Ahmed J. Delli and Åke Lernmark

History

Early histologic studies of pancreatic tissue of diabetic patients who died shortly after clinical onset revealed that the pancreatic islets were altered by fibrosis, hyalinosis, atrophy, and infiltration of inflammatory cells.⁶ The inflammatory lesion of the islets of Langerhans was later described as insulitis,⁷ and quantitative studies of the pancreatic islets showed a specific loss of insulin-producing cells in association with clinical onset of T1DM.^8,9 The rediscovery of insulitis⁹ was of major significance, especially because it was later observed that autoimmune thyroid disease often developed in diabetic patients treated with insulin or, conversely, that patients with diseases of autoimmune character (e.g., Grave’s disease, Hashimoto’s thyroiditis, pernicious anemia, and Addison’s disease) had an increased prevalence of T1DM.¹⁰ It was therefore suggested that the pathogenesis of T1DM involved autoimmune reactions directed toward the endocrine pancreas. This notion was supported by leukocyte migration inhibition to pancreatic islet antigens.¹¹ Numerous studies have confirmed the presence of insulitis^12,13; however, in spite of the assumption that T1DM is a T-cell mediated disease, reproducible and standardized tests of blood T-cell reactivity against islet autoantigens are yet to be established.¹⁴ Long-sought-for islet cell antibodies (ICA) were described in 1974,^15,16 islet surface antibodies (ICSA) in 1978,¹⁷ and complement-dependent antibody-mediated islet cell cytotoxicity in 1980.¹⁸ The first antigen recognized by islet antibodies, an islet protein of 64,000 relative molecular mass (Mr), or 64K, was described in 1982.^19,20 Later, the 64K protein was found to have glutamic acid decarboxylase (GAD) activity,²⁰ but molecular cloning showed that the human islet GAD was a novel isoform, GAD65.²¹ Autoantibodies to insulin were demonstrated in 1983,²² to insulinoma-associated antigen 2 (IA-2), a receptor-type protein tyrosine phosphatase, in 1994,²³ and to the ZnT8 transporter in 2007.²⁴ In contrast to T-cell analyses, GAD65 and IA-2 autoantibodies may be determined in standardized assays.²⁵ Taken together, ample evidence exists that islet cell autoimmunity is of major importance in the etiopathogenesis of T1DM.

Definition

T1DM results from selective destruction of the β cells in the pancreatic islets, leading to absolute lack of insulin and hyperglycemia.⁴ The β cells are principally destroyed by an aggressive autoimmune process, which is mediated but not limited to infiltration of CD4+ and CD8+ T cells, as well as macrophages, resulting in insulitis. An improved understanding of these processes is obtained in animals with spontaneous T1DM, most prominently the NOD mouse and the BB rat. These animals allow detailed genetic and experimental observations prior to onset of diabetes and facilitate preclinical trials to develop approaches of prevention and intervention, as recently reviewed.²⁶

Symptoms and Signs

T1DM is often thought to be a disorder of acute onset, and the clinical onset may be dramatic. Nevertheless, T1DM may be discovered accidentally²⁷ or associated with serious, life-threatening diabetic ketoacidosis (DKA). Over the years, however, numerous reports have noted that signs of subclinical diabetes precede the clinical onset. In addition, in adult diabetes patients classified with T2DM, a change sometimes occurs from an insulin-independent to insulin-dependent state.

T1DM is said to have four major clinical phases: preclinical diabetes, overt diabetes, partial remission phase (honeymoon), and chronic phase of lifelong dependency on injected insulin.²⁸ It is now accepted that autoantibodies against GAD65, insulin, IA-2, or ZnT8, alone or in combination, may be present up to several years before the clinical onset of the disease.^24,29,30 The possibility that islet autoimmunity might be present long before symptoms of hyperglycemia occur makes it difficult to define a causative factor. The clinical onset is not likely to occur until a major loss (80% to 90%) of the islet β cells has occurred. Currently it is not possible to determine the human β-cell mass or volume. β-Cell function tests are affected by both β-cell mass and insulin sensitivity.³¹ It is therefore not possible to relate clinical onset to β-cell mass, especially since some reports suggest that around 40% to 50% of β cells may be viable, owing to β-cell regeneration at the time of overt hyperglycemia.²⁷

The occurrence of DKA is more commonly seen with new-onset disease, especially in children younger than 4 years of age (Fig. 14-1), but it is not specific to T1DM and may also occur in T2DM.³² DKA occurs invariably in different populations, ranging from 15% to 67% of patients in Europe and North America, whereas in the developing world, around 80% of children with T1DM present initially with DKA.³³ Typically the child is acidotic with acetone fruity odor, air hunger and Kussmaul respiration, abdominal pain, nausea and vomiting, and polyuria and polydipsia (see Fig. 14-1). The child has hyperglycemia, glucosuria, ketonemia, and ketonuria. Without timely management, severe fluid and electrolyte depletion soon develop, with signs of hypoperfusion and deterioration in level of consciousness due to cerebral edema that may lead to coma and death (see Fig. 14-1).

Because T1DM is detected in the majority of patients after a relatively short period of symptoms, such as increased thirst, polyuria, and unexplained weight loss, the natural history of the disease has been poorly defined until recently. With the current ability to define individuals at high risk for developing T1DM based on high-risk HLA and autoantibody positivity, our understanding of the prediabetic period is improving. Current prospective studies of children with increased risk for T1DM (TEDDY, DIPP; DAISY, DiPiS, BABYDiab, PANDA)34,35 have revealed that autoantibodies to GAD65, IA-2, or insulin and decreased ability to release insulin in response to glucose³⁶ may develop several years before the clinical diagnosis. The sequence of events preceding the diagnosis of overt T1DM would include the following: (1) genetic predisposition; (2) overt immunologic abnormalities with normal glucose levels; (3) development of β-cell dysfunction; (4) development of overt hyperglycemia with detectable C peptide; and (5) the final stage of insulin dependency, with disappearance of C peptide (Fig. 14-2). The fact that T1DM develops in persons of all ages must be taken into account when studying the natural history in children and adults. It is of significance that T1DM is often associated with other autoimmune diseases such as autoimmune thyroiditis (15% to 30%), Addison’s disease (0.5%), and celiac disease (4% to 9%). Additionally, the risk of autoimmune diseases is increased among relatives to T1DM patients.³⁷

Diagnostic Criteria

The basis for distinction between T1DM and T2DM is islet autoimmunity and the patient’s dependence on insulin. Most patients have a history of polyuria, polydipsia, and unexplained weight loss (see Fig. 14-1). The American Diabetes Association (ADA)⁴ and the International Society for Pediatric and Adolescent Diabetes (ISPAD)²⁸ have recommended diagnostic criteria for T1DM (Table 14-1).

Evidence has been presented that adult-onset T2DM may progress to insulin dependence at a rate of 1% to 2% per year.³ This rate is increased in GAD65 autoantibody–positive patients classified with T2DM,³⁸ and this form of T1DM has variably been termed type 1.5 diabetes, latent autoimmune diabetes in adults (LADA), or slowly progressive T1DM.³⁹

Glucose tolerance tests, both oral and intravenous, are being used to evaluate diabetic states. The oral glucose tolerance test (OGTT) is a diagnostic criterion (see Table 14-1). Although glucose tolerance tests are more important in disorders of impaired glucose tolerance and T2DM, they may also find an increased use in the prediction and diagnosis of T1DM.⁴⁰

Classification

T1DM can be clinically classified into two main types: immune-mediated, or type 1A, and the uncommon idiopathic, or type 1B (~10% of patients). Unlike immune-mediated T1ADM, T1BDM is not associated with islet-cell antibodies or HLA, although both forms can involve ketosis acidosis.4,5

Epidemiology

Etiology

The absence of an unambiguous mode of inheritance, the presence of a period of subclinical islet autoimmunity preceding clinical onset of disease, human leukocyte antigen (HLA) genes that control the immune response, and age and seasonal variation must be taken into account in attempts to explain the cause of T1DM. A defined etiologic factor, endogenous or exogenous, capable of causing T1DM remains to be identified (see Table 14-5). Because evidence exists of genetic heterogeneity in T1DM, it is possible that different causative factors are responsible. In experimental animals (see Table 14-5), both viral and chemical agents have been used to induce diabetes reproducibly, and certain strains of animals are at higher risk for developing diabetes due to genetic factors. In addition, only indirect evidence suggests that environmental factors that are clearly diabetogenic in animals are involved in initiating T1DM in humans. The following is a brief summary of possible genetic or environmental factors that are associated with the appearance of T1DM.

Pathology

Studies of the pancreas in newly diagnosed T1DM patients have indicated that the gland is diminished in size compared with that in matched controls.8,109 An atrophic pancreas with little or negligible residual insulin is typical of a patient with longstanding T1DM. The atrophy affects primarily the tail of the pancreas. In this part, the composition of the endocrine pancreas is dominated by β and α cells, whereas in the pancreatic head, β and pancreatic polypeptide (PP) cells predominate. In addition to insulin deficiency, the pancreatic atrophy appears to be reflected in lower serum levels of pancreatic trypsin and isoamylase.^110,111 It is speculated that the pancreas atrophy is a result of an intrapancreatic insulin deficiency affecting the growth of the pancreas.

The insulin deficiency is the result of a specific loss of the β cells, which affects the total mass of the endocrine pancreas in T1DM (Table 14-6). The islets are small and appear pseudoatrophic.^112,113 In contrast to the normal pancreas, in which the β cells predominate, the endocrine cells in the diabetic pancreas are primarily α, δ, and PP cells. Lobular variation has been described, and areas with β-cell-containing islets without pancreatic atrophy also have been detected, suggesting that parts of the pancreas may be spared¹¹² in individuals with newly diagnosed T1DM. Sometimes β cells are seen in close proximity to duct cells, suggesting neoformation of cells. The understanding of the developing endocrine pancreas has improved, and a number of transcription factors controlling the process have been identified.¹¹⁴ However, one of the characteristics of the pancreas in many children with newly diagnosed T1DM is the presence of inflammatory cells adjacent to islets or cords of newly formed β cells.¹¹²

The presence of inflammatory cells in the pancreas of diabetes patients with short-duration disease was initially demonstrated at the turn of the 20th century. The term insulitis was first introduced in 1940,⁷ but the phenomenon was not established until later quantitative investigations reported insulitis in 16 of 23 individuals with T1DM who died within 6 months of diagnosis.⁸ It is believed that insulitis is not detected in a greater percentage of new-onset T1DM patients because the total mass of β cells is already markedly reduced at the time of clinical diagnosis.¹³ Immunocytochemical investigation in rare specimens of pancreas from patients who died shortly after the clinical onset of T1DM indicates that all cell types considered part of the immune system populate the islets to form the insulitis¹¹⁵; T lymphocytes, B lymphocytes, macrophages, and occasional natural killer (NK) cells may be seen. In agreement with earlier studies, examination of pancreatic islets in laparoscopically obtained biopsy specimens from newly diagnosed T1DM patients^116,117 demonstrated insulitis in about 60% of patients, with a T cell-predominant infiltration and increased expression of HLA class I.¹¹⁸ Notably, the presence of insulitis was strongly correlated with the presence of other autoimmune features, specifically positivity for GAD65 or IA-2 autoantibodies.¹¹⁸ In contrast, recent examination of specimens from 1507 pancreatic donors aged 25 to 60 years revealed 62 (4%) islet autoantibody–positive subjects. Insulitis was found in only 2 of the 62 (3%) subjects; the 2 subjects were positive for multiple islet autoantibodies and susceptible HLA. None of the 62 matched controls. These results suggest that positivity for islet autoantibodies does not immediately mean that insulitis is present. Islet autoantibodies may precede insulitis, which therefore may require the concurrent presence of multiple islet autoantibodies.¹¹⁹

Individuals at risk for development of T1DM have been found to have hyperproinsulinemia, a condition thought to reflect maximally stimulated or perhaps exhausted β cells.120,121 When compared with matched controls, HLA-identical siblings of patients with T1DM have been found to have evidence of both insulin resistance and impaired β-cell function.¹²² To estimate the residual mass of insulin-producing cells in humans, it is important to take into account such factors as the maximal rate of insulin release, extraction of insulin in the liver and peripheral tissues, and resistance to insulin action.¹²³ It has been shown that intensive therapy for T1DM helps sustain endogenous insulin secretion, which in turn is associated with better metabolic control and lower risk for hypoglycemia and chronic complications.^124,125

The role of immune cells in the process leading to the disappearance of β cells is well established in the NOD mouse and BB rat.²⁶ It is possible to transfer diabetes adoptively with clonal T lymphocytes in both species. Similarly, transfer of T1DM between HLA-identical siblings has been achieved by bone marrow transplantation.¹²⁶

Taken together, current observations support the hypothesis that T1DM is an immune-mediated disease and that immunocytes play a pivotal role in the β-cell killing. Although the total pancreatic insulin content in experimental animals appears to correlate well with the total β-cell mass, it cannot be excluded that a diminished β-cell mass alters the rate of insulin biosynthesis and secretion in remaining β cells, as well as insulin resistance in peripheral tissues.

Pathogenesis

The pathogenesis of T1DM is strongly associated with several immune abnormalities. These immune abnormalities, in particular autoantibodies directed against specific islet cell autoantigens such as insulin, GAD65, IA-2 and ZnT8, are dynamic markers of an ongoing disease process. These pathogenic markers are useful to predict and classify T1DM. The rate of β-cell destruction appears to be influenced by HLA. The HLA DQA1*0301-B1*0302/DQA1*0501–BI*0201 genotype may accelerate β-cell destruction.¹²⁷ The DQB1*0602 or 0603 alleles are dominantly protective, although the negative association is attenuated with increased age at onset.¹²⁸ In DQB1*0602/0603-positive patients, the second haplotype is most often DQA1*0201-B1*0302,¹²⁹ suggesting that HLA may influence the tempo of the disease process. Because the HLA molecules are important determinants in regulating the immune response in humans, the susceptibility to T1DM is speculated to be conferred by the functional importance of these molecules in the immune response. The role of the class II molecules in the immune response is to convey cell-cell interactions between T-helper (CD4+) lymphocytes and antigen-presenting cells (APC) or B lymphocytes. The CD4+ T cell provides help to cytotoxic T(CD8+) lymphocytes as well as to B lymphocytes. The importance of the immune system to T1DM pathogenesis is underscored by recent genome-wide association studies, which suggest that variants of genetic factors important to the immune response increase the risk of T1DM (see Table 14-4).

The development of diabetes in the NOD mouse and several strains of rats, including the BB, LEW, and Japanese rat, are similarly linked to the MHC of these animals. The autoantigens in these rodents are not as well defined as in humans. However, the ability to genetically manipulate both mice and rats has made it possible to design experiments which allow β-cell antigens to be presented by MHC class II molecules to be recognized by specific TCR on CD4+ T lymphocytes. These cells then signal to initiate specific cytotoxic T lymphocytes killing the β cells. These types of laboratory rodents are also used to define the cytokines such as interferon gamma (IFN-γ) and interleukin 2 (IL-2), which promote an immune response that is predominantly cell mediated and aggressive (a T_Hl response), or IL-4 and IL-10, which promote an immune response that is mostly humoral (a T_H2 response). These cytokines along with a large number of chemokines are local mediators. The large variety of laboratory mice genetically manipulated to develop T1DM should prove useful to dissecting the role of inflammatory mediators in the disease pathogenesis.

Immunologic Abnormalities

Prediction

Highly effective, precise, and reproducible screening assays for HLA genotypes, as well as for GAD65Ab, lA-2Ab, ZnT8Ab, and possibly IAA, are in use to detect individuals who are carriers of islet cell autoimmunity with an increased risk for T1DM (Table 14-9). Early detection of T1DM serves several purposes. Among them is the distinct possibility that ketoacidosis associated with a dramatic and traumatic onset of T1DM, in some cases leading to death, would be forestalled. In addition, immunotherapeutic modalities for disease prevention of β-cell destruction are under active investigation, with the hope that T1DM may someday be a preventable disease.

It is well established that the development of islet autoimmunity and T1DM may be triggered during early infancy or even intrauterine life among genetically susceptible subjects.29,30 Transplacentally-transferred autoantibodies may be detected in cord blood of newborn infants of diabetic mothers, but they mainly disappear by 6 months. On the other hand, nondiabetic mothers with detectable antibodies confer even higher disease risk to their offspring.²⁰⁸

The fact that clinical onset of T1DM is preceded by a long “prediabetes” phase marked by islet autoimmunity markers makes T1DM a candidate for prediction and prevention. The predictive value of these autoantibodies varies with age, and combining more than one autoantibody is increasing the positive predictive value. The improved ability to measure autoantibodies against GAD65, IA-2, and insulin made it possible to predict T1DM by up to 98% accuracy when ZnT8Ab were added to the arsenal of islet autoantibody tests.¹⁶⁸ A high predictive value of the screening tests is critical to designing interventional studies. This strategy is most useful in high-risk groups such as first-degree relatives, where high diagnostic specificity is required. The levels of autoantibodies reflect the degree of aggressiveness of the autoimmune reaction and are related to persistence of positivity and subsequent progression into clinical disease.²⁰⁹

HLA testing alone is not a primary indicator for the prediction of T1DM, but it has a significant role when used with autoimmune markers to increase sensitivity of prediction among subgroups with moderate risk. However, adding HLA-DQ did not affect the diagnostic sensitivity of islet autoantibodies.²¹⁰ Several other genetic loci have also been reported to be associated with T1DM genetic risk, but their contribution was less than HLA (see Table 14-4).

The prediction of β-cell function is assessed through metabolic tests using the first-phase insulin response (FPIR) as a marker among susceptible individuals tested following an intravenous glucose tolerance test (IVGTT). Low levels of FPIR below 50 mU/L confer a risk of 85% within 5 years and predict a 92% risk in the presence of one autoantibody, especially ICA or IAA.²¹¹

Prevention

The ability to prevent or reverse autoimmune diabetes in laboratory animals such as the NOD mouse and BB rat using different therapeutic approaches has incited several prevention/intervention studies in humans.²⁶ However, the possibilities of success in humans are significantly different from these animals. Studies in the NOD mouse and the BB rat showed that treatment with insulin or nicotinamide reduced spontaneous diabetes. These studies initiated large clinical trials, such as the Diabetes Prevention Trial-1, the Diabetes Prediction and Prevention Project, and the European Nicotinamide Diabetes Intervention Trial, all without effects (see following discussion). Preclinical studies in rodents may therefore not always be suitable to guide human trials. On the other hand, the spontaneous T1DM rodents may be useful to dissect mechanisms of preventive studies, previously shown to be successful in humans.

Whether to choose a preventive or intervention strategy is a matter of debate, which is related to several factors. First, it has been suggested that intervention trials should be reserved for therapies with greater risk that need to be used on a small number of newly diagnosed patients within limited follow-up periods. Second, prevention trials may be implemented on safer therapies that can be used in the preclinical phase with longer periods of follow-up.³⁴ Prevention trials are often grouped into antigen-specific and non-antigen-specific therapies.³⁵

Primary prevention trials would target high-risk groups (such as infants with high HLA risk or positive family history) prior to the initiation of the autoimmune insult. Environmental factors such as nutritional factors are of interest especially from birth up to 6 years of age; the period when autoimmunity is mostly triggered and highest incidence rise has been observed.⁴⁴ The Trial to Reduce IDDM in the Genetically At Risk (TRIGR) is a randomized, placebo-controlled, double-blind trial which is testing the effects of cow’s milk in genetically-at-risk infants with positive family history. Infants were randomized to receive cow’s milk or hydrolyzed casein formula following 6 to 8 months of breastfeeding. TRIGR is implemented in 17 countries and expected to provide results in 2009.²¹² The Nutritional Intervention to Prevent Diabetes (NIP-Diabetes) is recruiting pregnant women and high-risk infants younger than 5 months of age. NIP is using oral docosahexaenoic acid (DHA), a fatty acid thought to prevent islet autoimmunity, given to the mothers as a supplement. Infants will be followed up till 9 years of age. Results from this study will decide future larger trials.^35,212 The gluten-free diet trial, PREVFIN, tested the possible effect of eliminating gluten from the diet on the risk of T1DM. It ended in 2002 with no observed effects on islet autoantibodies or disease progression.³⁵ Meta-analysis of results from several earlier observational studies suggested that a vitamin D supplement given to children significantly reduces T1DM risk. There also was some evidence that this association was affected by the dose and timing of supplementation.²¹³ A randomized, open-label trial initiated in 2003 tested the use of 2000 IU/day of vitamin D₃ (cholecalciferol), compared to the currently used supplement dose of 400 IU/day, as a possible preventive factor. This pilot study (Manitoba, Canada) recruited infants up to 4 weeks of age who had high HLA genetic risk; results from phase 1 are awaited.³⁵

Secondary prevention strategies recruit children with high HLA genetic risk with positive autoantibodies and children and young adults with multiple autoantibodies. The aim is to retard and suppress β-cell destruction by aggressive immunity. Antigen-based secondary prevention trials using insulin as a specific antigen have been carried out. The Diabetes Prevention Trial-1 (DPT-1) was a large efficacy randomized trial that had two arms: parenteral insulin (high-risk subject, no placebo, completed in 2002) and oral insulin (moderate-risk subject, placebo-controlled, completed in 2005 and repeat study is ongoing).35,212 Both arms showed no effect on the progression of T1DM, although results from subanalysis of the oral arm gave strong evidence on reducing the incidence of T1DM in relatives with insulin autoimmunity (IAA ≥ 80 U).³⁵ Nicotinamide (vitamin B₃) was used orally as non-antigen-specific agent in the European Nicotinamide Diabetes Intervention Trial (ENDIT). The results of ENDIT showed no effect on T1DM outcome.^35,212 The Diabetes Prediction and Prevention Project (DIPP) was a randomized, placebo-controlled trial implemented in Finland; it recruited high-genetic-risk children to test the efficacy of intranasal insulin on the prevention of T1DM. Lately released results showed that intranasal insulin did not delay or prevent T1DM.²¹⁴ Other trials that used cyclosporine, vitamin E, or intensive insulin treatment in combination with nicotinamide were also without effects. Other prevention trials tested some drugs such as ketotifen, a histamine antagonist, with no effect observed.^35,211,212

Intervention

Intervention or tertiary prevention trials target newly diagnosed T1DM patients, aiming at preserving the residual β-cell mass and enhancing their functionality and regeneration. Like prevention trials, intervention trials can also be either antigen-specific or non-antigen specific. Immunologic vaccination with specific pancreatic antigens has been adopted by a group of trials. The NBI-6024 is a currently ongoing, randomized, placebo-controlled, double-blind trial testing the effects of the altered peptide ligand (APL) insulin B:9-23 vaccine, which is a significant islet autoantigen. This genetically engineered vaccine is injected subcutaneously to adolescents and adults with new-onset T1DM.³⁵

The DiaPep277 was also a randomized, placebo-controlled, double-blind trial that used an immunomodulatory peptide heat shock protein 60 (HSP60) given subcutaneously to subjects with new-onset T1DM. Results from DiaPep277 suggested prevention of β-cell destruction and preservation of C-peptide levels within 12 to 18 months in adults, but a similar effect was not found in T1DM children.34,35

GAD56 formulated with alum has been used in randomized, placebo-controlled immunomodulation trials in LADA²¹⁵ and 10- to 18-year-old T1DM patients.²¹⁶ Subcutaneous injection of 20 µg GAD-alum resulted in preservation of residual insulin secretion.^215,216 Other trials are using proinsulin-peptide vaccine or proinsulin-based DNA vaccine (BHT-3021) among high-risk children.^34,35

The non-antigen-specific approach has been used in numerous interventional studies. Randomized, placebo-controlled trials with oral cyclosporin-A showed reduced loss of residual C-peptide and insulin dosages; however, the effects were transient, and side effects outweighed the benefits.35,212 Although azathioprine trials showed no effects when used alone, its combination with prednisone showed partial, temporary remission of new-onset T1DM.³⁵ Antithymocyte globulin (aTG), used in organ transplantation, showed reduction in insulin requirements when combined with prednisone, but severe, transient thrombocytopenia emerged as a major side effect.³⁵ CD3 monoclonal antibodies including hOKT3gl (Ala-Ala) and ChAglyCD3 (TRX4), which suppress T-cell activity by blocking their proliferation and differentiation, showed preserved C-peptide levels and lowered insulin requirements for 18 to 24 months after therapy.^35,35 Trials with CD3 monoclonal antibodies have continued. The Anti-CD20, rituximab, is a monoclonal antibody which reduces blood β cells by blocking the CD20 receptors. Rituximab has shown effects in other autoimmune diseases such as rheumatoid arthritis, with possible benefits in T1DM.^34,212 Diazoxide, an inhibitor of insulin secretion, was used to allow residual β cells to rest and protect them from further immune-mediated destruction, but no effect was reported. Similarly, a pilot study with subcutaneous BCG vaccine showed no effects.³⁵

Newly designed trials using autologous umbilical cord blood cells or gene-engineered dendritic cells have been lately launched as tertiary-level interventional trials.²¹² Mesenchymal stem cells (MSC) have immunomodulatory effects and may be used to prevent and cure T1DM.²¹⁷ MSC may contribute through direct effects on regulatory T cells and autoreactive T cells and through correction of B cells and natural killer cells, or through indirect effects by regulating the function of dendritic cells or enhancing peripheral immunologic tolerance.²¹⁷ Tertiary intervention includes both whole-organ pancreatic transplantation and isolated islet transplantation. Both approaches have proved successful in terms of restoring glycemic levels and insulin independence, but isolated islet transplantation had lesser glycemic control, transient effects, and increased morbidity but higher costs.²¹⁸

Summary

The islet β cells appear to be the specific target in an autoimmune process that leads to the clinical onset of T1DM. T1DM develops in several stages, the presence of a genetic risk (HLA and non-HLA genes), initiation of autoimmune reaction against β cells, triggering or promoting environmental factors, β-cell destruction by cellular immunity, prediabetic metabolic disturbances, and finally overt diabetes. The process of β-cell autoimmunity is often initiated long before the clinical onset of the disease. The event that initiates this process is not yet understood, and the β-cell antigens GAD65, IA-2, insulin, or ZnT8 may serve as the recognition structure or structures for the cells in the immune system that eventually produce insulitis. Recent advances in molecular genetics have made it possible to better define the HLA-DQ and HLA-DR molecules that seem to be necessary, but not sufficient, for the development of T1DM. A screen of the human genome for susceptibility to T1DM has identified several additional genetic factors that may affect T1DM risk by accelerating or decelerating the disease process. Spontaneous diabetic rodents such as the NOD mouse and the BB rat are important to the dissection of mechanisms; however, their utility in preclinical trials to guide human studies has proven to be limited. The aim of future prevention and intervention studies in humans is to test whether antigen-specific immunosuppression or other immunomodulatory therapies in T1DM-susceptible individuals will prevent the loss of pancreatic β cells.

Acknowledgements

Studies in the authors’ laboratory were supported by the National Institutes of Health, the Robert H. Williams Endowment at the University of Washington, the Juvenile Diabetes Research Foundation, the American Diabetes Association, the Swedish Research Council, the Knut & Alice Wallenberg Foundation, the Swedish Diabetes Association, the European Union (DIAPREPP), the European Foundation for the Study of Diabetes, the UMAS Fund, and the Lund University Medical Faculty.

References