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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

Harvard Correspondent

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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Beyond Blood Sugar Control: New Target for Curing Diabetes Unveiled

By Helmholtz Munich March 22, 2024

Targeting the inceptor receptor could lead to breakthrough treatments for diabetes by protecting beta cells and improving blood sugar control, with German research institutions leading this promising discovery. Insulin-producing beta cells in the islet of Langerhans. Credit: Helmholtz Munich | Erik Bader

Research focusing on the insulin -inhibitory receptor, known as inceptor, has revealed promising paths for protecting beta cells, providing optimism for therapy that directly addresses diabetes. A groundbreaking study involving mice with obesity caused by diet shows that eliminating inceptor improves glucose management. This finding encourages further investigation into inceptor as a potential therapeutic target for treating type 2 diabetes.

These findings, led by Helmholtz Munich in collaboration with the German Center for Diabetes Research, the Technical University of Munich, and the Ludwig-Maximilians-University Munich, drive advancements in diabetes research.

Targeting Inceptor to Combat Insulin Resistance in Beta Cells

Insulin resistance, often linked to abdominal obesity, presents a significant healthcare dilemma in our era. More importantly, the insulin resistance of beta cells contributes to their dysfunction and the transition from obesity to overt type 2 diabetes. Currently, all pharmacotherapies, including insulin supplementation, focus on managing high blood sugar levels rather than addressing the underlying cause of diabetes: beta cell failure or loss. Therefore, research into beta cell protection and regeneration is crucial and holds promising prospects for addressing the root cause of diabetes, offering potential avenues for causal treatment.

With the recent discovery of inceptor, the research group of beta cell expert Prof. Heiko Lickert has uncovered an interesting molecular target. Upregulated in diabetes, the insulin-inhibitory receptor inceptor may contribute to insulin resistance by acting as a negative regulator of this signaling pathway. Conversely, inhibiting the function of the inceptor could enhance insulin signaling – which in turn is required for overall beta cell function, survival, and compensation upon stress.

In collaboration with Prof. Timo Müller, an expert in molecular pharmacology in obesity and diabetes, the researchers explored the effects of inceptor knock-out in diet-induced obese mice. Their study aimed to determine whether inhibiting inceptor function could also enhance glucose tolerance in diet-induced obesity and insulin resistance, both critical pre-clinical stages in the progression toward diabetes. The results were now published in Nature Metabolism .

Removing Inceptor Improves Blood Sugar Levels in Obese Mice

The researchers delved into the effects of removing inceptor from all body cells in diet-induced obese mice. Interestingly, they found that mice lacking inceptor exhibited improved glucose regulation without experiencing weight loss, which was linked to increased insulin secretion in response to glucose. Next, they investigated the distribution of inceptor in the central nervous system and discovered its widespread presence in neurons. Deleting inceptor from neuronal cells also improved glucose regulation in obese mice. Ultimately, the researchers selectively removed the inceptor from the mice’s beta cells, resulting in enhanced glucose control and a slight increase in beta cell mass.

Research for Inceptor-Blocking Drugs

“Our findings support the idea that enhancing insulin sensitivity through targeting inceptor shows promise as a pharmacological intervention, especially concerning the health and function of beta cells,” says Timo Müller. Unlike intensive early-onset insulin treatments, utilizing inceptor to enhance beta cell function offers promise in alleviating the detrimental effects on blood sugar and metabolism induced by diet-induced obesity. This approach avoids the associated risks of hypoglycemia-associated unawareness and unwanted weight gain typically observed with intensive insulin therapy.

“Since inceptor is expressed on the surface of pancreatic beta cells, it becomes an accessible drug target. Currently, our laboratory is actively researching the potential of several inceptor-blocking drug classes to enhance beta cell health in pre-diabetic and diabetic mice. Looking forward, inceptor emerges as a novel and intriguing molecular target for enhancing beta cell health, not only in prediabetic obese individuals but also in patients diagnosed with type 2 diabetes,” explains Heiko Lickert.

Reference: “Global, neuronal or β cell-specific deletion of inceptor improves glucose homeostasis in male mice with diet-induced obesity” by Gerald Grandl, Gustav Collden, Jin Feng, Sreya Bhattacharya, Felix Klingelhuber, Leopold Schomann, Sara Bilekova, Ansarullah, Weiwei Xu, Fataneh Fathi Far, Monica Tost, Tim Gruber, Aimée Bastidas-Ponce, Qian Zhang, Aaron Novikoff, Arkadiusz Liskiewicz, Daniela Liskiewicz, Cristina Garcia-Caceres, Annette Feuchtinger, Matthias H. Tschöp, Natalie Krahmer, Heiko Lickert and Timo D. Müller, 28 February 2024, Nature Metabolism . DOI: 10.1038/s42255-024-00991-3

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1 comment on "beyond blood sugar control: new target for curing diabetes unveiled".

Interesting study and hopefully another tool which will apply to diabetic patients.

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• 17 June 2021

Towards a stem-cell therapy for diabetes

• Anna Melidoni 0

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The isolation of the first human embryonic stem cell (hESC) lines in 1998 opened the possibility of stem cell therapies for a variety of conditions. Type 1 diabetes (T1D) is particularly suited to this approach, as transplantation of the insulin-producing pancreatic β-cells could provide long-lasting therapy or even a cure. By the early 2000s, the stem cell differentiation field was benefitting from embryo studies in model organisms that had identified the role of various signalling pathways in controlling pancreatic cell lineage specification.

In 2005, D’Amour et al. reported the production of hESC differentiation cultures containing >80% definitive endoderm cells: the embryonic progenitors of pancreatic cells. Differentiation occurred in 2D culture, using a low serum medium containing activin A, a protein that is essential for endoderm specification in the embryo.

Following this advance, in 2006, D’Amour et al. published a key paper reporting the generation of endocrine pancreatic cells, capable of secreting insulin, glucagon, somatostastin, pancreatic polypeptide and ghrelin from differentiating hESCs. Their differentiation protocol included five stages, during which hESCs went through a series of intermediate cellular states: definitive endoderm, primitive gut tube, posterior foregut, pancreatic endoderm and endocrine precursors and hormone-expressing endocrine cells. Specific growth factors were supplied at each step, in an effort to mimic embryonic pancreas development. Indeed, characterization of mRNA and proteins in the different cell states showed that they resembled the equivalent embryonic endodermal progenitors.

At stage five of this study, staining by zinc-chelating agent dithizone was used to identify the pancreatic endocrine cells. Their insulin content was similar to that of primary adult human islets and the de novo synthesis of insulin was confirmed by mRNA, C-peptide and pro-insulin protein measurement. However, compared with adult islets, the C-peptide content of hESC-derived cells was inferior, indicating a reduced efficiency in processing pro-insulin. C-peptide secretion was responsive to multiple secretory stimuli, albeit only minimally responsive to glucose.

Subsequently, in 2008, the same group (Kroon et al.) succeeded in generating glucose-responsive endocrine cells in vivo, following transplantation of hESC-derived stage-four pancreatic endoderm in mice. These cells expressed key β-cell transcription factors, showed efficient processing of pro-insulin and contained mature secretory granules. Importantly, the hESC-derived endocrine cells protected the mice against hyperglycaemia.

In 2014, Rezania et al. described a seven-stage hESC differentiation protocol that generated glucose-responsive insulin-producing β-cells that reversed diabetes in mice upon transplantation. In the same year, Pagliuca et al. reported the in vitro large-scale generation of glucose-responsive, insulin-expressing β-cells derived from human pluripotent stem cells (hPSCs), by sequentially modulating key signalling pathways in a 3D culture system. These hPSC-derived β-cells were very similar to human β-cells in terms of gene expression and ultrastructure and also ameliorated hyperglycaemia in diabetic mice upon transplantation.

In 2015, Russ et al. reported a simplified suspension-based, directed differentiation protocol to generate glucose-responsive insulin-producing human β-cells from hPSCs in vitro and in vivo. The resulting cells reduced blood levels of glucose in diabetic mice in a matter of weeks, as opposed to months in previous studies.

In 2019, Nair et al. reported the generation in vitro of mature β-cells from hESCs, by allowing the immature β-like cells to form islet-like clusters, thus recapitulating endocrine cell clustering in vivo. Mature β-cells showed enhanced metabolic and structural maturation of mitochondria and hyperglycaemia was reduced within days of transplantation in diabetic mice.

In 2020, Hogrebe et al. discovered that the state of actin polymerization influences pancreatic differentiation in vitro. Thus, timed actin depolymerization during differentiation led to the generation of β-cells from hPSCs that rapidly reversed diabetes in mice and maintained normoglycaemia for 9 months.

Fifteen years after the first insulin-secreting cells were generated by differentiating hESCs in vitro, we still do not have a β-cell replacement therapy for T1D. However, thanks to the studies mentioned here, and many others, we are much closer to this goal. Apart from further optimizing the efficiency and scalability of mature β-cell production, important issues, such as shielding the transplanted stem-cell-derived β-cells from immune rejection and ensuring their purity, need to be resolved before a stem-cell-based therapy becomes a reality.

Further reading

D’Amour, K. A. et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat. Biotechnol. 23 , 1534–1541 (2005).

Kroon, E. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26 , 443–452 (2008).

Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. 32 , 1121–1133 (2014).

Pagliuca, F. W. et al. Generation of functional human pancreatic β cells in vitro. Cell 159 , 428–439 (2014).

Russ, H. A. et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 34 , 1759–1772 (2015).

Nair, G. G. et al. Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells. Nat. Cell Biol. 21 , 263–274 (2019).

Hogrebe, N. J. et al. Targeting the cytoskeleton to direct pancreatic differentiation of human pluripotent stem cells. Nat. Biotechnol. 38 , 460–470 (2020).

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Due to the downward trend in respiratory viruses in Maryland, masking is no longer required but remains strongly recommended in Johns Hopkins Medicine clinical locations in Maryland. Read more .

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New Research Sheds Light on Cause of Type 2 Diabetes

St. Petersburg, Fla. – September 12, 2023 – Scientists at Johns Hopkins All Children’s Hospital, along with an international team of researchers, are shedding new light on the causes of Type 2 diabetes. The new research, published in the journal Nature Communications , offers a potential strategy for developing new therapies that could restore dysfunctional pancreatic beta-cells or, perhaps, even prevent Type 2 diabetes from developing.

The new study shows that the beta-cells of Type 2 diabetes patients are deficient in a cell trafficking protein called “phosphatidylinositol transfer protein alpha” (or PITPNA), which can promote the formation of “little packages,” or intracellular granules containing insulin. These structures facilitate processing and maturation of insulin “cargo.” By restoring PITPNA in the Type 2 deficient beta-cells, production of insulin granule is restored and this reverses many of the deficiencies associated with beta-cell failure and Type 2 diabetes.

Researchers say it’s important to understand how specific genes regulate pancreatic beta-cell function, including those that mediate insulin granule production and maturation like PITPNA to provide therapeutic options for people.

Matthew Poy, Ph.D. , an associate professor of Medicine and Biological Chemistry in the Johns Hopkins University School of Medicine and leader of the Johns Hopkins All Children’s team within the  Institute for Fundamental Biomedical Research , was lead researcher on the study. He adds that follow-up work is now focused on whether PITPNA can enhance the functionality of stem-cell-derived pancreatic beta-cells. Since stem cell-based therapies are still in their relatively early stages of clinical development, it appears a great deal of the potential of this approach remains untapped. Poy believes that increasing levels of PITPNA in stem cell-derived beta-cells is an approach that could enhance the ability to produce and release mature insulin prior to transplantation in diabetic subjects.

“Our dream is that increasing PITPNA could improve the efficacy and potency of beta-like stem cells,” Poy says. “This is where our research is heading, but we have to discover whether the capacity of these undifferentiated stem cells that can be converted into many different cell types can be optimized — and to what level — to be converted into healthy insulin producing beta-cells. The goal would be to find a cure for type 2 diabetes.”

Read more about this groundbreaking research.

This study was funded through grants from the  Johns Hopkins All Children’s Foundation , the  National Institute of Health, the Robert A. Welch Foundation, the Helmholtz Gemeinschaft , the European Foundation for the Study of Diabetes, the  Swedish Science Council , the  NovoNordisk Foundation  and the  Deutsche Forschungsgemeinschaft .     About Johns Hopkins All Children’s Hospital Johns Hopkins All Children’s Hospital in St. Petersburg is a leader in children’s health care, combining a legacy of compassionate care focused solely on children since 1926 with the innovation and experience of one of the world’s leading health care systems. The 259-bed teaching hospital, stands at the forefront of discovery, leading innovative research to cure and prevent childhood diseases while training the next generation of pediatric experts. With a network of Johns Hopkins All Children’s Outpatient Care centers and collaborative care provided by All Children’s Specialty Physicians at regional hospitals, Johns Hopkins All Children’s brings care closer to home. Johns Hopkins All Children’s Hospital consistently keeps the patient and family at the center of care while continuing to expand its mission in treatment, research, education and advocacy. For more information, visit HopkinsAllChildrens.org .

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How Ozempic Is Changing Diabetes Treatment

Millions of patients rely on insulin. But with new drugs, some have been able to lower their doses or stop taking it altogether.

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By Dani Blum

For over 20 years, Betsy Chadwell carried her insulin pens everywhere. Day in and day out, she carefully calibrated the doses needed to keep her Type 2 diabetes in check. “Every meal, and every morning and every night — it controls your life,” she said.

In late 2021, she started on the diabetes drug Ozempic. Within months, she was able to stop taking the short-acting insulin she typically took before each meal altogether, and she has substantially reduced the dose of long-acting insulin she uses daily. Scaling back on insulin has given her a sense of freedom, she said. She still uses a continuous glucose monitor to track her blood sugar, meticulously watching for slumps and spikes — but even as she took less insulin, she said, Ozempic has helped keep her glucose levels more under control.

Millions of Americans rely on some form of insulin, a lifesaving drug that has long been a mainstay of diabetes treatment. But it can also be a burden to patients like Ms. Chadwell, who must juggle different formulations and doses, and often must have insulin on hand at all times.

“I really feel for those patients, because you can never stop having it in the back of your mind,” said Dr. Scott Hagan, an assistant professor of medicine at the University of Washington who studies obesity.

But in recent years, Ozempic and a similar drug, Mounjaro — both weekly shots that can lower blood sugar, in part by mimicking a hormone that stimulates insulin production — have offered patients an enticing new option to try managing their Type 2 diabetes without relying as heavily on insulin.

And drugmakers are examining other ways these drugs might work alongside insulin: Novo Nordisk, the company that makes Ozempic, is studying a new drug called IcoSema, a weekly shot that combines insulin icodec (an ultra long-acting version of insulin) and semaglutide, the compound in Ozempic.

While it hasn’t yet published the full results, Novo Nordisk has said that promising but preliminary data from two trials suggest IcoSema might lead to better glucose control than insulin or semaglutide alone. Previous trials have suggested that people takin g semaglutide or tirzepatide , the substance in Mounjaro, alongside insulin had better blood sugar control and lost more weight than those taking insulin alone.

Patients who are already using these drugs in tandem often do so with the hope of lowering how much insulin they take, or weaning off it altogether. Dr. Hagan said patients are often eager to get off insulin, partly because it can be such a logistical pain, and partly because the medication can lead to weight gain .

There is no standard guidance on how to dose Ozempic and insulin together, though, so doctors said they are learning in real time how to manage patients on both medications. “It’s kind of a moving target,” Dr. Hagan said. Lower a person’s insulin dose too quickly, and their blood sugar might rise out of control.

“You don’t just lower the insulin on everyone, or you don’t just wait and see what happens for everyone,” said Dr. Andrew Kraftson, a clinical associate professor in the division of metabolism, endocrinology and diabetes at Michigan Medicine.

If the medications lower blood sugar too dramatically, it could fall to dangerously low levels, known as hypoglycemia. Taking drugs like Ozempic alongside insulin raises the risk of this happening, said Dr. Janice Jin Hwang, the division chief of endocrinology and metabolism at the University of North Carolina School of Medicine.

When she tells patients about this risk, she said, she also explains early signs of hypoglycemia: palpitations, shaking, sweating, dizziness and intense hunger. People experiencing severe hypoglycemia can have seizures, lose consciousness and struggle to walk, think or see clearly.

“We do everything we can to try to prevent that from happening,” she said.

She keeps particularly close watch on patients as they gradually increase their doses of Ozempic or Mounjaro. She sees them more frequently, makes sure they monitor their blood sugar levels closely and adjusts insulin doses as needed.

Dr. Padmaja Akkireddy, an endocrinologist at Nebraska Medicine, said that every time a patient increases their dose of Ozempic, she checks whether their insulin dose should change, too. These calculations can become even more difficult when patients taking Mounjaro or Ozempic struggle to get their next dose, whether that’s because there’s a shortage — as there often is — or because their insurance coverage lapsed .

With careful monitoring, though, Dr. Akkireddy said that most of her patients have been able to lower their insulin doses after starting Ozempic, and some have been able to go off insulin entirely. Not everyone will be able to go off the drug, experts said — some will always need it to keep their blood sugar in check.

But “my hope,” Dr. Hagan said, “is that in 10 years, we have many fewer patients who are needing to take insulin.”

Dani Blum is a health reporter for The Times. More about Dani Blum

A Close Look at Weight-Loss Drugs

Misbranded Ozempic: A woman in New York who was using TikTok to sell unauthorized weight-loss drugs, including products labeled Ozempic, is facing charges of smuggling and receiving  and distributing misbranded drugs, federal prosecutors said.

Supplement Stores: GNC and the Vitamin Shoppe are redesigning displays and taking other steps  to appeal to people who are taking or are interested in drugs like Ozempic and Wegovy.

Senate Investigation: A Senate committee is investigating the prices that Novo Nordisk charges  for Ozempic and Wegovy, which are highly effective at treating diabetes and obesity but carry steep price tags.

A Company Remakes Itself: Novo Nordisk’s factories work nonstop turning out Ozempic and Wegovy , but the Danish company has far bigger ambitions.

Transforming a Small Danish Town: In Kalundborg, population under 17,000, Novo Nordisk is making huge investments to increase production  of Ozempic and Wegovy.

Ozempic’s Inescapable Jingle: The diabetes drug has become a phenomenon, and “Oh, oh, oh, Ozempic!” — a takeoff of the Pilot song “Magic”  — has played a big part in its story.

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Experimental Treatments for Type 2 Diabetes

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Artificial Pancreas

Pancreas transplant, frequently asked questions.

Lifestyle changes such as eating a diabetes-friendly diet , exercising more, and maintaining a healthy body weight combined with existing treatment options are the best way to prevent or manage type 2 diabetes .

However, for people with type 2 diabetes who have trouble controlling their blood sugar by making healthier lifestyle choices or taking medications, experimental treatments could help.

This article provides an overview of type 2 diabetes experimental treatments and explains how the latest type 2 diabetes research has led to new Food and Drug Administration (FDA)–approved pharmacological treatments and devices like the "artificial pancreas."

Read on to learn more about other experimental treatments for type 2 diabetes that show promise but haven't been approved by the FDA yet.

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Pharmacological Treatments

Only about half of all U.S. adults with type 2 diabetes achieve good blood sugar level targets based on the A1c test , a simple blood test measuring blood sugar levels averaged over the past three months.

Fortunately, advances in type 2 diabetes research have led to some groundbreaking experimental treatments and drug combinations that show promise in preliminary studies.

Mounjaro (Tirzepatide)

The latest pharmacological treatment approved by the FDA for type 2 diabetes combines glucagon-like peptide-1 ( GLP-1 ) agonists and glucose-dependent insulinotropic polypeptides (GIP).

In May 2022, the FDA approved the novel type 2 diabetes injectable medication called Mounjaro (tirzepatide). Mounjaro is the first and only FDA-approved dual GIP and GLP-1 agonist medication for type 2 diabetes.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, also known as a glifozins , are another state-of-the-art class of drugs approved by the FDA to lower blood sugar in adults with type 2 diabetes. SGLT2 inhibitors are prescribed along with lifestyle changes like diet and exercise. Glifozins are not FDA-approved for patients with type 1 diabetes.

Accumulating evidence suggests that SGLT2 inhibitors have other health benefits such as promoting weight loss and improving cardiac functions. A meta-analysis (a formal assessment of previous research) of 10 clinical trials found that the use of SGLT2 inhibitors was associated with a 33% lower risk of life-threatening cardiovascular disease.

Wegovy (Semaglutide)

In June 2021, the FDA approved Wegovy, a weight-loss prescription drug, for people diagnosed with obesity and a weight-related condition such as high blood pressure or high cholesterol . In September 2022, researchers announced that weekly injections of this drug may reduce the risk of type 2 diabetes risk by 61%.

Tesaglitazar

Tesaglitazar is an experimental drug that showed promise as a treatment for type 2 diabetes in early studies. However, its development was put on hold by AstraZeneca in May 2006 before all of the phase 3 trials were completed. But this experimental treatment might be making a comeback.

In August 2022, a study in mice showed that combining tesaglitazar with GLP-1 agonists reduced the drug's adverse effects while increasing its positive effects on sugar metabolism. Still, human studies are needed.

Special Dietary and Nutritional Treatments

Eating a diet to help type 2 diabetes is one of the most effective ways for people with type 2 diabetes to control blood sugar. If you have diabetes, it's important to educate yourself about different types of carbohydrates and to monitor your blood sugar levels using a glucometer .

Research on supplements for type 2 diabetes has had mixed results. After years of research, a study of 2,423 people concluded that vitamin D supplements don't prevent type 2 diabetes and may not have long-term benefits. That said, a 2019 meta-analysis of other peer-reviewed studies concluded that vitamin D supplements may help people with type 2 diabetes control their blood sugar levels in the short term.

Over-the-counter (OTC) nutritional supplements that lower blood sugar can carry potential risks and are not intended to replace diabetes medications . Always use common sense and speak with a healthcare provider before making dietary changes or using nutritional supplements.

The "artificial pancreas" is a portable external device that controls blood glucose levels using a closed-loop insulin pump system. A 2021 study found that closed-loop artificial pancreas therapy helped people with type 2 diabetes safely manage their blood sugar levels and reduced the risk of severe hypoglycemia (low blood sugar) events.

Bariatric Surgery for Type 2 Diabetes

Bariatric weight-loss surgery is an effective treatment for many people with type 2 diabetes. Among bariatric procedures, a 2019 randomized trial found that gastric bypass surgery (creating and attaching a small pouch directly to the small intestine, bypassing the stomach) is superior to gastric sleeve surgery (removing a portion of the stomach) for remission of type 2 diabetes.

Although a pancreas transplant can benefit people with type 1 diabetes by restoring insulin production and improving blood sugar control, it's an extreme measure and isn't typically a treatment option for those with type 2 diabetes.

However, in certain patients with type 2 diabetes who have both a low production of insulin (hormone created by your pancreas that controls the sugar in your bloodstream) and insulin resistance (when cells stop responding to the insulin you make), a pancreas transplant may be considered.

However, the United Network for Organ Sharing (UNOS) eligibility criteria strictly limit access to pancreas transplantation in patients with type 2 diabetes.

Islet Transplant Surgery for Diabetics

Islet cell transplantation is a treatment option for some patients with type 1 diabetes but isn't currently an FDA-approved option for those with type 2 diabetes.

Diabetes research has led to some groundbreaking new treatment options. In May 2022, the FDA approved a potentially game-changing new drug called Mounjaro (tirzepatide) that targets both GLP-1 and GIP. In September 2022, researchers announced that another experimental drug, tesaglitazar, which didn't initially succeed in clinical trials, shows renewed promise when combined with a GLP-1 antagonist.

Other new treatments, like SGLT2 inhibitors, are effective for type 2 diabetes when combined with lifestyle changes related to diet and exercise. For people who have trouble losing weight, bariatric surgery and weight-loss drugs like Wegovy (semaglutide) can help people maintain a healthy weight and lower their risk of type 2 diabetes.

Experimental treatments for type 2 diabetes carry risks. Always speak to a healthcare provider before making changes to your diet or taking nutritional supplements.

No. There is no cure for type 2 diabetes. Losing weight, eating healthier, and exercising more can help to prevent and manage this type 2 diabetes. If diet, exercise, and weight loss fail to control blood sugar, antidiabetic medications or insulin therapy can help achieve glycemic targets.

If you have diabetes and want to take something other than metformin , speak to a healthcare provider about your options. Some alternatives to metformin that people with type 2 diabetes can use to control high blood sugar include, Farxiga (dapagliflozin), Invokana (canagliflozin), Jardiance (empagliflozin), and Nesina (alogliptin).

There's little to no evidence-based research showing that specific vitamins are helpful to people with diabetes in the long term. Vitamin D may help people with diabetes in the short term, but a yearslong National Institutes of Health–funded trial ultimately found that vitamin D supplements do not prevent type 2 diabetes.

American Diabetes Association Professional Practice Committee. 5. Facilitating positive health behaviors and well-being to improve health outcomes: Standards of Care in Diabetes-2024 [published correction appears in Diabetes Care. 2024 Apr 1;47(4):761-762]. Diabetes Care . 2024;47(Suppl 1):S77-S110. doi:10.2337/dc24-S005

Carls G, Huynh J, Tuttle E, Yee J, Edelman SV. Achievement of glycated hemoglobin goals in the us remains unchanged through 2014.   Diabetes Ther . 2017;8(4):863-873. doi:10.1007/s13300-017-0280-5

American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: Standards of Care in Diabetes -2024 . Diabetes Care . 2024;47(Suppl 1):S158-S178. doi:10.2337/dc24-S009

Gasbjerg LS, Gabe MBN, Hartmann B, et al. Glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists as anti-diabetic agents.   Peptides . 2018;100:173-181. doi:10.1016/j.peptides.2017.11.021

Food and Drug Administration.  MOUNJAROTM (tirzepatide) injection, for subcutaneous use  [drug label].

FDA. Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors.

Pharmacy Practice News. Evidence mounts for benefits of SGLT2 inhibitors and GLP-1 RAs .

Bhattarai M, Salih M, Regmi M, et al. Association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcomes in patients with type 2 diabetes and other risk factors for cardiovascular disease: a meta-analysis.   JAMA Netw Open . 2022;5(1):e2142078. doi:10.1001/jamanetworkopen.2021.42078

FDA. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014.

UAB News. Who will benefit from new ‘game-changing’ weight-loss drug semaglutide?

Hellmold H, Zhang H, Andersson U, et al. Tesaglitazar, a pparα/γ agonist, induces interstitial mesenchymal cell dna synthesis and fibrosarcomas in subcutaneous tissues in rats .  Toxicological Sciences . 2007;98(1):63-74. doi:10.1093/toxsci/kfm094

Quarta C, Stemmer K, Novikoff A, et al. GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice .  Nat Metab . 2022;4(8):1071-1083. doi:10.1038/s42255-022-00617-6

Tufts Medical Center. D2d (Vitamin D and Type 2 Diabetes) results .

Hu Z, Chen J, Sun X, Wang L, Wang A. Efficacy of vitamin D supplementation on glycemic control in type 2 diabetes patients: A meta-analysis of interventional studies .  Medicine . 2019;98(14):e14970. doi:10.1097/MD.0000000000014970

Zhou K, Isaacs D. Closed-loop artificial pancreas therapy for type 1 diabetes .  Curr Cardiol Rep . 2022;24(9):1159-1167. doi:10.1007/s11886-022-01733-1

Boughton CK, Tripyla A, Hartnell S, et al. Fully automated closed-loop glucose control compared with standard insulin therapy in adults with type 2 diabetes requiring dialysis: An open-label, randomized crossover trial . Nat Med . 2021;27(8):1471-1476. doi:0.1038/s41591-021-01453-z

ElSayed NA, Aleppo G, Aroda VR, et al. 8. Obesity and weight management for the prevention and treatment of type 2 diabetes: Standards of care in diabetes—2023 . Diabetes Care . 2023;46(Suppl 1):S128-S139. doi:10.2337/dc23-S008

Hofsø D, Fatima F, Borgeraas H, et al. Gastric bypass versus sleeve gastrectomy in patients with type 2 diabetes (Oseberg): A single-centre, triple-blind, randomised controlled trial . The Lancet Diabetes & Endocrinology . 2019;7(12):912-924. doi:10.1016/S2213-8587(19)30344-4

Kandaswamy R, Stock PG, Gustafson SK, et al. Optn/srtr 2016 annual data report: Pancreas .  Am J Transplant . 2018;18:114-171. doi:10.1111/ajt.14558

Bleskestad KB, Nordheim E, Lindahl JP, et al. Insulin secretion and action after pancreas transplantation. A retrospective single-center study . Scandinavian Journal of Clinical and Laboratory Investigation . 2021;81(5):365-370. doi:10.1080/00365513.2021.1926535

Stratta RJ, Farney AC, Fridell JA. Analyzing outcomes following pancreas transplantation: Definition of a failure or failure of a definition . American J Transplantation . 2022;22(6):1523-1526. doi:10.1111/ajt.17003

Pullen LC. Islet cell transplantation hits a milestone . Am J Transplant . 2021;21(8):2625-2626. doi:10.1111/ajt.16039

diaTribe Learn. What are my choices for metformin alternatives?

NIH. NIH-funded trial finds vitamin D does not prevent type 2 diabetes in people at high risk .

By Christopher Bergland Bergland is a retired ultra-endurance athlete turned medical writer and science reporter. He is based in Massachusetts.

A promising new pathway to treating type 2 diabetes

This year marks the 100th anniversary of the discovery of insulin, a scientific breakthrough that transformed Type 1 diabetes, once known as juvenile diabetes or insulin-dependent diabetes, from a terminal disease into a manageable condition.

Today, Type 2 diabetes is 24 times more prevalent than Type 1. The rise in rates of obesity and incidence of Type 2 diabetes are related and require new approaches, according to University of Arizona researchers, who believe the liver may hold the key to innovative new treatments.

"All current therapeutics for Type 2 diabetes primarily aim to decrease blood glucose. So, they are treating a symptom, much like treating the flu by decreasing the fever," said Benjamin Renquist, an associate professor in the UArizona College of Agriculture and Life Sciences and BIO5 Institute member. "We need another breakthrough."

In two newly published papers in Cell Reports , Renquist, along with researchers from Washington University in St. Louis, the University of Pennsylvania and Northwestern University, outline a new target for Type 2 diabetes treatment.

Renquist, whose research lab aims to address obesity-related diseases, has spent the last nine years working to better understand the correlation between obesity, fatty liver disease and diabetes, particularly how the liver affects insulin sensitivity.

"Obesity is known to be a cause of Type 2 diabetes and, for a long time, we have known that the amount of fat in the liver increases with obesity," Renquist said. "As fat increases in the liver, the incidence of diabetes increases."

This suggested that fat in the liver might be causing Type 2 Diabetes, but how fat in the liver could cause the body to become resistant to insulin or cause the pancreas to over-secrete insulin remained a mystery, Renquist said.

Renquist and his collaborators focused on fatty liver, measuring neurotransmitters released from the liver in animal models of obesity, to better understand how the liver communicates with the brain to influence metabolic changes seen in obesity and diabetes.

"We found that fat in the liver increased the release of the inhibitory neurotransmitter Gamma-aminobutyric acid, or GABA," Renquist said. "We then identified the pathway by which GABA synthesis was occurring and the key enzyme that is responsible for liver GABA production -- GABA transaminase."

A naturally occurring amino acid, GABA is the primary inhibitory neurotransmitter in the central nervous system, meaning it decreases nerve activity.

Nerves provide a conduit by which the brain and the rest of the body communicate. That communication is not only from the brain to other tissues, but also from tissues back to the brain, Renquist explained.

"When the liver produces GABA, it decreases activity of those nerves that run from the liver to the brain. Thus, fatty liver, by producing GABA, is decreasing firing activity to the brain," Renquist said. "That decrease in firing is sensed by the central nervous system, which changes outgoing signals that affect glucose homeostasis."

To determine if increased liver GABA synthesis was causing insulin resistance, graduate students in Renquist's lab, Caroline Geisler and Susma Ghimire, pharmacologically inhibited liver GABA transaminase in animal models of Type 2 diabetes.

"Inhibition of excess liver GABA production restored insulin sensitivity within days," said Geisler, now a postdoctoral researcher at the University of Pennsylvania and lead author on the papers. "Longer term inhibition of GABA-transaminase resulted in decreased food intake and weight loss."

Researchers wanted to ensure the findings would translate to humans. Kendra Miller, a research technician in Renquist's lab, identified variations in the genome near GABA transaminase that were associated with Type 2 diabetes. Collaborating with investigators at Washington University, the researchers showed that in people with insulin resistance, the liver more highly expressed genes involved in GABA production and release.

The findings are the foundation of an Arizona Biomedical Research Commission-funded clinical trial currently underway at Washington University School of Medicine in St. Louis with collaborator Samuel Klein, co-author on the study and a Washington University professor of medicine and nutritional science. The trial will investigate the use of a commercially available Food and Drug Administration-approved inhibitor of GABA transaminase to improve insulin sensitivity in people who are obese.

"A novel pharmacological target is just the first step in application; we are years away from anything reaching the neighborhood pharmacy," Renquist said. "The magnitude of the obesity crisis makes these promising findings an important first step that we hope will eventually impact the health of our family, friends and community."

• Liver Disease
• Chronic Illness
• Diseases and Conditions
• Hormone Disorders
• Diet and Weight Loss
• Personalized Medicine
• Diabetes mellitus type 1
• Diabetes mellitus type 2
• Stem cell treatments
• Liver transplantation
• Sports medicine

Story Source:

Materials provided by University of Arizona . Original written by Rosemary Brandt. Note: Content may be edited for style and length.

Journal Reference :

• Caroline E. Geisler, Susma Ghimire, Stephanie M. Bruggink, Kendra E. Miller, Savanna N. Weninger, Jason M. Kronenfeld, Jun Yoshino, Samuel Klein, Frank A. Duca, Benjamin J. Renquist. A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity . Cell Reports , 2021; 35 (13): 109301 DOI: 10.1016/j.celrep.2021.109301

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Breakthrough diabetes study could lead to end of regular insulin injections, researchers say

Researchers say they have made a breakthrough in the treatment of type 1 diabetes which could replace the need for regular insulin injections.

Research published by Baker Heart and Diabetes Institute scientists shows they have manipulated existing pancreatic stem cells to prompt them to produce insulin.

The study from the Melbourne researchers builds on previous work by Monash University scientists, using two existing cancer drugs. 

The research is still in its early days and the next step will be pre-clinical animal trials.

But lead researcher and Baker institute scientist, Sam El-Osta, said the potential treatment could be viable for children and adults in the future.

"What we've discovered is the ability to harness the patient's remaining pancreatic cells to influence those cells to behave like insulin-producing beta cells," Professor El-Osta told ABC Radio Melbourne.

"This could potentially modify the course of diabetes and potentially eliminate the need for round-the-clock insulin injections in some people living with type 1 diabetes."

Broadly, people with diabetes do not naturally produce enough insulin, or their bodies do not use the hormone as they should.

For many people with diabetes, it means multiple insulin injections are required daily to manage the illness.

Research could be 'holy grail'

The two cancer drugs used in the research are already approved by the US Food and Drug Administration.

Researchers said the potential treatment could be "rapid" compared to current treatment options for type 1 diabetes.

"We've been able to repurpose these drugs to determine whether we could influence the trajectory by using these small molecule inhibitors in pancreatic ductal cells," Professor El-Osta said.

"We can quickly influence insulin restoration in a number of days in a dish from tissues derived from type 1 diabetes donors, both children and adults."

Diabetes Australia estimates around 134,000 people in Australia are living with type 1 diabetes, which represents about 10 per cent of all diabetes cases.

The Baker Heart and Diabetes Institute researchers are optimistic their work could potentially help people living with insulin-dependent type 2 diabetes.

The research has been published in a Nature scientific journal, Signal Transduction and Targeted Therapy.

Chief executive of the Australian Diabetes Society and University of Melbourne associate professor, Sof Andrikopoulos, labelled the research as "remarkable". 

"For the 135,000 Australians with type 1 diabetes, this is the holy grail. This is it," he said. 

"There's a potential here that this research might lead to the cure of type 1 diabetes, at some point down the road.

"It also has the potential to make a significant improvement in type 2 diabetes."

Dr Andrikopoulos, who was not involved with the study, said the research would reduce the burden of the disease.

"This research has the potential for the body itself, to produce and secrete insulin. So you can see that you're getting rid of needles, you're getting rid of insulin pumps, you're getting rid of finger pricking, you're getting rid of continuous glucose monitors," he said.

While he was hopeful for the future, Dr Andrikopoulos warned steps towards a cure would require consistent funding for diabetes research.

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Changing our Future Through Research

The ADA is committed to innovation and breakthrough research that will improve the lives of all people living with diabetes.

ADA Research: Science. Progress. Hope.

ADA research provides critical funding for diabetes research. With 100% of donations directed to research, our goal is to ensure adequate financial resources to support innovative scientific discovery that will translate to life-changing treatments and eventual cures.

of our funded researchers remain dedicated to careers in diabetes science

publications per grant, cited an average of 28 times, proving expertise and credibility 

Every $1 the ADA invests in diabetes research leads to $12.47 in additional research funding

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Explore some of the latest innovations and discoveries and see how the ADA continues to advance science, leverage investments and retain scientists.

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Project topics span technology, islet transplantation, immunology, improving transition to self-management, and more.

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Projects include understanding the role of exercise, novel therapies, and more.

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• Open access
• 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

318 Accesses

Metrics details

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.

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

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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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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Stanford University School of Medicine blog

These are the tools for providing top-notch diabetes care to everyone

For 30 years, doctors have known that maintaining near-normal blood sugar has huge benefits for people with Type 1 diabetes.

A 1993 clinical trial found that participants who were taught methods for tightly managing their disease -- checking their blood sugar many times each day, making adjustments to insulin doses and receiving frequent help from their medical caregivers -- reduced their risk for long-term complications, including blindness, kidney failure and peripheral nerve damage, by 50% to 70%.

Yet since that trial, physicians have struggled to roll out intensive diabetes management programs to all patients. On average, patients across the U.S. still don't achieve the level of diabetes control that would minimize their long-term risks.

"It's not because people haven't been trying," said David Maahs , MD, PhD, a pediatric endocrinologist at Stanford Medicine Children's Health. "It's a complicated condition to take care of, and for the individual with diabetes and their family, it's constant work."

Stanford Medicine experts are making headway on the problem. A new scientific study published recently in Nature Medicine describes how the research team, led by Maahs and Priya Prahalad , MD, PhD, have implemented major advances in intensive diabetes management.

First, they tackled equity issues to ensure the latest diabetes technology got into the hands of every patient as soon as they were diagnosed. They also built artificial intelligence tools that gave diabetes caregivers the ability to quickly identify which patients most needed their help. Ultimately these steps enabled adolescent Type 1 diabetes patients to maintain better control of their blood sugar levels.

It's not because people haven't been trying. It's a complicated condition to take care of, and for the individual with diabetes and their family, it's constant work. David Maahs

Maahs talked about the methods used and the long-term ramifications. This interview was edited for length and clarity.

Your study built on recent technological advances that automate many tasks involved in living with diabetes. What are the advantages of the newer devices?

Patients can now wear continuous glucose monitors, which have a sensor inserted under the skin that reads a glucose value every 5 to 15 minutes. This is really helpful because you don't have to poke your finger six to 10 times a day to measure glucose levels, and the monitor can warn you if you're going low or high. If you're the parent of a child with Type 1 diabetes, you can get their glucose data from the cloud and onto your phone.

Another recent improvement in diabetes technology is that continuous glucose monitors can now communicate with an insulin pump. An algorithm helps control dosing to reduce or stop insulin if it predicts your blood sugar is going to go low, and it adds a bit more insulin if you're going high. You still have to give an insulin dose before you eat, but it really takes a lot of the burden out of managing Type 1 diabetes.

It's been a big challenge to get these improved diabetes devices into the hands of every U.S. patient; your earlier work shows that disadvantaged groups tend to be left behind. How did your new study tackle equity concerns?

We were testing the benefits of starting pediatric Type 1 diabetes patients on continuous glucose monitors as soon as possible after they were diagnosed, which we were usually able to do in the first week after diagnosis. Although insulin pumps were not a focus of this study, about half of our patients began using an insulin pump within a year of their diagnosis.

We all agreed that we wanted every new patient we saw to be included. If you look at earlier studies of diabetes technology, it tended to be tested in college-educated, white, privately insured people and not in other populations. We had to figure out how to meet challenges faced by less-advantaged patients. We learned that this went beyond the most obvious barriers we addressed, such as providing care in multiple languages.

For instance, at first, it seemed like some groups of patients were wearing their continuous glucose monitors less than we asked them to. But in fact, the transmission of their data to our system was incomplete because they had poor Wi-Fi access at home. That's an equity issue. We've been giving out devices to those who need them as part of the research so that everyone has enough internet connectivity to upload their data.

Also, at diagnosis, we sometimes can't tell whether someone has Type 1 or Type 2 diabetes. This  happens more in minoritized populations, in youth who have an elevated body mass index, and these children are more likely to be publicly insured or non-English speakers. We made a conscious decision to include all these patients while we waited to learn the details of their diagnosis, so as not to miss anyone who might be eligible for our study.

We made a conscious decision to include (a diverse mix of) patients while we waited to learn the details of their diagnosis, so as not to miss anyone who might be eligible for our study. David Maahs

Close to 90% of our new Type 1 diabetes patients participated in this study, and a lot of those who chose not to participate enrolled instead in a different study of artificial pancreas technology, so we did quite a good job of including everyone. It was a very diverse population: About 35% of patients were publicly insured, and only about 40% were non-Hispanic white.

Getting the new technology to every patient was important. What else was needed to make sure all patients could succeed in managing their blood sugar levels?

The 1993 trial showed that it was really useful for patients to have frequent communication with their diabetes team. That can be hard to do with the resources of a typical diabetes clinic, where each diabetes educator has many patients to track.

To address this problem, we built an AI-powered data dashboard, which filters our patients' continuous glucose monitor data and puts it into a format that helps our team identify who is struggling. Instead of spending a lot of time manually evaluating their data, we can automatically rank which patients most need our help.

We look at the percentage of time the continuous glucose monitor has been worn, and if it's below a certain threshold, that's our first starting point. Sometimes people have lost their prescription for their CGM, continuous glucose monitor, and need a new one. We're able to reach out and help them.

If a patient is having too many low blood sugar readings, which are dangerous, that's another reason for them to go to the top of the list. Our diabetes educators can contact them to help adjust their insulin dosing. Likewise, if their average glucose is out of the target range less than 70% of the time, we can flag that they need some extra attention between their visits to the clinic.

On the other hand, if someone is wearing their monitor, they're not having low blood sugar readings and they are in the right blood sugar range most of the time, they're doing well. We'll check in with them at their quarterly clinic visit, but they don't need outreach in between. That knowledge helps our team shift its attention to the patients who most need it.

How did you build the algorithm that powers this dashboard?

The platform was developed at Stanford with systems design expert David Scheinker , PhD, and his SURF team ; they use tools such as machine learning and statistics to improve how health care is delivered. He teaches a class in which engineering undergraduates and grad students solve technical problems in health care.

We presented our concept to his class. Our problem was that each brand of diabetes equipment has a different system to share data. A diabetes educator with 10 patients might have had five or six different places to go look at their data, log in and so on. This made it extremely time-consuming to figure out which patients needed help.

More on diabetes

• NIH grant establishes Stanford Medicine as center of national diabetes training program
• 'Smart speaker' shows potential for better self-management of Type 2 diabetes
• Improved blood sugar control helps normalize diabetic teens' brains, Stanford-led study finds
• Managing type 1 diabetes: Voices of the underserved

Instead, our system has all the data in one place. It was built through an iterative process between our diabetes educators and the engineering team, so that ultimately the data is presented in the way that is most useful to the diabetes educators.

We published a study showing that the dashboard has shifted the diabetes educators' workload in a helpful way. They spend less time sifting through troves of data - something an algorithm can do perfectly - and more time talking to patients who need extra help between clinic visits.

How do you know that your approach worked?

Compared with our past patients who were diagnosed with Type 1 diabetes before this research began, our newer patients were more likely to reach their glucose targets after a year of living with the disease.

One treatment target for our patients, after a year with diabetes, was a glycosylated hemoglobin A1c measurement below 7%. This laboratory test assesses patients' blood sugar control over the prior three months, and a reading below 7% is the target for optimum health.

In our earlier data, 28% of patients met this target 12 months after diagnosis; now we have 64% of our patients meeting this goal. We also looked at how many people had very high A1c measurements, with values above 9%, and that measure has reduced dramatically. Similarly, by one year after diagnosis, our patients' blood sugar was in the target range 68% of the time.

We also have data showing that compared with our historic cohort, everyone received a similar benefit from our intensive approach to treatment, meaning that if you looked at people who had public versus private insurance, or were or were not English speakers, every group had similar improvements when we implemented our study. There are still some gaps between more- and less-privileged patients, so we still have work to do, but everyone benefited a similar amount. Often, when new medical technology becomes available, more privileged people get more benefit; it is very encouraging that we could buck that trend.

Image: habrovich ( stock.adobe.com )

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Curing Diabetes

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At the Diabetes Research Institute and Foundation, the vision is a world without diabetes. To make that vision a reality, we are laser focused on one goal: to discover a biological cure. For millions of children and adults living with diabetes today, a cure would mean:

The ability to restore natural insulin production and normalize blood sugar levels without imposing other risks.

Why a Biological Cure?

Over the last century, advancements in new treatments aided by the remarkable developments in computer technology have helped many people better manage the disease, but achieving optimal glucose control remains an unattainable goal for the vast majority of those with diabetes, and particularly among young people. Despite patients’ best attempts, managing diabetes remains a challenging, daily balancing act that requires constant vigilance. That’s because insulin therapy cannot ideally mimic the exquisite biological function of a healthy pancreas. And that’s why the Diabetes Research Institute and Foundation remain passionately committed to achieving this singular goal. Learn more about our progress toward a cure and the steps we are taking to turn our vision into reality.

The DRI is intensely focused on advancing the most promising research to patients living with diabetes and is gearing up for a number of innovative clinical studies.

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The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?

• Current Opinion
• Published: 08 September 2023
• Volume 23 , pages 601–608, ( 2023 )

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• Theocharis Koufakis 1 ,
• Ioanna Zografou 2 ,
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During the last decade, the landscape of type 2 diabetes (T2D) management has been completely transformed, moving from a glucose-centric perspective to a holistic approach that also takes into account weight control and organ protection. Dipeptidyl peptidase-4 inhibitors (DPP4i) are oral agents that have been used for the treatment of T2D for almost 20 years. Although they present an excellent safety profile, including the risk of hypoglycemia, they lack the spectacular cardiorenal benefits and weight-loss effects of the newer antidiabetic agents. This poses the question of whether they still deserve a place in the arsenal of drugs against T2D. In this article, we use a hypothetical case scenario to illustrate possible patient profiles where DPP4i could prove useful in the clinical setting. We discuss the advantages and disadvantages of the category, focusing on glycemic control, weight management, and cardiorenal protection, which are the pillars of modern T2D management, also considering its safety profile and cost-effectiveness. We conclude that in most cases, DPP4i present a more favorable risk–benefit ratio compared to sulfonylureas, which are still widely prescribed throughout the world. We also suggest that future research should clarify the reasons behind the contradictory findings between human and animal studies on cardiorenal effects of the class and identify subgroups of patients who would derive most benefit with DPP4i treatment.

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Theocharis Koufakis & Kalliopi Kotsa

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Ioanna Zografou & Michael Doumas

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TK has received honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Pharmaserve Lilly, and Novo Nordisk and for advisory boards from Novo Nordisk and Boehringer Ingelheim, and has participated in sponsored studies by Eli-Lilly and Novo Nordisk. IZ has received honoraria for lectures from AstraZeneca, Pharmaserve Lilly, and Novo Nordisk and for advisory boards from Novo Nordisk, and has participated in sponsored studies by Eli-Lilly and Novo Nordisk. KK has received honoraria for lectures/advisory boards and research support from AstraZeneca, Boehringer Ingelheim, Pharmaserve Lilly, Sanofi-Aventis, ELPEN, MSD, and Novo Nordisk. MD declares no conflict of interest.

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TK reviewed the literature and wrote the first version of the manuscript. IZ, MD, and KK reviewed the literature and edited the manuscript. All authors have read and approved the final version of the manuscript.

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Koufakis, T., Zografou, I., Doumas, M. et al. The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?. Am J Cardiovasc Drugs 23 , 601–608 (2023). https://doi.org/10.1007/s40256-023-00610-8

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Accepted : 24 August 2023

Published : 08 September 2023

Issue Date : November 2023

DOI : https://doi.org/10.1007/s40256-023-00610-8

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