In this month’s podcast, QuickNews looks at a new Lancet study, “Non-autoimmune, insulin-deficient diabetes in children and young adults in Africa.” In this study, researchers report that a significant subset of what has previously been classified as Type 1 diabetes in sub-Saharan Africa may in fact be a distinct, novel form of the disease.
The individuals in this subset did not exhibit the typical autoimmune markers (islet autoantibodies) usually found in classic Type 1 diabetes in other parts of the world. The researchers instead identified a novel, non-autoimmune, insulin-deficient subtype of diabetes that is also distinct from Type 2 diabetes.
Further evidence of this new subtype was found in Black individuals in the USA, albeit less frequently, but not in White individuals. The discovery throws a spotlight on the heterogeneity of diabetes diagnoses in sub-Saharan Africa, and points to the need to consider alternative causes and explore new prevention and treatment strategies for this distinct form of the disease.
A 3D map of the islet density routes throughout the healthy human pancreas. Source: Wikimedia CC0
Cornell researchers have developed an implant system that can treat Type 1 diabetes by supplying extra oxygen to densely packed insulin-secreting cells, without the need for immunosuppression. The system could also potentially provide long-term treatment for a range of chronic diseases.
The findings appear in Nature Communications. The co-first authors were former postdoctoral researcher Tung Pham and doctoral candidate Lora (Phuong) Tran.
The technology builds off previous implantable encapsulation devices developed in the lab of Minglin Ma, professor of biological and environmental engineering in the College of Agriculture and Life Sciences (CALS) and the paper’s senior author.
Ma has explored a variety of ways to address Type 1 diabetes, which is typically managed through daily insulin injections or insulin pumps, but even with that treatment, patients still suffer the devastating effects of the disease.
Ma’s previous implantable devices have proved effective in controlling blood sugar in diabetic mice, but they can only last so long.
“One of the major challenges is the implant itself often dies due to the lack of oxygen after implantation,” Tran said. “In our lab, they had success in micethat lived over one year, and they controlled the diabetes very effectively with some small capsules without oxygen generation. However, when we scale up, we need more cells, we need more density, especially. We need a higher dose. If we implant without generating oxygen, the cells often die within two weeks.”
Ma’s team developed the new system in collaboration with electrochemical researchers from Giner Inc, including co-author Linda Tempelman, PhD ’93.
The key components of the system are a cylindrical capsule with a ring-shaped cross-section that contains transplanted insulin-secreting cells, and an electrochemical oxygen generator that is roughly the size of a dime and removeable. A nanofibrous membrane outside the capsule protects the cells from the host body’s immune system; a permeable membrane in the core of the capsule allows the central supply of oxygen to reach the ring of cells.
“We have to meet two requirements,” Tran said. “The first is immune protection. And second, you have to maintain mass transfer, like the glucose and other nutrients and molecules that can go in and out.”
Working with Dr James Flanders, associate professor emeritus in the College of Veterinary Medicine, the researchers successfully tested the system in rat models.
“It’s the proof of concept. We really proved that oxygenation is important, and oxygenation will support high cell-density capsules,” Tempelman said. “The capsules are immune protective and last for a long time without having some kind of fouling of the membrane. The body never likes when you put a foreign substance in. So that’s the engineering in the Ma Lab, to look for materials and coatings for the materials that are immune protective, but also don’t invoke excess response from the body because of the material.”
The new system would enable a much greater number of the 2 million people who suffer from Type 1 diabetes in the US to now have an islet transplant or cell therapy without requiring immune suppression, which is considered too dangerous for routine use. Also, the new system can provide much tighter sugar control, effectively curing the disease and enabling the person to eat, drink and exercise like everyone else.
The next step will be to implant the system in a pig model, and also test it with human stem cells. The researchers are interested in eventually trying to use the system for implanting different cell types in humans for long-term treatment of chronic diseases, according to Tempelman, who is CEO of Persista Bio Inc., a new startup she founded with Ma and Flanders that is licensing these technologies.
“We see an age where people will be getting implants with allogeneic cells from other human beings, from stem cell lines, and using it long term to treat things that your body is missing,” Tempelman said. “Here we’re missing insulin. In pain control, maybe you need more endorphins or some other molecule. In enzyme replacement therapy, you need more enzymes. We’re interested in things like other autoimmune diseases where there’s inflammation that’s out of control.
“So maybe you could put a small molecule in that would treat inflammation, and then someone, like a Lupus patient, wouldn’t have to take an oral medication. They could just have a low-level implant that provides a low amount of it.”
A new study in teenagers with type 1 diabetes shows promise in reducing chronic kidney disease and informing future precision care.
Photo by Nataliya Vaitkevich on Pexels
A clinical trial involving adolescents with type 1 diabetes (T1D) has found a combination therapy may reduce chronic kidney disease and improve health outcomes. The findings could help guide more precision care for young people with T1D.
Led by Dr Farid Mahmud, Associate Scientist in the Translational Medicine program and Staff Physician in the Division of Endocrinology at The Hospital for Sick Children (SickKids), and published in Nature Medicine, the study evaluated a therapy that combines standard insulin treatment with the investigational drug dapagliflozin. Results of this combination therapy showed improved blood sugar control and kidney function, and reduced weight gain in adolescents with T1D.
While most people with T1D are diagnosed as adults, the condition often starts in childhood and early adolescence. The lifelong insulin therapy needed can lead to side effects such as weight gain and chronic kidney disease. In the trial, participants who received dapagliflozin alongside insulin had fewer of these side effects and better overall health outcomes.
“Our findings showed that adolescents who received this combination therapy were able to improve many symptoms typically associated with insulin-managed type one diabetes,” says Mahmud. “This could inform a new early intervention strategy for the growing population of teenagers with type one diabetes.”
Patient partner key to trial success
While previous research has shown similar results in adults, Mahmud’s team focused on designing a clinical trial specifically for teenagers, a group often underrepresented in clinical trials. Hormonal changes, psychological development, and the shared responsibility between teens and their parents for managing treatment protocols can make trial participation more complex for this age group.
To address these challenges, the research team worked closely with patient partner Lynne McArthur. Together, they enrolled 98 participants between 12 and 18 years old in the study, known as the ATTEMPT study, across three sites.
McArthur’s involvement in research began when one of her twin sons was diagnosed with T1D following a trip to the SickKids emergency department at just 18 months old. A few years later, his twin was also diagnosed. That experience led McArthur to become more involved in research efforts to improve diagnosis and treatment options for families like hers.
“Deciding to participate in a clinical trial is an important decision, but my goal has always been disease prevention. I knew that our participation could help build a future where children don’t get T1D.”
Lynne McArthur
Now that her sons are older, McArthur continues to be involved as a patient advisor. She reviews recruitment materials and provides feedback on trial design, helping ensure the research stays connected to the lived experience of people managing T1D.
“Participating in research, whether in a trial or as an advisor, is hugely rewarding. With my experience as trial participant, I can see how the plans on paper would impact the real lives of people living with diabetes,” explains McArthur.
A new study in the European Heart Journal shows that people who develop type 1 diabetes in adulthood have an increased risk of cardiovascular disease and death, and that those diagnosed later in life do not have a better prognosis than those diagnosed earlier. The study, conducted by researchers at Karolinska Institutet, points to modifiable factors – smoking, poor glucose control and obesity – as the main risk factors.
Type 1 diabetes used to be called childhood diabetes but can start at any time during life – a situation for which there is limited research. The researchers behind the current study wanted to investigate the risk of cardiovascular disease and death in this group, particularly for those diagnosed after the age of 40.
The registry-based study identified 10 184 people diagnosed with type 1 diabetes in adulthood between 2001 and 2020 and compared them to 509 172 matched people in the control group.
The study shows that these people with adult-onset type 1 diabetes had a higher risk of cardiovascular disease and death from all causes, including cancer and infections, compared to the control group.
“The main reasons for the poor prognosis are smoking, overweight/obesity and poor glucose control. We found that they were less likely to use assistive devices, such as insulin pumps,” says first author Yuxia Wei, postdoctoral fellow at the Institute of Environmental Medicine, Karolinska Institutet.
The prognosis can be improved
The results emphasise the seriousness of type 1 diabetes, even when it starts later in life, the researchers say. But the prognosis can improved by avoiding smoking and obesity, especially for those diagnosed later in life.
The researchers plan to continue investigating adult-onset type 1 diabetes, including risk factors for developing the disease and the prognosis of other outcomes, such as microvascular complications. Optimal treatment in adult-onset type 1 diabetes, including the effect of pump use and other advanced technologies, also needs to be explored.
A study co-led by Indiana University School of Medicine researchers presents a potential new strategy to prevent or slow the progression of Type 1 diabetes by targeting an inflammation-related protein known to drive the disease. The findings, recently published in eBioMedicine, may help inform clinical trials of a drug that is already approved by the U.S. Food and Drug Administration for psoriasis as a treatment for Type 1 diabetes.
In laboratory studies using human cells and mouse models, the researchers found that applying a molecular method to block inflammation signalling through the tyrosine kinase 2 (TYK2) protein reduced harmful inflammation in the pancreas. This strategy not only protected the beta cells in the pancreas but also reduced the immune system’s attack on those cells. A medication that inhibits TYK2 is already approved for the treatment of psoriasis, an autoimmune condition that causes skin inflammation.
“Our study showed that targeting TYK2 could be a powerful way to protect insulin-producing beta cells while calming inflammation in the immune system at the same time,” said Carmella Evans-Molina, MD, PhD, co-author of the study and director of the Indiana Diabetes Research Center and the Eli Lilly and Company Professor of Pediatric Diabetes at the IU School of Medicine. “This finding is exciting because there is already a drug on the market that does this for psoriasis, which could help us move more quickly toward testing it for Type 1 diabetes.”
Past genetic studies have already shown that people with naturally lower TYK2 activity are less likely to develop Type 1 diabetes, further supporting the group’s approach for future treatments using this TYK2 inhibitor approach.
“Our preclinical models suggest that the treatment might work in people as well,” said Farooq Syed, PhD, lead author of the study and assistant professor in the Department of Diabetes-Immunology at the Arthur-Riggs Diabetes and Metabolic Research Institute of the City of Hope. “The next step is to initiate translational studies to evaluate the impact of TYK2 inhibition alone or in combination with other already approved drugs in individuals at-risk or with recent onset Type 1 diabetes.”
Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health
Exposure to antibiotics during a key developmental window in infancy can stunt the growth of insulin-producing cells in the pancreas and may boost risk of diabetes later in life, new research in mice suggests. The study, published this month in the journal Science, also pinpoints specific microorganisms that may help those critical cells proliferate in early life.
The findings are the latest to shine a light on the importance of the human infant microbiome—the constellation of bacteria and fungi living on and in us during our first few years. The research could lead to new approaches for addressing a host of metabolic diseases.
“We hope our study provides more awareness for how important the infant microbiome actually is for shaping development,” said first author Jennifer Hill, assistant professor in molecular, cellular and developmental biology at CU’s BioFrontiers Institute. “This work also provides important new evidence that microbe-based approaches could someday be used to not only prevent but also reverse diabetes.”
Something in the environment
More than 2 million U.S. adults live with Type 1 diabetes. The disease typically emerges in childhood, and genetics play a strong role. But scientists have found that, while identical twins share DNA that predisposes them to Type 1 diabetes, only one twin usually gets the disease.
“This tells you that there’s something about their environmental experiences that is changing their susceptibility,” said Hill.
For years, she has looked to microbes for answers.
Previous studies show that children who are breastfed or born vaginally, which can both promote a healthy infant microbiome, are less likely to develop Type 1 diabetes than others. Some research also shows that giving babies antibiotics early can inadvertently kill good bugs with bad and boost diabetes risk.
The lingering questions: What microbes are these infants missing out on?
“Our study identifies a critical window in early life when specific microbes are necessary to promote pancreatic cell development,” said Hill.
A key window of opportunity
She explained that human babies are born with a small amount of pancreatic “beta cells,” the only cells in the body that produce insulin. But some time in a baby’s first year, a once-in-a-lifetime surge in beta cell growth occurs.
“If, for whatever reason, we don’t undergo this event of expansion and proliferation, that can be a cause of diabetes,” Hill said.
She conducted the current study as a postdoctoral researcher at the University of Utah with senior author June Round, a professor of pathology.
They found that when they gave broad-spectrum antibiotics to mice during a specific window (the human equivalent of about 7 to 12 months of life), the mice developed fewer insulin producing cells, higher blood sugar levels, lower insulin levels and generally worse metabolic function in adulthood.
“This, to me, was shocking and a bit scary,” said Round. “It showed how important the microbiota is during this very short early period of development.”
Lessons in baby poop
In other experiments, the scientists gave specific microbes to mice, and found that several they increased their production of beta cells and boosted insulin levels in the blood. The most powerful was a fungus called Candida dubliniensis.
The team used faecal samples from The Environmental Determinants of Diabetes in the Young (TEDDY) study to make what Hill calls “poop slushies” and fed them to the mice.
When the researchers inoculated newborn mice with poop from healthy infants between 7 to 12 months in age, their beta cells began to grow. Poop from infants of other ages did not do the same. Notably, Candida dublineinsis was abundant in human babies only during this time period.
“This suggests that humans also have a narrow window of colonisation by these beta cell promoting microbes,” said Hill.
When male mice that were genetically predisposed to Type 1 diabetes were colonised with the fungus in infancy, they developed diabetes less than 15% of the time. Males that didn’t receive the fungus got diabetes 90% of the time.
Even more promising, when researchers gave the fungus to adult mice whose insulin-producing cells had been killed off, those cells regenerated.
Too early for treatments
Hill stresses that she is not “anti-antibiotics.” But she does imagine a day when doctors could give microbe-based drugs or supplements alongside antibiotics to replace the metabolism-supporting bugs they inadvertently kill.
Poop slushies (faecal microbiota transplants) have already been used experimentally to try to improve metabolic profiles of people with Type 2 diabetes, which can also damage pancreatic beta cells.
But such approaches can come with real risk, since many microbes that are beneficial in childhood can cause harm in adults. Instead, she hopes that scientists can someday harness the specific mechanisms the microbes use to develop novel treatments for healing a damaged pancreas—reversing diabetes.
She recently helped establish a state-of-the-art “germ-free” facility for studying the infant microbiome at CU Boulder. There, animals can be bred and raised entirely without microbes, and by re-introducing them one by one scientists can learn they work.
“Historically we have interpreted germs as something we want to avoid, but we probably have way more beneficial microbes than pathogens,” she said. “By harnessing their power, we can do a lot to benefit human health.”
People with type 1 diabetes require continuous insulin treatment and must regularly measure their glucose levels. With open-loop therapies*, insulin administration is manually controlled, while hybrid closed-loop systems* automatically regulate insulin delivery. A study with the involvement of the German Center for Diabetes Research showed that hybrid closed-loop systems offer improved long-term blood sugar values (HbA1c levels) and a lower risk of hypoglycaemic coma, but lead to a higher rate of diabetic ketoacidosis. The results were published in The Lancet Diabetes & Endocrinology.
Despite advances in insulin therapy, many people do not achieve their blood glucose targets and have a high risk of complications. Until now, the effect of insulin delivery in hybrid closed-loop systems on the risk of acute diabetes complications in people with type 1 diabetes has been unclear. Researchers have therefore now investigated whether the rates of severe hypoglycaemia and diabetic ketoacidosis are lower with hybrid closed-loop insulin therapy compared with sensor-augmented (open-loop) pump therapy.
Study with Nearly 14 000 Participants
In order to answer this question, the researchers, led by Professor Beate Karges, Faculty of Medicine at the RWTH Aachen, examined the data of nearly 14 000 participants. The study involved young people with type 1 diabetes from 250 diabetes centres in Germany, Austria, Switzerland, and Luxembourg. The participants were aged 2 to 20 years and had a type 1 diabetes duration of more than one year. They were identified from the Diabetes Prospective Follow-up Registry (DPV)**. The primary objectives of the study were to determine the rates of severe hypoglycaemia and ketoacidosis. Differences in HbA1c levels, time in the target range of 3.9 to 10.0mmol/L (70–180mg/dL), and fluctuations in blood sugar were also investigated. The data of 13 922 patients (51% male) were included in the analysis. Median age was 13.2 years; 7088 used a hybrid closed-loop system and 6834 used an open-loop system. The median observation time was 1.6 years.
Lower Rate of Hypoglycaemic Coma and More Ketoacidosis Events with Hybrid Closed-Loop Therapies
The results: People using hybrid closed-loop therapy had a significantly lower rate of rate of hypoglycaemic coma (0.62 per 100 patient-years) than those using open-loop therapy (0.91 per 100 patient-years). Furthermore, patients in the hybrid closed-loop group had a significantly lower HbA1c level (7.34% versus 7.50%). They had a higher percentage of time in the target glucose range of 3.9 to 10.0 mmol/L (64% versus 52% of the time). Their glycaemic variability was also lower (coefficient of variation of 35.4% versus 38.3%). There was no significant difference in the rate of severe hypoglycaemia.
However, individuals using a hybrid closed-loop system had a higher rate of ketoacidosis (1.74 events per 100 patient-years) than those using open-loop therapy (0.96 per 100 patient-years). The rate of ketoacidosis was particularly high in people with an HbA1c level of 8.5% or higher in the closed-loop therapy group (5.25 per 100 patient-years). In the comparison group, a rate of 1.53 events per 100 patient-years was observed.
Recommendation: Monitor Ketone Bodies Closely
Due to the higher risk of ketoacidosis, it is important to provide patients with targeted information and, in case of potential metabolic decompensation, to closely monitor ketone bodies in the blood or urine in order to prevent such adverse events, emphasize the authors of the study.
As global mobility surges, managing chronic conditions like diabetes during travel has become a significant concern. Diabetes remains one of the fastest-growing global public health issues1,affecting approximately 422 million people worldwide and causing 1.5 million deaths annually.2International SOS, the world’s leading health and security services company, has reported a significant year-on-year increase in diabetes-related assistance cases over the past three years, with a 28% increase in 2022 and a 32% increase in 2023.
Meanwhile, year-to-date 2024 data indicates a further uptick.3 With World Diabetes Day approaching on 14 November, organisations are urged to support diabetes prevention and management strategies. This year’s theme, ‘Breaking Barriers, Bridging Gaps’4 highlights the need for equitable, comprehensive and affordable diabetes care.
Dr Katherine O’Reilly, Regional Medical Director at International SOS, emphasises the importance of comprehensive health strategies: “It is important for organisations to understand the unique challenges that employees with diabetes face, particularly when travelling. By recognising these specific needs, companies can provide the necessary support and resources to help their employees manage their condition effectively. This ensures that employees can maintain their health and productivity, even when they are on the go. With thoughtful planning and the right resources, organisations can help their employees navigate the complexities of diabetes, fostering a supportive and inclusive work environment.”
People with diabetes face a double burden: a higher risk of life-threatening conditions like heart attack, stroke, and kidney failure, compounded by the psychological toll of diabetes distress. Individuals with diabetes are two to three times more likely to experience depression compared to those without the condition.5 These challenges can significantly impact employee wellbeing, leading to increased absenteeism, reduced productivity, and higher healthcare costs for employers.
According to The International Diabetes Federation (IDF), the global healthcare costs for individuals living with diabetes are expected to exceed $1054 billion by 2045.6 Furthermore, the prevalence of diabetes is projected to rise, with 643 million people affected by 2030, and 783 million by 2045.7 With this rising prevalence, it is crucial for organisations to implement strategies that help their workforce manage and prevent this chronic condition. Minor adjustments can reduce absenteeism, increase productivity, concentration and energy levels, and reduce the chance of on-the-job injury.
Dr Katherine O’Reilly continues, “Early diagnosis is crucial. Raising awareness about diabetes symptoms can prompt people to get screened, enabling early detection and intervention to prevent or delay its onset. This proactive approach can prevent undiagnosed diabetes from causing severe health complications, affecting various organ systems, including eye damage, heart and kidney disease, nerve damage and poor wound healing. By prioritising employee health, organisations can enhance productivity and foster a more engaged and resilient workforce. This approach also promotes a positive work environment and supports overall employee wellbeing.”
International SOS offers five tips for organisations to support employees in managing and preventing diabetes:
Education and awareness: Increase awareness about diabetes symptoms to encourage early diagnosis and effective management, thereby preventing severe health complications.
Provide comprehensive health solutions: Offer resources such as dietary guidelines, exercise programmes and regular health screenings to help employees manage their diabetes.
Supportive culture and policies: Develop and implement policies allowing for flexible work schedules and access to medical care while travelling. Foster a culture that prioritises health and wellbeing by accommodating regular meals and exercise, and ensuring employees have time to rest and recover from travel.
Promote a healthy lifestyle: Offer guidance on maintaining a healthy diet and regular exercise. Provide resources such as a list of healthy meal options and tips for finding nutritious food in different locations.
Facilitate health monitoring and provide adjustments: Ensure employees have scheduled breaks to take medication, check blood sugar levels and eat regular meals. Provide a private space for insulin administration and other medical needs.
A new paper surveying advances in diabetes pathogenesis and treatment explores the complex factors contributing to the onset and progression of the disease, suggesting that an understanding of these dynamics is key to developing targeted interventions to reduce the risk of developing diabetes and managing its complications.
In a paper in a special 50th anniversary issue of the peer-reviewed journal Cell, the authors surveyed hundreds of studies that have emerged over the years looking at the causes underpinning types 1 (T1D) and 2 (T2D) diabetes and new treatments for the disease. They examine the role that genes, environmental factors, and social determinants of health play and diabetes’ effect on cardiovascular and kidney disease.
What they found shows there are many advances in treatments that could stem the tide of a disease that has struck millions of people around the globe and continues to grow. In addition, some of these advances could be used to treat other disorders. But there are still challenges ahead.
“As the prevalence of diabetes continues to grow around the world, it is important to understand the latest advancements in research so that clinicians can provide the best care to their patients, and patients can make informed choices that support improved health outcomes,” said lead author Dr E. Dale Abel, chair of the UCLA Department of Medicine. “This is an educational resource that integrates the latest research and trends in diabetes management, which may have implications for clinical practice as the diabetic patient population continues to grow.
“This review will be the go-to reference for physicians and researchers, providing a state-of-the-art update of where the field is currently, and where it is headed,” Abel added.
Most people are affected by type 2 diabetes, for which inadequate diet and obesity are important underlying causes. Type 1 diabetes accounts for fewer than 5% of all cases. As of 2021 about 529 million people around the world were diagnosed with diabetes, representing about 6.1% of the global population, or about one in 16 people. Prevalence in some regions is as high as 12.3%. Type 2 diabetes comprises about 96% of cases, with more than half due to obesity. Some 1.31 billion people are projected to have the disease by 2050, with prevalence rising as high as 16.8% in North Africa and the Middle East and 11.3% in Latin America and the Caribbean, the researchers write.
Genetics, the central nervous system, and the interplay between various organs as well as social and environmental factors such as food insecurity and air pollution play a role in development of diabetes.
But some recent discoveries represent significant strides toward managing and perhaps even reversing the disease. For instance, a 2019 study found that a 14-day course of the antibody teplizumab delayed the progression of type 1 diabetes from stage 1 to stage 3 by 24 months. A follow-up analysis in 2021 showed that the delay could be up to 32.5 months.
Based on these results, the U.S. Food and Drug Administration approved teplizumab as the first disease-modifying therapy for type 1 diabetes, the researchers write.
Advances in insulins with optimised pharmacokinetics, algorithm-driven subcutaneous insulin pumps, continuous glucose monitoring, and improved tools for self-management have significantly improved the quality of life and outcomes for people with stage 3 type 1 diabetes.
In addition, stem cells could replace insulin-producing cells that are lost in type 1 diabetes, Abel said.
For type 2 diabetes, three classes of glucose-lowering medicines that were introduced in the last 20 years – GLP1RAs (glucagon like peptide-1 receptor agonists), DPP-4 inhibitors, and SGLT-2 inhibitors – have enabled people to control their glucose levels without gaining weight and with a low risk of developing hypoglycaemia. Personalised and precision medicine approaches are being explored to target the molecular mechanisms behind diabetes. However, they must demonstrate that benefits are clinically superior to standard care and are cost-effective. Also, it remains to be seen if precision approaches can be implemented in all settings worldwide, including those with few resources.
Combinations of GLP1Ras and with molecules that target other receptors such as GIP have shown even greater efficacy in treating diabetes. Recent trials have also shown that they are very effective in treating obesity, certain types of heart failure and even sleep apnoea, in part because of their potency to induce weight loss and reduce inflammation. Clinical trials are now underway to test their efficacy in treating other disorders such as Alzheimer’s disease, Abel said.
“Advances in therapy now raise the hope of preventing or curing T1D and treating T2D in ways that not only improve metabolic homeostasis, but also concretely reduce the risk and progression of cardio-renal disease,” the researchers write. “Finally, as we understand and develop tools for discerning the underlying heterogeneity leading to diabetes and its complications, the stage will be set for targeting therapies and prevention strategies to optimize their impact, in ways that will be broadly applicable across diverse populations and availability of health care resources.”
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.
