ABSTRACT

In the U.S. alone, more than one million people are living with type 1 diabetes (T1D) and approximately 50,000 individuals per year are newly diagnosed (1) (2). Recent epidemiological studies demonstrate that the global T1D incidence is increasing at a rate of approximately 3-4% per year, notably among younger children and among non-Hispanic Black and Hispanic individuals (3) (4). Despite improvements in insulins, insulin delivery methods, and home glucose monitoring, the vast majority of those with T1D do not achieve recommended levels of glycemic control. This is particularly true in childhood and adolescence, as reported by the T1D Exchange Quality Improvement Collaborative, which surveys people living with T1D from US adult and pediatric centers. Its most recent analysis of 2021-2022 glycemic trends reported a mean HbA1c of 8.6% in both the 1-15 and 16-25 age groups (5). In addition to the increased risk of morbidity and mortality, T1D places significant emotional and financial burdens on individuals, families, and society. These realities highlight the need for both better T1D therapies and the continued push towards the prevention of T1D. In recent decades, research efforts have described the natural history of T1D and expanded the ability to identify individuals at risk for the disease even before clinical onset, via the recognition of genetic markers or T1D-specific autoantibodies. The increasing ability to identify the at-risk population affords researchers the opportunity to intervene at progressively earlier stages in the disease. With the understanding that established islet autoimmunity, confirmed by the presence of multiple T1D autoantibodies, inevitably leads to symptomatic T1D, investigative efforts are shifting towards the delay or prevention of disease progression. Furthermore, with the mounting evidence that any amount of residual C-peptide improves long term clinical outcomes in T1D, some therapies aim to preserve remaining beta cell function in those with symptomatic disease. In this chapter, we review the epidemiology of T1D, genetic and environmental risk factors, the scientific underpinnings of previous and current approaches towards disease- modifying therapy, and future directions of clinical trials. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

EPIDEMIOLOGY OF DIABETES

T1D, or autoimmune diabetes, represents 5-10% of diabetes, and like autoimmunity in general, T1D is increasing worldwide. The increase is likely attributable to environmental factors or epigenetic changes, as genetic changes don’t occur rapidly enough to explain such a dramatic increase. The SEARCH for Diabetes in Youth Study is a multicenter observational study investigating trends in incidence and prevalence of diabetes in American youth < age 20. SEARCH data suggests that the prevalence of T1D among non-Hispanic White youth is ~1/300 in the US by age 20 years. Between 2002 and 2018, the incidence of T1D among non-Hispanic White youth < age 20 years increased by an average of ~2.0% per year, with higher increases observed in Asian/Pacific Islander (4.84%), Hispanic (4.14%) and non-Hispanic Black populations (2.93%). (4). Similarly, the EURODIAB study evaluated T1D incidence trends in 17 European countries from 1989-2003 in youth < age 15 years and found an average annual incidence increase of 3.9%. This trend predicts a 70% increase in T1D prevalence between 2005-2020 among European youth < 15 years old (6) with the peak of diagnosis between ages 10-14 (7). While incidence and prevalence are well documented in children, T1D occurs in adults as well, at a frequency that is less certain; estimates are that at least 50% of all T1D cases are diagnosed in adulthood. The uncertainty is likely due to a less dramatic clinical presentation than is typically seen in children who present with T1D. The incidence of T1D varies tremendously by geographic location, with higher rates generally seen in countries located farther from the equator. Worldwide incidence data was reported in 2000 by the DIAMOND project (8), a WHO- sponsored effort to address the public health implications of T1D. The incidence of T1D between 1990 and 1994 in 50 countries is shown in Figure 1. Between 1990 and 1994, the incidence of T1D in individuals aged 0-14 years in both Finland and Sardinia was 37/100,000 individuals, whereas the incidence in both China and Venezuela was 0.1/100,000 individuals, a 350-fold difference.

Figure 1.

Worldwide incidence of T1D 1990-1994, used with permission from International Diabetes Federation.

WHAT IS THE RISK OF TYPE 1 DIABETES?

As is true for Cindy, 85% of individuals who develop T1D have no family history of T1D; nonetheless, a family history of the disease does increase an individual’s relative risk. The prevalence of T1D in the US non-Hispanic White population by age 20 is ~0.3%, as compared with ~5% of those with a relative with T1D, a 15-fold increase in relative risk. This relative risk is depicted in Figure 2.

Figure 2.

Among 300 people without a family member with diabetes, 1 will have T1D. Among 300 people with a family member with diabetes, 15 will have T1D.

The risk of T1D among family members varies depending on who the affected family member is, as shown in Table 1.

The heritability pattern suggests that both genes and environment contribute to risk. Curiously, the risk of T1D in offspring is higher if the father has T1D (~6%) as compared to if the mother has T1D (~2%) (9) (10). Moreover, the risk to a dizygotic twin is slightly higher (~10%) than is the risk to a non-twin sibling with similar HLA risk genes (~6%) (11) (12) suggesting that the intrauterine environment and/or similar early life exposures may be important. Lastly, the risk to a monozygotic twin is upwards of ~50%; surprisingly the second twin’s diagnosis may occur many decades after the index twin, highlighting the complexities of gene and environmental interactions that underlie the disease (13).

THE NATURAL HISTORY TYPE 1 DIABETES

T1D is an immune-mediated disease that begins in the setting of genetic predisposition and then progresses along a predictable path: early islet autoimmunity (one autoantibody), established islet autoimmunity (two or more autoantibodies), abnormal glucose tolerance, symptomatic T1D with some remaining beta cell function, and finally, little or no remaining beta cell function. This understanding comes from decades of effort by multiple investigators and from participation by thousands of patients with T1D and their family members. George Eisenbarth’s description of T1D as a chronic autoimmune disease, manifested by autoimmunity and a gradual linear fall in beta cell function until there is insufficient beta cell mass to suppress symptomatic hyperglycemia, has served for decades as the T1D natural history paradigm (14). The “Eisenbarth” model has undergone refinements in recent years; namely, although autoimmunity and beta cell dysfunction do appear prior to diagnosis, these changes are often step-wise and non-linear. Furthermore, beta cell destruction may not be absolute. Nonetheless, the paradigm is largely correct and serves as the underlying rationale for T1D trials.

The long pre-symptomatic natural history of T1D presents an opportunity to intervene earlier than is done currently. Diabetes-specific autoantibodies can appear many years before clinical diagnosis and may reliably be used to predict disease progression. In 2015, JDRF (renamed Breakthrough T1D), the Endocrine Society, and the American Diabetes Association proposed a new T1D staging system which underscores that T1D begins with islet autoimmunity rather than with symptomatic hyperglycemia (15). Stage 1 T1D is defined as the presence of 2 or more autoantibodies with normoglycemia; stage 2 T1D is 2 or more autoantibodies, impaired glucose tolerance and no symptoms; stage 3 T1D is symptomatic disease. The staging system is depicted in figure 3.

Figure 3.

Current staging classification of Type 1 diabetes. Stages of Type 1 Diabetes. Adapted from internet image. Modified from https://www.trialnet.org/events-news/blog/type-1-diabetes-staging-classification-opens-door-intervention. Used with permission.

HOW TO DETERMINE RISK OF T1D

Risk of T1D may be determined by the identification of autoantibodies, usually in those identified as having genetic risk through HLA testing or by family history. Autoantibodies are detectable years before the onset of clinical T1D.

Determining Risk: Genes

With the knowledge that T1D runs in families and with advances in technology, investigators have described the genetic risk of T1D. T1D risk is strongly linked to HLA class II DR3 and DR4 haplotypes, with the highest risk in those with the DR3/DR4 genotype. The importance of HLA genes to T1D risk highlights the role of the adaptive immune system in the development of autoimmunity. Newer studies have discovered multiple other genes that also contribute to T1D risk (16). They are largely genes also known to impact immune function; however, their contribution is dwarfed by the impact of HLA genes. Interestingly, recent work suggests that HLA genes primarily contribute to development of autoantibodies, while non-HLA genes and environmental factors may be more important in the progression from autoantibodies to clinically overt disease (17) (18). The description of non-HLA risk genes (such as the genes for insulin, a major T1D autoantigen) highlights other potential pathways to disease and potential therapies. Although the contribution of HLA class II risk genes overwhelms the contribution of non-HLA risk genes, the HLA contribution may be decreasing as the overall incidence of T1D increases. This suggests that in a population with non-HLA genetic susceptibility, the environment may have become more conducive to the development of T1D. This was reported in a 2004 Lancet article by Gillespie, et al., in which the investigators compared the frequency of HLA class II haplotypes in a UK cohort of 194 individuals diagnosed with T1D between 1922-1946 (the Golden Years cohort) to a cohort of 582 individuals diagnosed between 1985-2002 (the BOX cohort) (19). In this comparison, shown in Figure 4, 47% of individuals in the Golden Years cohort were positive for the highest risk genotype DR3-DQ2/DR4-DQ8, compared to 35% of individuals in the BOX cohort.

Figure 4.

Decreased contribution of high-risk HLA haplotypes over time. HLA class II haplotypes in Golden Years and BOX cohorts, adapted from Gillespie et.al Lancet 2004 (19).

Determining Risk: Family History and Islet Cell Autoantibodies

Natural history studies of relatives such as Diabetes Prevention Trial (DPT-1) and Diabetes TrialNet Pathway to Prevention have helped define the risk of T1D in those with a family history of T1D. Since 2000, Diabetes TrialNet has screened over 250,000 relatives of people with T1D, aiming to enroll at-risk individuals in prevention trials. Among relatives of people with T1D, ~5% will have at least one of five islet autoantibodies (20). TrialNet screens for islet cell antibodies (ICA), autoantibodies to insulin (IAA or mIAA), antibodies to a tyrosine phosphatase (IA-2; previously ICA512), antibodies to glutamic acid decarboxylase (GAD), and antibodies to a zinc transporter (ZnT8). With each additional autoantibody, the risk of T1D increases predictably. Unsurprisingly, those with islet autoimmunity and abnormal glucose tolerance are at an even further increased risk of symptomatic T1D. The TrialNet strategy to identify islet autoimmunity among relatives of individuals with T1D is shown in Figure 5. There are other screening programs ongoing outside of TrialNet in both the US and outside the US, including some general population screening efforts.(21) (22) (23).

Figure 5.

Diabetes TrialNet process for identifying relatives with islet autoimmunity.

Natural history studies have shown not only that islet autoimmunity predicts T1D risk, but also that islet autoantibodies usually appear early in life; 64% of babies destined to develop T1D before puberty will have antibodies by age 2 and 95% by age 5 (24). Furthermore, the data from both prospective birth cohort studies (25) and cross-sectional studies (26) (27) (28) (29) are remarkably consistent and suggest that the risk of progression from established autoimmunity to clinical T1D is in the range of 40% after 5 years, 70% after 10 years, and 85% after 15 years. This risk overtime is depicted in Figure 6. The key understanding from natural history studies is that essentially all individuals with confirmed islet autoimmunity will eventually develop clinical T1D at a rate of 11% per year.

Figure 6.

Established islet autoimmunity inevitably progresses to clinical T1D. Extrapolated data from multiple studies in genetically at-risk individuals (27) (29) (26) (28).

Identifying individuals with islet autoimmunity has three potential benefits; namely, the opportunity to monitor closely for disease progression, conferring a reduced risk of morbidity and mortality at the time of T1D diagnosis, the opportunity to receive therapy to delay disease progression (currently teplizumab is the only FDA approved therapy, see section below), and the identification of individuals who may be eligible for clinical trials. It is perhaps underappreciated that there is potentially a direct clinical benefit to identifying those with islet autoimmunity. Individuals with islet autoimmunity followed regularly until symptomatic diagnosis present with lower HbA1c and experience less DKA than those diagnosed in the community (Table 2) (30) (31) (32) (33) (34). In addition to reduced acute DKA-associated morbidity and mortality, avoidance of DKA at the time of diagnosis may have longer term glycemic benefits that are independent of treatment-related, socioeconomic and demographic variables, although data are mixed on this finding (35) (36) (37) (38). For this reason, since 2025, the ADA has recommended that “autoantibody-based screening for presymptomatic type 1 diabetes should be offered to those with a family history of type 1 diabetes or otherwise known elevated genetic risk.” (39).

Table 2.

Individuals Diagnosed with T1D While Enrolled in a Clinical Trial have Less

Morbidity at the Time of Diagnosis. (30) (31) (32) (33) (34)

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STUDY	HbA1c at time of T1D diagnosis		% with DKA at time of T1D diagnosis
	Enrolled in study	Usual care	Enrolled in study	Usual care
SEARCH				25.5%
BABYDIAB	8.6%	11.0%	3.3%	29.1%
DPT-1	6.4%		3.7%
DAISY	7.2%	10.9%	< 4%
TEDDY < age 5			13.1%
SEARCH < age 5				36.4%
BABYDIAB < age 5				32.3%

STRATEGIES TO BRING SCREENING FOR RISK TO CLINICAL PRACTICE

Screening relatives identifies a population with pre-symptomatic T1D; however, at least 85% who get T1D have no relatives with disease. Thus, to truly prevent all symptomatic T1D, testing of the general population would have to occur. This could be done with current technology by testing all babies for genetic (HLA) risk at birth and then following with antibody testing. The Population Level Estimate of type 1 Diabetes risk Genes in children (PLEDGE) study enrolls newborns from the general population and offers one-time genetic testing and follow-up autoantibody testing at 2 and 4-6 years of age (21). The study aims to demonstrate feasibility and to develop evidence to support eventual inclusion of a T1D screening program in standard primary care.

Other studies, such as The Environmental Determinants of Diabetes in the Young (TEDDY) study, the Diabetes Autoimmunity Study in the Young (DAISY), and the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) are exploring similar methodologies to screen and monitor for risk (24, 39, 40). However, with an increasing number of individuals developing T1D even without the high-risk HLA types, such approaches may still miss some destined to develop disease.

An alternative risk detection strategy for those without a family history may be to perform point-of-care antibody testing in a routine pediatric visit. Since almost all who develop diabetes before puberty will have antibodies by age 5; such testing could be done at age 4-5 and perhaps once again in the teenage years. This method will still miss those who develop T1D before this age but would likely be a cost- effective approach to finding those at risk.

There are other projects aimed at screening members of the general population for diabetes autoantibodies even without prior HLA testing (22) (23) (40). Key to general population screening is the observation that once multiple autoantibodies are present, progression to symptomatic disease is inevitable, regardless of family history or HLA-defined genetic risk (26). The rate of progression from pre-symptomatic to symptomatic T1D is affected by a number of factors including age (41) and number of autoantibodies (42).

A general population screening program in Bavaria, Germany, the Fr1da study (43) enrolled children ages 1.75 – 5.99 between 2015 and 2019 and ages 1.75 – 10.99 since 2019. Over 165,000 children had been screened as of December 2022. Initial autoantibody testing is performed via capillary blood sampling during a pediatric well child visit and positive results are confirmed by a venous blood draw. Families are invited to participate in education, counseling, and glycemic monitoring programs. It is anticipated that Fr1da will provide a wealth of information including the prevalence of pre-symptomatic T1D; disease progression in a population without genetic enrichment; the feasibility of screening in the general population; and the benefits and hazards of general population screening (43).

A 2020 analysis of 2015-2019 Fr1da data showed an islet autoantibody prevalence rate of 0.3% in ~90,000 children screened to date, median age 3.1 years [2.1-4.2] (44). The same analysis showed that although parents whose children tested positive for islet autoantibodies had increased stress compared to parents whose children tested negative, stress levels declined after 12 months of follow-up. In 2023 Fr1da investigators reported that ~170,000 children had been screened to date, 473 (0.3%) children had tested positive with multiple islet autoantibodies, and 128 children had progressed to symptomatic T1D. They found that children with pre-symptomatic T1D enrolled in Fr1da had “milder” diabetes at the time of symptomatic diagnosis compared to a cohort of 736 children diagnosed without pre-symptomatic screening, from the German DiMelli study, a cohort and biobank study of incident diagnosis of childhood and adolescent T1D (45). Unsurprisingly, children who were enrolled in Fr1da at the time of symptomatic diagnosis had lower HbA1c and fasting blood glucose levels, higher fasting C-peptide levels, less ketonuria, a lower prevalence of DKA and less weight loss compared to children diagnosed without pre-symptomatic screening from the DiMelli cohort. (46).

An important unanswered question is the ideal age(s) to screen. A 2022 analysis of data from five prospective cohorts suggested that ages two and six might be optimal, with a sensitivity of 82% and a positive predictive value of 79% for diagnosis by age 15, but this approach would miss those who are diagnosed in adulthood, which represents up to 50% of all T1D diagnoses, and those diagnosed prior to age two (47).

PRENATAL INFLUENCES

The prenatal environment can have profound effects on the developing fetus. With the recognition that antibodies often develop early in life and that essentially all those with established islet autoimmunity (two or more autoantibodies) will eventually develop symptomatic T1D, investigators have studied the prenatal period to search for factors that could contribute to disease development in utero. As shown in Table 3, decades of observational studies have yielded inconsistent results. Yet this remains an important area of investigation and one that may lead to primary prevention strategies for T1D. The Environmental Determinants of Islet Autoimmunity (ENDIA) study is an ongoing prospective birth cohort study in Australia that enrolled infants and unborn infants of first degree relatives with T1D. Biologic samples including blood, stool, and saliva will be collected longitudinally for investigation of factors including viral exposures during pregnancy and early childhood, maternal and fetal microbiome, delivery method, maternal and early infant nutrition, pregnancy and early childhood body weight, and both innate and adaptive immune function. In 2018, the ENDIA study completed target enrollment of ~1500 subjects, who will be followed regularly until the development of islet autoimmunity (48).

Investigators also have studied the early childhood period for clues to the causes of islet autoimmunity and T1D; these have included both observational studies and randomized clinical trials. Such influences might be divided into early nutritional exposures and early microbial/infectious exposures, both of which can affect development of the normal immune system. The inconsistent findings relating to environmental factors reported from observational studies and clinical trials led to the design and implementation of a large international comprehensive evaluation of genetically at-risk babies using cutting edge technologies to study genetics, genomics (gene function), metabolomics, and the microbiome. The Environmental Determinants of Diabetes in the Young (TEDDY) is an international prospective birth cohort study that recruited almost 8,000 babies at increased risk for T1D (based on HLA and family history) from Finland, Germany, Sweden, and the US from 2004- 2010. Information on environmental exposures such as diet (including breastfeeding history), infections, vaccinations, and psychosocial stressors were collected. Participants are followed until the age of 15 for the development of islet autoimmunity or T1D and data collection will be finalized in 2025 (73). A 2024 review described key TEDDY findings to date, including the description of two islet autoimmunity phenotypes (“IAA-first” and “GADA-first”) and that environmental exposures such as enterovirus infection and gastroenteritis may affect the phenotypes differently (74). This observation was detailed in a 2023 paper that reported gastrointestinal infections prior to 1 year of age were associated with increased IAA risk whereas gastrointestinal infections during the second year of life were associated with a decreased IAA risk (75).

EARLY NUTRITIONAL EXPOSURES

MICROBIAL EXPOSURES

The Hygiene Hypothesis

Parallel to the rising incidence of T1D and other autoimmune diseases, there has been a worldwide trend towards urbanization, increased standard of living, smaller family sizes, less crowded living conditions, safer water and food supplies, less cohabitation with animals, wide use of antibiotics, childhood vaccination, etc. While these trends are generally considered improvements in human existence, the so-called “hygiene hypothesis,” proposed by Strachan in 1989 (97) suggests a possible downside; that is, that early microbial exposures might have a protective effect via the early education of the immune system and the development of normal tolerance to self-antigens. Data cited in support of the hygiene hypothesis comes from comparisons between eastern Finland and Russian Karelia (Figure 7) (98) (99) (100).

Figure 7.

Border between Finland and Russian Karelia, with a 6-fold difference in the incidence of T1D, from “Karelia today”. The countries share a common border and ancestry and thus have similar geography, climate, vitamin D levels, and prevalence of HLA risk haplotypes. However, Finland has 6- fold higher incidence of T1D. This markedly higher rate of T1D is accompanied by a much lower rate of infectious disease. In Finland as compared to Karelia 2% vs 24% had hepatitis A; 5% vs 24% had toxoplasma gondii; and 5% vs. 73% for helicobacter pylori. There is an ongoing study aiming to better understand the mechanisms that may underlie these differences.

DISEASE-MODIFYING THERAPY FOR PRE SYMPTOMATIC T1D

As previously discussed, the ability to recognize autoimmunity (via the detection of autoantibodies) in subjects before the symptomatic onset of T1D affords the possibility of designing trials specifically for the high-risk population. As codified by T1D stages, pre-symptomatic T1D is a disease that warrants treatment to delay symptomatic T1D, just as hypertension warrants treatment to prevent stroke and myocardial infarction.. Some potential strategies are discussed in the following section.

Many T1D studies have tested antigen-based therapies. With this type of therapy, the concept is that administration of a specific antigen could shift the immune response towards tolerance of the antigen. For example, in allergy desensitization therapy, small amounts of antigen are repeatedly administered to ‘teach’ the immune system to be tolerant of the foreign protein so that the immune system no longer reacts. In T1D, the aim is to administer self-antigens in order to tolerize the immune system to beta-cell-derived proteins and downregulate the immune attack. Theoretically this can be done through oral, nasal, subcutaneous, or parenteral administration of antigen, with or without repeated dosing. Conceptually, antigen therapy should be more effective early in the disease process (i.e., to prevent progression from islet immunity to symptomatic disease rather than in those already clinically diagnosed) and thus most studies have targeted the at-risk population.

Perhaps the most rigorously tested antigen therapy for pre-symptomatic T1D is insulin, as in the GGAP-03 POInt, DPT-1, TrialNet oral insulin, DIPP, and INIT II trials, described next. The Breakthrough T1D (formerly known as JDRF)-funded GGAP-03 POInT Trial, a primary intervention dose-finding study, is evaluating whether or not early exposure to oral insulin, even before those with high genetic risk develop autoantibodies, may confer greater benefit (119). Preliminary results from the pre-POINT pilot trial suggest that higher doses of oral insulin may elicit greater immunologic response (120). In the Diabetes Prevention Trial (DPT-1), 372 family members of T1D probands who were positive for both ICA and mIAA were assigned to receive either daily oral insulin or placebo (121). While this trial did not meet its primary endpoint, post-hoc analysis showed a delay in disease onset in participants with the highest levels of insulin autoantibodies. Specifically, those with a mIAA titer≥80 nU/ml showed a 4.5-year delay in disease onset and those with a mIAA titer ≥300nU/ml showed a 10-year delay in disease onset (122) (123). In response to these intriguing findings, Diabetes TrialNet launched a larger study to determine whether or not these results could be replicated. While the fully-powered TrialNet study showed no benefit to oral insulin in the primary cohort of more than 300 individuals, an independently- randomized cohort of 55 positive antibody individuals who had low first phase insulin response at baseline had a significant delay in disease progression in those treated with oral insulin (124). This finding raised the possibility that oral insulin may benefit those who are closer to symptomatic diagnosis; that is, those with more active disease.

In addition to studying oral insulin, the DPT-1 evaluated the effect of parenteral insulin on individuals who were considered to have the highest risk for T1D. These participants were ICA positive with abnormal beta-cell function (dysglycemia on an OGTT or low first phase insulin response on IVGTT). These 339 high risk participants were assigned to either close observation or low dose subcutaneous ultra-Lente insulin in addition to annual four-day continuous insulin infusions. While the therapy was found to be ineffective in preventing the progression to T1D, there was no excessive hypoglycemia, and a subset analysis found a temporary decrease in the immune response to beta cell proteins (125).

To date, trials with intranasal insulin have proven safe but ineffective in preserving insulin secretion. The Type 1 Diabetes Prediction and Prevention Study (DIPP), a randomized controlled trial evaluating the effects of intranasal insulin in children with high-risk genotypes and autoantibody positivity, was negative. When intranasal insulin was administered soon after the detection of autoantibodies, there was no delay in the progression to T1D (126). Similarly, the Intranasal Insulin Trial II (INIT II), which tested a different dose and dosing schedule of nasal insulin in a phase II prevention trial, showed that intranasal insulin was safe and induced an immune response, but this did not alter the progression to T1D. Participants were first- degree relatives of T1D probands with autoantibody positivity (127).

Another approach to antigen therapy is to use a plasmid to transfer DNA into cells, where it encodes for a given antigen, a technique that should decrease the anti-inflammatory response from intravenous, subcutaneous, oral, or nasal antigen delivery. This technique was tested in the TrialNet TOPPLE T1D Study, a phase 1 trial to evaluate the safety of a plasmid therapy called NNC0361-0041 in adults with recent-onset T1D. NNC0361-0041 encodes for four different human proteins: pre- proinsulin (PPI), transforming growth factor β1 (TGF- β1), interleukin-10 (IL-10), and interleukin-2 (IL-2) (128). Results of this trial are expected in 2025.

Antigen therapy may be more effective in both new- onset and at-risk populations when combined with other immune-modulating agents. For example, a phase 1b/2a study tested the safety and tolerability of different doses of an oral therapy called AG019 administered alone or in association with teplizumab infusions (see below) in individuals with recent-onset T1D. AG019 consists of live Lactococcus lactis bacteria, genetically modified to secrete human proinsulin and human interleukin 10. AG019 was shown to be safe and well tolerated both as monotherapy and in combination with teplizumab; for the combination group changes in pre-proinsulin specific CD8+ T cells were seen (129). While some trials have tested antigen-based therapies to treat islet immunity and prevent progression to symptomatic disease, others are building on successful studies of immunomodulating therapy in individuals with recently diagnosed T1D. Examples include abatacept (Orencia; CTLA4 Ig) and teplizumab (Anti-CD3), both of which have been shown to slow loss of beta cell function post diagnosis. (See Recent Clinical Trials with Compelling Results and Figure 8). Abatacept was tested in a trial of 212 participants with stage 1 T1D who received monthly infusions of abatacept or placebo for 12 months. The primary endpoint was progression to stage 2 or 3 T1D. Although abatacept treatment did not delay disease progression, immune cell subsets were impacted, and C-pepT1De secretion was preserved in abatacept treated individuals while on treatment (130).

In 2019, TrialNet published results of its placebo-controlled trial testing teplizumab in 76 individuals with Stage 2 T1D. The trial demonstrated that a two-week course of teplizumab delayed the onset of clinical T1D by two years and halved the rate of clinical diagnoses (131). This trial was highly significant in that it was the first ever to show that clinical T1D can be delayed in children and adults at high risk. The latest findings from this trial, published in March of 2021, show ongoing delay of clinical disease in the teplizumab treated group, with a median time to diagnosis of approximately 60 months (5 years) vs. approximately 27 months (2.3 years) in the placebo group (132). FDA approval for use of teplizumab in individuals with stage 2 T1D aged 8 years and older was granted in 2022—the first approved therapy to delay the symptomatic diagnosis of any autoimmune condition. Efforts are underway to lower the teplizumab approval age.

IMPORTANCE OF BETA CELL PRESERVATION IN LIGHT OF RISKS OF THERAPY

The preservation of residual beta cell function, as measured by C-peptide, has repeatedly been demonstrated to be clinically important in those with T1D, warranting ongoing efforts to develop therapies to prevent beta cell destruction both in individuals with islet autoimmunity and in those with new-onset disease. In addition to its primary finding that intensive insulin therapy results in better outcomes (136) (137) (138), the landmark Diabetes Control and Complications Trial (DCCT) showed that among intensively treated subjects, those who had ≥ 0.20 nmol/L stimulated C- peptide initially or sustained over a year had fewer complications, including 79% risk reduction in progression of retinopathy (139) (140). Importantly, these benefits were seen in the face of markedly less severe hypoglycemia. Subjects in the intensive insulin therapy group with ≥ 0.20 nmol/L C-peptide had about the same frequency of severe hypoglycemia as those in the standard care group; a 62% relative reduction as compared to those who received intensive therapy without this level of C-peptide. Subsequent analyses have demonstrated that even lower levels of preserved beta cell function in DCCT subjects were protective against complications (141). Importantly, a beneficial effect of preserved insulin secretion was also recently reported in those with type 2 diabetes. Endogenous insulin deficiency was strongly associated with hypoglycemia and a limited ability to control HbA1c in Type 2 subjects in the ACCORD study (142). Together, these data strongly support the concept that preserved insulin secretion coupled with intensive insulin therapy can reduce diabetes complications while averting severe hypoglycemia that has been a limiting factor in meeting glycemic targets (143) (144).

Islet transplant studies confirm a positive association between C-peptide secretion and a lower risk of hypoglycemia. Subjects eligible for islet transplantation are largely individuals suffering from severe hypoglycemic unawareness. Vantyghem et al. showed that while significant beta cell function was required to improve mean glucose, lower glucose excursions, and result in insulin independence in transplant patients, only minimal beta cell function was needed to abrogate severe hypoglycemic events (145).

Additionally, post islet-cell transplant patients with higher as compared to absent or minimal C-peptide levels are more likely to maintain fasting blood glucose values in the 60-140mg/dL (3.3 – 7.8 mmol/l) range, HbA1c values <6.5% (47.4 mmol/mol), and insulin independence after transplantation (146). The DCCT showed similar metabolic benefits in those with residual C-peptide. In this trial, patients with C-peptide ≥ 0.2nmol/L had lower fasting glucose and HbA1c values. A 9-year longitudinal analysis showed that for every 1 nmol/L increase in baseline stimulated C- peptide, there was an associated 1% reduction in HbA1c among intensively treated DCCT participants (147). Such positive clinical outcomes in those with preserved C-peptide reinforce the significance of efforts to protect beta cell function.

Of course, the benefits of beta cell preservation must be weighed against the intrinsic risks of therapies used to preserve C-peptide. Two therapies in particular highlight the challenges of balancing benefits with risk. First, one of the initial immunomodulatory therapies used in T1D was cyclosporine, a general immunosuppressant. Treatment with cyclosporine induced remission from insulin dependence in children with recently diagnosed T1D, with half of participants not requiring insulin after a full year of treatment (148). Unfortunately, the risks of using this drug were deemed to outweigh the benefits. Continuous effectiveness required continuous therapy, which induced nephrotoxicity (148).

More recently, studies with autologous hematopoietic stem cell transplant (HSCT) in the new onset population have further highlighted the risks of more aggressive approaches to treatment. Although the pooled data from HSCT trials suggests that this therapy imparts a high diabetes remission rate, the remission is not durable, and there are significant risks associated with the treatment, including neutropenic fever, serious infection, gonadal failure, and even death (149).

Importantly, there are dozens of immunotherapeutic agents or combinations of agents that are safely used in current clinical practice in other autoimmune diseases. For example, adults and children with juvenile idiopathic arthritis (JIA) are routinely treated with immunotherapy, an approach that has markedly transformed the lives of many living with this disease. Similarly, the aim for T1D is to use disease modifying therapies prudently and safely to improve the lives of those living with T1D. Possible approaches may include short term therapy aimed at inducing a long-term effect (tolerance), intermittent therapy, or limited doses of chronic therapy. Some of these methodologies are described below.

CLINICAL TRIALS WITH COMPELLING RESULTS IN NEW-ONSET T1D

Selecting therapies for clinical trials is based on multiple factors. We can now take advantage of the tremendous advances in understanding the disease process and basic and applied immunology. As illustrated in Figure 8, there are multiple therapies that target different specific mechanisms underlying disease. Trials are considered in the context of what is known about safety of the therapy and efficacy in animal models, pilot studies, and other autoimmune diseases. Using these approaches, we have succeeded in altering disease course without the excessive risk previously described.

Figure 8.

Major pathways leading to beta cell destruction and potential mechanisms underlying the use of selected therapies. Both CD4 and CD8 T effector cells infiltrate and impair/destroy beta cells along with inflammatory cytokines such as IL-21, IL-1 and IL12/23. Anti-IL21/LiragluT1De, Golimumab, Ustekinumab, Anakinra, Baracitinib, and Canakinumab are aimed at blocking these inflammatory pathways. Activation of Teff cells depends upon presentation of antigen to naïve T cells which result in both Teff turning the immune response “on” and Treg cells turning the immune response “off”. Rituximab decreases B cells and therefore decreases the presentation of antigen to the immune system. Abatacept blocks co-stimulation and oral insulin (and other antigen therapy including the use of antigen specific dendritic cells) alters the response to self-antigen. Frexalimab interrupts both B and T cell activation. The effect of these therapies is to deviate the response to Treg cells or keep Teff cells from fully activating. ATG and anti-CD3 agents modulate and/or deplete activated T cells. Alefacept has a similar mechanism although primarily aimed at memory T cells. By blocking IL-6, Tocilizumab should change the balance of immune activation towards T regulatory cells. Similarly, GSCF, IL-2 (at the “right dose”), and infusion of Treg cells should preferentially increase Treg cells.

It is well established that T1D is the result of an immune cell mediated destruction of the pancreatic beta cells. Many research efforts have thus targeted T-cells as well as the cells with which they interact. As in secondary prevention trials, anti-inflammatory agents, antigen therapies, and immunomodulatory drugs have all been used in tertiary prevention studies, which are designed to stop further beta cell destruction in the new onset population, therefore preventing complications. In addition, cellular therapies have been tested in this population. Excitingly, several therapies have now been shown to safely alter the disease course, particularly in the period soon after drug administration, allowing treated subjects to retain more C-peptide than controls 1-4 years later (Figure 9). Thus, while not yet ready for clinical use by endocrinologists, it is likely that immunotherapy with these or other agents will become a part of T1D new onset clinical care in the future.

OTHER APPROACHES

LESSONS FROM TRIALS WITH DISEASE MODIFYING THERAPIES

The trials that have successfully altered the course of disease by changing the rate of loss of C-peptide, even for a brief period of time, have taught us much about the immune system and the natural history of T1D. First, it appears that the time of administration in the course of T1D may determine the effectiveness of a therapy as there appears to be a window during which agents may elicit the greatest effect upon the autoimmune process. Interestingly, in the cases of rituximab, otelixizumab/teplizumab, alefacept, ATG, golimumab, anti-IL-21, ustekinumab, abatacept, and baricitinib, each of which has a different mechanism of action, treatment effected a marked delay in beta cell destruction/dysfunction initially, but thereafter, rates of decline in C-peptide paralleled those of the placebo groups (150) (154) (157) (159) (160) (172) (185) (157) (169) (186) (173).

Collectively, these observations suggest a difference in immune activity soon after diagnosis as compared with later on in the disease course (see Figure 9).

Figure 9.

Stylized representation of selected new onset clinical trial results. Studies with positive outcomes (150) (154) (157) (160) (159) (169) (186) (173) appeared to have the most pronounced effects early after treatment started. See text for details.

Because of the time-dependent nature of the therapeutic response, the traditional approach of testing therapies in those with new-onset T1D before moving them “upstream” for use in treating autoimmunity may not be optimal. Several medications or combinations of medications are more likely to be effective earlier in disease. Thus, demonstration of efficacy in new onset trials should not be required before testing whether therapies can effectively treat islet autoimmunity.

The results of several trials have demonstrated that not all T1D patients are alike, and they vary in their response to therapy. For instance, in the Abate trial, 45% of subjects treated with teplizumab appeared to respond to the drug, showing almost no change in C- peptide secretion at two years, whereas 55% were deemed “non-responders” as their C-peptide secretion was not distinguishable from controls. Post-hoc analysis suggests that responders had lower A1C levels, less exogenous insulin use, and fewer Th-1-like T cells than non-responders (154). Next, post-hoc analysis from the Protégé trial revealed that C-peptide preservation was better in teplizumab treated patients who were aged 8-17, randomized within 6 weeks of diagnosis, had mean C-peptide AUC > 0.2nmol/L, A1c< 7.5%, and insulin dose < 0.4 units/kg/day (187). Last, as previously discussed, upon initial analysis of DPT-1 data, oral insulin did not appear to prevent T1D in the at-risk population. However, subsequent analysis showed a marked delay in diabetes development among those participants who had high titer anti-insulin autoantibodies (122). These results suggest that individualized therapies, which take into account a patient’s unique characteristics, are not only a possibility, but may be a necessity.

Participant age also appears to play a role in response to therapy, suggesting that optimal disease modifying agents may differ between pediatric and adult populations. Pre-teen children have less C-peptide at diagnosis than older children and adults. All age groups of children have a markedly different rate of fall of C-peptide than adults in the first year after diagnosis (188). Additionally, prior to diagnosis, children progress much faster through the pre symptomatic stages of disease. Specifically, children with early autoimmunity (1 antibody) are more likely to develop established autoimmunity (2+antibodies) than adults; and children with established autoimmunity with or without abnormal glucose tolerance progress more rapidly to symptomatic diabetes than adults (189). Historically, the FDA has required that therapies first be tested in the adult population before they may be approved for use in the pediatric population. However, this approach may prevent identification of therapies that may be viable only in pediatric populations. Changing this paradigm was the focus of a key American Diabetes Association consensus conference on disease modifying therapy (189).

In the next few years, not only will new agents be tested, but the community will build on these results by using them in selected individuals (personalized medicine), in combination trials, and at different stages of disease. Each step takes us closer to clinical use of a disease modifying agent.

RESIDUAL INSULIN SECRETION

Traditional teaching holds that all subjects with T1D will eventually lose all of their beta cells. This statement is no longer true; multiple lines of research demonstrate that a proportion of those even with longstanding T1D may have residual beta cell function. The Joslin Medalist study showed that 67% of 411 T1D subjects at least 50 years from diagnosis had at least minimal (0.03 nmol/L) random serum C- peptide levels. Of these individuals, 2.6% had random serum C-peptide ≥ 0.20 nmol/L. Post-mortem analysis of pancreata from these same subjects revealed that insulin positive cells were noted in 9/9 pancreases studied (190). Since many of the Joslin Medalists were diagnosed at a time when life expectancy was markedly reduced in those with T1D, it was felt that this was a unique population, not representative of the majority of people with T1D and that the preservation of C-peptide itself may have contributed to their long- term survival. However, multiple studies have now confirmed that C-peptide is present in a significant proportion of individuals with T1D. At the time of diagnosis, essentially all individuals (both youth and adults) have clinically significant levels of C-peptide (134) (188) (191). Two years after diagnosis, more than 66% of individuals retain these high levels (188). Unfortunately, with increasing duration of disease, the proportion of those with detectable C-peptide falls (135) (188) (190). However, as recently reported by Davis et al.(135), about 6-7% of those even more than 40 years from diagnosis have measurable C-peptide and more sensitive assays can actually detect C- peptide in a greater proportion of individuals. Moreover, like the pancreata from the Joslin cohort, studies from those who have had T1D for at least 4 years have shown that residual (insulin-positive) β- cells can be found in ~ 40% of T1D pancreases upon autopsy (192). Careful studies of post-mortem samples using new technologies have suggested that insulin-positive cells may be scattered in the exocrine tissue, raising the tantalizing possibility that new beta cells could emerge. Longitudinal studies of those long from diagnosis with low levels of C-peptide are underway to better understand variation over time.

There are important take-aways from this new data. First, the presence of C-peptide does NOT rule out a T1D diagnosis. Yet, this data should not be over-interpreted; most individuals will eventually lose essentially all of their C-peptide secretion. The Davis study showed that 93% of those diagnosed as children had absent or extremely low levels of C-peptide >20 years from diagnosis (135).

To date, there are no therapies that have regenerated beta cells in humans but replacement of dead or dysfunctional beta cells is an area of active investigation. Beta cell replacement is currently done through either whole pancreas or islet transplantation in conjunction with immune therapies to suppress the alloimmune (tissue rejection) and recurrent autoimmune response. Historically, these therapies have been constrained by a limited supply of cadaveric donors and the need for lifelong immunosuppression in the recipient. Pancreas transplantation is usually performed simultaneously with a kidney transplant, to restore both kidney and islet function and to justify the need for lifelong immunosuppression (193). Islet cell transplants are reserved for those with severe hypoglycemia or hypoglycemia unawareness where it can reverse these life-threatening conditions even without restoring insulin independence (194). More recent work using pluripotent embryonic stem cells and engineered induced pluripotent stem cells has led to the potential for an unlimited supply of islet cells, hence removing one of the primary barriers to islet cell transplant; that is, the limited supply of donors (195) (196) (197). However, recipients of this therapy would still require immunosuppression. To eliminate the need for immunosuppression, transplanted cells would need to be edited with tools such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to enhance tolerance to antigens (198), or “encapsulated” using technology that allows transfer of nutrients and insulin while masking transplanted cells to the immune system (199).

FUTURE CONSIDERATIONS

Despite advances in glucose monitoring and insulin delivery, T1D management exacts a daily psychological, cognitive, and financial burden on individuals, families, and society. A minority of people living with T1D are able to sustain the therapeutic targets associated with a lower risk of complications. More than 100 years after insulin was first used to treat hyperglycemia, a different approach is needed; one that addresses the underlying pathophysiology of T1D.

In 2025, we know much about the natural history of disease. We know that T1D specific autoantibodies can develop early in life and that essentially all of those with established islet autoimmunity will develop clinically overt disease. We also know that identifying these individuals is of significant clinical benefit including a reduced risk of DKA at the time of symptomatic diagnosis, the option to consider teplizumab to delay symptomatic disease, and referral to clinical trials Those with islet autoimmunity followed carefully until symptomatic diagnosis have markedly less morbidity at the time of diagnosis and lower HbA1c values. As per current ADA Standards of Care, family members of people with T1D should be made aware of their disease risk and should be offered autoantibody screening. Broader population T1D risk screening and glycemic monitoring is not yet standard of care in 2025 but is anticipated in the future.

While the interaction of humans with their environment must contribute to disease; how this occurs is still being elucidated. It is likely that there are many different pathways by which individual gene/environment interactions result in T1D; suggesting that dissecting this heterogeneity will provide better insights and therapies.

Whatever the primary cause, we know that the immune system is involved in disease progression. There have been successes in delaying beta cell destruction before and after clinical diagnosis, and in beta cell replacement. Looking ahead, we will see the development of more targeted immunotherapies to personalize therapy for those most likely to benefit from a particular treatment. We anticipate more trials to test combination, sequential, or chronic immunotherapy aiming to preserve beta cell function, similar to how immunotherapy is used in other autoimmune conditions.

Yet, there are non-scientific barriers to the use of disease modifying therapies for either islet cell autoimmunity or new-onset T1D. One barrier is the lack of familiarity with these therapies amongst clinicians. Immune-modulating medications are used routinely by rheumatologists; whereas endocrinologists and others who care for people with T1D are generally less comfortable with these therapies. This lack of familiarity exaggerates the risks and minimizes the benefits of immune- modulating medications. However, with a shift in mindset and training, and in anticipation of successful clinical trials, one can envision a not-too- distant future in which endocrinologists might use immune modulating therapies to treat their patients in all stages of T1D, before and after clinical diagnosis.

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