechanism involved in the upregulation of ACE2 induced by inflammation, ACE2 levels were measured in human pancreatic islets pre-treated with Jak1/2 and TYK2 inhibitors, which block inflammation in beta cells, and then exposed to pro-inflammatory conditions. 

Prof Dotta said: “We showed that these drugs prevent the ACE2 increase induced by inflammation in human pancreatic islets, demonstrating that SARS-CoV-2 receptor ACE2 is regulated through specific molecular pathways and that its increased expression can be prevented.

“We studied the mechanisms of SARS-CoV-2 virus entry into insulin producing beta cells and we discovered that these cells express the SARS-CoV-2 receptor ACE2.” Other authors have independently confirmed such data.

Of note, additional published data confirmed that SARS-CoV-2 can indeed infect pancreatic insulin-producing cells causing their dysfunction or death. Moreover, during inflammation, ACE2 expression increases several times above standard values.

Prof Dotta concluded: “This means that these insulin-producing beta cells could be even more susceptible to viral infection when inflamed. This finding is also important from a clinical standpoint, since keeping inflammatory status under control in patients with COVID may reduce the expression of ACE2 receptor in beta cells with beneficial effects on blood sugar and metabolic control of patients.”

Source: EurekAlert!

Why Antipsychotic Drugs Cause Weight Gain

A University of Pittsburgh study has discovered that the reason antipsychotic medications have weight gain as side effects is because the pancreas also produces and responds to dopamine.

Dopamine is a neurotransmitter involved in mood regulation, pleasure and reward signalling. Many psychological disorders are thought to involve dopamine imbalances and are treated by medications designed to this end.
“There are dopamine theories of schizophrenia, drug addiction, depression and neurodegenerative disorders, and we are presenting a dopamine theory of metabolism,” said lead author Despoina Aslanoglou, PhD, at the University of Pittsburgh. “We’re seeing now that it is not only interesting to study dopamine in the brain, but it is equally interesting and important to study it in the periphery.”

Senior author Zachary Freyberg, MD, PhD, assistant professor of psychiatry and cell biology at Pitt, observed that the dopamine theory is not as simple or as well understood as we would like to think.

“We still don’t really understand how dopamine signals biologically,” said Dr Freyberg. “Even decades after dopamine receptors have been discovered and cloned, we still deploy this ‘magical thinking’ approach: something happens that’s good enough. We use drugs that work on dopamine receptors, but how they intersect with this ‘magical system’ is even less understood.”

The researchers found that dopamine is not only produced in the brain but also in the alpha and beta cells of the pancreas, which secrete glucagon and insulin, respectively.

Alpha cells can produce their own dopamine with no precursors in response to glucose levels, while beta cells require an L-DOPA precursor. It may be possible that alpha cells secrete dopamine for their own receptors, while also supplying it to beta cells to suppress the release of insulin.

Surprisingly, the researchers also discovered that pancreatic dopamine can affect other receptors, such as noradrenaline and adrenaline.
At low concentrations, dopamine binds to D2-like dopamine receptors, blocking the release of glucagon or insulin. At high concentrations, dopamine binds to beta-adrenergic receptors, becoming stimulatory and pushing up glucagon levels while inhibiting insulin levels by blocking alpha-adrenergic receptors.

The study revealed how blocking inhibitory dopamine receptors causes an unchecked release of insulin and glucagon, leading to metabolic disorders and eventually, obesity and diabetes. This finding will help to formulate better drugs that target the dopamine system, reducing the effect on the pancreas.

Source: News-Medical.Net