A Cure for Type 1 Diabetes: Are We There Yet?

Abstract

Type 1 diabetes (T1D) affects over 2 million people in the United States and has no known cure. The discovery and first use of insulin in humans 102 years ago marked a revolutionary course of treatment for the disease, and although the formulations and delivery systems have advanced, insulin administration remains the standard of care today. While improved treatment options represent notable progress in T1D management, finding a functional cure for the disease remains the ultimate goal. Approaches to curing T1D have historically focused on blunting the autoimmune response, although sustained effects of immune modulation have proven elusive. Islet transplant therapies have also proven effective, although a lack of available donor tissue and the need for immunosuppression to prevent both host–graft rejection and the autoimmune response have reserved such treatments for those who already require immunosuppressive regimens for other reasons or undergo severe hypoglycemic events in conjunction with hypoglycemic unawareness. With the advent of human stem cell research, the focus has shifted toward generating an abundance of allogeneic, functional beta-like cells that can be transplanted into the patients. Immunoisolation devices have also shown some promise as a method of preventing immune rejection and the autoimmune destruction of transplanted cells. Finally, advances in new immune therapies, if used in the early stages of T1D progression, have proven to delay the onset of diabetes. Stem cell-based therapies are a promising approach to curing T1D. The ongoing clinical trials show some success, although they currently require immunosuppressant agents. Encapsulation devices provide a method of immunoisolation that does not require immunosuppression; however, the devices tested thus far eventually lead to cell death and fibrotic tissue growth. Substantial research efforts are underway to develop new approaches to protect the stem cell-derived beta cells upon transplantation.

Introduction

Type 1 diabetes (T1D) is an autoimmune disease that targets the insulin-producing beta cells of the pancreas. The lack of endogenous insulin production results in highly dysregulated glucose homeostasis, causing the body to alternatively consume fat and muscle tissue to meet its energetic needs. This process generates large amounts of acidic ketones, lowers physiological pH levels, and, if untreated, the resulting diabetic ketoacidosis will lead to death. Until the early 20th century, the treatment for T1D was an extreme calorically limited diet that, if successful at all, eventually led to starvation. Between January 11 and February 4, 1922, a young patient was injected with a solution of complete ox pancreas extract and, for the first time in history, human T1D was effectively treated.¹ This breakthrough was awarded the 1923 Nobel Prize in Physiology or Medicine,² and 102 years later, insulin therapy is still the prescribed treatment for T1D. Despite this groundbreaking discovery, patients undergoing insulin therapy remain susceptible to severe complications, and require rigorous, daily monitoring and dosage adjustments to maintain relatively normal blood glucose (BG) levels. Historically, research efforts have focused on the following: (1) synthesizing more effective insulin formulations and developing improved delivery systems, (2) attempting to blunt the autoimmune response, and (3) gaining a better understanding of the disease pathogenesis with hopes that this will lead to novel therapies. With the advent of human stem cell-based systems as a research tool, the focus has rapidly shifted toward stem cell-based therapies aiming to replace insulin delivery as the new standard of treatment. In this study, we discuss the current efforts toward finding a cure for T1D, the ongoing challenges faced by the field, and the progress that has been made.

History

Before the discovery of insulin and its first use in patients by Banting and Best in the early 20th century, diabetes was a death sentence. The first indicator of the importance of their research was in 1921, when Banting hypothesized that the digestive enzymes secreted by the exocrine tissue of pancreas were degrading the islet-produced insulin in previously obtained pancreatic extracts. Soon after, in facilities provided by the physiologist John Macleod, Banting and Best isolated islet extract from healthy dogs and tested its efficacy on dogs that had previously undergone a pancreatectomy. After 20 days of treatment, “Dog 33” was said to be in “excellent condition” and after 70 days was “…still able to walk and wag her tail.”³ This was the first indication that extract of the islets specifically, rather than the whole pancreas, was a potent source of what has come to be known as insulin and that it could be used to treat diabetes.

Meanwhile, 14-year-old Leonard Thompson had been admitted to Toronto General Hospital; he weighed 64 pounds and was drifting in and out of diabetic coma. His diet had been reduced to 450 calories per day, in consensus with diabetes treatment protocols of that time. Out of desperation, Leonard’s father agreed to let him undergo an experimental treatment, in which whole ligated pancreatic extract from ox would be administered intravenously. On January 11, 1922, Leonard was injected with 7.5 cc. of the extract. Within 24 h, his BG levels dropped from 0.440 to 0.320, although he displayed an allergic reaction at the injection site. In response to the allergic reactions, biochemist James Collip was recruited to help refine the purification process, and on January 23, Leonard was injected with 5 cc. of the new extract at 11 am and then, after displaying no adverse reaction, an additional 20 cc. at 5 pm. Within 24 h, his BG levels dropped from 0.520 to 0.120, and his ketonuria disappeared entirely. With this, Leonard Thompson became the first human with diabetes to be treated with insulin.⁴

Upon learning of these developments, Macleod quickly shifted the focus of his entire laboratory over to studying and purifying insulin extracts, and shortly thereafter Banting and Macleod were awarded the Nobel Prize for their, and others’, efforts. Banting, Best, and Collip were awarded the patent rights to the insulin purification method and in December 1922 sold those rights to the University of Toronto for $1 each, with Banting stating that “insulin does not belong to me, it belongs to the world.”⁵

Current therapies

The diabetes therapies that exist today are predominantly insulin-centric, and the insulin formulations, the methods of insulin administration, and insulin monitoring technology have all advanced markedly (Fig. 1). Instead of manually measuring and injecting insulin, the majority of individuals with T1D now use an insulin pump to administer their doses. This device is prefilled with insulin and administers doses in increments as small as 0.01 units. The modern devices are able to deliver a constant basal rate of insulin and can supply a larger on-demand bolus for meals and high BG-level corrections.⁶ The insulins that are delivered are genetically engineered insulin analogues, with a much faster acting time (5–30 min) when compared with islet extracts and the original porcine and bovine insulins (2–6 h).

FIG. 1.

Comparison of current insulin delivery methods. Figure created in BioRender.

BG monitoring has also advanced rapidly (Fig. 2). Instead of measuring glucose in the urine or manually checking BG levels, a continuous glucose monitor (CGM) is worn on the body and used to measure BG levels every 5 min with readouts on a smartphone or other compatible receiver devices. Most recently, insulin pumps and CGMs have gained the ability to communicate in what is known as a “closed-loop system,” where insulin pumps will now adjust basal insulin levels automatically based on how BG levels are trending, automatically administer an insulin bolus dose if BG levels reach high enough to require that, or halt insulin delivery completely if the patient’s BG levels are low. The effects of these advances on the daily lives of people with diabetes cannot be understated. There is a huge mental burden associated with the regular maintenance and management of diabetes,^7,8 and closed-loop systems have done an impressive job at both increasing the standard of care and decreasing these mental burdens.

FIG. 2.

Comparison of glucose-level measurement and monitoring methods.

Despite these advances, there are still complications that arise, and even the most advanced closed-loop systems are susceptible to occasional failure. Insulin pump tubing can become kinked and cannulas can become bent or occluded, preventing the delivery of insulin. CGM sensors are placed in the interstitium, and as a result measure interstitial fluid (ISF) glucose levels instead of BG levels, which lag behind BG levels at a mean of 6.8 min.⁹ Although the lag time is continually decreasing with advances in newer sensors. ISF glucose levels do not reflect accurate BG levels during times of rapid BG-level changes, such as after a high glycemic index meal or during physical activity. Given the dangers of rapidly occurring hypoglycemic events, even with the relatively short lag times there is room for improvement with the current technologies. In addition, both technologies require wearing a physical device on the body at all times, which can be inconvenient, draw unwanted attention, and leaves the devices prone to damage. These drawbacks are generally considered worthwhile given the tight control that is afforded by the closed-loop systems. As a treatment, these advances have been noteworthy, especially considering the short time frame in which they were developed and adapted.

Islet Transplantation

The first successful organ transplants occurred in the early 1950s, when the identical-twin Herrick brothers volunteered to undergo a kidney transplant.¹⁰ After successful reciprocal skin grafts, a full kidney transplant was performed, and the recipient lived for 8 years posttransplant. Before this, transplants had been attempted but were attributed to failure largely because of ABO blood group incompatibility. Researchers and>doctors recognized the limitation that finding genetically identical donors posed and the focus shifted into methods that would allow for allogeneic transplants.¹⁰ In 1962, Calne, Alexandre, and Murray reported the use of the immunosuppressant 6-mercaptopurine as being therapeutically effective in preventing rejection in 106 cases of allogeneic canine renal transplants.¹¹

There have been many adaptations and advances in immunosuppression since 1962, but the use of immunosuppressive drugs for allogeneic transplants remains necessary. Efforts are ongoing to continue to improve transplant therapies for individuals with T1D. As of 2022, approximately 64,000 pancreas transplants have been reported worldwide, with survival rates increasing yearly largely due to improved immunosuppressive regimens.¹² Full organ transplants are highly invasive and not generally considered if individuals maintain exocrine function. In the 1970s, research began to focus on endocrine islet transplantation. In 1980, the first autogenic islet transplantation in humans was achieved,¹³ and 10 years later, Scharp et al. reported the first case of transient insulin independence after islet allotransplantation, in the context of immunosuppression.¹⁴ From then until 1999, only 8% of recipients remained insulin independent after more than a year.¹⁵ In 2000, Shapiro et al. published the Edmonton Protocol that had been modified to include 17 changes to the existing procedure.¹⁶ Remarkably, seven patients successfully received islet transplants into the hepatic portal vein and maintained insulin independence for many years posttransplantation. Although this represented a groundbreaking therapeutic advance, each transplant required not only an extensive immunosuppressive regimen but also islet mass from two to four donor pancreata, presenting a huge barrier to the feasibility of this approach as a widespread cure.

Enter stem cell-derived beta cells. In 2021, Vertex Pharmaceuticals released data from their Phase 1 trial of VX-880: a transplant of stem cell-derived beta cells in combination with an immunosuppressive regimen.¹⁷ Several patients in the trial displayed A1c levels <7% without the use of exogenous insulin. This trial marked a substantial leap forward toward the goal of finding a functional cure. Although a life on immunosuppressants remains a barrier to using this approach, this cell replacement therapy trial provided a proof of principle for utilizing stem cell-derived beta cells as a potential cure. As the trial progressed into Phase 2, the data presented at the 2022 ADA Scientific Sessions were promising, with all 12 patients showing islet engraftment and producing endogenous insulin posttransplant. As of November 4, 2024, the company announced the conversion of the ongoing Phase 1/2 study into a Phase 1/2/3 study, which will enroll a total of 50 patients to be infused with a single dose of the VX-880 treatment, with a primary endpoint of insulin independence and absence of severe hypoglycemic episodes.

Stem Cells

While great progress has been made in treating T1D with advanced insulin delivery approaches, better insulin formulations, and new BG monitoring techniques, the advent of human stem cell-derived beta cells, as both a research model and as a therapeutic tool, has highlighted the potential of regenerative medicine and cell therapies. As a result, research efforts are shifting from focusing on how to provide better treatment for T1D to striving for a cure.

Pluripotent stem cells possess a unique and inherent characteristic of being able to give rise to all somatic cell types found in the human body. Human stem cell lines therefore provide great promise in the replacement of highly specialized tissues and cell types. Generation of insulin-producing cells from human stem cells requires meticulously developed differentiation protocols that recapitulate human development and generate homogenous populations of mature, functional cells. Historically, human embryonic stem cell (hESC) lines derived from excess biological material generated during in vitro fertilization procedures¹⁸ have been the primary source of hESC lines. Despite these cell lines being made from biological samples that would be otherwise discarded, and from material that is being generated for other purposes, the use of hESC lines has recently come into the political limelight, and the legal status of using such cell lines is subject to intense regulatory scrutiny.¹⁹ Furthermore, there are moral and ethical considerations that must be reconciled in using embryonic tissue, regardless of its origins.

In 2012, the Nobel Prize in Physiology or Medicine was awarded to Sir John B. Gurdon and Shinya Yamanaka “for the discovery that mature cells can be reprogrammed to become pluripotent.”²⁰ This discovery circumvented the use of embryonic tissue and showed that adult dermal fibroblasts could be reprogrammed into stem cells. This has opened the floodgates for research into personalized, autologous medicine. Reprogramming a patient’s own cells into different cell types could completely circumvent the need for immunosuppressive regimens following transplant therapies. Since these discoveries, there has been a tidal shift in the diabetes research fields into using human-induced pluripotent stem cells (hiPSCs) to generate insulin-producing beta cells to be used as a replacement therapy and as a functional cure for diabetes.

There currently exist three main barriers to using stem cell-derived beta cells as therapeutic approaches to curing diabetes. First, the differentiation protocols that currently exist do not produce truly mature, functional beta-like cells that recapitulate human beta cell glucose responsiveness. Second, the beta cell differentiation protocols that currently exist are not truly directed or efficient. These protocols result in a mixed population of cells, including alpha, beta, delta, pancreatic polypeptide (PP), and enterochromaffin cells. While beta-like cells are the majority product, a truly directed differentiation resulting in pure beta-like cell populations remains an elusive goal of stem cell researchers. Furthermore, the future application of cell-based therapies will likely require transplantation of the correct ratio of some or all of the islet endocrine cell populations to achieve optimal paracrine regulation, although this is currently under debate. Third, the transplanted cells will still be subjected to an autoimmune environment necessitating long-term immune suppression.

Beta-like cell differentiation protocols

From the early 2000s, protocols were discovered that generated insulin-producing cells from hESCs.^21,22 While these protocols did not generate cells that would secrete insulin at physiologically relevant levels to glucose stimulation, they did set the stage for other investigators to begin pushing toward a more mature, functional beta-like cell differentiation protocol. More specific developmental markers were identified that more closely identify beta-cell-specific transcriptional pathways and proinsulin processing^23
–25 and with the identification of these markers came better differentiation protocols.^26
–28 While these newer protocols could generate cells that produce and process insulin properly, the functionality was still lacking. In 2021, a new protocol reported the generation of beta-like cells with a dynamic, glucose-responsive function, although these cells were still lacking essential markers of mature human beta cells, such as UCN3 and MAFA.²⁹ This marked advancement in beta-like cell differentiation protocols pushed the field closer to generating mature beta-like cells that recapitulate human function. Ongoing efforts to improve beta-like cell differentiation protocols have been successful in improving the functionality of sc-beta cells,³⁰ but important maturation markers are still missing. The best advances toward achieving expression of these markers have been achieved by guiding stem cells through a beta cell differentiation protocol and then transplanting them under the kidney capsule of streptozotocin-induced diabetic mice. Retrieval of the cells after 6 months indicates there is an increase in beta cell function, and the subsequent transcriptional profiling demonstrates an increase in maturation markers,³¹ detailing the persisting limitations of current in vitro differentiation protocols in generating mature, functional beta-like cells.

Ongoing work to improve upon the maturation of stem cell-derived islet cells shifted into using microencapsulation devices to allow for vascularization of the engrafted cells. Viacyte Inc. developed a stem cell-derived pancreatic endoderm cell line (PEC-01) that was used in combination with their microencapsulation device (VC-02) to achieve this. Preliminary data from the Phase 1/2 study of the Viacyte Inc. combinatorial therapy showed that of the 17 enrolled patients, 6 displayed circulating C-peptide after a mixed-meal tolerance test. Of the retrieved VC-02 units, 63% displayed engraftment and insulin expression.³² This demonstrated the possibility of hESC-derived cells to mature into insulin-positive, and in some cases glucose-responsive, beta-like cells when allowed to mature in vitro when vascularization was achieved.

The 1-year follow-up results of the Viacyte trial showed that of the 10 patients enrolled, 3 showed increased BG time-in-range (TIR) and decreased insulin administration needs. The fourth showed induced beta cell function but did not meet the secondary efficacy endpoint measured as mean glycemia levels. The remaining six cases showed no induced beta cell function, and no improvement in glycemic management. Furthermore, one of the patients who saw no improvement exhibited strong detrimental side effects from the immunosuppressive regimen. Retrieval of the encapsulation devices and analysis of the implanted cells revealed that <1%−3% of the initial cell mass developed into insulin-positive cells, while 7%−16% of the initial cell mass was glucagon positive. While three patients were able to achieve increased glucose-level control, seven saw no benefit or even detrimental effects from the immunosuppression side effects.³³

Although the results from the Viacyte trial showed mixed efficacy, the ability of sc-beta cells to mature in vivo has given researchers faith that the functional cure lies therein. An unlimited source of beta cells for replacement therapies is a promising step toward such a cure; however, the largest barriers to this strategy are the ever-present endogenous autoimmune response in a patient and the side effects of immunosuppressive regimens. There have been multiple different approaches to circumventing this, including encapsulating the sc-beta cells in a protective device before transplantation, as observed in the Viacyte trial, and ongoing studies to genetically edit the stem cells to provide immune-evasive characteristics.

Immunoisolation devices

First described in the 1960s,³⁴ immunoisolation devices encapsulate cells for transplantation with the goal of isolating cells from the immune system while allowing for the transfer of oxygen, nutrients, and hormones. Immunoprotection devices for islet transplants were first described in 1977³⁵ and then applied in 1980³⁶ in rats. Two significant barriers to these approaches are the devices allowing insufficient oxygen supply to the transplanted cells,³⁷ leading to central necrosis of the encapsulated cells and fibrotic overgrowth of the device.^38,39 Vertex is currently in Phase 1/2 trials of an encapsulated version of their VX-880 cells, being called VX-264.⁴⁰ Although no data have been published on the novel aspects of this encapsulation device, they indicate that the device is aiming to allow for vascularization of the encapsulated cells. Reports from several research groups have been published recently detailing alternate approaches to cell encapsulation^41

–44 largely focusing on using hydrogels and copolymer membranes to achieve the desired parameters of encapsulation.

Immune-privileged stem cell-derived beta cells

Another approach to circumventing both the allogeneic immune response and the endogenous autoimmune response is to generate immune-privileged stem cell-derived beta cells. A major advantage of working with cell lines is the ability to genetically manipulate them, and this approach has been taken advantage of since the mid-80s.^45,46 Currently the CRISPR-Cas9-based system, which was the recipient of the 2020 Nobel Prize in Chemistry,⁴⁷ has shown substantial promise for genetically editing cells for therapeutic uses. Perhaps one of the most highly publicized applications is in that of CAR-T cell therapies, in which T cells are removed from the blood of a patient and genetically modified with a chimeric antigen receptor before being infused back into the patient, where the CAR-T cells bind and kill cancer cells.⁴⁸ More recently, similar approaches have been used to facilitate cell therapies for T1D.

One interesting approach to disengaging the immune system from transplanted cells is to activate the intrinsic inhibitory immune activation pathways. PD-L1, CTLA-4, and CD-47 are potential targets that have been previously targeted in cancer patients for breaking tolerance.⁴⁹ In 2020, Yoshihara et al. demonstrated that PD-L1 overexpression of stem cell-derived beta-like cells provided immune privilege when the cells were transplanted into either immune-competent mice or immunodeficient mice that had been implanted with human immune cells.⁵⁰ This study did not measure the efficacy of using this approach to reduce an autoimmune response in diabetic models; however, this provides a promising direction for future studies of genetically edited cell therapies for T1D.

A similar approach taken by Parent et al. in 2021 focused on genetically deleting the human leukocyte antigens (HLAs) on stem cell-derived beta cells to prevent immune rejection.⁵¹ The HLAs are the main instigators of immune rejection in transplanted cells, activating both CD8⁺ and CD4⁺ T cells. It has been shown that in the context of T1D, beta cells are known to upregulate HLAs, leading to increased immunogenicity.⁵² Parent et al. found that deletion of all HLAs except for HLA-A2, which inhibits natural killer (NK) cell activation, prevented T cell-mediated rejection in peripheral blood mononuclear cell (PBMC) coculture models.⁵¹

In follow-up studies, Gerace and colleagues demonstrated that combinatorial deletion of PD-L1 and HLAs was not sufficient to protect against xeno- or allogeneic rejection in vivo.⁵³ To alleviate this, they engineered sc-islets that would also secrete the cytokines interleukin (IL)-2, IL-10, and transforming growth factor beta (TGF-β) to induce a tolerogenic microenvironment surrounding the sc-islets. These engineered sc-islets displayed resistance to allo- and xeno-rejection and delayed graft rejection in humanized mice by 5 weeks. While these mark advances in our mechanistic understanding of graft rejection and immune tolerance in murine and cell-based models, neither of these approaches has yet been translated into human patient trials.

CRISPR Therapeutics has also recently begun clinical trials with transplants of an “allogeneic, gene-edited, immune-evasive stem cell-derived-beta cell” therapy for T1D. This study is currently in Phase 2 trials, and although the study is using a cell containment device, the device is used strictly for retrieval of the transplanted cells. The device is filled with allogeneic stem cell-derived pancreatic endoderm cells, which are then genetically edited with CRSIPR-Cas9 to provide immune privilege (the exact approach for providing immune privilege in this trial has not been published) and transplanted into the patient to mature. At the conclusion of the study, the devices will be retrieved, and the cells will be analyzed. This phase of the trial began in January 2023 and is expected to conclude in mid-2025. This is the first-ever gene-edited T1D therapy that has made it to human trials and, if successful, could provide a solution to the allogeneic and autoimmune responses that have plagued previous attempts at curing T1D.

Most recently, in October of 2024, Wang et al. reported the successful generation and transplantation of hiPSC-derived beta-like cells into a patient with diabetes.⁵⁴ The patient had glycemic TIR of 96% 4 months after transplantation, and 75 days post-transplantation achieved insulin independence. At the 1-year follow-up, the patient showed >98% TIR and 5% HbA1c level and was displaying no side effects. The patient was already on an immunosuppressive regimen for a prior liver transplant, and remained on that regimen throughout the duration of the study. While the use of immunosuppression in this study undoubtedly blunted the autoimmune response and allowed for the survival of the engrafted cells, this was the first instance of patient-specific iPSC-generated beta-like cells being used successfully as a therapy for T1D.

Delaying Onset

While the ongoing efforts to find a cure cannot be understated, the ultimate goal is to prevent the onset of diabetes completely. Thanks to an abundance of studies from basic researchers, many islet autoantibodies have been identified,^55

–60 and screens have been developed to identify their presence in early-stage diabetes.^61,62 With identification of autoantibodies in asymptomatic patients, early intervention can allow for sustained beta cell function. Some initial attempts at delaying onset of T1D involved blocking cytokine signaling. Drugs such as golimumab⁶³ and anti-IL-21 antibody⁶⁴ allowed for better endogenous insulin production; however, these require continuous administration. Other approaches were to target the T or B cells^65

–68 but have resulted in long-term depletion of immune cells. While these approaches have shown promise in delaying the onset of T1D, the side effects and/or expense of continuous administration are not compatible with generating widely available treatments.

In 1994, an anti-CD3 antibody was shown to inhibit the autoimmune response in nonobese diabetic (NOD) mice.⁶⁹ Importantly, protective effects were observed after only short-term (5 consecutive days) treatment with the antibody. When administered to newly diagnosed NOD mice, a complete remission was observed in up to 80% of mice. Furthermore, the immunosuppression provided by anti-CD3 appeared to be specific to the beta cell-associated antigens, as the mice in remission rejected histoincompatible skin grafts. This provided major possibilities for its use as a therapeutic in delaying diabetes in human patients.

A series of research studies followed, demonstrating that the anti-CD3 antibodies with modifications in the Ig heavy chain allowed for lower dosing levels and prevented the T cell depletion that was observed in nonmodified versions.^70
–72 Among the most consequential study was the generation of a humanized anti-CD3 antibody, now known as teplizumab, by the Bluestone Laboratory and the R.W. Johnson Pharmaceutical Research Institute.⁷² This led to the first human trials of the drug, which ultimately showed that it effectively prevented allograft rejection in renal and pancreas transplants.⁷³ Upon determining that the same T lymphocytes suppressed by teplizumab played a key role in the progression of T1D,^74
–76 researchers then turned toward its use in patients with diabetes with hopes of delaying disease progression. Initial trials in 24 patients with stage 3 diabetes showed that a year after a single course of the drug resulted in significantly increased levels of C-peptide after a mixed meal tolerance test, reduced HbA1c levels, and reduced exogenous insulin administration.⁷⁷ A follow-up trial enrolled 42 patients and continued to show improvement in C-peptide levels up to 2 years after a single dose of teplizumab.⁷⁸ The Protégé trial⁷⁹ followed the licensing of teplizumab to Lilly and studied the effects of teplizumab in patients with stage 3 diabetes. The strictness of the primary endpoint was increased for the trial, with a goal of achieving HbA1c levels <6.5% and insulin administration of <0.5 U/(kg·d) a year after treatment. The primary endpoint was not met in this trial, but patients still displayed increases in C-peptide in response to a mixed meal. As a result of the primary endpoint not being met, Lilly ceased pursuit of teplizumab, and interest in the drug faltered.

In efforts to further how the immune response might affect early disease progression, a Phase 2 clinical trial of teplizumab was performed on relatives of patients with T1D who were at high risk for developing the disease themselves (stage 2 diabetes). These individuals were treated with a 14-day course of teplizumab. Of the 76 patients admitted into the study, those in the teplizumab group had a median time to T1D onset of 48.4 months, compared with 24.4 months in the placebo group. The annualized rates of diagnosis were 14.9% in the treated group and 35.9% in the placebo. This resulted in a hazard ratio for T1D diagnosis of 0.41^80,81 and demonstrated this therapy as a promising avenue for delaying the onset of T1D.

In 2002, Phase 3 trials with teplizumab (now under the brand name Tzield) began in patients with recent-onset (stage 3) T1D.⁶⁸ Five separate trials, three Phase 2 and two Phase 3, all showed positive results in preserving the presence of C-peptide in newly diagnosed patients with T1D.^{77,79,80,82,83} Two separate trials in patients with stage 2 T1D also showed significant increases in C-peptide response and less exogenous insulin administration.^78,84 In November 2022, teplizumab became the first U.S. Food and Drug Administration (FDA)-approved drug for delaying the onset of stage 3 T1D in adults and pediatric patients (8 years and older) with stage 2 T1D.⁸⁵

Conclusions

“The cure is 5 years away.” This is a phrase that has continually been promised to people with T1D for decades. While it has seemed like the cure is right around the corner for decades now, the constant delays and pushbacks, and reported cures in rodent models that fail to translate in human patients, have led to an enormous amount of disbelief among the patient population. Although there have been remarkable advances in many areas of research, reporting these as “cures” is a disservice to both the researchers whose work is misrepresented and the patients who are misled about the significance of the research findings.

That said, the advances in research have truly been remarkable. For decades, the diabetes research fields have been making discoveries at a blazing pace, winning multiple Nobel Prizes along the way. Only 100 years ago T1D was a death sentence. Today, T1D is a disease that, while certainly must still be accounted for in everyday activities, can be lived with in a way that does not limit those who are diagnosed with it. Patients with T1D are climbing mountains, flying commercial planes, running ultra-marathons, and enjoying cake on their birthdays. This is all due to the extraordinary efforts of researchers worldwide who are working to advance treatments and therapies, ultimately with the goal of finding a cure.

To say that this is an exciting time for diabetes research is a gross understatement. In the past 20 years, we have transitioned heavily from creating better treatments, to trying to find a functional cure, to outright preventing the disease from progressing. The transition into closed-loop insulin pump and CGM therapy with automated algorithms to maintain BG levels without patient input has been a huge milestone in the level of care that patients with diabetes receive. Stem cell-based therapies are very promising in their goals of providing a source of replacement beta cells that can possibly be programmed, or physically protected from the immune system, and clinical trials are showing promising outlooks for the data that are beginning to trickle out from them. Drugs to delay the onset of T1D have now been approved by the FDA for use in both adults and children who are newly diagnosed with diabetes, preventing full-blown insulin dependence for up to 7 years. While it may still be more than 5 years until there is an available cure, it is unrealistic to say that we are not close.

“Insulin does not belong to me, it belongs to the world.”⁵ While the progress that has been made in diabetes treatments, therapies, and potential cures cannot be understated, it is important to keep the true goal in proper focus. A cure for diabetes means nothing if it is inaccessible to the people who need it most. While it is inevitable that brand-new therapies, treatments, and cures will be expensive, we must strive to ensure that we are not setting our sights only on finding a cure but on delivering that cure to everyone who needs it.

Footnotes

Acknowledgment

The authors thank members of the Sussel Laboratory and Dr. Kimber Simmons for their helpful reading and discussion of this article.

Authors’ Contributions

CS and LS co-wrote the manuscript.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work is supported by the National Institutes of Health R01 DK082590, R01 DK118155, U01 DK127505, P30 DK116073 (L.S.).

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