ABSTRACT

In the U.S. alone, more than one million people are living with type 1 diabetes (TID) and approximately 80 people per day, or 30,000 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 (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, where a recent U.S. study reported mean HbA1c values exceeding 9.5%, and a high frequency of both DKA and severe hypoglycemia (5). In addition to the increased risk of morbidity and mortality, TID places significant emotional and financial burdens on individuals, families, and society. These realities highlight the need for both better TID therapies and the continued push towards the prevention of TID. In recent decades, research efforts have described the natural history of type 1 diabetes and expanded the ability to identify individuals at risk for the disease even before clinical onset, via the recognition of genetic markers or TID-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 clinical TID, investigative efforts are shifting towards the prevention or modification of autoimmunity. Furthermore, with the mounting evidence that any amount of residual C-peptide improves long term clinical outcomes in TID, some therapies aim to preserve remaining beta cell function in those with clinical disease. In this chapter, we review the epidemiology of TID, 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, TID is increasing worldwide. The increase likely is 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 TID among non-Hispanic white youth is ~1/300 in the US by age 20 years (6). Between 2002 and 2009, the incidence of TID among non-Hispanic white youth < age 20 years increased by an average of 2.7% per year (7). Similarly, the EURODIAB study evaluated TID 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 TID prevalence between 2005-2020 among European youth < 15 years old (8) with the peak of diagnosis between ages 10-14 (9). While incidence and prevalence are well documented in children, TID occurs in adults as well, at a frequency that is less certain; estimates are that 25-50% of all TID cases are diagnosed in adulthood. The uncertainty likely is due to a less dramatic clinical presentation than is typically seen in children who present with TID. The incidence of TID 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 (10), a WHO-sponsored effort to address the public health implications of TID. The incidence of TID between 1990 and 1994 in 50 countries is shown in Figure 1. Between 1990 and 1994, the incidence of TID 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. The increased incidence coupled with reduced early mortality has contributed to the increasing prevalence of disease.

Figure 1.

Worldwide incidence of TID 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 TID have no family history of TID; nonetheless, a family history of the disease does increase an individual’s relative risk. The prevalence of TID in the US non-Hispanic white population by age 20 is ~0.3%, as compared with ~5% of those with a relative with TID, 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 TID. Among 300 people with a family member with diabetes, 15 will have TID

The risk of TID 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 TID in offspring is higher if the father has TID (~6%) as compared to if the mother has TID (~2%) (11, 12). 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%) (13, 14) 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 (15).

THE NATURAL HISTORY TYPE 1 DIABETES

It is now understood that TID 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, clinical TID 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 TID and their family members. George Eisenbarth’s description of TID 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 TID natural history paradigm (16). 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 TID trials.

The long pre-symptomatic natural history of TID 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, the Endocrine Society, and the American Diabetes Association proposed a new TID staging system which underscores that TID begins with islet autoimmunity rather than with symptomatic hyperglycemia (17). Stage 1 TID is defined as the presence of 2 or more autoantibodies with normoglycemia; stage 2 TID is 2 or more autoantibodies, impaired glucose tolerance and no symptoms; stage 3 TID is clinical disease. The staging system is depicted in figure 3.

Figure 3.

New staging classification of Type 1 diabetes. Stages of Type 1 Diabetes. Adapted from internet image. https://beyondtype1.org/clinical-trials-and-the-type-1-diabetes-cure/final-trialnet-stages-of-diabetes-graph-2/ Used with permission.

HOW TO DETERMINE RISK OF TID

Risk of TID 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 TID.

Determining Risk: Genes

With the knowledge that TID runs in families and with advances in technology, investigators have described the genetic risk of TID. TID 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 TID 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 TID risk (18). They are largely genes known also 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 (19, 20). The description of non-HLA risk genes (such as the genes for insulin, a major TID 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 TID increases. This suggests that in a population with non-HLA genetic susceptibility, the environment may have become more conducive to the development of TID. 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 TID between 1922-1946 (the Golden Years cohort) to a cohort of 582 individuals diagnosed between 1985-2002 (the BOX cohort) (21). 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 (21).

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 TID in those with a family history of TID. Since 2000, Diabetes TrialNet has screened over 200,000 relatives of people with TID, aiming to enroll at-risk individuals in prevention trials. Among relatives of people with TID, ~5% will have at least one of five islet autoantibodies (22). 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 TID 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 TID is shown in Figure 5. There are many other screening efforts ongoing outside of TrialNet. (23-25)

Figure 5.

Diabetes TrialNet process for identifying relatives with islet autoimmunity.

Natural history studies have shown not only that islet autoimmunity predicts TID 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 (26). Furthermore, the data from both prospective birth cohort studies (27) and cross-sectional studies (28) (29) (30, 31) is remarkably consistent and suggests that the risk of progression from established autoimmunity to clinical TID is in the range of 40% after 5 years, 70% after 10 years, and 85% after 15 years. This risk over time 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; Ziegler et al. JAMA 2013; DPT-1 Study Group Diabetes 1997; Sosenko et al. Diabetes Care 2014; Mahon et al. Pediatric Diabetes 2009

Identifying individuals with islet autoimmunity has two potential benefits; namely, the opportunity to monitor closely for disease progression, conferring a reduced risk of morbidity and mortality at the time of TID diagnosis, and the identification of individuals who are eligible for prevention 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 clinical diagnosis present with lower HbA1c and experience less DKA than those diagnosed in the community (Table 2) (32-36). For this reason, since 2009, the ADA has recommended that all individuals with a relative with T1D be counseled about the opportunity to be screened for diabetes autoantibodies in the context of a clinical research trial (37).

Table 2.

Individuals Diagnosed with T1D While Enrolled in a Clinical Trial have Less Morbidity at the Time of Diagnosis. (32-36)

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STUDY	HbA1c at time of TID diagnosis		% with DKA at time of TID 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 does identify a population of those at risk for clinical T1D; however, at least 85% who get T1D have no relatives with disease. Thus, to truly prevent all 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 years of age (38). 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 will 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. If these at-risk subjects are monitored regularly until development of clinical disease they would benefit from reduced morbidity at time of diagnosis even if a prevention therapy were not yet available.

There are many ongoing projects aimed at screening members of the general population for diabetes autoantibodies even without prior HLA testing (23, 25, 41, 42).

As risk-screening programs employ varying assays and recruit from different populations, interpretation and translation of results is unclear. It is not yet known whether those found to be autoantibody positive through one program will experience the same rates of T1D progression and/or benefit from the same therapies as individuals who have participated in other screening and intervention efforts.

Source:(37)

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 TID, investigators have looked to 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 (43).

Source: (67)

Investigators also have studied the early childhood period for clues to the causes of islet autoimmunity and TID; 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 TID (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 will be collected. Participants will be followed until the age of 15 for the development of islet autoimmunity or TID. The wealth of data from this study will provide a foundation for future randomized clinical trials (24). One interesting finding reported in December 2019 is that there are subtle differences in the gut microbiome—such as, persistent stool enterovirus B species--in children who develop islet autoimmunity compared to children who do not develop autoimmunity (68).

EARLY NUTRITIONAL EXPOSURES

MICROBIAL EXPOSURES

The Hygiene Hypothesis

Parallel to the rising incidence of TID 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 (89) 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) (90-92).

Figure 7.

Border between Finland and Russian Karelia, with a 6-fold difference in the incidence of TID, 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 TID. This markedly higher rate of TID is accompanied by a much lesser 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.

Vaccinations

In recent decades, an increasing number of parents in Western countries have declined routine childhood vaccination of their children, which has created a situation with significant personal and public health consequences. Multiple high-quality studies have thoroughly investigated vaccinations and TID, and none have found any association with islet autoimmunity or TID (103-107)

Sources: (88, 103-108)

DISEASE-MODIFYING THERAPY FOR PRECLINICAL TID

As previously discussed, the ability to recognize autoimmunity (via the detection of autoantibodies) in subjects even before the clinical onset of T1D affords the possibility of designing trials specifically for the high-risk population. One might consider established islet autoimmunity not only a marker of impending T1D, but a condition in its own right. Just as hypertension warrants treatment to prevent stroke and myocardial infarction, in the future, TID may be treated in its earliest stages to prevent symptomatic hyperglycemia. Some potential strategies are discussed in the following section.

Many TID 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 TID, 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-clinical T1D is insulin, as in the GGAP-03 POInt, DPT-1, TrialNet oral insulin, DIPP, and INIT II trials, described next. The 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. Results are expected in early 2025. Preliminary results from the pre-POINT pilot trial suggest that higher doses of oral insulin may elicit greater immunologic response (109). 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 (110). 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 ≥80nU/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 (111, 112). 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 antibody positive individuals who had low first phase insulin response at baseline had a significant delay in disease progression in those treated with oral insulin (113). This intriguing finding raised the possibility that oral insulin may benefit those who are closer to clinical 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 (114).

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 (115). 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 (116, 117).

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 is being tested in the TrialNet TOPPLE T1D Study, a phase 1 trial launched in 2021 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) (118). In preclinical trials in NOD mice, the treatment was well-tolerated and led to beta cell preservation. If this phase 1 trial shows no safety concerns, then a larger study of the same treatment is planned to assess whether or not NNC0361-0041 can slow disease progression in the at-risk human population.

Antigen therapy may be more effective in both new-onset and at-risk populations when combined with other immune-modulating agents. Such combination trials are currently underway. In late 2020, enrollment was completed for a phase 1b/2a study assessing 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. Results are pending (119).

While some trials have tested antigen-based therapies to treat islet immunity and prevent progression to clinical disease, others are building on successful studies of immunomodulating therapy in individuals with recently diagnosed TID. 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). TrialNet recently completed enrollment of a placebo controlled trial testing abatacept in individuals with Stage 1 TID with results expected in late 2021 (120). In 2019, TrialNet published results of its placebo-controlled trial testing teplizumab in 76 individuals with Stage 2 TID. The trial demonstrated that a two-week course of teplizumab delayed the onset of clinical type 1 diabetes by two years and halved the rate of clinical diagnoses (121). This trial was highly significant in that it was the first ever to show that clinical type 1 diabetes 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 diabetes 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 (122). Teplizumab has been granted Breakthrough Therapy Designation by the FDA, and the manufacturer of teplizumab is pursuing full FDA approval.

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 (125, 126), 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 (127, 128). 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 (129). 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 (130). Together, these data strongly support the concept that preserved insulin secretion coupled with intensive insulin therapy can reduce diabetes complications while averting the severe hypoglycemia that has been a limiting factor in attaining glycemic control.

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 (131).

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, HbA_1c values <6.5% (47.4 mmol/mol), and insulin independence after transplantation (132). 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 HbA_1c among intensively treated DCCT participants (133). 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 TID, with half of participants not requiring insulin after a full year of treatment (134). Unfortunately, the risks of using this drug were deemed to outweigh the benefits. Continuous effectiveness required continuous therapy, which induced nephrotoxicity (134).

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 (135).

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 truly 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 now therapies that target 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/Liraglutide, Golimumab, Ustekinumab, Anakinra, 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. The aim in both cases 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 if 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, and abatacept, 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 (136, 140, 142-144, 155, 165, 166). 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, whether using a single course of treatment (136, 140, 142) or continuous therapy (144) 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 (140). 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 (167). 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 (111). 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 (168). Additionally, prior to diagnosis, children progress much faster through the preclinical 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 clinical diabetes than adults (169). 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 researchers from identifying therapies that may only be viable in pediatric populations. Changing this paradigm was the focus of a recent American Diabetes Association consensus conference on disease modifying therapy (169).

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 (170). 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 (123, 168, 171). Two years after diagnosis, more than 66% of individuals retain these high levels (168). Unfortunately, with increasing duration of disease, the proportion of those with detectable C-peptide falls (124, 168, 170). However, as recently reported by Davis et al. (124), 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 (172). 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 two important take-aways from these 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 (124).

To date, there are no therapies that have regenerated beta cells in humans. It is abundantly clear that mouse and human beta cells are markedly different, and therapies touted to grow cells in mice have not had such effects in humans. Instead of regeneration, replacement of dead or dysfunctional beta cells may be a viable option. 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 autoimmune (initial disease process) response. While outside the scope of this chapter, it has been recently recommended that those with severe hypoglycemic unawareness be referred for islet transplant (173). Other efforts to replace beta cells include placing them in capsules to allow viability and function while blocking immune cells from entering the capsules. These efforts remain experimental.

FUTURE CONSIDERATIONS

Despite advances in glucose monitoring and insulin delivery, the daily psychological and financial burden of disease on individuals, their families, and society together with the persistence of complications and reduced life span demand a paradigm shift.

As of 2021, we know much about the natural history of disease. We know that antibodies 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. Those with islet autoimmunity followed carefully until diagnosis have markedly less morbidity at the time of diagnosis and lower HbA1c values. Family members of T1D probands should be made aware of their disease risk and should be offered autoantibody screening and enrollment in monitoring trials. Correspondingly, patients with TID should be informed of the opportunity to have their relatives screened for TID risk in the setting of a clinical research study.

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 paths 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. Looking ahead, we will likely see the development of more targeted immunotherapies as well as more trials with combination therapies. Advances in treating childhood cancers have relied upon combining multiple approaches; this will be mimicked in T1D as well. More studies will be done in those with islet autoimmunity and variations in dose and route of administration of drugs will be tested in the search for greater efficacy. With newer and safer drugs, studies are likely to test chronic intermittent treatment for both islet cell autoimmunity and in new-onset TID to prevent further beta cell loss. Future studies will reflect the heterogeneity of TID. As medicine in general becomes more personalized, TID disease modifying therapies will target those most likely to benefit, whether because they are more likely to respond to therapy, or because their underlying disease is predicted to be worse.

Yet, there are non-scientific barriers to the use of disease modifying therapies for either islet cell autoimmunity or new-onset TID. 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 TID are generally less comfortable with these therapies. This lack of familiarity exaggerates the risks and minimizes the benefits of immune-modulating medications. If we consider islet cell autoimmunity a silent disease in the same way that we consider hypertension a silent disease, then it makes sense to prevent the consequences of that disease, such as hyperglycemia in the case of islet cell autoimmunity, or cardiovascular disease in the case of hypertension. Similarly, if we consider new-onset TID in the same way we consider JIA, our goal in TID is to preserve beta cell function, just as in JIA, the goal is to preserve joint function.

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 who have islet cell autoimmunity and/or new-onset TID.

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*

Contributed equally

†

Contributed equally