Summary

Type 1 diabetes is a progressive disease. There is a genetic predisposition to type 1 diabetes, particularly conferred by alleles present within the major histocompatibility complex (HLA region) on the short arm of chromosome six. It is thought that in susceptible individuals, an environmental trigger initiates an immune response. Immune infiltration into pancreatic islets results in beta cell damage, impairment of beta cell function, and potential destruction of beta cells. One would expect that if type 1 diabetes is an immunologically mediated disease, then immune intervention should alter the natural history of the disease and potentially abrogate the clinical syndrome.

Intervention trials have been conducted at a number of stages of the disease process. Primary prevention trials have been conducted in individuals with a genetic predisposition who have not yet developed immunologic markers (“Pre-Stage 1”). Secondary prevention trials have been conducted in individuals with two or more diabetes-related autoantibodies, either during Stage 1 of type 1 diabetes (normal metabolic function) or Stage 2 of type 1 diabetes (abnormal metabolic function). Intervention trials, also called tertiary prevention trials, have been conducted in individuals with Stage 3 of type 1 diabetes (clinical hyperglycemia), usually shortly after clinical onset of disease.

This chapter provides brief summaries of the randomized controlled clinical trials that have been conducted and also mentions some non-randomized pilot studies. Unfortunately, none of the primary or secondary prevention trials have clearly arrested the disease process. Some tertiary intervention trials have demonstrated improved beta cell function, at least for some period of time, after which beta cell function has generally declined in parallel to that in the respective control group. This could be a consequence of most studies focusing on only a single immunologic mechanism; whereas, what may be required are studies that deal with multiple immunologic mechanisms, including attempting to improve regulatory immunity, while also addressing beta cell function by including interventions that improve beta cell health.

Introduction

Type 1 diabetes is a slowly progressive disease, with a genetic predisposition, where a putative environmental trigger initiates an immune response that results in pancreatic islet beta cell damage, impairment of beta cell function, and destruction of beta cells (1,2,3). Although the initial characterization suggested a slow, linear progression of disease (Figure 37.1) (1), more recent thought is that there is more variability in the progression, perhaps with waxing and waning or with intermittent immune attacks (3). Moreover, the disease may be a consequence of imbalance between the immune system and the ability of the pancreatic beta cell to withstand attack (4).

A genetic basis for the disease in association with human leukocyte antigen (HLA) was first described in the early 1970s (5). Subsequently, that relationship has been extensively characterized (6,7,8,9), with both Class II (9,10) and Class I HLA (11) contributing to genetic susceptibility, and even the identification of protective HLA haplotypes (12). Although multiple other potential genes have been identified as possible contributors to type 1 diabetes (13,14), the HLA region remains the major contributor to genetic predisposition (15). Indeed, based on a study of the general population of Denver newborns, children born with the high-risk genotype HLA-DR3/4-DQ8 comprise almost 50% of children who develop anti-islet autoimmunity by age 5 years (16). In addition, the cumulative burden of non-major histocompatibility complex (MHC) susceptibility genes may play a role in determining the rate of disease progression. Genetic factors associated with type 1 diabetes are described in detail in Chapter 12 Genetics of Type 1 Diabetes.

In genetically susceptible individuals, the disease process eventuating in type 1 diabetes likely is initiated by an environmental trigger (17,18). It is unclear whether such a trigger is an infectious agent, such as an enterovirus, a dietary factor, alteration of the intestinal microbiome, or some other factor. Moreover, the association between environmental factors and the course of the disease is complicated by observations that not only initiation of the disease process, but also the rate of progression to clinical onset, may be affected by environmental determinants and that metabolic decompensation at disease onset may be a consequence of another unrelated or nonspecific environmental event. Ongoing observational cohort studies, such as The Environmental Determinants of Diabetes in the Young (TEDDY) study (19,20), are designed to ascertain environmental determinants that may trigger islet autoimmunity and either speed up or slow down the progression to clinical onset in subjects with persistent islet autoimmunity. Please see Chapter 11 Risk Factors for Type 1 Diabetes for more discussion of putative environmental triggers of type 1 diabetes.

The type 1 diabetes immune response is initiated by antigen presentation and then mediated by T lymphocytes (21,22), resulting in a lymphocytic inflammatory response in pancreatic islets that has been called insulitis (23). It appears to involve an autoreactive response by both effector CD4 (24) and cytotoxic CD8 (25) T lymphocytes. These have the capacity to mediate damage both via cytokine effects (possibly involving such cytokines as interleukin-1 [IL-1] and tumor necrosis factor alpha [TNF-α]) or direct cytotoxic T lymphocyte-mediated lysis. This initial immune response, with continued lysis, creates the potential of a vicious cycle of inflammation, which also may engender secondary and tertiary immune responses that contribute to the impairment of beta cell function and potential destruction of beta cells (3,4,21). This insidious process evolves over a variable amount of time—even many years in some individuals. The eventual overt manifestation of clinical symptoms becomes apparent only when most beta cells have lost function and many may have been destroyed.

The initial laboratory manifestation of this beta cell injury is seroconversion, i.e., the appearance of diabetes-related autoantibodies. These antibodies are generally thought not to mediate beta cell injury but rather to be markers of such injury. Diabetes-related autoantibodies were first described in the early 1970s, when islet cell antibodies (ICA) were identified by immunofluorescence (26). Subsequently, additional antibodies were identified with specific antigen targets, including insulin autoantibodies (IAA), antibodies to glutamic acid decarboxylase (GAD), antibodies to an aborted tyrosine phosphatase, which has been called islet antibody-2 (IA2), and antibodies to the zinc transporter (ZnT8) (27), all of which are components of beta cells.

FIGURE 37.1

Natural History of Type 1 Diabetes, 1986. A model of the natural history of type 1 diabetes, as proposed by Dr. George S. Eisenbarth in 1986. GAD65, glutamic acid decarboxylase 65 kD; IA2Ab, islet antibody-2; IAA, insulin autoantibodies; ICA, islet cell (more...)

FIGURE 37.2

Stages of Type 1 Diabetes, 2015. A model of type 1 diabetes staging, as proposed in a joint scientific statement of the JDRF, Endocrine Society, and American Diabetes Association in 2015.

Seroconversion is an important marker of the type 1 diabetes disease process. Indeed, in longitudinal studies of birth cohorts identified by genetic screening, such as DAISY (Diabetes AutoImmunity Study in the Young) (28), BABYDIAB (29), and DIPP (DIabetes Prediction and Prevention study) (30), if two or more antibodies appear, there is near certain progression to type 1 diabetes over the next two decades (31). This finding has led to a new classification of type 1 diabetes (Figure 37.2), in which the presence of two or more antibodies defines Stage 1 of type 1 diabetes (32).

During further evolution of the disease, progressive metabolic changes are observable (33). Lack of beta cell sensitivity to glucose, i.e., failure of the beta cell to recognize glucose and appropriately secrete insulin, is an early defect (34), similar to that seen in type 2 diabetes (35). This may be manifested by loss of first phase insulin response to intravenous glucose (36) and dysglycemia (abnormal glucose levels not reaching the threshold for clinical diagnosis), which defines Stage 2 type 1 diabetes. Ultimately, there is progression to clinical type 1 diabetes (37), now also called Stage 3 (32). A risk score, taking into account several of these metabolic changes, has been developed (38) and validated (39). After the clinical onset of type 1 diabetes, there is further progressive decline of beta cell function (40).

One would expect that if type 1 diabetes is an immunologically mediated disease, then immune intervention should alter the natural history of the disease and potentially abrogate the clinical syndrome. This has certainly been the case in animal models of type 1 diabetes (41,42,43). The first reported attempt at immune intervention in type 1 diabetes was in the late 1970s in a handful of subjects (44). In the 1980s, a number of small trials were conducted with a variety of immunologic agents (45,46). Since then, initially stimulated by a provocative pilot study with cyclosporine (47), a large number of studies have been conducted, mostly in recent-onset type 1 diabetes in an attempt to interdict the disease process and preserve beta cell function (48,49). A few studies have been conducted prior to any evidence of autoimmunity (primary prevention) or after the development of diabetes-related autoantibodies (secondary prevention) (50). The goal of such primary and secondary interventions is to arrest the immune process and, thus, prevent or delay clinical disease.

Table 37.1 lists both completed and ongoing primary and secondary prevention trials. Table 37.2 lists a large number of contemporary intervention trials in subjects with clinical Stage 3 type 1 diabetes, mostly in recent-onset subjects, but some in established disease. Most studies listed are randomized controlled clinical trials, although a few pilot studies of significance are included.

Primary Prevention Trials

Primary prevention trials (Table 37.1) have been conducted in birth cohorts identified by genetic screening, with the interventions initiated at a time when there are neither signs of autoimmunity nor metabolic impairment. Since there is uncertainty as to whether those infants identified by genetic screening will progress to type 1 diabetes, any interventions tested must be extremely safe. As a consequence, virtually all primary prevention trials to date have involved dietary interventions directed at putative environmental triggers of type 1 diabetes (51,52,53,54,55,56).

A meta-analysis had demonstrated a correlation between onset of type 1 diabetes and either early introduction of cow’s milk formula or a short period of breastfeeding (57). Consequently, two studies evaluated whether at the time of weaning, replacement of breast milk with a formula based on casein hydrolysate rather than conventional cow’s milk-based formula could reduce the development of autoimmunity (51,52). Eligible infants had HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes. A pilot study in Finland enrolled 230 infants (51). The investigators reported that the group assigned to casein hydrolysate formula had a reduced risk of development of beta cell autoimmunity (appearance of one or more antibodies) (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.29–0.95; HR adjusted for observed difference in duration of exposure to study formula 0.51, 95% CI 0.28–0.91) (51). The larger Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study, a multinational trial involving 77 centers in 15 countries, registered over 5,000 newborns and randomized 2,159 newborns with risk genotypes (approximately 45% of those screened) (52). After 7 years, the TRIGR Study Group found no difference in the rate of appearance of diabetes autoantibodies (52). In the group assigned to casein hydrolysate formula, 13.4% had two or more islet autoantibodies versus 11.4% among those randomized to the conventional formula (unadjusted HR 1.21, 95% CI 0.94–1.54). When the hazard ratio was adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region of the world, it was 1.23 (95% CI 0.96–1.58). Nonetheless, TRIGR is continuing follow-up because it was designed with a primary outcome of the development of type 1 diabetes by age 10 years.

To evaluate whether bovine insulin might be the component of cow’s milk that serves as a trigger for type 1 diabetes, the Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes (FINDIA) compared three formulas: cow’s milk formula (control), whey-based hydrolyzed formula, or whey-based FINDIA formula essentially free of bovine insulin, whenever breast milk was not available during the first 6 months of life (53). Of 5,003 infants screened, 1,113 were found eligible, 1,104 were randomized, and 908 provided at least one follow-up sample. By age 3 years, the group assigned to the FINDIA formula had a reduced risk of development of beta cell autoimmunity, defined as the appearance of one or more antibodies (in the intention-to-treat analysis, odds ratio [OR] 0.39, 95% CI 0.17–0.91, p=0.03; in the actual treatment-received analysis, OR 0.23, 95% CI 0.08–0.69, p<0.01, in the FINDIA group when compared with the cow’s milk formula group) (53).

TABLE 37.1

Trials for Primary and Secondary Prevention of Type 1 Diabetes.

The BABYDIET study, a randomized controlled trial, evaluated whether delayed exposure to gluten reduces the risk of diabetes autoimmunity (54). The rationale for the study was based on the investigators’ earlier observation of increased risk of islet autoimmunity in children who are exposed to gluten early in life (58). The trial randomized 150 infants with a first-degree relative with type 1 diabetes and an HLA genotype consistent with type 1 diabetes risk. They were assigned either to first gluten exposure at age 6 months (control group) or at age 12 months (late-exposure group) and were followed every 3 months until age 3 years and yearly thereafter. BABYDIET found that delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity (3-year risk: 12% vs. 13%, p=0.6) (54).

The TrialNet Nutritional Intervention to Prevent (NIP) Type 1 Diabetes Pilot Trial assessed the feasibility of implementing a study to determine the effect of nutritional supplements with the omega-3 fatty acid docosahexaenoic acid (DHA), which has anti-inflammatory effects, during the last trimester of pregnancy and the first few years of life (55). NIP found that supplementation of infant diets with DHA was safe and resulted in an increased level of DHA in infant erythrocytes but did not find consistent changes in inflammatory cytokines (55).

Based on putative observations that vitamin D may be protective against type 1 diabetes, a group of Canadian investigators showed in a small pilot study that it was possible to recruit babies from the general population for identification of HLA-associated risk status followed by enrollment by age 1 month to a randomized controlled prevention trial of vitamin D supplementation (56). Therefore, they have proposed a nationwide study (in Canada) to evaluate the hypothesis that vitamin D supplementation can decrease the risk of islet autoimmunity and type 1 diabetes.

The Primary Oral Insulin Therapy (Pre-POINT) study was a pilot safety study of the use of oral insulin in children age 2–7 years at risk of developing type 1 diabetes (59). The study found that daily oral administration of 67.5 mg insulin is safe and can actively engage the immune system with features of immune regulation in children who are genetically at risk of developing type 1 diabetes. Consequently, a larger randomized controlled trial has been initiated (60).

It would seem desirable to conduct more studies in those with genetic predisposition, particularly if a safe vaccine-type approach can be studied. This might involve an antigen-based vaccine (such as that used in the Pre-POINT study) or a vaccine directed against potential viral triggers of disease. In order to conduct such trials, it will be necessary to screen various populations at or shortly after birth, looking for high-risk genetic predisposition. Theoretically, if such trials resulted in prevention of type 1 diabetes, this would change public health practice, leading to routine screening at birth for high genetic risk of type 1 diabetes. Further, if the intervention were totally safe, it could ultimately be included in routine neonatal or infant vaccination programs.

Secondary Prevention Trials

Secondary prevention trials (Table 37.1) are those conducted in individuals with Stage 1 (autoantibodies alone) or Stage 2 type 1 diabetes (autoantibodies and metabolic dysfunction) (Figure 37.2) (32). Most of these studies have been conducted in individuals, generally first- or second-degree relatives of people with type 1 diabetes, who initially have been identified by screening for diabetes-associated autoantibodies. Because not all of those with antibodies will progress to type 1 diabetes, selection of interventions to be tested has been done cautiously. Indeed, all completed secondary prevention studies have used either nicotinamide (a water soluble vitamin [B6] derived from nicotinic acid) or insulin given in one form or another (61,62,63,64,65,66,67,68,69). Ongoing secondary prevention trials are either antigen-based—using insulin (nasal (70) or oral (71)) or GAD (72)—or use immunomodulatory therapies that have previously been found to be relatively safe and with beneficial effects on beta cell function in tertiary prevention studies in recent-onset type 1 diabetes, namely teplizumab (73) and abatacept (74).

Tertiary Prevention Trials

Tertiary prevention trials (Table 37.2) have been conducted in subjects with Stage 3 clinical type 1 diabetes (i.e., classic symptomatic type 1 diabetes requiring insulin therapy) (Figure 37.2) (32), mostly recent onset, but some in established disease. As noted, there were many early pilot trials with a variety of immune interventions (45,46) that will not be discussed here. Rather, this discussion is confined to randomized controlled trials and studies that have either tested contemporary immunologic approaches or ones that offer special insights.

Early Intervention Studies

Cyclosporine

A pilot study by Stiller et al. (47), reported in 1984, used cyclosporine, an immunosuppressive agent targeting T lymphocytes, which served to stimulate the field, including the conduct of a number of cyclosporine studies (75,76,77,78,79,80). Two large randomized controlled trials compared “remission” rates with cyclosporine versus placebo in subjects with new-onset Stage 3 type 1 diabetes (75,76). In the French study (75), “complete remission” was defined as good metabolic control (aiming at fasting blood glucose <140 mg/dL [<7.77 mmol/L], postprandial blood glucose <200 mg/dL [<11.10 mmol/L], and glycosylated hemoglobin [A1c] <7.5% [<58 mmol/mol]) in the absence of insulin treatment. “Partial remission” was defined by the same metabolic criteria obtained with <0.25 units/kg per day of insulin. In the Canadian-European study (76), the same metabolic targets were used, but “remission” also required a stimulated C-peptide level >0.6 nmol/L or a non-insulin requiring (NIR) state. Doses of cyclosporine were progressively lowered and stopped after a period of time if remission was not achieved.

Both studies showed a greater proportion of subjects in remission with cyclosporine than with placebo, but the rate of remission progressively declined in both groups during the 1-year course of the study. Two smaller studies, in Miami (77) and Denver (78), also were conducted. The Miami study showed a slower rate of decline of stimulated C-peptide with cyclosporine compared to placebo. The Denver study showed a slightly greater, but not statistically significant, difference in the rate of remission in the cyclosporine group than the placebo group. Meanwhile, buoyed by two randomized controlled trials showing the beneficial effects of cyclosporine, a French team initiated a study of cyclosporine in which all eligible subjects received the drug (79). In that study, 27 of 40 subjects (67.5%), all of whom were children, achieved remission. Enrollment was expanded, and subjects were followed for a protracted period of time, during which subjects lost their remission in spite of continued cyclosporine therapy (80). This lack of long-term benefit, coupled with the then-emerging recognition of cyclosporine side effects (particularly renal disease), led to virtual abandonment of this therapy in type 1 diabetes.

Azathioprine

In the same era, the mid-1980s, several studies were conducted with azathioprine, an immunomodulatory agent, in recent-onset Stage 3 type 1 diabetes (81,82,83). One study initiated therapy with a 10-week course of corticosteroids followed by 1 year of treatment with azathioprine and found better beta cell function at 1 year, as measured by peak C-peptide/glucose ratio, than in the randomized but untreated control group (81). Another, nonrandomized study gave alternate patients azathioprine and found that most azathioprine subjects achieved “remission,” whereas only one comparison subject did (82). A third azathioprine study was a double-masked placebo-controlled study that enrolled 49 people age 2–20 years with newly diagnosed type 1 diabetes (83). This study found nearly equal rates of remission in both groups. Given the nonrandomized nature of the other studies and the side effects of azathioprine, further studies with azathioprine were not pursued.

Linomide

The immunomodulatory agent linomide (quinoline-3-carboxamide), thought to activate or modulate regulatory T lymphocytes, was evaluated in a randomized placebo-controlled trial in 63 subjects age 10–20 years with recent-onset Stage 3 type 1 diabetes (84). Subjects were treated for 1 year, and beta cell function was evaluated by glucagon-stimulated C-peptide. Although the initial analysis suggested no difference between groups, when the analysis was confined to those with residual C-peptide at baseline (40 of 63 subjects), a beneficial effect was observed. Although side effects were minimal, the manufacturer did not continue development of linomide, and thus, this was not further pursued.

Bacille Calmette-Guerin Vaccine

Two double-masked placebo-controlled trials in the 1990s evaluated the effects of BCG (bacille Calmette-Guerin) vaccine, an immune regulatory agent that showed benefit in animal models, in subjects with recent-onset Stage 3 type 1 diabetes (85,86). One, conducted in Alberta, Canada (85), enrolled 26 subjects with mean age 13 years, while the other, conducted in Colorado and Massachusetts (86), enrolled 94 subjects age 5–18 years. Similar outcomes were seen in both studies, namely that there was no effect of BCG on preservation of beta cell function. Indeed, in both studies, there was a trend to greater decline of beta cell function in the BCG group than in the control group.

TABLE 37.2

Intervention Studies in Recent-Onset Type 1 Diabetes.

Oral Insulin

Three studies used oral insulin (in various doses) in recent-onset Stage 3 type 1 diabetes (87,88,89). In the French (87) and Italian (88) studies, no effect was seen on beta cell function. In the study conducted in the United States (89), retention of endogenous beta cell function was said to be dependent upon initial stimulated C-peptide response, age at diabetes onset, and numbers of specific islet cell autoantibodies found. The complex analysis did not permit a clear conclusion to be drawn, particularly in view of the two negative European studies.

Anti-CD5 Monoclonal Antibody

Using an anti-CD5 monoclonal antibody, which targets T lymphocytes, linked to ricin A-chain, a toxin, a small open-label dose-escalation pilot study was conducted in 15 subjects with recent-onset Stage 3 type 1 diabetes (90). With only 5 days of treatment, there appeared to be a slower than anticipated decline in beta cell function (tested by a mixed meal tolerance test [MMTT]) over 1 year, but in the absence of a control group, it was not possible to infer a beneficial effect. Nonetheless, the use of a monoclonal antibody directed at T lymphocytes served to stimulate other investigations of monoclonal antibodies in type 1 diabetes.

List of Abbreviations

A1c

glycosylated hemoglobin

AAT

alpha-1 antitrypsin

AHSCT

autologous hematopoietic stem cell therapy

ATG

antithymocyte globulin

BCG

bacille Calmette-Guerin

CI

confidence interval

DENIS

German (Deutsch) Nicotinamide Diabetes Intervention Study

DHA

docosahexaenoic acid

DIPP

Diabetes Prediction and Prevention Study

DPT-1

Diabetes Prevention Trial-Type 1

ENDIT

European Nicotinamide Diabetes Intervention Trial

FINDIA

Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes

GAD

glutamic acid decarboxylase

GCSF

granulocyte colony-stimulating factor

GLP

glucagon-like peptide

HLA

human leukocyte antigen

HR

hazard ratio

IA2

islet antibody-2

IAA

insulin autoantibodies

ICA

islet cell antibodies

IL

interleukin

INIT

Intranasal Insulin Trial

ITN

Immune Tolerance Network

MMTT

mixed meal tolerance test

NIP

Nutritional Intervention to Prevent Type 1 Diabetes

OR

odds ratio

Pre-POINT

Primary Oral Insulin Therapy Study

TNF

tumor necrosis factor

TRIGR

Trial to Reduce the Incidence of Diabetes in the Genetically at Risk

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CONVERSIONS

Conversions for A1c and glucose values are provided in Diabetes in America Appendix 1 Conversions.

DUALITY OF INTEREST

Dr. Skyler received personal fees from Dexcom, Debiopharm, Genentech, ImmunoMolecular Therapeutics, Intarcia, Intrexon, INNODIA, Eli Lilly and Company, Merck, Novo Nordisk, Orgenesis, and Sanofi Genzyme outside the submitted work. Drs. Krischer, Becker, and Rewers reported no conflicts of interest.

ACKNOWLEDGMENTS/FUNDING Dr. Skyler received grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK061041) and JDRF, as well as non-financial support from the American Diabetes Association, non- financial support from Eli Lilly and Company, and grants and non-financial support from the Diabetes Research Institute Foundation.