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“When my son was diagnosed [with Type 1], I knew nothing about diabetes. I changed my research focus, thinking, as any parent would, ‘What am I going to do about this?’” says Douglas Melton.

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Breakthrough within reach for diabetes scientist and patients nearest to his heart

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100 years after discovery of insulin, replacement therapy represents ‘a new kind of medicine,’ says Stem Cell Institute co-director Douglas Melton, whose children inspired his research

When Vertex Pharmaceuticals announced last month that its investigational stem-cell-derived replacement therapy was, in conjunction with immunosuppressive therapy, helping the first patient in a Phase 1/2 clinical trial robustly reproduce his or her own fully differentiated pancreatic islet cells, the cells that produce insulin, the news was hailed as a potential breakthrough for the treatment of Type 1 diabetes. For Harvard Stem Cell Institute Co-Director and Xander University Professor Douglas Melton, whose lab pioneered the science behind the therapy, the trial marked the most recent turning point in a decades-long effort to understand and treat the disease. In a conversation with the Gazette, Melton discussed the science behind the advance, the challenges ahead, and the personal side of his research. The interview was edited for clarity and length.

Douglas Melton

GAZETTE: What is the significance of the Vertex trial?

MELTON: The first major change in the treatment of Type 1 diabetes was probably the discovery of insulin in 1920. Now it’s 100 years later and if this works, it’s going to change the medical treatment for people with diabetes. Instead of injecting insulin, patients will get cells that will be their own insulin factories. It’s a new kind of medicine.

GAZETTE: Would you walk us through the approach?

MELTON: Nearly two decades ago we had the idea that we could use embryonic stem cells to make functional pancreatic islets for diabetics. When we first started, we had to try to figure out how the islets in a person’s pancreas replenished. Blood, for example, is replenished routinely by a blood stem cell. So, if you go give blood at a blood drive, your body makes more blood. But we showed in mice that that is not true for the pancreatic islets. Once they’re removed or killed, the adult body has no capacity to make new ones.

So the first important “a-ha” moment was to demonstrate that there was no capacity in an adult to make new islets. That moved us to another source of new material: stem cells. The next important thing, after we overcame the political issues surrounding the use of embryonic stem cells, was to ask: Can we direct the differentiation of stem cells and make them become beta cells? That problem took much longer than I expected — I told my wife it would take five years, but it took closer to 15. The project benefited enormously from undergraduates, graduate students, and postdocs. None of them were here for 15 years of course, but they all worked on different steps.

GAZETTE: What role did the Harvard Stem Cell Institute play?

MELTON: This work absolutely could not have been done using conventional support from the National Institutes of Health. First of all, NIH grants came with severe restrictions and secondly, a long-term project like this doesn’t easily map to the initial grant support they give for a one- to three-year project. I am forever grateful and feel fortunate to have been at a private institution where philanthropy, through the HSCI, wasn’t just helpful, it made all the difference.

I am exceptionally grateful as well to former Harvard President Larry Summers and Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, who supported the creation of the HSCI, which was formed specifically with the idea to explore the potential of pluripotency stem cells for discovering questions about how development works, how cells are made in our body, and hopefully for finding new treatments or cures for disease. This may be one of the first examples where it’s come to fruition. At the time, the use of embryonic stem cells was quite controversial, and Steve and Larry said that this was precisely the kind of science they wanted to support.

GAZETTE: You were fundamental in starting the Department of Stem Cell and Regenerative Biology. Can you tell us about that?

MELTON: David Scadden and I helped start the department, which lives in two Schools: Harvard Medical School and the Faculty of Arts and Science. This speaks to the unusual formation and intention of the department. I’ve talked a lot about diabetes and islets, but think about all the other tissues and diseases that people suffer from. There are faculty and students in the department working on the heart, nerves, muscle, brain, and other tissues — on all aspects of how the development of a cell and a tissue affects who we are and the course of disease. The department is an exciting one because it’s exploring experimental questions such as: How do you regenerate a limb? The department was founded with the idea that not only should you ask and answer questions about nature, but that one can do so with the intention that the results lead to new treatments for disease. It is a kind of applied biology department.

GAZETTE: This pancreatic islet work was patented by Harvard and then licensed to your biotech company, Semma, which was acquired by Vertex. Can you explain how this reflects your personal connection to the research?

MELTON: Semma is named for my two children, Sam and Emma. Both are now adults, and both have Type 1 diabetes. My son was 6 months old when he was diagnosed. And that’s when I changed my research plan. And my daughter, who’s four years older than my son, became diabetic about 10 years later, when she was 14.

When my son was diagnosed, I knew nothing about diabetes and had been working on how frogs develop. I changed my research focus, thinking, as any parent would, “What am I going to do about this?” Again, I come back to the flexibility of Harvard. Nobody said, “Why are you changing your research plan?”

GAZETTE: What’s next?

MELTON: The stem-cell-derived replacement therapy cells that have been put into this first patient were provided with a class of drugs called immunosuppressants, which depress the patient’s immune system. They have to do this because these cells were not taken from that patient, and so they are not recognized as “self.” Without immunosuppressants, they would be rejected. We want to find a way to make cells by genetic engineering that are not recognized as foreign.

I think this is a solvable problem. Why? When a woman has a baby, that baby has two sets of genes. It has genes from the egg, from the mother, which would be recognized as “self,” but it also has genes from the father, which would be “non-self.” Why does the mother’s body not reject the fetus? If we can figure that out, it will help inform our thinking about what genes to change in our stem cell-derived islets so that they could go into any person. This would be relevant not just to diabetes, but to any cells you wanted to transplant for liver or even heart transplants. It could mean no longer having to worry about immunosuppression.

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Value of DCESs

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Kellie Rodriguez , Donna Ryan , Jane K. Dickinson , Victor Phan; Improving Quality Outcomes: The Value of Diabetes Care and Education Specialists. Clin Diabetes 1 July 2022; 40 (3): 356–365. https://doi.org/10.2337/cd21-0089

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Given the growing prevalence and accelerating cost of diabetes, there is an urgent need to expand strategies in health care that improve access and outcomes and reduce the financial and human burden of the disease. Diabetes care and education specialists (DCESs) are well positioned to assist health care systems with delivery models that enhance diabetes care through evidence-based standards and quality improvement strategies. DCESs have increased opportunities to apply their competencies in primary, specialty, hospital, and acute care settings; accountable care organizations; community settings; research; and academia. Two national certification programs provide an evidence-based foundation for quality in the specialty, with updated competencies guiding practice. This article serves as a call to action for health care systems to integrate specialists in diabetes care and education into diabetes care delivery models and raise awareness of the positive impact these professionals have on the lives of people with diabetes.

In the United States, the traditional role of diabetes care and education specialists (DCESs) has been the provision of evidence-based diabetes self-management education and support (DSMES). DSMES has long been recognized as a tool for improving health and is a critical element of care for people with diabetes ( 1 ). DCESs represent multiple disciplines and are skilled in DSMES delivery ( 2 ). This specialty comprises nurses, dietitians, pharmacists, and other health professionals who demonstrate expertise in collaborative, person-centered care, education, and support for people with diabetes and their families and other support people. Although often underused in U.S. health care models, DCESs deliver comprehensive DSMES that addresses clinical, educational, psychosocial, and behavioral aspects of care. In addition, they teach people how to reduce risks associated with diabetes and related cardiometabolic conditions. DSMES, guided by national standards, provides a foundation for the daily self-care behaviors of diabetes management ( Table 1 ) ( 3 – 6 ).

ADCES7 Self-Care Behaviors ( 3 – 6 )

Two credentials exist to recognize the advanced knowledge and skills needed for practice within this specialty. The Certification Board for Diabetes Care and Education (CBDCE) oversees the certified diabetes care and education specialist (CDCES) credential, which validates expertise and knowledge base in diabetes care and education ( 7 ). The BC-ADM (board certified– advanced diabetes management) credential, administered by the Association of Diabetes Care and Education Specialists (ADCES), demonstrates advanced diabetes-related clinical practice skills and therapeutic problem-solving ( 8 ). Table 2 ( 7 , 8 ) highlights some of the differences. CBDCE provides a resource for finding local CDCESs ( https://www.cbdce.org/locate ) ( 9 ).

CDCES Compared With BC-ADM Credential

The DCES role has evolved significantly in response to a changing health care landscape and emerging health care models ( 10 ). In 2018, ADCES articulated a vision of comprehensive care delivery for diabetes and cardiometabolic conditions. The overarching goal is to provide health care that is quality driven, effective, accessible, and affordable in a changing health care delivery system. This goal requires skills to deliver the level of service and care that address the complex needs of people living with diabetes and health care organizations ( 11 ). The ADCES vision outlines six areas of focus for the specialty to demonstrate effectiveness, efficiency, and impact on clinical outcomes across diabetes management, education, and care delivery ( Table 3 ) ( 11 ). The ADCES vision inspired retitling and rebranding efforts for the specialty, with a subsequent transition from the title “diabetes educator” to “diabetes care and education specialist” in recognition of expanded roles and impact beyond traditional DSMES ( 10 ).

ADCES Vision for Diabetes Care and Education Delivery ( 11 )

The 2020 Competencies for Diabetes Care and Education Specialists ( 12 ) provide a quality assurance framework for the specialty. The competencies encompass six domains, including program management, service administration, and care coordination, among others ( Table 4 ). The DCES competencies have been applied at patient and population health levels, providing strong evidence for quality and value. Essential skills and knowledge include clinical and systems-based practice, integrated care, person-centered care, behavioral health support, and a focus on equitable, quality-driven care. DCESs also have roles in workforce training, capacity building, outcomes monitoring, and process improvement activities ( 12 – 14 ). Competence in these six domains differentiate DCESs from general practitioners. This article highlights the value of DCESs as integral members of team-based diabetes and cardiometabolic care, who provide evidence-based interventions, improve outcomes, and enhance cost-effective care ( 6 ).

DSMES Competencies ( 12 )

Although “value” can be defined in a variety of ways, in this article, the word refers to something’s usefulness, importance, and worthiness ( 15 ). Value in health care systems can also be described as the provision of the best quality care for the lowest cost. Evidence shows that the value of DCESs to health care delivery systems is directly related to quality outcomes and reduced health care costs of diabetes ( 16 ). A systematic review and meta-analysis found diabetes educators to be effective in mitigating therapeutic inertia and improving outcomes ( 16 ). Another meta-analysis of 50 high-quality systematic reviews found three types of quality-improvement interventions that were effective in improving diabetes care: patient education and support, multidisciplinary teams, and technology-enabled health care ( 17 , 18 ). These interventions, as well as population health and disease management strategies, have implementation costs that are largely offset by short-term reductions in health expenditures ( 18 ). There is a crucial need and an opportunity to further integrate DCESs into diabetes care delivery models and services, especially in supporting primary care practices, where the majority of diabetes and cardiometabolic disease prevention and management occurs. The following sections outline the value of DCESs in care processes, delivery, and outcomes across a variety of settings.

Cost-Effective Care

By 2060, the number of U.S. adults with diagnosed type 2 diabetes is projected to nearly triple, and the prevalence of diabetes is likely to double ( 19 ). As incidence rates continue to rise, the projected economic impact on direct and indirect costs related to diabetes and cardiometabolic conditions will be increasingly taxing to health care systems, payers, and society ( 20 – 23 ). The evidence clearly indicates an urgent need for health care leaders to identify cost-effective, evidence-based solutions that meet quality standards.

The diabetes epidemic has resulted in a corresponding surge in diabetes-related costs, rising 26% from 2012 to 2017 to $327 billion annually ( 19 ). The medical costs alone, for a person with diabetes, are 2.3 times more than for a person without diabetes ( 23 ). Confounding the diabetes epidemic and high costs, therapeutic targets are not being met, despite medical advances ( 24 ). For these reasons, the Quadruple Aim, expanded from the Institute for Healthcare Improvement’s Triple Aim, outlined the need to focus on the four areas: 1 ) quality care delivery at scale, 2 ) patient experience, 3 ) provider experience, and 4 ) reduced cost of care ( 25 ). The financial impact of diabetes, in particular, threatens the viability of health care systems and communities and supports the need for using DCESs in implementing cost-effective strategies.

Reduced emergency and inpatient services ( 30 – 34 )

Lower Medicare and insurance claims ( 30 – 34 )

Higher adoption of best-practice treatment recommendations ( 30 , 31 , 35 )

Improved clinical outcomes, quality of life, and health care utilization ( 30 – 37 )

DCESs deliver interdisciplinary care and practice efficiencies that support lower-cost, preventive care strategies as opposed to high-cost, acute care services. These costs include direct health care costs and indirect costs associated with disability, premature mortality, workplace absenteeism, and reduced productivity ( 23 ). As quality metrics are achieved, the costs of care decrease because of reductions in lifetime costs ( 38 ).

Team-Based Care

Inpatient diabetes care and education provides another opportunity for health systems to improve care and reduce costs. DCESs are important team members in acute care settings; they provide specialized diabetes care and education services at the bedside, beyond usual care. Inpatient DCESs support quality and safety measures, coordinate glucose management, monitor and support patient-owned diabetes technology, and educate patients and care teams. They also guide development of order sets and provide policy and protocol education and implementation. As part of quality and safety teams, DCESs assist with root cause analyses to meet quality metrics and ensure diabetes-related performance outcomes. Inpatient DCESs also support safe transitions of care from discharge to post-acute settings and home, reducing patients’ risk for avoidable readmissions ( 39 ).

In the outpatient setting, DCESs help to achieve individual, system, and payer goals by contributing to post-acute and transitional care ( 40 ). As integral members of the diabetes care team, DCESs increase patient access to quality care, implement therapeutic recommendations, and support both person-centered and clinically focused approaches. DCESs furnish care coordination and improve the provider experience by reducing provider tasks such as collecting and reporting data, especially in complex cases ( 3 , 40 ). In particular, there is value in integrating DCESs in the management of patients with type 1 diabetes in primary care settings, where clinical experience is primarily in the management of type 2 diabetes. For organizations supported by outcomes-based payment models, these are particularly essential contributions.

Accountable care organizations (ACOs) are responsible to their network of patients and third-party payers for the quality, appropriateness, and efficiency of the health care provided. This quality care framework makes ACOs an ideal health care delivery model for people with diabetes. Diabetes is a progressive chronic disease with substantial morbidity and mortality and, therefore, enormous personal and societal costs. DSMES, provided by a DCES as opposed to a non-DCES, reduces these burdens to payers, providers, and patients. ACOs that implement interventions that result in lower costs, including DSMES, team-based care, and diabetes disease management plans, are poised to receive incentive payments from health insurers when quality process and outcome measures are met ( 38 , 40 ).

Population Health Management

DCESs implement population health management through their broad focus on physical, biological, social, psychological, and environmental influences on health. Within the health care system, DCESs serve as a primary contact and advocate for patients, families, the health care team, and communities. According to Dr. Ken Moritsugu, former U.S. Surgeon General, “The DCES expands access to the full range of science, tailoring the message to specific populations, and thereby reducing health disparities” (K. Moritsugu, personal communication). DCESs play a key role in enhancing the responsiveness of the health care system to the needs of individuals and populations ( 40 ). They identify issues affecting the health and well-being of people with diabetes, discern patterns across patient populations, link patients with community resources and social services, and develop broad-based interventions ( 41 , 42 ).

Given projections that, by 2050, the U.S. health care system will be unable to afford the costs of diabetes care ( 20 ), population health strategies aim to deliver more effective and efficient disease prevention and management at scale. DCESs endorse population health models that direct care when and where it is needed, resulting in timely and cost-effective care delivery ( 40 ). DCESs engage in activities that support patients’ self-management between health care visits, which, in turn, promote preventive care models over high-cost acute care services. DCESs are core team members in population health methods who promote improved access to quality care. They drive point-of-care decision support to achieve desired health and organization outcomes.

Integrated care is a proposed solution for fragmented diabetes care delivery. Integrated diabetes care means integration between primary, community, specialist, and tertiary care, through provision of the same or similar services (horizontal integration) or connecting with organizations delivering different services or care levels (vertical integration). The goal of integrated care is community partnership in owning the health outcomes of people with diabetes ( 43 , 44 ). DCESs function within an interprofessional team and blend the clinical and behavioral components of care into their practice ( 12 , 40 ). Through involvement across the life span of patients and presence across all layers of health care delivery, DCESs provide a skilled clinical resource to foster horizontal and vertical integrated care ( 40 ).

DCESs integrate population health care delivery through workforce training and leveraging; stratified care management; and clinical and business coordination, including pre-visit planning, reimbursement, and follow-up ( 40 ). Simmons et al. ( 45 ) proposed that integrating care across disciplines and organizations and supporting the assessed needs of people with diabetes are approaches that could improve care delivery and reduce cost. In one study, a multidisciplinary team that included a CDCES identified patients with an A1C >8%; undertook care team visits, including covisits; utilized interdisciplinary case conferences; and developed and implemented person-centered care plans. This approach resulted in reduced A1C, improved medication management, and cost reduction through improved Medicare part A utilization ( 46 ). Integration is optimized when all team members, including DCESs, contribute their own expertise while sharing common goals and plans of care.

Mitigation of Therapeutic Inertia

Therapeutic inertia is a multifactorial and pervasive problem arising from complex barriers encountered at the clinician, patient, and health system levels ( 47 , 48 ). Therapeutic inertia is a failure to advance or to de-intensify pharmacological therapy when it is appropriate or necessary to do so ( 49 ). Previously called “clinical inertia,” this phenomenon refers to the underuse of interventions known to prevent negative outcomes. It also encompasses care deficits such as lack of screening, risk assessment, preventive measures and referrals, and attention to patient engagement barriers. Therapeutic inertia can delay a person’s ability to attain target glucose levels, as well as other important clinical and individualized goals, resulting in negative outcomes and higher costs of care. This is especially relevant in the primary care setting, where the vast majority of diabetes care occurs. DCESs have a direct impact on patients’ understanding of the complex science of the disease and actions they must take to maximize their health. DCESs also directly influence patients’ engagement in and satisfaction with their self-management, and, in turn, the reduction of risk for negative outcomes.

At diagnosis

Annually and/or when not meeting treatment targets

When complicating factors develop

When transitions in life and care occur

DSMES is a crucial clinical intervention that is underutilized and has been identified as a priority in the campaign to reduce therapeutic inertia ( 49 ). Through relationship-based DSMES, DCESs provide behavioral, educational, psychosocial, and clinical support ( 50 ). They play a role in improving timely treatment modification and, in turn, outcomes, by promoting the adoption and expansion of person-centered diabetes care and shared decision-making. DCESs assess and address social determinants of health to identify potential and actual barriers to implementing therapeutic recommendations. They help people with diabetes problem-solve and develop individualized diabetes management plans. DCESs also help patients achieve the mutual goals of reducing risk for diabetes-related complications, mortality, and health care costs through their advanced skills in diabetes technology and population health approaches ( 31 – 33 , 35 , 36 ).

“DSMES contributes to an individual’s ability to achieve health literacy: to hear, understand, and embrace the message, and to ultimately put the information into action. This is more than clinical intervention, but rather a concept of how, rather than what” (K. Moritsugu, personal communication).

Embedding automated prompts for DCES/DSMES referrals at the four critical times

Tracking process metrics to assess rates of referrals to DCES/DSMES

Developing treatment algorithms or decision support prompts for DCES/DSMES referrals

Risk stratifying elevated glucose (A1C) and other cardiometabolic results for DCES/DSMES referrals

Identifying medication-taking processes and outcomes for referral to a DCES

Referrals to telehealth education and consultation programs or digital coaching as alternatives to in-person diabetes education and support

Technology Integration

DCESs advocate for technology use by people with diabetes and are leading the way in encouraging clinical practices and the broader health care system to incorporate diabetes technology into standard care ( 51 ). People with diabetes are using technology, including diabetes devices, and software, at increasing rates. These tools are improving management of glucose and cardiometabolic conditions, point-of-care decision support, and quality of life ( 4 ). Systematic reviews focused on technology-enabled DSMES have identified significant A1C reductions with implementation of technology interventions that incorporated tailored communication and education strategies, patient-generated health data, and individualized feedback ( 52 , 53 ). Beyond reducing A1C, DCESs expand individuals’ understanding of glycemic time in range, an increasingly important metric in diabetes management.

DCESs are competent and passionate advocates for incorporating technology through their provision of education on the use of continuous glucose monitoring, insulin pump therapy, connected insulin pens, remote patient monitoring, and telehealth services. DCESs developed and published the Identify, Configure, and Collaborate Framework and the Technology-Enabled Self-Management Taxonomy ( 53 ). These resources outline standardized approaches to adopting and implementing technology-enabled interventions for diabetes and cardiometabolic health ( 53 , 54 ). Positioning DCESs as the key team members to lead technology integration in all settings, given the evolution of the specialty’s role from conveyor of information to full partner in diabetes care and self-management, establishes their value for people with diabetes, the care team, and the health system.

The recent national expansion of access to telehealth services and the Centers for Medicare & Medicaid Services updating of its guidance on acceptable provider types highlight the value of such patient communication platforms ( 55 ). The use of remote and real-time telecommunication technologies in delivering health care demonstrates improvements in the quality of, access to, and costs of care ( 54 ). There remain even broader opportunities in which to harness the value of DCESs within the technology landscape.

Quality Improvement

The quality of diabetes care can vary widely, and gaps in care can lead to complications, death, and increased costs ( 56 ). Quality improvement interventions led or supported by DCESs result in the achievement of glucose targets ( 29 , 57 , 58 ). They also increase value from the health system perspective by improving health outcomes and quality measures ( 12 , 13 , 31 , 32 , 35 , 38 , 56 , 59 – 67 ). Studies show that DSMES provided by DCESs has a positive impact on clinical, psychosocial, and behavioral aspects of diabetes ( 29 ).

The ADCES7 Self-Care Behaviors framework ( Table 1 )

Identification of conditions ( 4 )

Treatment recommendations and referrals ( 70 )

Evidence-based guidelines ( 4 , 71 , 72 )

Shared decision-making ( 70 )

DCESs also advocate for routine cardiovascular risk assessments and, in collaboration with patients and their diabetes and/or primary care team, facilitate the management of modifiable risk factors and treatment of abnormal cardiovascular screenings or clinical findings according to current guidelines ( 4 ). A full table of documented outcomes of diabetes care and education are outlined in Table 5 ( 12 – 15 , 23 , 26 , 27 , 29 , 31 , 32 , 35 , 37 , 38 , 45 , 46 , 49 , 57 – 60 , 62 – 70 , 73 – 75 ). Supplementary Figure S1 provides a comprehensive overview of the ways in which DCESs improve workflow in multiple health care settings.

Sixteen Areas in Which There Are Documented Positive Outcomes From DSMES

DCESs are highly skilled and qualified health professionals who lead timely, cost-effective, evidence-based diabetes care and education delivery and impart broad value to people with diabetes, care teams, health care organizations, and payers. The interprofessional composition of the specialty and inherent roles across all layers of the health care system provide a rich framework for integrated individual and population health approaches to care. DCESs contribute to lower costs, improved access, and achievement of clinical and health care organization goals, with improved patient engagement, self-care, and satisfaction.

DSMES, led by DCESs, addresses the comprehensive blend of clinical, educational, psychosocial, and behavioral aspects of care needed for daily self-management and provides the foundation to help all people with diabetes navigate their daily self-care with confidence and improved outcomes ( 1 , 4 ). Interprofessional teams that include DCESs support a strong path forward to improve quality of life and clinical metrics.

We intend this article to serve as a call to action for health care systems to include DCESs as integral partners in the care of people with or at risk for diabetes and cardiometabolic conditions. It is clear that this specialty is useful, important, and worthy and therefore holds immense value for every clinical setting in which people with diabetes seek care.

Between initial publication of this article online and its publication in print, the authors requested revisions to Table 2 to more completely describe the CDCES credential. A new version was posted online, and the print issue also reflects those revisions.

Acknowledgments

The authors acknowledge Joanne Rinker and Leslie Kolb of ADCES for coordinating the writing team and providing guidance during the writing process, respectively.

Duality of Interest

K.R. has received a stipend as part of her ADCES presidency from 2020 to 2022. No other potential conflicts of interest relevant to this article were reported.

Author Contributions

All authors contributed intellectual content during manuscript writing and revision and approved the final version for submission. V.P. is the guarantor of this work and, as such, accepts responsibility for the integrity and accuracy of the work.

This article contains supplementary material online at https://doi.org/10.2337/figshare.19322852 .

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Recent Advances

ADA-funded researchers use the money from their awards to conduct critical diabetes research. In time, they publish their findings in order to inform fellow scientists of their results, which ensures that others will build upon their work. Ultimately, this cycle drives advances to prevent diabetes and to help people burdened by it. In 2018 alone, ADA-funded scientists published over 200 articles related to their awards!

Identification of a new player in type 1 diabetes risk

Type 1 diabetes is caused by an autoimmune attack of insulin-producing beta-cells. While genetics and the environment are known to play important roles, the underlying factors explaining why the immune system mistakenly recognize beta-cells as foreign is not known. Now, Dr. Delong has discovered a potential explanation. He found that proteins called Hybrid Insulin Peptides (HIPs) are found on beta-cells of people with type 1 diabetes and are recognized as foreign by their immune cells. Even after diabetes onset, immune cells are still present in the blood that attack these HIPs.

Next, Dr. Delong wants to determine if HIPs can serve as a biomarker or possibly even targeted to prevent or treat type 1 diabetes. Baker, R. L., Rihanek, M., Hohenstein, A. C., Nakayama, M., Michels, A., Gottlieb, P. A., Haskins, K., & Delong, T. (2019). Hybrid Insulin Peptides Are Autoantigens in Type 1 Diabetes. Diabetes , 68 (9), 1830–1840.

Understanding the biology of body-weight regulation in children

Determining the biological mechanisms regulating body-weight is important for preventing type 2 diabetes. The rise in childhood obesity has made this even more urgent. Behavioral studies have demonstrated that responses to food consumption are altered in children with obesity, but the underlying biological mechanisms are unknown. This year, Dr. Schur tested changes in brain and hormonal responses to a meal in normal-weight and obese children. Results from her study show that hormonal responses in obese children are normal following a meal, but responses within the brain are reduced. The lack of response within the brain may predispose them to overconsumption of food or difficulty with weight-loss.

With this information at hand, Dr. Schur wants to investigate how this information can be used to treat obesity in children and reduce diabetes.

Roth, C. L., Melhorn, S. J., Elfers, C. T., Scholz, K., De Leon, M. R. B., Rowland, M., Kearns, S., Aylward, E., Grabowski, T. J., Saelens, B. E., & Schur, E. A. (2019). Central Nervous System and Peripheral Hormone Responses to a Meal in Children. The Journal of Clinical Endocrinology and Metabolism , 104 (5), 1471–1483.

A novel molecule to improve continuous glucose monitoring

To create a fully automated artificial pancreas, it is critical to be able to quantify blood glucose in an accurate and stable manner. Current ways of continuously monitoring glucose are dependent on the activity of an enzyme which can change over time, meaning the potential for inaccurate readings and need for frequent replacement or calibration. Dr. Wang has developed a novel molecule that uses a different, non-enzymatic approach to continuously monitor glucose levels in the blood. This new molecule is stable over long periods of time and can be easily integrated into miniaturized systems.

Now, Dr. Wang is in the process of patenting his invention and intends to continue research on this new molecule so that it can eventually benefit people living with diabetes.

Wang, B. , Chou, K.-H., Queenan, B. N., Pennathur, S., & Bazan, G. C. (2019). Molecular Design of a New Diboronic Acid for the Electrohydrodynamic Monitoring of Glucose. Angewandte Chemie (International Ed. in English) , 58 (31), 10612–10615.

Addressing the legacy effect of diabetes

Several large clinical trials have demonstrated the importance of tight glucose control for reducing diabetes complications. However, few studies to date have tested this in the real-world, outside of a controlled clinical setting. In a study published this year, Dr. Laiteerapong found that indeed in a real-world setting, people with lower hemoglobin A1C levels after diagnosis had significantly lower vascular complications later on, a phenomenon known as the ‘legacy effect’ of glucose control. Her research noted the importance of early intervention for the best outcomes, as those with the low A1C levels just one-year after diagnosis had significantly lower vascular disease risk compared to people with higher A1C levels.

With these findings in hand, physicians and policymakers will have more material to debate and determine the best course of action for improving outcomes in people newly diagnosed with diabetes.

Laiteerapong, N. , Ham, S. A., Gao, Y., Moffet, H. H., Liu, J. Y., Huang, E. S., & Karter, A. J. (2019). The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care , 42 (3), 416–426.

A new way to prevent immune cells from attacking insulin-producing beta-cells

Replacing insulin-producing beta-cells that have been lost in people with type 1 diabetes is a promising strategy to restore control of glucose levels. However, because the autoimmune disease is a continuous process, replacing beta-cells results in another immune attack if immunosorbent drugs are not used, which carry significant side-effects. This year, Dr. Song reported on the potential of an immunotherapy he developed that prevents immune cells from attacking beta-cells and reduces inflammatory processes. This immunotherapy offers several potential benefits, including eliminating the need for immunosuppression, long-lasting effects, and the ability to customize the treatment to each patient.

The ability to suppress autoimmunity has implications for both prevention of type 1 diabetes and improving success rates of islet transplantation.

Haque, M., Lei, F., Xiong, X., Das, J. K., Ren, X., Fang, D., Salek-Ardakani, S., Yang, J.-M., & Song, J . (2019). Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes. JCI Insight , 4 (7).

A new target to improve insulin sensitivity

The hormone insulin normally acts like a ‘key’, traveling through the blood and opening the cellular ‘lock’ to enable the entry of glucose into muscle and fat cells. However, in people with type 2 diabetes, the lock on the cellular door has, in effect, been changed, meaning insulin isn’t as effective. This phenomenon is called insulin resistance. Scientists have long sought to understand what causes insulin resistance and develop therapies to enable insulin to work correctly again. This year, Dr. Summers determined an essential role for a molecule called ceramides as a driver of insulin resistance in mice. He also presented a new therapeutic strategy for lowering ceramides and reversing insulin resistance. His findings were published in one of the most prestigious scientific journals, Science .

Soon, Dr. Summers and his team will attempt to validate these findings in humans, with the ultimate goal of developing a new medication to help improve outcomes in people with diabetes.

Chaurasia, B., Tippetts, T. S., Mayoral Monibas, R., Liu, J., Li, Y., Wang, L., Wilkerson, J. L., Sweeney, C. R., Pereira, R. F., Sumida, D. H., Maschek, J. A., Cox, J. E., Kaddai, V., Lancaster, G. I., Siddique, M. M., Poss, A., Pearson, M., Satapati, S., Zhou, H., … Summers, S. A. (2019). Targeting a ceramide double bond improves insulin resistance and hepatic steatosis. Science (New York, N.Y.) , 365 (6451), 386–392.

Determining the role of BPA in type 2 diabetes risk

Many synthetic chemicals have infiltrated our food system during the period in which rates of diabetes has surged. Data has suggested that one particular synthetic chemical, bisphenol A (BPA), may be associated with increased risk for developing type 2 diabetes. However, no study to date has determined whether consumption of BPA alters the progression to type 2 diabetes in humans. Results reported this year by Dr. Hagobian demonstrated that indeed when BPA is administered to humans in a controlled manner, there is an immediate, direct effect on glucose and insulin levels.

Now, Dr. Hagobian wants to conduct a larger clinical trial including exposure to BPA over a longer period of time to determine precisely how BPA influences glucose and insulin. Such results are important to ensure the removal of chemicals contributing to chronic diseases, including diabetes.

Hagobian, T. A. , Bird, A., Stanelle, S., Williams, D., Schaffner, A., & Phelan, S. (2019). Pilot Study on the Effect of Orally Administered Bisphenol A on Glucose and Insulin Response in Nonobese Adults. Journal of the Endocrine Society , 3 (3), 643–654.

Investigating the loss of postmenopausal protection from cardiovascular disease in women with type 1 diabetes

On average, women have a lower risk of developing heart disease compared to men. However, research has shown that this protection is lost in women with type 1 diabetes. The process of menopause increases rates of heart disease in women, but it is not known how menopause affects women with type 1 diabetes in regard to risk for developing heart disease. In a study published this year, Dr. Snell-Bergeon found that menopause increased risk markers for heart disease in women with type 1 diabetes more than women without diabetes.

Research has led to improved treatments and significant gains in life expectancy for people with diabetes and, as a result, many more women are reaching the age of menopause. Future research is needed to address prevention and treatment options.

Keshawarz, A., Pyle, L., Alman, A., Sassano, C., Westfeldt, E., Sippl, R., & Snell-Bergeon, J. (2019). Type 1 Diabetes Accelerates Progression of Coronary Artery Calcium Over the Menopausal Transition: The CACTI Study. Diabetes Care , 42 (12), 2315–2321.

Identification of a potential therapy for diabetic neuropathy related to type 1 and type 2 diabetes

Diabetic neuropathy is a type of nerve damage that is one of the most common complications affecting people with diabetes. For some, neuropathy can be mild, but for others, it can be painful and debilitating. Additionally, neuropathy can affect the spinal cord and the brain. Effective clinical treatments for neuropathy are currently lacking. Recently, Dr. Calcutt reported results of a new potential therapy that could bring hope to the millions of people living with diabetic neuropathy. His study found that a molecule currently in clinical trials for the treatment of depression may be valuable for diabetic neuropathy, particularly the type affecting the brain.

Because the molecule is already in clinical trials, there is the potential that it can benefit patients sooner than later.

Jolivalt, C. G., Marquez, A., Quach, D., Navarro Diaz, M. C., Anaya, C., Kifle, B., Muttalib, N., Sanchez, G., Guernsey, L., Hefferan, M., Smith, D. R., Fernyhough, P., Johe, K., & Calcutt, N. A. (2019). Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189. Diabetes , 68 (11), 2143–2154.

ADA-funded researcher studying link between ageing and type 2 diabetes

One of the most important risk factors for developing type 2 diabetes is age. As a person gets older, their risk for developing type 2 diabetes increases. Scientists want to better understand the relationship between ageing and diabetes in order to determine out how to best prevent and treat type 2 diabetes. ADA-funded researcher Rafael Arrojo e Drigo, PhD, from the Salk Institute for Biological Studies, is one of those scientists working hard to solve this puzzle.

Recently, Dr. Arrojo e Drigo published results from his research in the journal Cell Metabolism . The goal of this specific study was to use high-powered microscopes and novel cellular imaging tools to determine the ‘age’ of different cells that reside in organs that control glucose levels, including the brain, liver and pancreas. He found that, in mice, the cells that make insulin in the pancreas – called beta-cells – were a mosaic of both old and young cells. Some beta-cells appeared to be as old as the animal itself, and some were determined to be much younger, indicating they recently underwent cell division.

Insufficient insulin production by beta-cells is known to be a cause of type 2 diabetes. One reason for this is thought to be fewer numbers of functional beta-cells. Dr. Arrojo e Drigo believes that people with or at risk for diabetes may have fewer ‘young’ beta-cells, which are likely to function better than old ones. Alternatively, if we can figure out how to induce the production of younger, high-functioning beta-cells in the pancreas, it could be a potential treatment for people with diabetes.

In the near future, Dr. Arrojo e Drigo’s wants to figure out how to apply this research to humans. “The next step is to look for molecular or morphological features that would allow us to distinguish a young cell from and old cell,” Dr. Arrojo e Drigo said.

The results from this research are expected to provide a unique insight into the life-cycle of beta-cells and pave the way to novel therapeutic avenues for type 2 diabetes.

Watch a video of Dr. Arrojo e Drigo explaining his research!

Arrojo E Drigo, R. , Lev-Ram, V., Tyagi, S., Ramachandra, R., Deerinck, T., Bushong, E., … Hetzer, M. W. (2019). Age Mosaicism across Multiple Scales in Adult Tissues. Cell Metabolism , 30 (2), 343-351.e3.

Researcher identifies potential underlying cause of type 1 diabetes

Type 1 diabetes occurs when the immune system mistakenly recognizes insulin-producing beta-cells as foreign and attacks them. The result is insulin deficiency due to the destruction of the beta-cells. Thankfully, this previously life-threatening condition can be managed through glucose monitoring and insulin administration. Still, therapies designed to address the underlying immunological cause of type 1 diabetes remain unavailable.

Conventional approaches have focused on suppressing the immune system, which has serious side effects and has been mostly unsuccessful. The American Diabetes Association recently awarded a grant to Dr. Kenneth Brayman, who proposed to take a different approach. What if instead of suppressing the whole immune system, we boost regulatory aspects that already exist in the system, thereby reigning in inappropriate immune cell activation and preventing beta-cell destruction? His idea focused on a molecule called immunoglobulin M (IgM), which is responsible for limiting inflammation and regulating immune cell development.

In a paper published in the journal Diabetes , Dr. Brayman and a team of researchers reported exciting findings related to this approach. They found that supplementing IgM obtained from healthy mice into mice with type 1 diabetes selectively reduced the amount of autoreactive immune cells known to target beta-cells for destruction. Amazingly, this resulted in reversal of new-onset diabetes. Importantly, the authors of the study determined this therapy is translatable to humans. IgM isolated from healthy human donors also prevented the development of type 1 diabetes in a humanized mouse model of type 1 diabetes.

The scientists tweaked the original experiment by isolating IgM from mice prone to developing type 1 diabetes, but before it actually occurred. When mice with newly onset diabetes were supplemented with this IgM, their diabetes was not reversed. This finding suggests that in type 1 diabetes, IgM loses its capacity to serve as a regulator of immune cells, which may be contribute to the underlying cause of the disease.

Future studies will determine exactly how IgM changes its regulatory properties to enable diabetes development. Identification of the most biologically optimal IgM will facilitate transition to clinical applications of IgM as a potential therapeutic for people with type 1 diabetes.    Wilson, C. S., Chhabra, P., Marshall, A. F., Morr, C. V., Stocks, B. T., Hoopes, E. M., Bonami, R.H., Poffenberger, G., Brayman, K.L. , Moore, D. J. (2018). Healthy Donor Polyclonal IgM’s Diminish B Lymphocyte Autoreactivity, Enhance Treg Generation, and Reverse T1D in NOD Mice. Diabetes .

ADA-funded researcher designs community program to help all people tackle diabetes

Diabetes self-management and support programs are important adjuncts to traditional physician directed treatment. These community-based programs aim to give people with diabetes the knowledge and skills necessary to effectively self-manage their condition. While several clinical trials have demonstrated the value of diabetes self-management programs in terms of improving glucose control and reducing health-care costs, whether this also occurs in implemented programs outside a controlled setting is unclear, particularly in socially and economically disadvantaged groups.

Lack of infrastructure and manpower are often cited as barriers to implementation of these programs in socioeconomically disadvantaged communities. ADA-funded researcher Dr. Briana Mezuk addressed this challenge in a study recently published in The Diabetes Educator . Dr. Mezuk partnered with the YMCA to evaluate the impact of the Diabetes Control Program in Richmond, Virginia. This community-academic partnership enabled both implementation and evaluation of the Diabetes Control Program in socially disadvantaged communities, who are at higher risk for developing diabetes and the complications that accompany it.

Dr. Mezuk had two primary research questions: (1) What is the geographic and demographic reach of the program? and (2) Is the program effective at improving diabetes management and health outcomes in participants? Over a 12-week study period, Dr. Mezuk found that there was broad geographic and demographic participation in the program. The program had participants from urban, suburban and rural areas, most of which came from lower-income zip codes. HbA1C, mental health and self-management behaviors all improved in people taking part in the Greater Richmond Diabetes Control Program. Results from this study demonstrate the value of diabetes self-management programs and their potential to broadly improve health outcomes in socioeconomically diverse communities. Potential exists for community-based programs to address the widespread issue of outcome disparities related to diabetes.  Mezuk, B. , Thornton, W., Sealy-Jefferson, S., Montgomery, J., Smith, J., Lexima, E., … Concha, J. B. (2018). Successfully Managing Diabetes in a Community Setting: Evidence from the YMCA of Greater Richmond Diabetes Control Program. The Diabetes Educator , 44 (4), 383–394.

Using incentives to stimulate behavior changes in youth at risk for developing diabetes

Once referred to as ‘adult-onset diabetes’, incidence of type 2 diabetes is now rapidly increasing in America’s youth. Unfortunately, children often do not have the ability to understand how everyday choices impact their health. Could there be a way to change a child’s eating behaviors? Davene Wright, PhD, of Seattle Children’s Hospital was granted an Innovative Clinical or Translational Science award to determine whether using incentives, directed by parents, can improve behaviors related to diabetes risk. A study published this year in Preventive Medicine Reports outlined what incentives were most desirable and feasible to implement. A key finding was that incentives should be tied to behavior changes and not to changes in body-weight.

With this information in hand, Dr. Wright now wants to see if incentives do indeed change a child’s eating habits and risk for developing type 2 diabetes. She is also planning to test whether an incentive program can improve behavior related to diabetes management in youth with type 1 diabetes. Jacob-Files, E., Powell, J., & Wright, D. R. (2018). Exploring parent attitudes around using incentives to promote engagement in family-based weight management programs. Preventive Medicine Reports , 10 , 278–284.

Determining the genetic risk for gestational diabetes

Research has identified more than 100 genetic variants linked to risk for developing type 2 diabetes in humans. However, the extent to which these same genetic variants might affect a woman’s probability for getting gestational diabetes has not been investigated.

Pathway to Stop Diabetes ® Accelerator awardee Marie-France Hivert, MD, of Harvard University set out to answer this critical question. Dr. Hivert found that indeed genetic determinants of type 2 diabetes outside of pregnancy are also strong risk factors for gestational diabetes. This study was published in the journal Diabetes .

The implications? Because of this finding, doctors in the clinic may soon be able to identify women at risk for getting gestational diabetes and take proactive steps to prevent it. Powe, C. E., Nodzenski, M., Talbot, O., Allard, C., Briggs, C., Leya, M. V., … Hivert, M.-F. (2018). Genetic Determinants of Glycemic Traits and the Risk of Gestational Diabetes Mellitus. Diabetes , 67 (12), 2703–2709.

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  • Published: 08 May 2024

Advances and challenges of the cell-based therapies among diabetic patients

  • Ramin Raoufinia 1 , 2 ,
  • Hamid Reza Rahimi 2 ,
  • Ehsan Saburi 2 &
  • Meysam Moghbeli   ORCID: orcid.org/0000-0001-9680-0309 2  

Journal of Translational Medicine volume  22 , Article number:  435 ( 2024 ) Cite this article

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Diabetes mellitus is a significant global public health challenge, with a rising prevalence and associated morbidity and mortality. Cell therapy has evolved over time and holds great potential in diabetes treatment. In the present review, we discussed the recent progresses in cell-based therapies for diabetes that provides an overview of islet and stem cell transplantation technologies used in clinical settings, highlighting their strengths and limitations. We also discussed immunomodulatory strategies employed in cell therapies. Therefore, this review highlights key progresses that pave the way to design transformative treatments to improve the life quality among diabetic patients.

Diabetes mellitus poses a formidable global public health challenge due to its rapid growing prevalence and associated morbidity, disability, and mortality [ 1 ]. According to the International Diabetes Federation, over 537 million adults aged 20–79 had diabetes worldwide in 2021 that is expected to rise to around 783 million cases by 2045 [ 2 ]. Obesity, unhealthy diets, physical inactivity as well as genetic and epigenetic predispositions are important risk factors of diabetes [ 3 , 4 , 5 ]. Diabetes is typically classified into type 1 diabetes mellitus (T1DM), gestational diabetes mellitus (GDM), and type 2 diabetes mellitus (T2DM) [ 2 ]. T1DM primarily arises from autoimmune-related damage of insulin-secreting beta cells, resulting in severe hyperglycemia and ketoacidosis [ 6 ]. In contrast, T2DM generally has a more gradual onset characterized by insulin resistance along with diminished compensatory insulin secretion from pancreatic beta cell dysfunction [ 7 ]. Diabetes is associated with macrovascular complications such as heart disease and stroke, as well as microvascular issues in eyes, kidneys, and nervous system [ 8 ]. Cancer is also a leading cause of diabetes-related death, and dementia-associated mortality has risen in recent decades [ 9 , 10 , 11 , 12 ]. Cell therapy involves transferring autologous or allogenic cellular material into patients [ 13 ]. The global market size of cell therapy is estimated to grow from $9.5 billion in 2021 to $23 billion by 2028 [ 14 ]. It combines stem and non-stem cell therapies consisting of unicellular or multicellular preparations. Cell therapies typically use autologous or allogenic cells via injection and infusion [ 15 ]. In the present review, we discussed the recent advances in cell-based therapy of diabetes, from foundational islet transplantation to regenerative strategies to highlight key developments that improve the effective treatments for diabetic patients.

Cell replacement therapy for diabetes

Pancreatic transplantation was firstly used in 1966 to treat type 1 diabetes using whole organ transplants. During the 1970s–80s, segmental pancreatic grafts were combined with techniques to divert digestive secretions away from transplanted cells. Three main techniques emerged; simultaneous pancreas-kidney transplants, pancreas transplants following kidney transplants, and pancreatic transplants. International collaboration on tracking outcomes began in 1980 with the formation of several pancreatic transplant registries and associations. However, whole organ transplantation was faced with several challenges including organ rejection, vascular complications, limited organ availability, and the effects of lifelong immunosuppression [ 16 , 17 ]. Islet cell transplantation was explored as an alternative, however isolating and transplanting pancreatic islets proved difficult due to donor availability, rejection, and immunosuppression side effects. Recent research has focused on stem cell sources that could reconstitute immune tolerance and preserve beta cell function such as mesenchymal stem cells, bone marrow cells, and embryonic stem cells [ 18 ]. A novel stem cell therapy called VX-880 was developed using proprietary technology to grow insulin-producing beta cells from allogeneic stem cells. Clinical trials began in 2021 after FDA approval to deliver the cells intrahepatically under immune suppression. A second approach called VX-264 encapsulates the same cells, avoiding immunosuppression but requiring surgical implantation [ 17 ]. In 2023, FDA approved the first allogeneic pancreatic islet cell therapy called Lantidra for adults with type 1 diabetes experiencing severe hypoglycemia. Approval was based on two studies where 21–30% of participants no longer required insulin one year post-treatment, with benefits lasting over five years in some cases. However, this treatment have mild and serious adverse events that are associated with treatment dose and the methods of islet cell infusion [ 19 , 20 ].

Emerging strategies for cell delivery via microencapsulation and biological devices in clinical trials

Alginate capsules as cell delivery systems.

A seminal investigation conducted in 1994 demonstrated the successful transplantation of alginate-encapsulated islets into the peritoneum of kidney transplant patients who were receiving immunosuppression therapy. Remarkably, these patients achieved insulin independence for up to nine months [ 21 ]. However, subsequent trials conducted without immunosuppression yielded inconsistent outcomes. In a study conducted in 2006, islets were encapsulated in triple-layer alginate capsules and implanted intraperitoneally in type 1 diabetes (T1D) patients. There was a positive correlation between the encapsulation and insulin production that reduced exogenous insulin requirements during one year. Despite this progress, the entry of cytokines remained a potential concern [ 22 ]. Another study employed the single-layer barium-alginate capsules that sustained insulin production for up to 2.5 years [ 23 ]. It has been reported that the microneedle, comprising a calcium alginate frame with polydopamine-coated poly-lactic-co-glycolic acid microspheres encapsulating insulin, enables light-triggered insulin release. Microneedle provided a suitable insulin dose to maintain blood glucose levels in line with daily fluctuations. These results established the efficacy and safety of the developed microneedle for diabetes treatment [ 24 ]. Another therapeutic approach explored the encapsulation of pancreatic islets with mesenchymal stem cells (MSCs) and decellularized pancreatic extracellular matrix (ECM). ECM derived from the pancreas supported islet cell growth and maintenance to enhance insulin expression [ 25 ]. Sodium alginate and hyaluronic acid were incorporated due to their roles in collagen production, wound healing, and physical crosslinking. The 3D porous membranes allowed optimal water and oxygen transfer while diverting excess exudate from diabetic wounds. Hydrogel accelerated re-epithelization, while decreased inflammation, indicating potential as the diabetic wound dressings [ 26 ]. Additionally, the incorporation of specific ECM components, such as collagen IV and RGD, into alginate-based microcapsules significantly improved the survival, insulin secretion, and longevity of microencapsulated islets [ 27 ].

Encaptra® device from ViaCyte

In contrast to microencapsulation techniques, ViaCyte developed a semipermeable pouch method named Encaptra, which contains pancreatic precursor cells derived from the embryonic stem cells [ 28 ]. In the initial trial conducted in 2014, the “VC-01” device was implanted in T1D individuals without the use of immunosuppression [ 29 ]. The trial confirmed the safety of the device; however, the occurrence of hypoxia induced cellular necrosis [ 30 ]. The device was modified as “VC-02” with larger pores, and two trials (NCT03162926, NCT03163511) demonstrated promising outcomes, including increased fasting C-peptide levels and a 20% reduction in insulin requirements during one year in the majority of participants [ 31 ]. In order to eliminate the necessity for immunosuppressants, ViaCyte collaborated with Gore to develop an expanded polytetrafluoroethylene (ePTFE) device with both immuno-isolating and pro-angiogenic properties [ 32 ]. This device (NCT04678557) aimed to prevent immune cell attachment and T-cell activation [ 33 ]. Additionally, ViaCyte is exploring the integration of CRISPR technology to modify stem cells, specifically by eliminating β2-microglobulin expression and PD-L1 up regulation. It is hypothesized that these genetic modifications will further hinder immune cell attachment and T-cell activation [ 30 , 34 ].

Semipermeable device from Semma therapeutics

Semma Therapeutics, which has been acquired by Vertex, pioneered the utilization of differentiated stem cell-derived islet cell clusters in clinical trials. Semma houses these cells between two semipermeable polyvinylidene fluoride membranes and is designed for subcutaneous implantation (NCT04786262) [ 31 , 35 ]. Vertex reported a significant breakthrough by infusing differentiated beta cells via the portal vein in a participant who was receiving immunosuppressants. This approach led to substantial C-peptide production and improved glycemic control during 90 days [ 36 ].

βAir device from Beta O2

Beta O2’s innovative βAir device utilizes an alginate-PTFE membrane complex to encapsulate islets, providing partial immunoisolation while ensuring a continuous supply of oxygen, which is crucial for optimal islet function [ 37 , 38 ]. The βAir device that was seeded with human islets was subcutaneously implanted in T1D individuals (NCT02064309). Although, low insulin levels were produced for up to eight weeks, there was not any reduction in the required exogenous insulin [ 37 ]. While, increasing the number of islets could potentially enhance their function, it is important to note that the continuous reliance on oxygen poses a risk of infection, despite efforts to optimize the survival of encapsulated islets [ 39 , 40 ].

Cell pouch™ device from Sernova

Sernova has developed the Cell Pouch device, which offers pre-vascularized polypropylene chambers for islet transplantation without the need for immunoprotection. The device consists of multiple cylindrical chambers that are prefilled with PTFE plugs, which are then removed after implantation to create the empty space [ 41 ]. In a 2012 trial (NCT01652911), islets were placed in the vascularized pouches of three recipients who were also receiving immunosuppression that resulted in a transient increase in C-peptide levels [ 41 ]. In a 2018 trial (NCT03513939), immunosuppression was administered after implantation and islet introduction. This trial reported sustained C-peptide production for up to nine months in two recipients, along with improved glycemic control [ 42 ]. Regarding the limitations of immunosuppression, Sernova is exploring the possibility of encapsulating islets in hydrogel as an alternative approach [ 43 ].

Shielded living therapeutics™ from Sigilon Therapeutics

Sigilon has developed the Shielded Living Therapeutics sphere, which consists of cell clusters enclosed within an alginate-TMTD coating [ 44 ]. Preclinical studies demonstrated that murine islet transplants encapsulated within these spheres maintained normoglycemia for a period of six months [ 45 ]. In a 2020 trial conducted for hemophilia (NCT04541628), the spheres were evaluated for their ability to express Factor VIII [ 46 ]. However, the trial was paused due to the development of antibodies in the third recipient receiving the highest cell doses. While, preclinical studies have shown promising efficacy, there are safety concerns regarding the TMTD coating that need to be addressed before these spheres can be used for human islet transplantation as a treatment for diabetes [ 31 ]. Emerging technologies have been investigated in clinical trials for delivering insulin-producing islets or stem cell-derived beta cells via microencapsulation or use of implantable biological devices (Table 1). Optimizing encapsulation and developing alternative implantable devices moves the field toward delivering safe and effective islet replacement without chronic immunosuppression dependency that represented an important new frontier for the cell-based treatment of diabetes. However, continued refining will be required to fully realize this promising vision and using these preclinical concepts in clinic.

Immunoengineering strategies: biomaterials for modulating immune responses

Islet encapsulation aims to prevent immune responses toward transplant antigens. However, foreign body response (FBR) against biomaterials induces inflammation around encapsulated islets that obstructs oxygen/nutrient access and causes graft failure [ 31 ]. Extensive research revealed biomaterial properties profoundly influence FBR severity, with high purity/biocompatibility moderating inflammation [ 47 ]. Deeper understanding of biomaterial immunobiology enabled developing immune-modulating constructs to steer host interactions. By altering topology/chemistry to hinder nonspecific binding and cell adhesion, these “immune-evasive biomaterials” intended to attenuate xenograft rejection at inception [ 44 ]. Both innate and adaptive immune responses have crucial roles in the context of pancreatic islet transplantation. These responses encompass the activation of tissue macrophages and neutrophils following injury, leading to the release of inflammatory cytokines that subsequently activate antigen-presenting cells (APCs), CD8 + T cells, CD4 + T cells, and cytotoxic T lymphocytes (Fig.  1 ). Zwitterionic polymers conferred anti-fouling attributes but crosslinking limitations constrained their application [ 48 ]. Novel mild zwitterionization introduced alginate modifications that prolonged prevention of fibrotic overgrowth by mitigating initial responses [ 49 , 50 , 51 ]. The prevention of graft rejection following islet cell transplantation necessitates the systemic administration of immunosuppressive agents. While, these agents effectively suppress immune responses, their continuous use exposes patients to an increased risk of infection and cancer. To mitigate these concerns, an alternative approach involving the localized delivery of immunosuppressants at the transplantation site has emerged. This localized delivery system offers several advantages, including targeted drug delivery, reduced systemic exposure, and potentially reduces the immunosuppressants doses [ 52 ]. Polymeric carriers dispersed cyclosporine A continuously at the graft site to dynamically tamp down proinflammatory cascades and T-cell activation [ 53 , 54 ]. TGF-β/IL-10 co-delivery at the microencapsulation interface hindered innate antigen presentation, obstructing adaptive response priming [ 55 , 56 ]. Regulatory T-cells emerged as the potent immunomodulators when coated on islets to improve insulin production in vitro [ 57 ]. Similarly, recombinant Jagged-1 surface patterning increased regulatory lymphocytes in vitro while enhancing glycemic oversight in vivo [ 58 ]. Targeting proinflammatory effector T-cells or presenting their Fas ligand death receptor improved long-term viability when combined with rapamycin prophylaxis [ 52 , 59 ]. Immobilizing thrombomodulin or urokinase mitigated local inflammation, with the latter conferring lifelong xenotransplant survival [ 60 ]. Peptides recognizing IL-1 receptors provided robust protection from destabilizing proinflammatory cytokines [ 61 ]. Leukemia inhibiting factor improved islet performance over polyethylene glycol encapsulation alone by inducing regulatory T-cell lineages [ 62 ]. Silk scaffolds facilitated IL-4/dexamethasone emancipation that meaningfully decreased immune reactions to grafts [ 63 ]. Therefore, the localized delivery of immunosuppressants at the transplantation site represents a promising strategy for islet cell transplantation. Compared to systemic administration, local delivery can achieve targeted immune modulation only at the graft location while reducing drug exposure throughout the body. This localized approach aims to sufficiently suppress the immune response to prevent rejection, while limiting negative side effects that may occur from systemic immunosuppression. A variety of biomaterials and surface modification strategies have been developed and investigated for the local delivery of immunosuppressive agents and immunomodulatory cytokines [ 64 , 65 , 66 ]. Understanding how biomaterial properties influence the immune response is critical to design biomaterials that can modulate inflammation and improve islet graft survival through localized immunomodulation.

Cell-based therapy through the integration of additive manufacturing techniques

Additive manufacturing utilizes computer modeling to fabricate complex 3D structures on-site with minimal post-processing. Common methods for the biomedical application are fused filament fabrication (FFF), stereolithography (SLA), and bioprinting [ 67 ]. FFF is a layer-by-layer technique that extrudes heated thermoplastics [ 68 ]. Commonly used feedstocks include acrylonitrile butadiene styrene (ABS) and polylactic acid (PLA). Other thermoplastics that have been utilized with FDM include thermoplastic polyurethane (TPU), polycarbonate (PC), polystyrene (PS), polyetherimide (PEI), polycaprolactone (PCL), polyaryletherketone (PAEK), and polyetheretherketone (PEEK), with the latter demonstrating high strength and heat tolerance. A major advantage of FDM is its ability to fabricate multi-material objects through continuous printing and alteration of the build material. In addition to typical polymers like PC and polystyrene (PS), FDM can print composites reinforced with glass, metals, ceramics, and bioresorbable polymers via integration of the constituent powders with a binding matrix. This enables enhanced control over the experimental component fabrication. While, ceramic and metal filaments traditionally contain the corresponding powder mixed with a binder, FDM provides versatility in the functional prototype construction from a wide range of thermoplastic feedstocks using precise and additive layer manufacture [ 68 , 69 , 70 , 71 , 72 ]. It provides geometric reproducibility and reduced variability compared to traditional techniques. FFF prints served as scaffolds for the transplanted cells [ 67 ]. However, minimum feature size is limited to ? ∼  250 μm by nozzle diameter [ 68 ]. SLA employs light-curable liquid resins and achieves higher 50–150 μm resolution than FFF but with restricted material choices. Bone grafts and surgical guides are common applications [ 67 ]. Incorporating biomaterials like hydroxyapatite has expanded utility, though processing is required to mitigate cytotoxicity. Additive manufacturing can address limitations in oxygen transport, cell/material placement control and vasculature formation, and clinically translatable insulin-secreting implants [ 67 ]. Therefore, additive manufacturing technologies have the potential to enhance various aspects of the cell-based transplant design, from improving nutrient transport through optimized implant geometry to achieving precision integration of therapeutic agents (Table 2).

Enhancing nutrient transport through optimization of implant geometry

Tissue engineering for the islet transplantation requires maximizing nutrient transport [ 73 , 74 ]. Traditional scaffold fabrication introduces macroporosity but lacks precision that results in inflammation [ 67 ]. Cell encapsulation provides immunoprotection by limiting interactions between transplanted cells and the host immune system. However, this protective barrier also poses challenges for the efficient transport of essential nutrients, including oxygen, to the encapsulated cells. Modifying the geometries of encapsulation devices using conventional methods to enhance oxygen delivery has proven to be inconsistently challenging [ 67 ], so that novel approaches are required to address these challenges. Additive manufacturing allows customizing biomaterial scaffolds with defined geometries and micropore sizes to improve transport [ 75 , 76 , 77 , 78 , 79 ]. The 3D printed PLA scaffolds with islets have successful vascularization and cellular survival after subcutaneous transplantation [ 80 , 81 ]. Interlocking toroidal hydrogel-elastomer constructs also increased surface area and cell viability [ 82 , 83 , 84 ].

Enhancing vascularization and engraftment

Rich host vascularization of transplant devices is essential to support long-term islet survival through efficient nutrient delivery and insulin kinetics. Early platforms modified bulk material properties to promote vessel infiltration and anastomoses [ 85 , 86 , 87 , 88 , 89 ]. Additive manufacturing can further optimize microscale geometry to both accelerate host vessel connections and control intra-device vasculature homogeneity beyond traditional fabrication. Initial work reproduced macroscale vessels but scales were diverged from cell-based therapies [ 73 , 90 , 91 , 92 ]. Leveraging Additive manufacturing designed structures guided vessel formation in vitro and in vivo [ 80 , 89 , 93 ]. Shifting to bioprinting complex branching conduits in supportive hydrogels facilitated clinical translation for diverse cell therapies [ 94 , 95 , 96 , 97 , 98 ]. Researchers focused on developing a 3D scaffold platform to improve the transplantation outcomes of islet cells in T1D. The scaffold featured a heparinized surface and immobilized vascular endothelial growth factor (VEGF) to enhance vascularization. Scaffold effectively promoted angiogenesis and facilitated the growth of new blood vessels. Additionally, encapsulated islets within the scaffold had functional responses to glucose stimuli. These findings suggested that the developed scaffold platform holds potential for successful extra-hepatic islet transplantation, offering new possibilities for T1D treatment [ 99 ]. Research on vascularization of islets via additive manufacturing techniques has primarily focused on the fundamental discoveries. In one study, engineered pseudo islets (EPIs) were created by combining the mouse insulin-secreting beta cells with rat heart microvascular endothelial cells. EPIs demonstrated extensive outgrowth of capillaries into the surrounding matrix. Although, EPIs containing both cell types that underwent capillarization maintained viability and function over time in culture, non-vascularized EPIs lacking endothelial cells could not sustain viability or functionality long-term. This supported the potential for inducing angiogenesis within bioengineered islet constructs. Future work may combine patient-specific stem cell-derived human beta cells with endothelial cells using this approach to promote long-term graft survival for treating type 1 diabetes [ 98 ]. While, large-scale 3D printed vascularized structures are currently limited for the islet transplantation, advancements in leveraging additive manufacturing for the optimization vascularization conditions through the pore sizes and material choices, may facilitate translation to β-cell therapy in type 1 diabetes.

Precision placement of cells and matrix for enhanced control

Beyond distributing biomaterials, additive manufacturing enables micro-level cell and protein control. For islet transplantation, optimal cellular distribution and supportive extracellular matrix niche reduce rapid dysfunction and apoptosis [ 100 , 101 , 102 ]. Traditional techniques heterogeneously load cells after fabrication or struggle with incomplete encapsulation [ 103 , 104 ]. Bioprinting allows in situ encapsulation and printing of multiple cell types and matrix components while dictating 3D placement and dimensions [ 105 , 106 ]. Islet transplant research prints hydrogel-encapsulated clusters surrounded by supportive cells and doped with immune modulators to improve the transplant environment [ 107 ]. Progress in bioprinting offers consistency and defines physical/chemical graft properties beyond traditional fabrication.

Achieving controlled integration of therapeutic agents for enhanced efficacy

In addition to the cell and matrix placement, additive manufacturing enables precision therapeutic integration. Incorporating therapeutics aims to recapitulate the in vivo environment through angiogenesis, islet health promotion, and immunomodulation [ 67 , 108 ]. Growth factors promote vessel formation and insulin secretion while decrease apoptosis [ 108 , 109 , 110 , 111 ]. Local immunomodulators regulate the immune system in a specific site of the body. They decrease inflammation and promote the successful integration of transplanted cells or tissues by minimizing the need for widespread immune suppression in whole body [ 67 ]. Traditional homogeneous delivery methods restrict the ability to customize the spatial distribution of substances and pose a risk of harmful effects on transplants or hosts [ 112 ]. The use of discreet gradients in bioprinting can offer precise physiological signals. By combining traditional drug release methods with AM, it becomes possible to create tissues that exhibit distinct therapeutic localization. Bioprinted composites have the ability to release factors with gradients throughout the entire construct that enables a more comprehensive and targeted approach in tissue engineering [ 112 , 113 , 114 ].

Cell based gene therapy

Gene therapy holds great promise for diabetes management, offering innovative approaches to deliver and manipulate the insulin gene in various tissues. Viral methods, such as lentivirus, adenovirus, and adeno-associated virus (AAV), along with non-viral techniques like liposomes and naked DNA, have been utilized to deliver the insulin gene to target tissues [ 115 ]. This section aims to provide an overview of important studies in the field of gene therapy for diabetes management, emphasizing advancements in insulin gene delivery and manipulation (Table 3).

Enteroendocrine K-cells and pancreatic β-cells

Enteroendocrine K-cells in the intestines and pancreatic β-cells share similarities in their production of glucose-dependent insulinotropic polypeptide (GIP) and their regulatory mechanisms. Understanding these similarities offers insights into T2D management and improving glucose homeostasis. However, attempts to reverse diabetes effectively through K-cell transplantation have been unsuccessful. Nevertheless, research on gene editing techniques has shown promising results in management of the diabetes mellitus [ 116 , 117 ]. AAV vectors have been employed to co-express insulin and glucokinase genes in skeletal muscles, demonstrating long-term effectiveness in achieving normo-glycemia without exogenous insulin [ 118 , 119 ].

Gene editing techniques

Gene editing techniques using AAV vectors effectively improved normo-glycemia in animal models. Co-expression of insulin and glucokinase in transgenic mice increased glucose absorption and regulated insulin production. Duodenal homeobox 1 (PDX1) gene transfer via AAV2 in a humanized liver mouse model also led to insulin secretion and glycemic control [ 120 ]. Adenovirus-mediated transfection of hepatic cells with neurogenin 3 (NGN3) resulted in insulin production and trans-differentiation of oval cell populations [ 121 , 122 ]. Targeting specific promoters in liver cells such as phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), albumin, and insulin-like growth factor binding protein-1 (IGFBP-1) enhanced hepatic insulin gene therapy [ 123 , 124 ]. AAV-mediated overexpression of SIRT1 reduced inflammation, hypoxia, apoptosis and improved neural function in the retina of diabetic db/db mice [ 125 ]. Another study developed a plasmid expressing a single-strand insulin analogue for intramuscular injection using a specialized gene delivery technique. A single administration provided sustained insulin expression for 1.5 months and effectively regulated blood glucose levels without immune responses or tissue damage in diabetic mice.

Non-viral gene delivery methods

Non-viral approaches have also key roles in achieving glycemic control. The combination of insulin fragments with DNA plasmid, administered via intravenous injection improved normo-glycemia for extended periods. DNA transposon facilitated gene integration into the host chromosome that addressed the short-term liver expression. Additionally, the co-injection of DNA plasmid containing insulin with furin significantly enhanced insulin production within muscles [ 126 ]. Non-viral plasmids were engineered to carry proinsulin and pancreatic regenerating genes to ameliorate streptozotocin-induced T1DM [ 127 ]. The pVAX plasmid vectors prolonged therapeutic effects in achieving normo-glycemia without the need for further treatment [ 127 ]. Bioreducible cationic polymers, such as poly-(cystamine bisacrylamide-diamino hexane) (p(CBA-DAH)), have been employed to deliver RAE-1 to pancreatic islets, resulting in improved insulin levels [ 128 ]. Furthermore, ex vivo gene transfer and autologous grafts have shown promising outcomes in animal models. The introduction of the human insulin gene into pancreatic or liver cells followed by autologous grafts improved insulin secretion, glycemic control, and alleviated the diabetic complications in pigs. However, gene silencing eventually occurred, necessitating a deeper understanding of the underlying mechanisms [ 128 , 129 ].

Stem cell based therapy in diabetes

Efforts are ongoing to develop standardized processes for donor and recipient selection/allocation to increase pancreas utilization [ 130 , 131 , 132 , 133 ]. Techniques for isolating pancreatic islets are being optimized to become more standardized and consistent. Noninvasive imaging technologies allow the monitoring of the transplanted islets without surgery [ 134 , 135 ]. Biomarkers could also evaluate how immunomodulation strategies are working [ 136 , 137 , 138 ]. Researchers are also exploring alternative transplant sites in the body beyond just the liver, to see if the other locations may better support islet graft survival and function. Together, these areas of refinement aim to improve the safety and reliability of islet transplantation procedures as a potential therapy for diabetes [ 139 ]. Bioengineering approaches are being developed to optimize the islet transplantation microenvironment using biomaterials which enhance islet engraftment and function through engineered extracellular niches [ 140 , 141 ]. For example, encapsulation techniques aim to protect pancreatic islets against immune reponse by enclosing them within semipermeable hydrogel polymer capsules [ 142 , 143 ]. This localized immunoisolation strategy utilizes biomaterials like alginate to create a physical barrier preventing immune cell contact while still allowing nutrient and oxygen diffusion. Researchers concurrently seek alternative unlimited cellular sources to address limited islet availability. Mesenchymal stem cells possess immunomodulatory properties and their adjuvant delivery, either early in disease onset or simultaneously with islet transplantation, has shown promising signs of improving outcomes in preclinical investigations. By dampening inflammatory responses and favoring regenerative processes, stem cells may help to establish a more tolerogenic transplant environment. These bioengineering and cell therapy approaches offer potential pathways towards eliminating the exogenous insulin requirement [ 144 , 145 ]. A variety of stem cell types have therapeutic potential for diabetes (Fig.  2 ). Pluripotent stem cells possess immense promise for overcoming the limitations of islet transplantation. Human embryonic stem cells and induced pluripotent stem cells are especially attractive candidates due to their unique ability to both self-renew indefinitely and differentiate into any cell type. This makes them an ideal source of replacement pancreatic beta cells. Significant research effort across academic and industrial laboratories has led to advancement in differentiation protocols that can convert pluripotent stem cells into functional beta-like cells in vitro. However, establishing consistent, well-characterized cellular production methods that comply with stringent safety and efficacy standards remains a priority for clinical translation. Ongoing work aims to generate therapeutic stem cell-derived beta cell replacements exhibiting stable, glucose-responsive insulin secretion comparable to primary islets. Although, technological and regulatory hurdles still must be cleared, pluripotent stem cells have the greatest potential to finally solve the problem of limited cell availability and provide an unlimited source of transplantable tissue suitable for widespread treatment of diabetes [ 145 , 146 , 147 , 148 ]. There are currently six registered clinical trials evaluating the use of human pluripotent stem cells for the T1D treatment. All trials except one use PEC-01 cells, which consist of a mixture of pancreatic endoderm and polyhormonal cell population derived from CyT49 stem cells that are fully committed to endocrine differentiation upon implantation [ 149 ]. The initial trial implanted PEC-01 cells within an encapsulation device, hypothesizing no need for immunosuppression. While, well-tolerated with minor adverse effects, insufficient engraftment occurred due to foreign body responses that eliminated the cells [ 150 ]. The trial transitioned in 2017 to use an open encapsulation device that required immunosuppression. Subcutaneous engraftment, differentiation of cells into islet-like clusters, and glucose-responsive insulin production provided the first evidence that pancreatic progenitor cells can survive, mature, and function as the endocrine cells in humans. Potential benefits on stimulated C-peptide levels and glycemic control were observed in one patient [ 151 , 152 ]. Two reports in late 2021 described results in 17 patients receiving PEC-01 cells in an open device. Engraftment and insulin expression occurred in the majority, glucose-responsive secretion in over one-third, and various glycemic improvements were observed at six months. Explanted tissues contained heterogeneous pancreatic compositions including mature beta cells, with no teratoma formation and mild adverse effects related to surgery/immunosuppression. VX-880 uses fully differentiated insulin-producing stem cell-derived islet cells in phase 1/2 trial evaluating portal infusion and different doses requiring immunosuppression. Preliminary results suggest early engraftment and insulin secretion. The manin challenge was controlling immune rejection without systemic immunosuppression [ 149 ]. Several strategies are being explored to address the challenges of immune rejection in stem cell therapies for diabetes. They include generating stem cell lines that are universally compatible through HLA silencing, developing milder regimens of immunosuppression, and refining encapsulation and containment approaches to protect transplanted cells toward immune response. Establishing standardized stem cell banks is also an area of investigation [ 153 , 154 ]. Xenotransplantation using gene-edited porcine islets remains an exciting avenue of research given advances to improve engraftment and reduce immunogenicity in preclinical studies [ 155 ]. Novel approaches continue to emerge as well, such as decellularization techniques, 3D bioprinting of tissue constructs, and creating interspecies chimeras. Rapid evolution of cell-based therapies across both academic and commercial sectors is promising to restore normoglycemic control in diabetic cases. Refinement of existing methods and development of new strategies hold potential to perform a safe and effective cell replacement without reliance on systemic immunosuppression. Stem cell and regenerative therapies may ultimately manage diabetes through restored endogenous insulin production [ 156 ]. Recently a meta analysis evaluated the safety and efficacy of MSC-based therapy for diabetes in humans. This comprehensive analysis was conducted on 262 patients across six trials that met the inclusion criteria within the last five years. The results reveal that treatment with MSCs significantly reduced the dosage of anti-diabetic drugs over a 12-months. Following treatment, HbAc1 levels decreased by an average of 32%, fasting blood glucose levels decreased by an average of 45%, and C-peptide levels showed a decrease of 38% in two trials and an increase of 36% in four trials. Notably, no severe adverse events were reported across all trials. Therefore, it can be concluded that MSC therapy for type 2 diabetes is safe and effective [ 157 ].

Advances in islet transplantation and stem cell-derived Beta cells

Limited number of the islet transplantation donors highlights the importance of cell therapy in diabetes. Although, higher islet numbers from multiple donors increase the success, limited pancreas availability restricts widespread use [ 158 ]. Using multiple donors also increases rejection risk, while isolation of the islets can cause tissue damage [ 159 ]. To overcome these challenges, researchers have explored the differentiation of stem cells into beta cells in vitro to generate an unlimited supply of insulin-producing cells with standardized and characterized products. Genetic engineering techniques have also been investigated to confer advantages such as stress resistance or immune evasion [ 158 ]. ViaCyte has developed a stem cell-derived pancreatic progenitor called PEC-01, which has the ability to mature into endocrine cells in rodent models. To protect the transplanted cells from immune response, retrieval encapsulation devices were also created [ 160 , 161 , 162 ]. In an initial human clinical trial conducted in 2014 (NCT02239354), the Encaptra device was utilized with the aim of providing complete immunoprotection of transplanted cells through the use of a cell-impermeable membrane. Although, the PEC-Encap product showed reliable tolerance and minimal adverse effects, the trial was stopped due to the inadequate engraftment of functional products. While, a few endocrine cells were observed, fibrosis around the capsule led to graft loss and supression of the insulin secretion. To address this challenge, a more recent development called the PEC-Direct device was introduced, which featured openings in the membrane to facilitate vascularization, thereby improving nutrient exchange and supporting cell viability. However, since host cells could infiltrate the device, immunosuppression was necessary following the transplantation [ 163 , 164 , 165 ]. Protocols were developed to generate clusters of stem cell-derived beta cells that secreted glucose-responsive insulin. These clusters, referred to SC-islets, also contained other endocrine cells, including glucagon-producing cells. SC-islets improved glycemic control in diabetic mice and nonhuman primates [ 146 , 166 , 167 , 168 ]. In a trial conducted in 2017 (NCT03163511), the transplantation of progenitor cells resulted in the maturation of endocrine cells, and glucose-responsive C-peptide secretion was observed 6–9 months post-transplantation. Notably, the majority of these mature endocrine cells exhibited glucagon-positive characteristics. The porous regions housing the endocrine cells allowed for the infiltration of host vessels to facilitate vascularization. However, non-cellular regions were isolated by the presence of fibrosis [ 164 , 165 ]. Although, there was not a sufficient levels of circulating C-peptide in these trials, the findings underscored the significance of promoting vascularization and minimizing fibrotic reactions [ 164 , 169 ]. Vertex conducted a human trial in 2021 (NCT04786262) involving the transplantation of half-dose VX-880 cells (SC-islets) without a device to avoid previous problems, which necessitated immunosuppression. Preliminary results reported improved glycemic control, although it took longer to achieve the same outcome compared to rodent models [ 158 ]. Overall, progresses in islet transplantation and stem cell-derived beta cells pave the way for overcoming the limitations of traditional approaches. Further research and refinements are also required to achieve consistent and clinically significant outcomes in the treatment of diabetes.

Chalenges and limitations

Cell-based therapies have been significantly progressed for diabetes; however, there are still several challenges that need to be overcome. Clinical trials investigating encapsulation devices and islet transplantation techniques have provided valuable insights but face several obstacles including oxygenation, host immune responses, and insufficient long-term engraftment success. Immunoengineering of biomaterials and additive manufacturing for the development of 3D islet structures aim to modulate inflammation and promote graft revascularization. Nevertheless, achieving consistent normalization of blood glucose levels without exogenous insulin remains a challenge in human studies. In the field of gene therapy and stem cell differentiation, research focuses on genetically-modified or progenitor-derived insulin-secreting β-like cells to optimize protocols that ensure safety and functionality. The main challenge is to establish stable and functional cells capable of permanently restoring normoglycemia without the need for external intervention. One major barrier is the immune response, which targets allogeneic and xenogeneic islet grafts. Although, local immunotherapy minimizes the systemic effects, evading graft destruction through biomaterials without the requirement of immune suppression remains a significant challenge. The translation of precision 3D islet constructs and genetically reprogrammed cells also necessitates scalable manufacturing processes to ensure consistent function and long-term safety across batches. When critically appraising progress in the field of cell-based diabetes treatments, it is imperative to consider the regulatory, ethical, economic, and safety factors that shape translational applications. At the regulatory level, oversight bodies play a pivotal role in establishing standards to ensure patient welfare while enabling therapeutic innovation. FDA oversees clinical trials and product approvals in the United States (US), while in Europe the EMA provides parallel regulatory guidance. Within the US, organizations like the United Network for Organ Sharing (UNOS) and Organ Procurement and Transplantation Network (OPTN) govern organ and cell allocation protocols [ 17 , 170 ]. However, as regenerative approaches diverge from traditional organ transplantation, regulatory pathways require ongoing harmonization between the agencies and jurisdictions. Continual dialogue between researchers, oversight boards, and policymakers will be crucial to streamline guidelines in a patient-centric manner that balances safety, efficacy, and timely access to cutting-edge therapies. For instance, as stem cell-derived beta cells and 3D bioprinted tissue constructs emerge, traditional drug and device frameworks may not adequately address product characterization and manufacturing complexities for these advanced therapeutic products [ 67 ]. Within clinics, maintaining compliance with evolving regulations impacts research directives and ultimately patients’ access to the novel treatments. Addressing informed consent, clinical trial design, and privacy protections for sensitive health data are also paramount from an ethical perspective [ 128 , 129 ]. Autonomy and agency of research participants in decision-making related to experimental therapies demand prudency. Equitable accessibility of new treatment options also warrants attention to avoid certain populations facing undue barriers. Cell sourcing presents ethical issues depending on derivation from embryonic, fetal or adult tissues. Logistical matters like shipping and processing stem cell-derived islets prior to transplantation necessitate scrutiny. Tumorigenic potential of the undifferentiated pluripotent stem cells should be optimized through rigorous preclinical testing. Transitioning therapies between animal and early human investigations necessitates well-characterized cellular products showing consistent safety and glucose-responsive insulin secretion profiles comparable to pancreatic islets. Long-term animal model data substantiating lack of malignant transformation following transplantation aids allaying ethical safety concerns as the therapies progress clinically. Researchers carefully screen new concepts to prevent side effects in participants while pursuing curative goals. In terms of economic costs, islet and stem cell transplant procedures remain prohibitively expensive for broad applicability despite promising clinical signals. The field requires sustained study to validate techniques, track long-term outcomes, assess healthcare costs offsets from mitigating diabetes’ debilitating complications, and establish cost-benefit ratios for national reimbursement paradigms. Public-private partnerships may accelerate large, interventional trials and longitudinal research to precisely quantify the cellular therapies’ safety profiles and real-world efficacies compared to intensive management versus costs of intensive diabetes care. Ongoing developments like 3D bioprinting offer catalytic manufacturing potential fundamentally recalibrating economics by enhancing yields, standardizing procedures, and reducing costs through scale. By thoroughly and sensitively examining regulatory frameworks, informed consent processes, risks and benefits, as well as financial considerations at both micro and macro levels, researchers, oversight boards and broader stakeholder networks can advance cell-based therapies towards delivering life-changing benefits for all communities. A multidisciplinary, conscientious approach balances progress against patient welfare. A combination of multiple strategies may help to overcome these limitations. For instance, gene-modified islets integrated within vascularized biomaterial implants or sequenced therapies have promising results to prime grafts in pro-regenerative environments before transplantation. Collaboration across disciplines offers hope that refined individualized therapies may eventually achieve durable insulin independence through functional pancreatic cell or tissue engraftment, not only for diabetes but also for chronic pancreatitis. Regarding, ongoing progresses in unraveling these barriers, cell replacement approaches have the potential to improve diabetes management.

Conclusions

This review provides a comprehensive overview of the advances, challenges, and future directions in various cell-based therapeutic approaches for the treatment of diabetes. Significant progresses have been achieved in microencapsulation design, immunomodulation, tissue constructs, genetic and cellular reprogramming techniques, as well as initial clinical translation. However, the complete restoration of normoglycemia without the need for lifelong immunosuppression is still considered as a significant therapeutic challenge. Therefore, addressing the transplant environment of the hostile nature, developing minimally invasive delivery methods, and overcoming limitations in engraftment efficiency and longevity are crucial issues for the future researches. Through the sustained multidisciplinary efforts for the improvement of existing strategies and establishing novel paradigms, achieving durable insulin independence can be a realistic goal for all diabetic cases through the personalized cell replacement or regeneration.

figure 1

Immune Responses toward pancreatic islets following transplantation. This figure illustrates the immune responses, including the innate and adaptive immunity that are triggered upon pancreatic islet transplantation. Immune response begins with the activation of tissue macrophages and neutrophils in response to injury. Subsequent, release of inflammatory cytokines stimulates antigen-presenting cells (APCs), CD4 + T cells, CD8 + T cells, and cytotoxic T lymphocytes to orchestrate the immune response

figure 2

Potential stem cell sources for the treatment of diabetes

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Acrylonitrile butadiene styrene

Activate antigen-presenting cells

Adeno-associated virus

Duodenal homeobox 1

Engineered pseudo islets

Expanded polytetrafluoroethylene

Extracellular matrix

Foreign body response

Fused filament fabrication

Gestational diabetes mellitus

Glucose 6-phosphatase

Insulin-like growth factor binding protein-1

Mesenchymal stem cells

Neurogenin 3

Organ Procurement and Transplantation Network

Phosphoenolpyruvate carboxykinase

Polyaryletherketone

Polycaprolactone

Polycarbonate

Polyetheretherketone

Polyetherimide

Poly-lactic acid

Polystyrene

Stereolithography

Thermoplastic polyurethane

Type 1 diabetes

Type 1 diabetes mellitus

Type 2 diabetes mellitus

United Network for Organ Sharing

United States

Vascular endothelial growth factor

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Ramin Raoufinia

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Raoufinia, R., Rahimi, H.R., Saburi, E. et al. Advances and challenges of the cell-based therapies among diabetic patients. J Transl Med 22 , 435 (2024). https://doi.org/10.1186/s12967-024-05226-3

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This study investigates the causal relationship between lipid traits and GDM in an effort to better understand the aetiology of GDM.

Employing a two-sample Mendelian Randomization (MR) framework, we used Single Nucleotide Polymorphisms (SNPs) as instrumental variables to examine the impact of lipids and apolipoproteins on GDM. The research comprised univariable and multivariable MR analyses, with a prime focus on individual and combined effects of lipid-related traits. Statistical techniques included the fixed-effect inverse variance weighted (IVW) method and supplementary methods such as MR-Egger for comprehensive assessment.

Our findings revealed the following significant associations: apoA-I and HDL cholesterol were inversely correlated with GDM risk, while triglycerides showed a positive correlation. In multivariable analysis, apoA-I consistently exhibited a strong causal link with GDM, even after adjusting for other lipids and Body Mass Index (BMI).

The study demonstrates a significant causal relationship between apoA-I and GDM risk.

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Introduction

Gestational Diabetes Mellitus (GDM) represents a major public health concern due to its increasing prevalence and profound effects on both maternal and foetal health [ 1 , 2 ]. Approximately 5–7% of pregnancies are estimated to be impacted by GDM, with variations depending on the population studied and diagnostic standards [ 3 ]. Characterised by glucose intolerance first identified during pregnancy, GDM is linked to an elevated risk of various adverse outcomes [ 4 ]. These include a higher likelihood of cesarean delivery, pre-eclampsia, and the development of type 2 diabetes in later life for mothers [ 5 , 6 , 7 ]. For infants, the risks extend to macrosomia, hypoglycaemia, and a predisposition to obesity [ 8 , 9 ].

Effective strategies for prevention, early detection, as well as management of GDM can mitigate short-term complications and offer a chance to improve long-term health outcomes [ 10 , 11 ]. This underscores the need for continued research into its pathophysiology, risk factors, and effective interventions. Environmental factors, lifestyle choices, and genetics all have a role in the pathophysiology of GDM [ 12 , 13 ]. Research into the role of lipid metabolism in GDM highlights its significance in the pathogenesis of this condition. Observational studies have demonstrated that dysregulated lipid profiles, including elevated triglycerides and low HDL cholesterol levels, are commonly observed in GDM. These lipid imbalances contribute to insulin resistance, a hallmark of GDM [ 14 ]. Additionally, a lot of attention has been given to the role of specific apolipoproteins, particularly Apolipoprotein A-I (apoA-I) and Apolipoprotein B(apoB), in modulating lipid metabolism and influencing GDM risk. Wu et al. found that apoA-I protects rats from pregnancy-induced insulin resistance by increasing insulin sensitivity and inhibiting inflammation in adipose tissue and skeletal muscle [ 15 ]. Zheng et al. reported that the serum levels of triglycerides, LDL cholesterol, and Apolipoprotein B during the first trimester of pregnancy have important clinical value in predicting GDM [ 16 ]. However, the causal nature of this association is yet unclear and requires further investigation.

Mendelian Randomization (MR) is a method that leverages genetic variations as tools to infer causal relationships between risk factors and diseases [ 17 ]. In MR studies, genetic variants known to affect lipid levels (such as those affecting HDL cholesterol, LDL cholesterol, and triglyceride levels) are employed as instrumental variables. These variants are generally unaltered by environmental factors and disease states, making them ideal for examining the causal effect of lipid levels on GDM risk. This robust methodology may provide valuable insights into the underlying mechanisms while shedding light on the biological pathways linking lipid-related traits to GDM.

Materials and methods

Study design.

In this research, we conducted a two-sample Mendelian randomization (MR) analysis in order to assess the causal link between lipids and apolipoproteins and GDM. SNPs served as instrumental variables (IVs) [ 18 ]. To enhance result accuracy, validating three key hypotheses throughout the entire process is crucial [ 19 ]. We identified genetic variants significantly associated with lipid levels and calculated the corresponding F-statistics to assess the strength of each variant as an instrumental variable. We conducted an analysis of confounding factors to ensure that the selected variants are not associated with known confounders, such as BMI. We also used methods such as MR-Egger regression to evaluate the potential pleiotropy of the genetic variants, further confirming that their effects on GDM are primarily mediated through lipid levels (Fig.  1 ).

figure 1

Overview of the MR analysis process. Abbreviations: MR, mendelian randomization; IVs, instrumental variables; IVW, Inverse variance weighted; HDL-C, High density lipoprotein cholesterol; LDL-C, Low density lipoprotein cholesterol

The univariable MR analysis sought to analyse the correlation between specific lipid-related traits and GDM. The multivariable MR analysis, on the other hand, aimed to assess the individual impacts of interrelated lipid-related traits on GDM [ 20 ]. Both analyses aimed to comprehend the relationship between lipid-related traits and the risk of GDM, with the univariable focusing on individual traits and the multivariable concentrating on their interactions. All original studies obtained ethical review approval and informed consent. Genetic instruments for apoA-I, apoB, LDL cholesterol, HDL cholesterol, and triglycerides were extracted from the IEU Open GWAS database (Supplementary Table S1 ).

Statistical analyses

Our main approach for MR analysis was the fixed-effect inverse variance weighted (IVW) method. In cases where potential heterogeneity among selected SNPs was present, random effects modelling was employed [ 21 ]. Additionally, we utilised four other effective methods—MR-Egger, weighted median, weighted mode, and simple mode—to comprehensively analyse the potential relationship. It is noteworthy that although these methods offer a comprehensive evaluation, they might have less statistical power compared to the IVW test. We employed Cochran’s Q statistic and the MR-Egger test for assessing heterogeneity and pleiotropy, respectively.

Genetic instrument selection

In univariable MR analysis, independent SNPs linked to apoA-I, apoB, LDL cholesterol, HDL cholesterol, and triglycerides were isolated using a threshold of linkage disequilibrium clumping (r 2  = 0.001) and a window size of 10 megabases. Specifically, we focused on genome-wide significant SNPs ( p  < 5e-8) associated with each trait so as to reduce redundancy.

Sensitivity analyses

To ensure the reliability of the identified causal effect of lipids and apolipoproteins on GDM, we carried out a thorough set of sensitivity analyses. Cochran’s Q statistic was utilised to assess potential heterogeneity within the data [ 22 ]. The MR-Egger intercept analysis was employed to investigate horizontal pleiotropy [ 23 ]. We also conducted a Leave-one-out analysis to examine if any single SNP substantially affected the outcomes by systematically removing SNPs individually. Additionally, reverse MR analyses were performed to explore the potential reverse causal link between lipids and apolipoproteins (as seen in the forward MR analysis) and GDM.

For multivariable MR analysis, we applied two models to further understand the connection between lipid-related traits and GDM risk. In Model 1, five lipid-related traits (apoA-I, apoB, LDL cholesterol, HDL cholesterol, and triglycerides) were included in multivariable analysis.

In Model 2, we included BMI for analysis, along with the three traits that showed positive associations in univariable analysis: apoA-I, HDL cholesterol, and triglycerides.

All analyses were performed using R (version 4.2.0) and RStudio, employing the R packages “TwoSampleMR” and “MR-PRESSO”.

Univariable Mendelian randomization analysis

After excluding SNPs associated with confounders, we identified 261 instrumental variables for apoA-I, 179 IVs for apoB, 86 IVs for HDL cholesterol, 147 IVs for LDL cholesterol, and 216 IVs for triglycerides. F-statistics of Instrument Variables for lipids and apolipoproteins are shown in Supplementary Table S7.

A significant correlation between apoA-I and the risk of GDM was determined through the IVW technique (OR [95%CI] = 0.76 [0.68–0.86]; p  < 0.001). Moreover, HDL cholesterol was found to be significantly associated with a lower risk of GDM (OR [95%CI] = 0.79[0.69–0.89]; p  < 0.001). Triglycerides were found to be significantly linked to an elevated risk of GDM (OR [95%CI] = 1.28[1.12–1.46]; p  < 0.001). (Fig.  2 and Supplementary Table S3).

figure 2

Univariable Mendelian randomization results using different methods. Abbreviations: SNP, Single nucleotide polymorphism; HDL-C, High density lipoprotein cholesterol; LDL-C, Low density lipoprotein cholesterol; OR, Odds ration; CI, Confidence interval

A reverse MR analysis was conducted to explore the potential causal effect of GDM on lipid-related traits. The findings suggested no reverse causal relationship between GDM and each trait (Supplementary Table S4).

Multivariable Mendelian randomization analysis

Figure  3 presents the outcomes of the multivariable MR analysis in model 1. When adjusting simultaneously for apoA-I, apoB, LDL cholesterol, HDL cholesterol, and triglycerides, apoA-I continued to have a strong causal link with GDM; the OR was 0.59 (95% CI = 0.38, 0.91). However, the effects for HDL cholesterol and triglycerides were greatly reduced (Supplementary Table S5).

figure 3

Multivariable Mendelian randomization using the inverse-variance weighted method in model 1. Model 1 included Apolipoprotein A-I, Apolipoprotein B, LDL cholesterol, HDL cholesterol and triglycerides. Abbreviations: SNP, Single nucleotide polymorphism; HDL-C, High density lipoprotein cholesterol; LDL-C, Low density lipoprotein cholesterol; OR, Odds ration; CI, Confidence interval

Figure  4 exhibits the outcomes of the multivariable MR analysis in model 2. Body mass index is known as a risk factor for GDM. For model 2, the subjects included the three traits with positive results in univariable analysis (apoA-I, HDL cholesterol, and triglycerides) and BMI. When adjusting simultaneously for apoA-I, HDL cholesterol and triglycerides, and BMI, apoA-I consistently showed a strong causal association with GDM; the OR was 0.59 (95% CI = 0.38, 0.92). However, the estimates of HDL cholesterol and triglycerides were significantly reduced (Supplementary Table S6).

figure 4

Multivariable Mendelian randomization using the inverse-variance weighted method in model 2. Model 2 included Apolipoprotein A-I, HDL cholesterol, triglycerides and Body mass index. Abbreviations: SNP, Single nucleotide polymorphism; HDL-C, High density lipoprotein cholesterol; OR, Odds ration; CI, Confidence interval

Sensitivity analysis

In our analysis of apoB and HDL cholesterol causal impacts on GDM, instrumental heterogeneity was detected (Cochran’s Q test, p  < 0.05; Supplementary Table S2), leading us to employ the random-effects IVW method. On the other hand, for other analyses where no heterogeneity was observed (Cochran’s Q test, p  > 0.05), the fixed-effects IVW method was applied.

There was no evidence of horizontal pleiotropy in the MR-Egger intercept analysis results. Scatter plots illustrated the causal effect of lipid-related traits on GDM across the five MR methods; a positive relationship is indicated by a slope greater than zero, and vice versa (Supplementary Figure S1 ). Furthermore, no discernible heterogeneity was shown by the Funnel plot symmetry (Supplementary Figure S2).

The incidence of gestational diabetes mellitus (GDM) is increasing worldwide and poses a major concern for the health of pregnant women and their fetuses [ 24 , 25 ]. Our comprehensive investigation into the role of lipids and apolipoproteins in GDM is essential because they play a key role in metabolic pathways that may have an important impact on pregnancy outcomes [ 26 ].

Our study explored the intricate interplay between lipids, apolipoproteins, and GDM. ApoA-I is the major protein component of HDL and plays a critical role in reverse cholesterol transport, a key process in removing cholesterol from tissues and returning it to the liver for excretion. Conversely, apoB is a primary component of LDL, very-low-density lipoprotein, and intermediate-density lipoprotein, which are involved in the transport of cholesterol and triglycerides from the liver to peripheral tissues.

The noteworthy associations revealed between these biomarkers and GDM provide novel insights into their potential roles in the pathogenesis of this condition. In the univariable Mendelian randomization analysis, compelling associations were discovered between lipid and apolipoprotein levels and the risk of GDM. Importantly, apoA-I has demonstrated an inverse correlation with GDM risk, suggesting its potential protective role. This is consistent with the established function of apoA-I in facilitating reverse cholesterol transport and its anti-inflammatory properties, which could potentially mitigate GDM risk through enhanced lipid metabolism as well as reduced inflammation [ 27 , 28 ]. Similarly, the inverse association between HDL cholesterol and the risk of GDM is indicative of the protective role of high-density lipoproteins in cardiovascular health, potentially exerting a similar influence on GDM by modulating lipid homeostasis and insulin sensitivity [ 29 , 30 ]. On the other hand, dysregulated triglyceride levels may increase vulnerability to GDM, as suggested by the positive connection found between triglycerides and GDM risk. This relationship highlights the effect of high triglyceride levels on insulin resistance and impaired glucose metabolism.

In multivariable Mendelian randomization analyses, two distinct models provided intriguing insights into the relationship between lipid profiles and gestational diabetes mellitus (GDM). Model 1, which encompassed adjustments for all pertinent lipid and apolipoprotein features, notably highlighted apoA-I’s sustained significant association with GDM. This reinforces the robustness of apoA-I’s impact on GDM risk independent of other lipid factors. Interestingly, although there were initial significant correlations between HDL cholesterol and triglycerides in the univariable analysis, their effects diminished in Model 1, suggesting a potential attenuation or mediation of their individual associations with GDM when adjusting for other lipid factors.

The critical role of apoA-I in GDM was further highlighted in Model 2 by the inclusion of BMI. Even after adjusting for BMI, apoA-I maintained a robust association with GDM, emphasising its independent contribution to GDM risk [ 31 ]. However, the effects of HDL cholesterol and triglycerides were notably attenuated in this adjusted model, suggesting a potential interplay between these lipid traits and BMI in influencing GDM susceptibility. These findings underscore apoA-I’s consistent and considerable relationship with GDM, irrespective of BMI adjustments, while also pointing to the need for deeper exploration into the complex interrelationships among lipids, BMI, and GDM susceptibility to gain a more comprehensive understanding of their collective impact.

Our study has identified a robust causal association between apoA-I and GDM, wherein elevated levels of apoA-I correspond to a significant reduction in GDM risk. This is partly in line with previous research. Metformin is a widely used insulin sensitizer [ 32 ]. As claimed by Karavia et al., the sensitizing effect of metformin is diminished in mice with apoA-I gene knock-down (apoA-I (-/-)), revealing that apoA-I may be involved in insulin sensitization [ 33 ]. A cross-sectional study found that low apoA-I was associated with insulin resistance in patients with impaired glucose tolerance [ 27 ]. However, Retnakaran et al. found no significant association between serum apoa-1 levels and the risk of insulin resistance or GDM in pregnant women in an observational study [ 34 ]. This discrepancy may be attributed to variations in study design and methodology, underlining the complexity involved in determining the precise role of apoA-I in GDM pathogenesis.

Our study uncovers a potential causal relationship between apoA-I levels and the risk of gestational diabetes, which could facilitate early prediction of GDM, inform prevention strategies and treatment interventions, and promote the advancement of personalized medicine.

It is important to note that our study has a number of limitations. Firstly, MR studies rely on certain assumptions, such as the absence of pleiotropy and horizontal pleiotropy, which could have an effect on the validity of the causal inference. While employing robust genetic instruments and sensitivity analyses to mitigate these concerns, complete elimination of residual confounding remains challenging. Secondly, our research also concentrated on the genetic effects of lipid-related traits on GDM risk. Although we adjusted for BMI in multivariable MR analysis, other factors, including environmental and lifestyle factors, were not taken into account. Subsequent studies should strive to incorporate these elements into their analyses, contributing to a more holistic comprehension of the causal mechanisms underlying the relationship between lipid-related traits and GDM. Thirdly, the summary statistics used in our study encompass data from both male and female participants and do not distinguish between lipid levels or BMI measured before and after pregnancy. This limitation may impact the specificity of our findings related to the risk of GDM, as the physiological conditions of these distinct groups can differ substantially. Additionally, a significant limitation of this study is the reliance on summary statistics, which restricts our ability to investigate non-linear relationships between lipid levels and the risk of GDM. The analysis operates under the assumption that these relationships are linear, which may not adequately capture the complexities inherent in lipid metabolism. This methodological simplification might fail to detect clinically significant non-linear effects, indicating that future research would benefit from employing more sophisticated methods capable of exploring these dynamics in greater detail.

In conclusion, our study strongly suggests a potential causal relationship between genetic susceptibility to apoA-I and a reduced risk of GDM. Further validation of our findings and investigation into the underlying biological mechanisms warrant additional research, which may advance personalised approaches to GDM prevention and management.

Availability of data and materials

Original data generated and analyzed during this study are included in this published article or supplementary material.

Abbreviations

Gestational Diabetes Mellitus

Apolipoprotein A-I

Apolipoprotein B

High-density lipoprotein cholesterol

Low-density lipoprotein cholesterol

Body mass index

Genome-wide association study

  • Mendelian randomization

Single nucleotide polymorphism

Instrumental variable

Inverse variance weighted

Mendelian randomization pleiotropy residual sum and outlier

Linkage disequilibrium

Odds ration

Confidence interval

High density lipoprotein

Low-density lipoprotein

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We sincerely thank the contributors in the openGWAS project.

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Dan Shan and Ao Wang interpreted and analyzed the data, and drafted the manuscript. Dan Shan and Ke Yi concepted and designed the study and revised the manuscript. All authors contributed to and approved the final manuscript.

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Shan, D., Wang, A. & Yi, K. Lipids, apolipoproteins and gestational diabetes mellitus: a Mendelian randomization study. BMC Pregnancy Childbirth 24 , 347 (2024). https://doi.org/10.1186/s12884-024-06556-2

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research article diabetes

ScienceDaily

How night shift work can raise risk of diabetes, obesity

Just a few days on a night shift schedule throws off protein rhythms related to blood glucose regulation, energy metabolism and inflammation, processes that can influence the development of chronic metabolic conditions.

The finding, from a study led by scientists at Washington State University and the Pacific Northwest National Laboratory, provides new clues as to why night shift workers are more prone to diabetes, obesity and other metabolic disorders.

"There are processes tied to the master biological clock in our brain that are saying that day is day and night is night and other processes that follow rhythms set elsewhere in the body that say night is day and day is night," said senior study author Hans Van Dongen, a professor in the WSU Elson S. Floyd College of Medicine. "When internal rhythms are dysregulated, you have this enduring stress in your system that we believe has long-term health consequences."

Though more research is needed, Van Dongen said the study shows that these disrupted rhythms can be seen in as little as three days, which suggests early intervention to prevent diabetes and obesity is possible. Such intervention could also help lower the risk of heart disease and stroke, which is elevated in night shift workers as well.

Published in the Journal of Proteome Research , the study involved a controlled laboratory experiment with volunteers who were put on simulated night or day shift schedules for three days. Following their last shift, participants were kept awake for 24 hours under constant conditions -- lighting, temperature, posture and food intake -- to measure their internal biological rhythms without interference from outside influences.

Blood samples drawn at regular intervals throughout the 24-hour period were analyzed to identify proteins present in blood-based immune system cells. Some proteins had rhythms closely tied to the master biological clock, which keeps the body on a 24-hour rhythm. The master clock is resilient to altered shift schedules, so these protein rhythms didn't change much in response to the night shift schedule.

However, most other proteins had rhythms that changed substantially in night shift participants compared to the day shift participants.

Looking more closely at proteins involved in glucose regulation, the researchers observed a nearly complete reversal of glucose rhythms in night shift participants. They also found that processes involved in insulin production and sensitivity, which normally work together to keep glucose levels within a healthy range, were no longer synchronized in night shift participants. The researchers said this effect could be caused by the regulation of insulin trying to undo the glucose changes triggered by the night shift schedule. They said this may be a healthy response in the moment, as altered glucose levels may damage cells and organs, but could be problematic in the long run.

"What we showed is that we can really see a difference in molecular patterns between volunteers with normal schedules and those with schedules that are misaligned with their biological clock," said Jason McDermott, a computational scientist with PNNL's Biological Sciences Division. "The effects of this misalignment had not yet been characterized at this molecular level and in this controlled manner before."

The researchers' next step will be to study real-world workers to determine whether night shifts cause similar protein changes in long-term shift workers.

  • Workplace Health
  • Insomnia Research
  • Chronic Illness
  • Sleep Disorders
  • Intelligence
  • Child Development
  • Diabetes mellitus type 2
  • Sleep disorder
  • Diabetic diet
  • Hyperglycemia
  • Delayed sleep phase syndrome

Story Source:

Materials provided by Washington State University . Original written by Judith Van Dongen. Note: Content may be edited for style and length.

Journal Reference :

  • Jason E. McDermott, Jon M. Jacobs, Nathaniel J. Merrill, Hugh D. Mitchell, Osama A. Arshad, Ryan McClure, Justin Teeguarden, Rajendra P. Gajula, Kenneth I. Porter, Brieann C. Satterfield, Kirsie R. Lundholm, Debra J. Skene, Shobhan Gaddameedhi, Hans P. A. Van Dongen. Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment . Journal of Proteome Research , 2024; 23 (5): 1547 DOI: 10.1021/acs.jproteome.3c00418

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  • Published: 10 May 2024

Prevalence of hypertension and diabetes mellitus in Peruvian patients with chronic kidney disease: a systematic review and meta-analysis

  • Darwin A. León-Figueroa 1 ,
  • Edwin Aguirre-Milachay 1 ,
  • Joshuan J. Barboza 2 &
  • Mario J. Valladares-Garrido 3 , 4  

BMC Nephrology volume  25 , Article number:  160 ( 2024 ) Cite this article

Metrics details

Chronic Kidney Disease (CKD) represents a major challenge for public health, with hypertension and diabetes being the main causes of its occurrence. Therefore, this study aims to determine the prevalence of hypertension (HTN) and diabetes mellitus (DM) in Peruvian patients with CKD.

A systematic search for studies about CKD in Peru was carried out in PubMed, Scopus, Embase, Web of Science, ScienceDirect, Google Scholar, Virtual Health Library (VHL), and Scielo from 2011 to December 2023. The protocol of this research was registered in the international registry of systematic reviews, the Prospective International Registry of Systematic Reviews (PROSPERO), with registration number CRD42023425118. Study selection, quality assessment, and data extraction were performed independently by two authors. Study quality was assessed using the Joanna Briggs Institute Statistical Meta-Analysis Assessment and Review Instrument. A random-effects model with inverse variance weighting was used to estimate the combined prevalence of HTN and DM in Peruvian patients with CKD. To analyze data heterogeneity, the I 2 statistical test was used. Statistical analysis was performed with R version 4.2.3.

A total of 1425 studies were retrieved, of which 23 were included in the final meta-analysis. A total of 43,321 patients with CKD were evaluated, of whom 52.22% were male and 47.78% were female. The combined prevalence of HTN in Peruvian patients with CKD was 38% (95% CI: 30–46%; 41,131 participants; 21 studies, I 2  = 99%, p  = 0), while the combined prevalence of DM in Peruvian patients with CKD was 33% (95% CI: 26–40%; 43,321 participants; 23 studies, I 2  = 99%, p  = 0).

Approximately one-third of Peruvian patients with CKD have HTN and DM. These findings highlight the importance of implementing prevention and control measures for these chronic noncommunicable diseases in the Peruvian population, such as promoting healthy lifestyles, encouraging early detection and proper management of hypertension and diabetes, and improving access to medical care and health services.

Peer Review reports

Introduction

Chronic kidney disease (CKD) is typically defined by a glomerular filtration rate of less than 60 ml/min/1.73 m2 or the presence of other indicators of kidney damage, such as albuminuria [ 1 , 2 ]. CKD represents a global public health challenge, impacting about 10–14% of the adult population worldwide [ 3 , 4 ]. Moreover, CKD is closely linked to the increased prevalence of conditions such as diabetes mellitus (DM), hypertension (HTN), obesity, and aging, which continue to be the main causes of morbidity and premature mortality in the population affected by this disease [ 5 , 6 ].

Diabetes mellitus represents an important risk factor for the development of CKD [ 7 ], and several studies have explored its role as an independent risk factor in the incidence of CKD [ 8 , 9 ]. The prevalence of DM has been steadily increasing worldwide. Currently, about 450 million people suffer from this disease, and this figure is projected to reach 690 million by 2045 [ 10 ]. On the other hand, HTN plays a significant role in the onset and worsening of CKD [ 11 ]. The prevalence of HTN increases as renal function deteriorates, affecting approximately 60–90% of individuals with CKD [ 12 ]. HTN is the most common chronic disease in developed societies and claims about 7.1 million lives worldwide each year [ 7 ].

In Peru, the prevalence of CKD in some regions of the country can reach 16.8% [ 13 ] to 28.4% in the city of Lima [ 14 ]. In addition, it has been observed that among people with CKD, there is a prevalence of DM of 20% and HTN of 55.9% [ 14 ]. According to a 2024 press release, the Peruvian Ministry of Health reported that about 10% of adults suffer from CKD, with HTN and DM being the main causes of this condition [ 15 ]. In this context, the presence of chronic comorbidities, such as HTN and DM, in patients with CKD not only contributes to the development and progression of kidney disease but also exacerbates the risk of cardiovascular and renal complications, increasing the burden of disease and the costs associated with medical care [ 16 ].

In Peru, as in many Latin American countries, the availability of information related to the epidemiology of CKD and its association with other chronic diseases is limited [ 7 , 17 , 18 ]. This field of research is in constant development and is still being explored in depth. Due to its wide diversity in terms of socioeconomic trends, climatic and geographic zones, and social determinants of health (access to health services, economic stability, and education), Peru presents a unique opportunity to assess the burden of CKD [ 17 , 19 ].

The study aims to fill a significant gap in the understanding of renal health in the Peruvian population, focusing specifically on the prevalence of HTN and DM in patients with CKD. This research not only seeks to quantify the prevalence of these comorbid conditions but may also shed light on the risk factors and possible interactions between CKD, HTN, and DM in this specific context. By providing solid and systematized data, the study could inform more effective health policies aimed at prevention, early detection, and optimal management of these conditions in the Peruvian population, thus improving the care and quality of life of patients with CKD. In addition, it can lay the groundwork for future research and more precise and targeted intervention strategies [ 20 ].

Materials and methods

Protocol and registration.

The present research was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [ 21 ] (Table S1 ), as well as a protocol registered in PROSPERO with the identification number CRD42023425118.

Eligibility criteria

This review included observational studies, such as cross-sectional studies and prospective and retrospective cohorts, that examined the prevalence of HTN and DM in Peruvian patients over 18 years of age diagnosed with CKD. Studies that did not meet the criteria, such as editorials, letters to the editor, randomized clinical trials, conference abstracts, and narrative or systematic reviews, were excluded.

Information sources and search strategy

Searches were conducted in various databases, including PubMed, Scopus, Embase, Web of Science, ScienceDirect, Google Scholar, Virtual Health Library (VHL), and Scielo, until December 1, 2023, with no language or development period restrictions. Studies were identified using Medical Subject Headings (MeSH) terms such as “chronic kidney disease” and “Peru”. The search strategy was independently tested by two authors and is detailed in Table S2 . In addition, other search methods were used, including a review of literature studies, consultation of article references, and review of publications in Peruvian journals specializing in chronic kidney disease. However, the potential studies identified were within the scope of the search strategy employed.

Study selection

The search strategy results were stored in the Endnote software. Subsequently, duplicate articles, titles, and abstracts were removed. Next, two investigators independently reviewed the titles and abstracts of the articles to select those that met the inclusion criteria. Then, two additional investigators conducted a thorough review of the full articles to determine if they met the inclusion criteria. Any discrepancies identified were resolved through mutual agreements.

The main outcome is to determine the prevalence of HTN and DM in Peruvian patients diagnosed with CKD.

Quality assessment

The JBI-MAStARI tool was employed to assess the quality of the articles included in the meta-analysis. The evaluation encompassed various aspects, such as the study context, outcome and explanatory variables, specific inclusion criteria, measurement standards, topic description, and precise statistical analysis. The quality of the studies was categorized as high (≥ 7 points), moderate (4 to 6 points), or low (< 4 points) based on their scores, and any discrepancies were resolved through researcher discussions (Table S3 ) [ 22 ].

Data collection process and data items

Three independent researchers were responsible for collecting relevant data from the selected articles and recording it in an Excel spreadsheet. The collected information included various details such as the author, publication year, study design, study location, sample size, and the number of participants with CKD. The prevalence of CKD, study subjects, participants’ age, and gender (both male and female), as well as the presence of HTN and DM were also recorded. Subsequently, to ensure the accuracy and quality of the extracted data, two additional researchers conducted a rigorous review and verification process.

Data analysis

The data obtained from Excel was utilized for conducting the analysis in R, specifically version 4.2.3. In order to present the research findings, tables and narrative graphs were employed. A random-effects model with inverse variance weighting was used to estimate the combined prevalence of HTN and DM in Peruvian patients with CKD. The Cochrane Q statistic was used to examine the variability among the trials. Additionally, the I2 index was used to quantify this variability. Values of 25%, 50%, and 75%, respectively, were regarded as indicating low, moderate, and high heterogeneity.

A funnel plot was employed to investigate the possibility of publication bias. Egger’s regression test was also used to investigate this matter further. When the resultant p value was less than 0.05, it was believed that there was a possibility of bias in the results.

The pooled prevalence of HTN and DM in Peruvian patients with CKD was shown graphically as a forest plot, with 95% confidence intervals included for enhanced precision in the presentation of the data.

A total of 1425 articles were found through searches in eight different databases. The selection process is detailed in the PRISMA flowchart, depicted in Fig.  1 . After eliminating duplicate articles ( n  = 497), the investigators analyzed the remaining 928 articles. Subsequently, the titles and abstracts of these articles were evaluated, and 90 were selected for a comprehensive full-text review. Once this process was completed, 23 articles that met the inclusion criteria for the systematic review and meta-analysis were included [ 14 , 17 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ].

figure 1

illustrates the process of study selection according to the PRISMA flowchart

Characteristics of the included studie

The analysis was based on a review of 23 observational studies published between 2011 and 2023 that examined the prevalence of HTN and DM in Peruvian patients diagnosed with CKD (Table  1 ). A total of 43,321 patients with chronic kidney disease were evaluated, of whom 52.22% (22,622) were male and 47.78% (20,699) were female [ 14 , 17 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. The mean age of the participants was approximately 64 years, and most of the studies were centered in Lima, the capital of Peru (Table  1 ).

Quality of the included studies and publication bias

The quality of the studies was assessed using the JBI Critical Appraisal Tools, specifically designed for cross-sectional research. It was determined that all the studies included in the analysis demonstrated a moderate level of quality, as indicated in Table S3 [ 14 , 17 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. In the analyses aimed at evaluating HTN in Peruvian patients with CKD, it was observed that when Egger’s test was applied to evaluate publication bias, a value of p  = 0.5339 (t = -0.63, df = 19) was obtained. This result suggests that the null hypothesis of symmetry is accepted, indicating that there is no evidence of publication bias in the studies examined (Figure S1 ). In the analyses aimed at evaluating DM in Peruvian patients with CKD, it was evident that when Egger’s test was used to evaluate publication bias, a value of p  = 0.0063 (t = 3.04, df = 21) was obtained. This result indicates an asymmetry in the data, which could explain the considerable disparities in the reported prevalence values. However, it should be noted that we were unable to conclusively demonstrate the presence of publication bias (Figure S1 ).

Joint prevalence of HTN and DM in Peruvian patients with CKD

The combined prevalence of HTN in Peruvian patients with CKD was 38% (95% CI: 30–46%; 41,131 participants; 21 studies). The I 2 test indicated significant heterogeneity among the included studies (I 2  = 99%, p  = 0) (Fig.  2 ) [ 14 , 17 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 40 , 42 , 43 ]. The combined prevalence of DM in Peruvian patients with CKD was 33% (95% CI: 26–40%; 43,321 participants; 23 studies). The I 2 test indicated significant heterogeneity among the included studies (I 2  = 99%, p  = 0) (Fig.  3 ) [ 14 , 17 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. The combined prevalence of HTN and DM in Peruvian patients with CKD was 21% (95% CI: 19–23%; 32,860 participants; 4 studies). The I 2 test indicated significant heterogeneity among the included studies (I 2  = 89%, p  = 0) (Figure S2 ) [ 14 , 29 , 34 , 36 ].

figure 2

Forest plot illustrating the joint prevalence of Hypertension in Peruvian patients with chronic kidney disease

figure 3

Forest plot illustrating the joint prevalence of diabetes mellitus in Peruvian patients with chronic kidney disease

Chronic kidney disease constitutes a challenge of great relevance for public health at a global level, with an ever-increasing incidence and prevalence. In addition to its considerable medical and economic burden, CKD implies a notable increase in morbidity and mortality rates among the affected population. CKD is a non-communicable disease generally caused by diabetes and hypertension [ 44 ]. Therefore, the purpose of this systematic review and meta-analysis was to determine the prevalence of HTN and DM in Peruvian patients with CKD. The most relevant results showed that the combined prevalence of HTN in this population reached 38%, while the combined prevalence of DM was 33%.

The Centers for Disease Control and Prevention’s CKD Surveillance System reported that about 14% of adults in the United States have CKD stages 1 to 4 [ 45 ]. Kovesdy CP reported that CKD affects more than 10% of the general population worldwide and is more prevalent in older people, women, racial minorities, and people who experience DM and HTN [ 3 ].

In a meta-analysis by Hill NR, et al. reported an overall prevalence of 5-stage CKD of 13.4%, and stages 3–5 was 10.6% [ 46 ]. In addition, the prevalence of individual stages of CKD was 3.5% (stage 1), 3.9% (stage 2), 7.6% (stage 3), 0.4% (stage 4), and 0.1% (stage 5) [ 47 ]. According to the National Health and Nutrition Examination Survey (NHANES), the prevalence of CKD among adults aged 70 years and older was lower in 2017–March 2020 (42.6%) than in 2001–2004 (52.1%) [ 48 ]. Hill NR, et al. reported a linearly higher prevalence for CKD stages 1–5 associated with advancing age, ranging from 13.7% in the 30–40 year age group to 27.9% in patients > 70–80 years [ 46 ].

A study by Sundström J. et al. in 2.4 million patients from 11 countries reported a CKD prevalence of 10% [ 49 ]. In Asia, the prevalence of stage 3–5 CKD in low- and middle-income countries was 11.2% [ 50 ]. Another study found that 14% of the general population and high-risk groups in South Asia had CKD [ 51 ]. In Peru, Bravo-Zúñiga J, et al. reported a prevalence of CKD of 28.4% in patients evaluated in a health network in the city of Lima [ 14 ]. Another study by Herrera-Añazco P. et al. reported a CKD prevalence of 18% [ 29 ].

The combined prevalence of HTN in Peruvian patients with CKD was 38%. In the United States, the prevalence of CKD stages 1–4 among hypertensive adults was 26.34% in 2017–2020, compared with a prevalence of 7.8% among nonhypertensive individuals [ 52 ]. Hill NR et al., in their meta-analysis, reported an association between HTN and CKD prevalence [ 46 ]. In Tanzania, Stanifer JW et al. reported that among adults with CKD, 19.3% had HTN [ 53 ]. Another study found that the prevalence of CKD was 27% in adults with HTN [ 51 ]. In Peru, Bravo-Zúñiga J. et al. evaluated a total of 20,354 participants with CKD; 38.7% had HTN [ 34 ]. These results are based on the fact that HTN is a medical condition distinguished by elevated blood pressure, which is a significant risk factor in the development and progression of CKD. This condition can cause damage to the blood vessels in the kidneys, compromising their ability to efficiently filter waste and excess fluids from the body [ 54 ].

The combined prevalence of DM in Peruvian patients with CKD was 33%. In the United States, according to NHANES (2017–2020), the prevalence of CKD stages 1–4 in diabetic adults was 38.67% [ 55 ]; in addition, the prevalence of CKD stages 3–4 (NHANES 2001–March 2020) was 10% among adults with prediabetes or undiagnosed DM and 18% among adults with diagnosed DM [ 56 ]. A study by Fernandez-Fernandez L. et al. in Spain reported a CKD prevalence of 25.3% in patients with DM [ 57 ]. Gatwood J. et al. reported that CKD was evident in 31.6% of veterans before being diagnosed with DM [ 58 ]. A meta-analysis by Hill NR et al. reported an association between DM and the prevalence of CKD [ 46 ]. In Tanzania, Stanifer JW et al. reported that among adults with CKD, 7% had DM and 14.0% had DM and HTN [ 53 ]. Another study found that the prevalence of CKD was 31% in adults with DM [ 51 ]. Sundström J. et al. reported that DM was present in 38% of patients with CKD [ 49 ]. In Peru, Bravo-Zúñiga J, et al. evaluated a total of 20,354 participants with CKD; 13.74% had DM [ 34 ]. Diabetes is positioned as one of the leading causes of CKD, triggering a number of nephropathic complications. This disorder exerts a significant influence, as elevated blood glucose levels cause progressive damage to the small blood vessels that supply blood to the kidneys. This detrimental interference compromises kidney function, creating an environment conducive to the development and aggravation of kidney disease [ 59 ].

The present study has some limitations. First, the included studies may be subject to biases and confounding factors that cannot be individually quantified. Second, it was not possible to perform a subgroup analysis by gender because the studies provided only baseline demographic data for the CKD population. Third, the prevalence of HTN and DM according to CKD stages could not be determined. Finally, the sample sizes of the included studies varied considerably, ranging from 20,354 to only 30 participants. However, among the strengths of this study, it is noteworthy that this research represents the first systematic review and meta-analysis focused on the evaluation of HTN and DM in Peruvian patients with CKD. To guarantee the quality of the included studies, the “JBI-MAStARI” tool was used as the evaluation method. In addition, a specific search strategy was designed for each database, and article selection and data extraction were carried out independently by two or more investigators. It should be noted that the studies included in this review shared the same definitions of CKD, and the recommendations established by the PRISMA guidelines were rigorously followed.

Conclusions

Data availability.

No datasets were generated or analysed during the current study.

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Conceptualization, D.A.L.F., M.J.V.G. and J.J.B.; methodology, J.J.B. and E.A.M.; software, D.A.L.F.; validation, E.A.M.; formal analysis, D.A.L.F.; investigation, M.J.V.G.; resources, A.J.R.M.; data curation, D.A.L.F.; writing—original draft prepa-ration, D.A.L.F., E.A.M. and J.J.B.; writing—review and editing, D.A.L.F., M.J.V.G., J.J.B., and E.A.M.; visualization, D.A.L.F.; supervision, J.J.B. All authors have read and agreed to the published version of the manuscript.

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León-Figueroa, D.A., Aguirre-Milachay, E., Barboza, J.J. et al. Prevalence of hypertension and diabetes mellitus in Peruvian patients with chronic kidney disease: a systematic review and meta-analysis. BMC Nephrol 25 , 160 (2024). https://doi.org/10.1186/s12882-024-03595-x

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Arecor and Medtronic Diabetes establish collaboration to develop a novel thermostable insulin for implantable pump delivery

Published: May 09, 2024

  • Medtronic to fund Arecor’s development of Arestat™ enabled novel, high concentration, thermostable insulin, specifically tailored for use in combination with a next-generation implantable pump

Cambridge, UK, 9 May 2024: Arecor Therapeutics plc (AIM: AREC), the biopharmaceutical group advancing today’s therapies to enable healthier lives, today announced a research collaboration with Medtronic plc (NYSE: MDT), a global leader in healthcare technology, to develop a novel, high concentration, thermostable insulin for use by Medtronic ’s Diabetes business in a next-generation implantable pump.

This new insulin has the potential to bring significant advancements in the current insulin treatment options for a small population of patients who have limited options for controlling their diabetes with traditional therapy. This collaboration has the potential to allow for the continued care of these patients with an insulin that may minimise the need for pump maintenance interventions and expand the utility for physicians, whilst saving healthcare costs.

Sarah Howell, Chief Executive Officer of Arecor, said: “ Our leadership in this field has been demonstrated through our best-in-class ultra-rapid acting clinical development programmes (AT278 & AT247). Within the diabetes field more broadly we are seeing the rise of innovative delivery devices, including longer-wear and miniaturised pumps that are continually improving treatment options for patients. We are excited to play our part in this progress with the development of a highly differentiated insulin with the potential to transform treatment for an extremely vulnerable patient group. This collaboration is one of many we hope to enable, to further enhance the benefits of these next-generation devices.”

Gary Dulak, Senior Director, New Venture Programs Medtronic Diabetes, said: “Medtronic Diabetes is a pioneer in implantable insulin pump systems for people living with type 1 diabetes, who are unable to tolerate conventional therapy that delivers insulin subcutaneously (under the skin). With intraperitoneal therapy via an implantable insulin pump system, insulin delivery is targeted for direct absorption by the liver via the implantable pump. We are pleased to collaborate with Arecor to explore new ways to develop this critical therapeutic option for the subset of individuals who may benefit from it.”

This announcement contains inside information for the purposes of the retained UK version of the EU Market Abuse Regulation (EU) 596/2014 (“UK MAR”).

Product not approved by the FDA for any use and not available for research or commercial use in the US.

For more information, please contact:

Notes to Editors

About Arecor Arecor Therapeutics plc is a globally focused biopharmaceutical company transforming patient care by bringing innovative medicines to market through the enhancement of existing therapeutic products. By applying our innovative proprietary technology platform, Arestat™, we are developing an internal portfolio of proprietary products in diabetes and other indications, as well as working with leading pharmaceutical and biotechnology companies to deliver therapeutic products. The Arestat™ platform is supported by an extensive patent portfolio.

The collaboration adds to Arecor’s broad programme of diabetes focused activities, led by its two lead proprietary clinical development programmes – AT278 and AT247, two ultra-rapid acting insulin candidates that offer the potential to simplify and improve blood glucose control for people living with diabetes and could enable the development of next- generation miniaturised insulin delivery systems and a fully closed loop artificial pancreas system. In March 2024, Arecor established a research collaboration with TRx Biosciences for the formulation development of an oral glucagon-like peptide-1 (GLP-1) receptor agonist product that would provide a more convenient treatment option for patients with diabetes and obesity. The Group’s specialty pharmaceutical business, Tetris Pharma, commercialises Ogluo®, a glucagon prefilled autoinjector pen for patients living with diabetes suffering from severe hypoglycaemia.

For further details please see our website, www.arecor.com

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H20 for healthy aging

Could staying hydrated help you live a longer, healthier life.

Try to drink about eight glasses of fluids every day.

Try to drink about eight glasses of fluids every day.

Water is essential for just about every function in our bodies, from keeping our organs working properly to regulating our body temperature. Losing more water than we take in can lead to dehydration , which happens when your body doesn’t have enough fluid to function properly. 

Our bodies are constantly losing fluids. Sweating during exercise or in hot weather, dealing with an illness such as diarrhea or vomiting, and even breathing and going to the bathroom all cause our bodies to lose water. And as we age, our bodies don’t retain fluids as well. We may also become less aware of our thirst. This makes staying hydrated even more important.  

But here’s a splash of good news! A study from the National Heart, Lung, and Blood Institute (NHLBI) found that people who stay hydrated throughout their lives are less likely to develop chronic diseases and may even live longer, healthier lives. 

Linking hydration to long-term health

The research was part of the Atherosclerosis Risk in Communities (ARIC) study, which investigates heart health in adults living in different U.S. communities. The researchers tracked the health of more than 11,000 adults for 30 years. This included measuring levels of blood sodium, an electrolyte that helps regulate fluids in the body. When we're dehydrated, our blood sodium levels tend to go up.

Researchers found that people with higher sodium levels were more likely to develop chronic diseases (such as heart failure, diabetes, and dementia) later in life. They also tended to show more signs of advanced biological aging, such as raised systolic blood pressure, cholesterol, and blood sugar—signs that indicate how well your body is functioning. These participants were more likely to die at younger ages, but those who stayed well hydrated developed fewer chronic health conditions and tended to live longer.

Will you live longer if you drink more water? 

Not necessarily. While these findings show a link between staying hydrated and healthy aging, they don’t prove cause and effect. We need more research to know whether good hydration actually prevents disease or extends your life. In the meantime, this study is a good reminder that staying hydrated is a simple (but impactful!) way you can invest in your health and well-being. 

How much fluid should you drink? 

It depends on factors like your age, activity level, and climate. But a good general rule is to aim for about eight glasses of fluids every day. Water is the best choice, but fluids from other sources (such as juices, herbal teas, and fruits and vegetables with high water content) can also help you stay hydrated. 

Learn more about hydrating for health , including tips for staying hydrated. 

National Heart, Lung, and Blood Institute ; NIH News in Health

May 07, 2024

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  1. New Aspects of Diabetes Research and Therapeutic Development

    I. Introduction. Diabetes mellitus, a metabolic disease defined by elevated fasting blood glucose levels due to insufficient insulin production, has reached epidemic proportions worldwide (World Health Organization, 2020).Type 1 and type 2 diabetes (T1D and T2D, respectively) make up the majority of diabetes cases with T1D characterized by autoimmune destruction of the insulin-producing ...

  2. Trends in Diabetes Treatment and Control in U.S. Adults, 1999-2018

    Glycemic, blood-pressure, and lipid control improved from 1999 to 2010 in U.S. adults with diabetes, 10 but recent analyses suggest that progress may have stalled or reversed in later periods. 11 ...

  3. Diabetes: a defining disease of the 21st century

    New estimates published this week in The Lancet indicate that more than 1·31 billion people could be living with diabetes by 2050 worldwide. That's 1·31 billion people living with a disease that causes life-altering morbidity, high rates of mortality, and interacts with and exacerbates many other diseases. The increase in prevalence (up from 529 million in 2021) is expected to be driven by ...

  4. Diabetes

    Prevention of Cardiovascular Disease in Type 1 Diabetes. C. Manrique-Acevedo, I.B. Hirsch, and R.H. EckelN Engl J Med 2024;390:1207-1217. More than half of newly diagnosed cases of type 1 diabetes ...

  5. Diabetes

    Diabetes articles from across Nature Portfolio. Diabetes describes a group of metabolic diseases characterized by high blood sugar levels. Diabetes can be caused by the pancreas not producing ...

  6. Global, regional, and national burden of diabetes from 1990 to 2021

    Diabetes remains a substantial public health issue. Type 2 diabetes, which makes up the bulk of diabetes cases, is largely preventable and, in some cases, potentially reversible if identified and managed early in the disease course. However, all evidence indicates that diabetes prevalence is increasing worldwide, primarily due to a rise in obesity caused by multiple factors. Preventing and ...

  7. The burden and risks of emerging complications of diabetes ...

    Fig. 1: Major traditional complications and emerging complications of diabetes mellitus. The traditional complications of diabetes mellitus include stroke, coronary heart disease and heart failure ...

  8. To tackle diabetes, science and health systems must take into ...

    In their timely article 'Social determinants of health and diabetes: a scientific review', published in Diabetes Care 4, the authors provide an overview of key definitions and social ...

  9. Diabetes

    Follow Diabetes on X . Join us on X @Diabetes_ADA to connect with the diabetes research community and share ideas with fellow professionals. Find the newest published articles, latest podcasts, new professional books, and up-to-date diabetes news. You can also follow ADA Publications on Facebook @adaPublications.

  10. Type 2 diabetes

    Type 2 diabetes accounts for nearly 90% of the approximately 537 million cases of diabetes worldwide. The number affected is increasing rapidly with alarming trends in children and young adults (up to age 40 years). Early detection and proactive management are crucial for prevention and mitigation of microvascular and macrovascular complications and mortality burden. Access to novel therapies ...

  11. Harvard diabetes researcher details science behind potential

    For Harvard Stem Cell Institute Co-Director and Xander University Professor Douglas Melton, whose lab pioneered the science behind the therapy, the trial marked the most recent turning point in a decades-long effort to understand and treat the disease. In a conversation with the Gazette, Melton discussed the science behind the advance, the ...

  12. Improving Quality Outcomes: The Value of Diabetes Care and Education

    They help people with diabetes problem-solve and develop individualized diabetes management plans. DCESs also help patients achieve the mutual goals of reducing risk for diabetes-related complications, mortality, and health care costs through their advanced skills in diabetes technology and population health approaches (31-33,35,36).

  13. Diabetes Research and Clinical Practice

    About the journal. Diabetes Research and Clinical Practice is an international journal for health-care providers and clinically oriented researchers that publishes high-quality original research articles and expert reviews in diabetes and related areas. The role Diabetes Research and Clinical Practice is to provide …. View full aims & scope.

  14. Journal of Diabetes Research

    29 Apr 2024. 29 Apr 2024. 28 Mar 2024. 28 Mar 2024. Journal of Diabetes Research publishes articles related to type 1 and type 2 diabetes. Topics include etiology, pathogenesis, management, and prevention of diabetes, as well as associated complications such as nephropathy.

  15. Recent Advances

    Ultimately, this cycle drives advances to prevent diabetes and to help people burdened by it. In 2018 alone, ADA-funded scientists published over 200 articles related to their awards! Identification of a new player in type 1 diabetes risk. Type 1 diabetes is caused by an autoimmune attack of insulin-producing beta-cells.

  16. Diabetes: Following the science in the search for a cure

    Making insulin-resistant cells more sensitive to insulin is another goal of novel therapeutics for diabetes. In preclinical research, insulin sensitivity has been improved with gene therapy ...

  17. Advances and challenges of the cell-based therapies among diabetic

    Diabetes mellitus is a significant global public health challenge, with a rising prevalence and associated morbidity and mortality. Cell therapy has evolved over time and holds great potential in diabetes treatment. In the present review, we discussed the recent progresses in cell-based therapies for diabetes that provides an overview of islet and stem cell transplantation technologies used in ...

  18. Lipids, apolipoproteins and gestational diabetes mellitus: a Mendelian

    Gestational Diabetes Mellitus (GDM) represents a major public health concern due to its increasing prevalence and profound effects on both maternal and foetal health [1, 2].Approximately 5-7% of pregnancies are estimated to be impacted by GDM, with variations depending on the population studied and diagnostic standards [].Characterised by glucose intolerance first identified during pregnancy ...

  19. What To Know About Artificial Sweeteners and Diabetes

    Research is ongoing regarding some potential risks. If you're living with diabetes, you know to limit added sugars and simple carbs, but what about artificial sweeteners? Two diabetes educators ...

  20. Cell therapy fails to slow type 1 diabetes, but safety is ...

    T olerance is the holy grail in calming autoimmune disease, a truce in the immune system's faulty battle against the body's own fabric. In type 1 diabetes, immune fighters attack beta cells in ...

  21. How night shift work can raise risk of diabetes, obesity

    The finding provides new clues as to why night shift workers are more prone to diabetes, obesity and other metabolic disorders. ... Journal of Proteome Research, 2024; 23 (5): 1547 DOI: 10.1021 ...

  22. Diabetes

    There is a growing awareness that type 1 diabetes mellitus (T1DM) is a heterogeneous disease that can be characterized into distinct endotypes. This Review discusses the evidence for endotypes in ...

  23. Prevalence of hypertension and diabetes mellitus in Peruvian patients

    Chronic Kidney Disease (CKD) represents a major challenge for public health, with hypertension and diabetes being the main causes of its occurrence. Therefore, this study aims to determine the prevalence of hypertension (HTN) and diabetes mellitus (DM) in Peruvian patients with CKD. A systematic search for studies about CKD in Peru was carried out in PubMed, Scopus, Embase, Web of Science ...

  24. Arecor and Medtronic Diabetes establish collaboration to ...

    Arecor Therapeutics plc announced a research collaboration with Medtronic plc, a global leader in healthcare technology, to develop a novel, high concentration, thermostable insulin for use by Medtronic's Diabetes business in a next-generation implantable pump. ... Within the diabetes field more broadly we are seeing the rise of innovative ...

  25. H20 for healthy aging

    Research from the National Heart, Lung, and Blood Institute (NHLBI) suggests staying hydrated might help you live a longer, healthier life! The study found links between good hydration and reduced risk of chronic diseases, including heart failure, diabetes, dementia, and more. Discover how dehydration impacts your body and signs you might be dehydrated and get tips for staying hydrated.