Introduction

Autoimmune diabetes mellitus or T1DM is an organ-specific autoimmune disease that affects the insulin-producing pancreatic beta cells, after an inflammatory process leads to a chronic deficiency of insulin in genetically susceptible individuals (1). The clinical manifestation (i.e., hyperglycemia) represents the final stage of insulitis (i.e., inflammation in pancreatic islets). At the time of diagnosis, only 10 to 20% of the insulin-producing beta cells continue to function (2). To date, there are no preventive or immunosuppressive therapies that can prevent damage or disease manifestations. However, our increasing knowledge of pathophysiology and immunogenetics has important therapeutic implications for measures aimed at prevention. New approaches for immune therapy such as anti-CD3 antibodies have shown success in modulating the natural history of the disease without the need for chronic immunosuppression. In the near future, it is likely that combination approaches will be needed to bring about lasting remission of the disease (3).

In 1997, the Committee of Experts of the American Diabetes Association recommended dividing T1DM into type 1A diabetes (i.e., immune-mediated) and type 1B (i.e., other forms of diabetes with severe insulin deficiency but without proof of autoimmune etiology or also known as idiopathic) (1) (Table 1). The best method to diagnose T1DM is to demonstrate the presence of autoantibodies directed against antigens present in the pancreatic islets detected by highly specific methods (4). However, with the current methods for detecting these autoantibodies, the autoimmune component cannot be demonstrated in a subgroup of children (around 10% of cases) with T1DM (5-7). One explanation for this finding is that the autoantibody titer decreases as the immune and pathological process progresses from the pre-diabetic period to the clinical phase (7). Table 2 presents the main parameters for the differential diagnosis of T1DM. Type 1A, despite being an autoimmune disease, has some features that differentiate it from other autoimmune diseases (ADs). This pathology is presented on a one to one ratio (male: female) unlike other AD widely described in this book, e.g., systemic lupus erythematosus and rheumatoid arthritis, that present a high female predominance.

Table 1

Etiological classification of diabetes mellitus.

Table 2

Differential diagnosis of T1DM.

Epidemiology

The incidence is increasing worldwide while it is also presenting at younger ages (8). The disease has always been considered a childhood disease, but recent epidemiological studies have suggested that the incidence is comparable in adults (9). There is a huge difference in the incidence according to the population study. A child in Finland is 40 times more likely to develop the disease than a child in Japan and 100 times more likely than a child in Zunyi (China) (8). The incidence of the disease has been estimated at 0.1/100,000 population per year in countries like China and Venezuela and as high as 36.8/100,000 per year in Sardinia and 36.5/100,000 in Finland (10). This represents a greater than 350-fold variation in incidence for 100 different populations worldwide (10). The EURODIAB study, which involved records in 44 countries from Europe, showed an annual increase in incidence that was between 3 and 4% (11). The largest increase was seen in children between 0 and 4 years. The disease is diagnosed more in winter months in countries with high incidence, suggesting an environmental component at least as a trigger (10).

T1DM is associated with the presence of other autoimmune diseases, mainly autoimmune thyroid disease (AITD) and celiac disease (CD) (12). The Belgian Diabetes Registry showed a prevalence of thyroid autoantibodies in 22% of the patients with T1DM. About 1 of 10 patients presented anti-transglutaminase IgA antibodies and more than half of these patients had CD demonstrated in intestinal biopsy specimens. At least 1 of 50 patients with T1DM had anti-21 hydroxylase antibodies, and approximately 25% of these patients progress to the clinical presentation of Addison’s disease (Table 3). There is also a familial aggregation (FA) of AD in families of T1DM patients (Table 4).

Table 3

AD associated with T1DM.

Table 4

Familial aggregation of other AD in first-degree relatives of patients with type 1A diabetes mellitus.

Genetics

Different alleles or genetic variants are associated, both as a risk or protective factor, with T1DM development. The concordance of T1DM is approximately 50% in monozygotic twins, and the risk of developing the disease in a first degree relative is about 6% (13). Comparing this last incidence with the presentation of the disease in the general population (0.4%), the risk of having T1DM is 15 times higher in a sibling of a patient with T1DM (Table 5). Although the risk of developing the disease is much higher in relatives of patients with T1DM, it is important to note that the majority (over 85%) of individuals who develop the disease do not have a first degree relative with this pathology. This high frequency of sporadic cases is mainly because almost 40% of individuals in the general population are carriers of high-risk HLA alleles. Different susceptibility genes have been determinants in the pathology as defined by both association and linkage studies. Thus, at least 60 loci have been identified and contribute to the risk of developing the disease. Table 6 summarizes the single-nucleotide polymorphism (SNP) associated with T1DM (14).

Table 5

Risk of developing T1DM.

Table 6

Genetic variants associated with T1DM.

The major genetic determinant for the pathology is the major histocompatibility complex (MHC) on the short arm of chromosome 6 (called DDM1 site). Over 90% of people who develop T1DM carry either the DR3, the DR4 marker, or both, compared to only 40% of normal controls possessing these HLA (15). DR3-DR4 heterozygosity is higher in children who develop the disease before 5 years of age (50%) and lower in adults who develop the disease (20–30%) compared to only 2.4% in the U.S. population. Table 7 presents the haplotypes of HLA class II DR and DQ that are associated with both susceptibility and protection from the disease. A significant correlation associated with susceptibility or resistance to disease has been described in the amino acid at the position of HLA-DQβ on the chain. If an aspartic acid residue at position 57 occupies both alleles of the chain, there is little likelihood that diabetes will occur. On the other hand, its absence is an important marker of susceptibility. Individuals not carrying the aspartic acid on both alleles have a relative risk (RR) of 10⁷ of developing the disease. More recently, it has been shown that the presence of the amino acid arginine at position 52 of the DQα chain confers an increased risk for the disease. This risk is additive with the increase conferred by the lack of aspartic acid at position 57 of the DQβ chain. It is believed that the absence of this last amino acid at position 57 and the presence of arginine at position 52 of the DQα chain allow an autoantigen to engage in the HLA antigen presentation site manager to be recognized by the T-cell receptor (TCR) (15). Another site of genetic susceptibility called IDDM2 has been identified. It corresponds to the insulin gene located on chromosome 11. This gene contributes to about 10% of the FA of disease (16). This locus corresponds to a polymorphic region which maps to a variable number of nucleotide repeats (VNTR). Studies have shown that the different sizes of VNTRs of the insulin gene are associated with the risk of T1DM. The longer form of the VNTR (> 100 repeats or class III) is associated with protection from disease (17). This finding has been explained by improved immunological tolerance to a larger insulin gene with a higher level of thymic expression and with the consequent tolerance. There are other genes associated with monogenic forms of polyendocrinopathy [AIRE gene (autoimmune regulator associated with type 1 autoimmune polyendocrine syndrome) and XPID gene], which includes within its manifestations the presence of diabetes.

Table 7

Diabetes Risk of Representative DR and DQ Haplotypes.

PTPN22, a gene encoding for a lymphoid-specific phosphatase that influences TCR signaling has been identified for T1DM risk (18). Polymorphisms in the CTLA4 (IDDM 12) are apparently associated with the development of Graves’ disease and autoimmune diabetes but not in all populations (19). A locus associated with the IL-2 receptor also has a statistical association (20). In summary, many genetic loci have been identified as a risk for developing diabetes. Of these, the HLA typing at birth is being used in some populations to define the risk of the disease depending on the relationship of the individual with an index case of diabetes. For example, siblings of patients with T1DM and the genotype DR3-DQ2/DR4-DQ8 have a risk of developing diabetes that exceeds 50% (21).

Environmental aspects

Several features suggest that T1DM has a significant environmental component. The rapid increase in the incidence together with the variability found between genetically similar populations (e.g., double incidence in the United Kingdom compared to France) suggest that an environmental agent may trigger the autoimmune process in different countries. Two hypotheses could explain the recent increase in the incidence. The first one is that an infectious agent such as a virus in the general population is increasing and causing infectious processes (22). The most common appearance of the disease in winter months and some epidemic flares of T1DM suggest that certain viruses such as rotavirus (23) and Coxsackie virus (24) and some dietetic aspects may influence the risk of developing T1DM. Multiple associations have been described with various environmental agents and viruses. However, despite more than four decades of research in this area, the only consistent association of T1DM with a viral agent is congenital rubella infection (25). Children affected with this type of diabetes usually present high-risk HLA alleles and high prevalence of AITD (26,27). The exact mechanism by means of which congenital rubella infection increases the risk of T1DM is unknown. In addition, associations with a particular viral agent have been based on antibodies or viral antigen detection at the time of diagnosis. Because clinical manifestations appear after a long-standing immunological process, it is difficult to identify a pathological relationship between these infectious agents and the disease. The finding of viral particles at the diagnosis may be explained by a higher insulin requirement in the course of an undercurrent infection with the presence of the infectious agent being an incidental finding.

Another environmental agent implicated in the development of the pathology has been early feeding with cow’s milk [bovine serum albumin (BSA)]. This hypothesis was based on retrospective studies in which this factor was suggested (28). However, several prospective studies did not validate these data. For instance, a study done in Denver, Colorado, in which children were assessed at birth, showed no evidence of disease association with bovine milk feeding, enteric viral infections, or vaccination history (29).

Some studies provided evidence that early (<3 months) introduction of cereals may increase the development of islet autoimmunity (30). Vitamin D and ω-3 fatty acids, which can influence the immune function, have also been associated with the risk of diabetes (31). Another environmental factor involved lately is the toxins derived from Streptomyces bacteria found in soil, which can colonize foods like vegetables. In mice models, these toxins can cause damage to the pancreatic cells (32). Vaccination has been implicated as a trigger for diabetes in genetically susceptible children. However, different studies have not confirmed this possibility (33, 34).

The second scenario, called “hygiene hypothesis” suggests that environmental factors may inhibit the development of autoimmunity. The environment for children is cleaner today, which may lead to defective immuno-regulatory mechanisms that result in a Th2 mediated-response pattern (such as asthma) or diseases characterized by a Th1 pattern such as T1DM (35,36). Other epidemiological observations suggest the environmental component of the pathology. The non-twin brothers and dizygotic twins share 50% of their genetic material unlike identical twins who share the entire genome. However, the concordance of the disease is higher in dizygotic twins than non-twin siblings which suggests an environmental component because the former are generally exposed to the same environmental stimuli (i.e., same food, infections, etc.).

Autoantibodies

As previously described, over 90% of the patients with new onset T1DM possess at least one autoantibody against components of the pancreatic islets. A significant variety of specific antibodies against constituents of pancreatic beta cells have been identified. They include insulin, the isoform of glutamic acid decarboxylase 65 and 67 (GAD 65 and GAD 67 respectively) and the IA-2 secretory protein, which has a domain like-tyrosine phosphatase. These autoantibodies are markers of the autoimmune process rather than the direct effectors of damage. GAD antibodies (GADA) can be detected in 50 to 80% of Caucasian patients with newly diagnosed diabetes (37, 38). It has been also demonstrated that these autoantibodies appear several years before clinical manifestations and diagnosis, and tend to persist in the serum of patients for many years (39). Anti-IA-2 autoantibody (IA-2 Ab) prevalence ranges from 55 to 75% and has a tendency to be higher in patients with new-onset diabetes and early onset (i.e., preschool) (40, 41). These autoantibodies are found mainly in patients who are under 15 years of age and are, therefore, more useful in the study of young patients with diabetes (42). A new auto-antigen, called ZnT8 has been described. ZnT8 is a member of the large cation efflux family (10 mammalian homologues, almost 100 family members) of which at least 7 are expressed in pancreatic islets. Autoantibodies against ZnT8 are found in 60–80% of new-onset T1DM compared to <2% of healthy controls, <3% of type 2 diabetic patients, and up to 30% of patients with other autoimmune disorders with a T1DM association (43). ZnT8 have been found in 26% of T1DM subjects classified as autoantibody-negative on the basis of existing GADA, IA-2 Ab, and anti-islet antibodies markers (43). The insulin autoantibodies are the only specific autoantibodies of beta cell autoimmunity and are found primarily in children younger than 5 years old (44). However, a negative result for these autoantibodies does not exclude the diagnosis of T1DM. The presence of autoantibodies in relatives of patients with T1DM or in healthy individuals has a significant positive predictive value for disease development.

Pathogenesis

The main specific damage in this disease is the selective destruction of beta cells in the pancreas with the presence of inflammatory infiltrates or insulitis (Figure 1). Several studies have determined that the presence of autoantibodies in children with T1DM from birth suggest the future development of the disease (45). However, the role of autoantibodies in the pathogenesis of T1DM has not been fully elucidated. In fact, they seem to be an epiphenomenon secondary to autoimmune destruction of β cells mediated mainly by cell immunity mechanisms. In support of these findings, one case report showed the development of the pathology in a patient with X-linked agammaglobulinemia which suggests that autoantibodies are not required for the progression of the pathology (46). Generally speaking, the disease is considered a T-cell mediated disease. Histological and immuno-phenotypical evaluation confirms insulitis with an infiltrate composed of CD4 and CD8 T lymphocytes, B lymphocytes, and macrophages thereby suggesting a role for this group of cells in the beta cell destruction (47) (Figure 2). Although the main cells involved in the T1DM pathogenesis are the CD4 and CD8 T cells, another population of T cells, the Th17 cells, has recently been described. Taken together, defective regulatory T cells lose control of Th17 expansion. The abnormalities on Th17 cells are also mediated by the secretion of IL-1b and IL-6 by antigen-presenting cells and macrophages. The pathogenic Th17 cells can cause the imbalance between T effectors and T regulatory cells. The new description of Th17 cells on T1DM is being studied as a potential target to treat the disease.

Figure 1

insulitis. inflammatory infiltrates on langerhans’ islets of pancreas.

Figure 2

Autoimmune diabetes pathogenesis. Immune-mediated β-cell destruction begins when macrophages and dendritic cells present β-cell to naïve CD4 T cells through the MHC. Through cytokine signaling, CD4 T cells are activated, which (more...)

Concerning the T cells as therapeutic targets, previous studies have shown the utility of anti-CD3 antibodies in mice as a therapeutic strategy to prevent the development of the disease. Studies using these drugs in humans are currently being done (48). Figure 3 describes a general model that shows the process of destruction of pancreatic beta cells from inception to clinical presentation. The initial interaction of genes and environmental factors triggers an immune-mediated response with the appearance of different autoantibodies as the first sign of beta cell destruction. This is followed by the loss of first-phase insulin response. The progression to clinical diabetes is triggered by the development of a more aggressive T-cell phenotype, which changes the balance of Th1 and Th2 to produce a more inflammatory background. The expression of Fas–Fas ligand molecules on cytotoxic T cells also promotes the clinical presentation of diabetes. The evaluation of pancreatic islets during insulitis suggests that Fas-mediated apoptosis occurs and provides a possible mechanism of beta cell destruction (49).

Figure 3

Natural history of Type 1 Diabetes. This graphic model shows the process of destruction of pancreatic β cells from inception to clinical presentation. The initial interaction of genes and environmental factors triggers an immune-mediated response (more...)

More recently, an increasing importance is being given to some subgroups of regulatory T cells which have shown the ability to control the development of pathology in both NOD mice and BioBreeding rats (BB) (50,51). Three main groups of T cells have been described in the pathophysiology: Th2 cells, which appear after administration of soluble beta cell autoantigens; T regulatory cells characterized by the expression of CD4, CD25, and the transcription factor FoxP3; and natural killer cells, which probably appear spontaneously during ontogeny. A large number of T cell clones that react to insulin or to other antigens has been described. There is doubt about whether any given autoantigen is the main target of autoimmune recognition although some studies have provided evidence for a central role for T-cell autoimmunity directed against the insulin (52). The role of several proinflammatory and anti-inflammatory cytokines is being studied as potential therapeutic targets. A large number of cytokines are involved in the differentiation and activation of T cells that contribute to the pathogenesis of T1DM. Thus, the utility of blocking cytokines, e.g., IFN-γ receptor, IL-2, or IL-12, has been demonstrated. Prevention has also been shown in animals with blocking proinflammatory cytokines such as IL-1, IL-6, or TNF-α. The uses of cytokines with regulatory properties such as IL-4, IL-10, and IL-13 have shown utility in delaying the progression of the pathology (50).

In summary, the immune-mediated beta cell destruction begins when macrophages and dendritic cells present beta cell to naïve CD4 T cells through the MHC. Through cytokine signaling, CD4 T cells are activated, which in turn activates CD8 T cells directly responsible for causing beta cell death. Beta-cell destruction results in the release of additional intracellular antigens and allows antigen-presenting cells further access to typically sequestered auto-antigens. This activation leads to activation of additional autoreactive T cells through epitope spreading. In contrast, the presence of autoantibodies does not appear to be directly pathogenic to beta cells although they are useful markers for T1DM risk and prediction as they indicate autoreactive T cell activation.

Clinical presentation

The peak of disease presentation is around puberty. The symptoms and signs are associated with the presence of hyperglycemia and the effects result from an imbalance in fluid and electrolytes. These symptoms usually include polyuria, polydipsia, polyphagia, and weight loss. Because some infectious diseases can precipitate the initial presentation, symptoms of infection like fever, sore throat, cough, or dysuria, etc. may be present. The onset of symptoms may be of short evolution, especially when it manifests as ketoacidosis, although it may be insidious. When the clinical presentation begins with ketoacidosis, other manifestations such as abdominal pain, nausea, and vomiting occur in addition to disturbances in the mental state, from a slight alteration to a deep coma.

Laboratory findings

The plasma glucose levels at the time of diagnosis are elevated with variable ranges (generally greater than 300 mg/dl). If clinical presentation is not complicated, fluids and electrolytes parameters may be completely normal. Moreover, if ketoacidosis is present, acidosis, and dehydration are present. In these patients, serum sodium is usually at the lower limit of normal, or is low and reflects the osmotic effect of hyperglycemia. Despite significant loss of potassium in urine and total body potassium deficiency, the presence of acidosis usually leads to a high concentration of serum potassium at the time of presentation. Serum bicarbonate levels are usually low (less than 15 mEq/L.) Ketone body elevation is also presented. In conjunction with the increase in serum glucose, the increases in ureic nitrogen invariably increase the serum osmolality, often to greater than 300 mmol/kg.

Prediction of disease

The prolonged prodromal phase preceding the onset of symptoms suggests it can be predicted and studies could be designed seek a way to prevent T1DM development. The development of T1DM in relatives of patients can now be predicted with relative certainty by determining the number of autoantibodies against pancreatic islets. Antibodies specific for pancreatic islet cells, insulin, 65 Kd GAD (GAD-65), and IA-2 protein are predictive markers for T1DM. Their positive predictive value (PPV) is 43%, 55%, 42%, and 29% respectively. The risk of first-degree relatives of patients with T1DM developing the disease grows progressively with the duration of follow-up and with the number of positive autoantibodies and is of 2%, 25%, and 70%, with one, two, and three or four positive Abs respectively (53,54). Antibodies against the zinc transporter ZnT8 have recently been described as useful in prediction (55, 56). A study published by Mrena et al. (57) shows interesting models for predicting T1DM in siblings of affected children based on autoantibody, genetic, and sociodemographic variables. The study analyzed 701 siblings of affected children. During the 15-year observation period, a total of 47 siblings (6.7%) developed T1DM. Of 47 patients, 38 initially tested positive for at least one diabetes-associated autoantibody. The risk of developing T1ADM was associated with younger age at the first sampling, HLA DR-conferred disease susceptibility, the number of initially detectable diabetes-associated autoantibodies, and the number of affected family members. Based on the Cox regression model, the authors calculated an individual prognostic risk, and a cutoff index of 0.25 separated progressors from non-progressors. Thus, at present, we have an advanced capability to predict T1DM, especially in high risk populations.

Other studies have assessed T1DM-specific antibodies in the general population (58). In this study, 12 of 4,502 children (median age 14 years) had more than one T1DM-associated autoantibody, and six developed the disease over an 8-year follow-up. Thus, the presence of two antibodies was over 99.5% specific and the PPV was 50%. In another study, Kupila et al. (59) did a population-based, birth-to-age-four screening study that combined both HLA typing and autoantibodies in 31,526 children in Finland. Using this strategy, they were able to identify 75% of those developing T1DM. However, the costs of this strategy are expensive. In this case, it would probably be better to do the immunological screening only on those subjects with increased risk based on HLA typing. In the DAISY study, which evaluated high-risk children with positive autoantibodies (without intervention), there was a lower incidence of ketoacidosis at onset of the disease, improved glycosylated hemoglobin levels at baseline, and fewer hospitalizations due to its closer clinical monitoring (60). This study suggests that despite not being able to take preventive measures in high-risk patients, closer clinical follow-up may encourage better clinical outcomes until effective preventive measures become available. The use of autoantibodies has spread to subdivide patients previously classified as type 2 diabetics. The results of the UK Prospective Diabetes (UKPDS) indicate that at least 30% of young patients with “type 2 diabetes” presented an autoimmune process and that, over the course of three years, these patients progressed to insulin-dependance (61). This subgroup of patients has been called latent autoimmune diabetes in adults (LADA). In summary, prediction in T1DM has been widely studied. With the analysis of genetic susceptibility factors in first-degree relatives of patients and several autoantibody tests, one can predict the development of the disease. The main goal after predicting T1DM is to introduce preventive actions to delay or prevent the development of disease (62) (Figure 4).

Figure 4

Representation of pathogenesis of T1DM indicating the points for primary prevention, secondary prevention, and treatment.

Immune therapy in type 1 diabetes

Immune therapy for T1DM is approached at three stages: primary prevention, secondary prevention, and treatment. Primary prevention involves the immunological tolerance to islet tolerance in individuals with increased risk of T1DM. Secondary prevention can be done with nonantigen-specific or antigen-specific approaches in genetically susceptible individuals who had developed islet autoantibodies. Immune therapy treatment at onset of T1DM can involve both nonautoantigen-specific and autoantigen-specific therapies in order to reduce insulin requirements and complications. The most common primary outcome in clinical studies and trials is the preservation of C-peptide levels. Figure 3 shows the points of primary prevention, secondary prevention, and treatment based on the physiopathology model.

Prevention targets and immune therapy interventions

To date, no treatment has been shown to prevent human T1DM. More than 100 different treatments can prevent illness in NOD mice (63). These targets and treatments are summarized in Table 8.

Table 8

Autoimmune diabetes animal models.

Two major studies have been carried out to study prevention of T1DM. In the United States, the study of the prevention of diabetes (DPT-1) was launched in 1994 in order to determine whether a regimen based on the antigen (i.e., insulin), both oral and parenteral, would prevent or delay the development of diabetes in families with high or moderate risk. These treatments generally did not delay disease development. The European study of intervention with nicotinamide (ENDIT) also found no difference in protection from disease when participants were assigned to either placebo or oral nicotinamide.

Early studies of therapies used to prevent the destruction of pancreatic βeta cells were based on immunosuppressive therapies. Studies with cyclosporine indicated that while this drug was administered there was a prevention of further loss of beta cells and better metabolic function (64-66). However, if this therapy were initiated after the development of clinical diabetes, its benefits were minimal and transient. The inability of therapy to “cure” diabetes and the high toxic effects resulting from this (particularly nephrotoxicity and increased risk of malignancy) has caused its clinical use to be dismissed for this purpose. Other immunosuppressive therapies such as prednisolone or azathioprine have shown relatively little effect (67, 68). Studies using methotrexate have not demonstrated efficacy (69).

To date, although diabetes is mediated by the immune system, it is not treated with immunomodulating agents or current suppressors. Because of this, studies focused on preventing the development of T1DM are necessary and many of them are already in progress. Phase 2 and Phase 3 studies, involving treatment of subjects with new-onset T1DM, were initiated with the modified anti-CD3. They showed preservation of C-peptide response as a measure of insulin production, a decrease in exogenous insulin use, and improved glycemic control following a 12- to 14-day of modified anti-CD3 (e.g., teplizumab) infusion in patients diagnosed with T1DM within the previous 6 weeks. However, one Phase 3 trial failed to find the same benefits (70-72). As mentioned previously, at least 100 therapies have been shown be effective in prevention or disease treatment in NOD mice. These therapies are summarized in Table 9(50)

Table 9

Immunotherapeutic agents or other treatments used in NOD mice.

Vaccination

In animal models, multiple therapies have been used to prevent the development of diabetes. The immunological vaccination is a striking strategy mainly because of its specificity and low risk compared to the conventional immunosuppression. The basic concept is the induction of lymphocytes that recognize a given antigen of the islets. Once this recognition has occurred, they generate the production of cytokines that suppress autoimmunity and tissue destruction (73, 74). Th2 T cells produce more Interleukin 4 (IL-4) than IFN-γ or IL-2 (produced by Th1 cells) and decrease cell-mediated destruction. Induction of the protective immune response may depend on the route of administration of the given antigen (e.g., oral tolerance) or the use of modified antigens. For example, oral or subcutaneous insulin prevents the development of diabetes in NOD mice (75, 76). However, no intact insulin is required to produce this response (77).

Treatment

Insulin remains the mainstay of treatment for patients with T1DM. The Diabetes Control and Complications Trial (DCCT) demonstrated the importance of strict metabolic control in order to delay and prevent the chronic complications of diabetes (78). However, the risk of inducing hypoglycemia during treatment is still a major constraint on achieving adequate metabolic control. The introduction of rapidly absorbed insulin analogues reduced the variability in the absorption and made its application possible even during meals (79). In the last few years, new insulin analogues with a behavior that is more similar to basal insulin secretion without the presence of peaks have been introduced to the market. The available insulin can be divided on a pharmacokinetic basis into three broad categories: rapid-acting, intermediate, and long-acting (80). In Tables 10 and 11 the main goals of insulin therapy, derived from intensive therapy and the presentations of the drug available, are summarized.

Table 10

Glycemic targets.

Table 11

Pharmacokinetic properties of insulin preparations.

An alternative method of delivering insulin is by an external mechanical pump. The pump delivers insulin as a pre-programmed basal infusion in addition to patient-directed boluses given before meals or snacks or in response to elevations in the blood glucose concentration outside the desired range. The insulin pump should be used only by candidates who are strongly motivated to improve glucose control and willing to work with their health care provider in assuming substantial responsibility for their day-to-day care (81).

The use of metformin added to insulin is increased in patients with T1DM. Some studies have suggested that metformin could be beneficial for T1DM patients who are overweight and are receiving high doses of insulin or have a HbA1c over 8% (82). The coexistence of insulin resistance in patients with T1DM is an area of current interest, which was previously only applicable in type 2 diabetes. Pancreatic islet transplantation combined with appropriate immunosuppressive therapy may eventually cure diabetes. This transplant is considered for the limited but important group of patients with recurrent episodes of severe hypoglycemia unresponsive to proper medical management (83). The inability to control autoimmunity and alloimmunity, added to the lack of donor organs, limits the further application of islet transplantation. Another strategy added to pancreatic islet transplantation is bone marrow transplantation. Both allogeneic and syngeneic transplantation can be useful in the control or prevention of pathology, probably through immunoregulatory cytokine production and production of regulatory mechanisms that outweigh effector mechanisms (84, 85).

Gene therapy can be used many ways to prevent or cure diabetes. Gene therapy can be done based on insulin or other therapeutic strategies. Furthermore, gene therapy has been done on the immune system in several lines of research. A possible approach is the development or overexpression of cytokines or receptors to the pharmacological effects of the endogenous molecule. Among them, there have been experiments with cytokine release in the pancreatic islets or systemically. Several vectors have been used (both viral and non-viral) for this type of research, in which the use of IL-4, the fusion protein IL-4-Ig, IL-10, IFN-γ-receptor, and TGF-β protected mice from developing the disease (86). Numerous clinical trials using antigen-specific strategies and immune-modifying drugs have been published although most have proven to be toxic or have failed to provide long-term -cell protection. Strategies under consideration include infusion of several types of stem cells, dendritic cells, and regulatory T cells either manipulated genetically ex-vivo or non-manipulated. Their use in combination approaches is another therapeutic alternative. Cell-based treatments directed to block the uncontrollable autoimmune response may become a clinical reality in the future for the treatment of patients with T1DM (87).

Abbreviations

AD:

autoimmune diseases

AITD:

autoimmune thyroid disease

CTLA-4:

cytotoxic T lymphocyte antigen-4

FA:

familial aggregation

GADA:

glutamic acid decarboxylase antibodies

HLA:

human leukocyte antigen

IA-2 Ab:

islet antigen-2 antibodies

IFN:

interferon

IL:

interleukin

LADA:

latent autoimmune diabetes in adults

MCH:

major histocompatibility complex

NOD:

non-obese diabetic mice

PPV:

positive predictive value

PTPN22:

protein tyrosine phosphatase, nonreceptor 22

SNP:

single-nucleotide polymorphism

T1DM:

type 1 diabetes mellitus

TGFβ:

transforming growth factor β

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