Best Treatments to Cure Autoimmune Diseases

Autoimmune Paleo Cookbook

If you have an autoimmune disease, recipes can often be hard to find and you are often told the huge amounts of things like chocolate and certain foods with too high of a fat content that you can and can't eat. This eBook gives recipes that anyone can prepare without too much trouble. Even if you don't like cooking, this book makes cooking easy and breaks it down into steps. Best of all, the recipes do not taste like healthy medicine recipes. These recipes are delicious foods that anyone would want to eat, even if they didn't have to eat healthy. This book contains over 70 amazing recipes for anyone with an autoimmune disorder. The book comes with two free ebooks: 7 Steps to Living Well With an Autoimmune Disorder and The Top 10 Autoimmune Diseases Checklist. If you want to learn about your autoimmune disease and the best and worst foods for you, this is the book for you! Read more here...

Autoimmune Paleo Cookbook Overview

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My Autoimmune Paleo Cookbook Review

Highly Recommended

Recently several visitors of blog have asked me about this book, which is being advertised quite widely across the Internet. So I purchased a copy myself to find out what all the excitement was about.

In addition to being effective and its great ease of use, this eBook makes worth every penny of its price.

Autoimmunity In Type Diabetes

The presence of circulating islet autoantibodies can be used to identify p-cell autoimmunity and therefore confirm the diagnosis of type 1 diabetes. Diabetes was originally hypothesized to be an autoimmune disease for a number of reasons, including familial clustering with other organ-specific diseases such as thyroid autoimmunity. Autopsy studies showed that lymphocytic infiltration was evident in the pancreatic islets of patients with type 1 diabetes.9 The concept of type 1 diabetes as an autoimmune disease emerged in the mid-1970s with the identification of islet cell antibodies (ICA) in 1974 by Botazzo et al10 and Nerup et al,11 establishing HLA associations for genetic susceptibility to the disease. Not all p-cell loss is due to demonstrable autoimmunity, a fact which has led to the subclassification of type 1 diabetes into type 1a, related to autoimmune disease, and type 1b, which constitutes non-immunemediated disease. A minority of people, usually of African or Asian descent,...

Pcell Protection From Recurring Autoimmunity

Once sufficient numbers of differentiated P-cells for transplantation become available, they will need to be protected from recurring autoimmunity, as well as from graft rejection. Although improved immunosuppression protocols are being developed (11), the risks of lifelong immunosuppression are probably not justified by the potential improvements in insulin delivery, when compared to insulin administration. Cell encapsulation in semipermeable membrane devices may provide partial protection. The pore size of these membranes can be designed to exclude immune effector cells and large molecules, such as immunoglobulins and components of the complement system, while allowing free passage of small molecules, such as nutrients and insulin. However, in spite of successful protection of xenograft islets in experimental animals (28-30), as well as survival of allogeneic insulinoma cells in a mouse model of autoimmune diabetes (the nonobese diabetic NOD mouse) (31), P-cell encapsulation still...

Therapies Targeting Autoimmunity

Immune intervention with human intravenous immunoglobulin (IVIg) has become appropriate in some patients with forms of peripheral diabetic neuropathy that are associated with signs of antineuronal autoimmunity (94,95). Chronic inflammatory demyelinating polyneuropathy associated with diabetes is particularly responsive to IVIg infusion. Treatment with immunoglobulin is well tolerated and is considered safe, especially with respect to viral transmission (96). The major toxicity of IVIg has been an anaphylactic reaction, but the frequency of these reactions is now low and confined mainly to patients with immunoglobulin (usually IgA) deficiency. Patients may experience severe headache because of aseptic meningitis, which resolves spontaneously. In some instances, it may be necessary to combine treatment with prednisone and or azathioprine. Relapses may occur requiring repeated courses of therapy.

Myasthenia Gravis

Clean up dentalware, diet and environment. Keep no indoor pets since any new parasite, however tiny, will surely find the niche left behind by the flukes and give you a new myasthenia gravis-like disease. The whole family must be parasite-free to protect the member with myasthenia gravis. But it is a task easily accomplished and desirable in its own right, so discuss your plan immediately with family members. Don't delay. The flukes don't waste a single minute. They go right on feeding and breeding.

Uncommon But Specific Forms Of Immunemediated Diabetes Mellitus

Diabetes may be associated with several immuno-logical diseases with a pathogenesis or etiology different from that which leads to the Type 1 diabetes process. Post-prandial hyperglycemia of a severity sufficient to fulfill the criteria for diabetes has been reported in rare individuals who spontaneously develop insulin autoantibodies. However, these individuals generally present with symptoms of hypoglycemia rather than hyperglycemia (80). The 'stiff man syndrome' is an autoimmune disorder of the central nervous system, characterized by stiffness of the axial muscles with painful spasms. Affected people usually have high titres of the GAD autoantibodies and approximately one third to half will develop diabetes (2,3). Patients receiving interferon alpha have been reported to develop diabetes associated with islet cell auto-antibodies and, in certain instances, severe insulin deficiency (81-83). Anti-insulin receptor antibodies can cause diabetes by binding to the insulin receptor...

Aps Autoimmune Polyendocrinopathycandidiasisectodermal Dystrophy

There are two known autosomal recessive autoimmune diseases autoimmune lym-phoproliferation syndrome (29) and APECED, which is the more common one. The clinical hallmarks of APECED are mucocutaneous candidiasis and hypoparathyroidism, but neither of these is always present (see Table 2). Although rare, APECED

Donor Hematopoietic Cells

In addition to the tolerance to alloantigens, hematopoietic stem cell transplantation (HSCT) is emerging as a feasible and efficient therapeutic modality for severe autoimmune diseases. The concept that the natural course of autoimmune disease might be altered by cytoablation and reconstitution with autologous stem cells has been tested in numerous animal models and is gaining increasing support (196). A multicenter, prospective phase I II trial of 74 patients with severe autoimmune disease treated by autologous HSCT after various conditioning protocols reported a favorable response in at least 65 of patients, but the 1-yr procedure-related mortality of 9 still needs to be reduced before this approach can be applied in indolent autoimmune disease processes (197). In lethally irradiated NOD mice, autoimmune insulitis can be prevented by reconstitution with allogeneic bone marrow (198), and even reversed when combined with pancreatic tissue (199). More interestingly, mixed chimerism...

Thyroid Disease in Type Children

Because type 1 diabetes is an autoimmune disease (see Chapter 2), it is not surprising that children with type 1 have other autoimmune diseases more commonly than unaffected children. The disease that is found most commonly in association with type 1 diabetes is autoimmune thyroiditis. This condition is discovered by obtaining a blood test that shows an abnormal increase in proteins in the blood called thyroid autoantibodies. In a study of 58 patients with type 1 diabetes (Diabetes Care, April 2003), 19 were found to have autoimmune thyroiditis.

Examining diabetes caused by destructive diseases of the pancreas

Other autoimmune diseases associated with T1DM The occurrence of hyperthyroidism or hypothy-roidism (insufficient thyroid hormone) along with T1DM is greater than expected by chance. Many autoimmune diseases occur together in the same person. In particular, celiac disease (intolerance to gluten in wheat and other grains) is found in up to 5

Handling the Physical and Emotional Consequences of Type Diabetes

Not only does T1DM have short- and long-term physical consequences, but as an autoimmune disease, T1DM also is associated with other autoimmune diseases such as celiac disease, an inflammation of the gastrointestinal tract thyroid disease and skin diseases. Chapter 5 explains the importance of checking for those diseases and correcting them, if present.

Genetic Susceptibility And Protection

Microsatellite polymorphism in the major histocompatibility complex class I chain-related gene A (MICA) has been associated with different autoimmune diseases including type 1 diabetes. MICA5 is associated with type 1 diabetes under the age of 25 years, whereas MICA5.1 is associated with both LADA and type 1 diabetes over 25 years of age (65,70). Other associations reported include an allelic polymorphism within the promoter region of the tumor necrosis factor-a (TNF-a) gene, and a significantly lower frequency of the TNF2 allele in LADA compared with type 1 diabetes or nondiabetic control subjects (71).

The Ins and Outs of Insulin

That make insulin have been destroyed by the immune system. Eventually, all of the cells that make insulin are destroyed and no insulin is produced. That is why type 1 diabetes is also called an autoimmune disorder. People with type 1 diabetes must take injections of insulin in order to live.

Insulindependent Diabetes Mellitus in African American Children

Type 1 diabetes is an autoimmune disorder. Polymorphism among certain class II immunor-egulatory amino acid residues is strongly associated with Type 1 diabetes. In humans, the class II genes are found in the major histocompatibility complex in the HLA-D region of the short arm of chromosome 6. Specific alterations in amino acid sequences affect peptide-binding and antigen-presenting capacities of the major histocompatibility complex (121). There is an increased frequency of HLA DR3 and HLA DR4 in Type 1 diabetes populations, the highest frequency being associated with heterozygous HLA DR3 HLA DR4 genotypes (122). While the frequency of HLA DR3 and HLA DR4 is lower in the African American population (123) compared to whites, their frequencies are increased in both African American, Afro-Caribbean (black) and white Type 1 diabetes populations (124-126). HLA DR7 and HLA DR9 are also positively associated with Type 1 diabetes in blacks but not in whites (127). Among blacks, the HLA DR...

Infant feeding patterns

An early introduction of cow's milk-based infant formulas and other cow's milk products may increase the risk of type 1 diabetes according to case-control evidence, although the results remain inconclusive (Virtanen et al. 1991 Virtanen & Knip 2003). An early introduction of cow's milk or a short exclusive breastfeeding were not related to early stages of beta-cell autoimmunity in birth cohort studies of individuals with increased genetic risk of type 1 diabetes (Norris et al. 1996 Couper et al. 1999 Hummel et al. 2000 Kimpimaki et al. 2001 Norris et al. 2003 Ziegler et al. 2003), but inversely to the development of four type 1 diabetes-associated autoantibodies out of the four studied (Kimpimaki et al. 2001). The findings from a pilot study of the only randomised trial available suggest that beta-cell autoimmunity can be prevented or delayed by giving hydrolysed infant formula instead of regular cow's milk-based one (Akerblom et al. 1999). Several theories try to explain the...

Prevention Of Type A Diabetes Introduction

In general, the prevention of a disease process requires that certain underlying criteria be met. First, there must be an accurate means of identifying subjects at risk for developing the disease (or an extremely safe intervention such as vaccination) and, second, there must be some intervention that can modulate the disease process. Prediction of type 1 diabetes was discussed in the previous section, and the latter is the focus of this subsequent section. The prevention of type 1 diabetes can theoretically be implemented with three different strategies a primary, secondary, or tertiary approach. The primary prevention strategy involves initiation of an intervention before the onset of autoimmunity. This involves the identification of modulating or precipitating factors in the disease process and intervening in subjects at genetic risk that have no evidence of P-cell damage. The secondary prevention strategy would delay or suppress continued P-cell destruction in subjects with...

Diagnosis of Rejection

An interesting issue is whether rejection affects kidney and pancreatic grafts in parallel. Although this is mostly so (permitting to use the renal function as a surrogate marker of rejection of the pancreas), it is by no means obligatory, but episodes of isolated rejection of the pancreas are rare so that monitoring the kidney graft is the usual procedure. The pancreatic graft can be monitored by duplex sonography, if necessary, or pancreas graft biopsy. Pancreas grafts are usually lost because of alloimmunity reactions, but in rare cases, graft loss resulting from destruction by autoimmune mechanisms (with GAD-antibodies and IA2-antibodies) has been observed (97). Recurrence of autoimmune inflammation with selective loss of insulin-producing P-cells (whereas sparing glucagon, somatostatin, and pancreatic polypeptide-secreting cells) and lymphocytic infiltration have been noted in the pioneer era when segmental pancreatic grafts were performed in monozygotic twins and when insulitis...

Latent autoimmune diabetes in adults

Screening patients clinically diagnosed with type 2 diabetes who are not treated with insulin has identified a significant subgroup with evidence of p-cell autoimmunity.45,46 They appear to have a slowly progressive form of type 1 diabetes that has been termed latent autoimmune diabetes in adults (LADA).47 A substudy of the UKPDS identified that LADA has a frequency of approximately 10 of all adult-onset diabetes,48 and 94 of patients aged < 45 years with ICA required insulin 6 years after diagnosis, compared with 14 of the antibody-negative patients.

Prevention Strategies

Of relatives will have identifiable autoimmunity (12). Yet, a problem is in newly diagnosed Type 1 diabetes, there is a first-degree family history of Type 1 diabetes only in 10-15 of children. For example, in one series from England, 12.8 of children had a first-degree relative with the disease, the relative affected being the father in 4.5 , the mother in 2 , and a sibling in 4.5 (19). 1. A case-finding strategy, perhaps involving genetic screening at birth, followed by autoanti-body screening in those genetically at risk, followed by appropriate intervention. This case-finding approach is being taken in the DAISY (Diabetes Autoimmunity Study in the Young) (59), DIPP (Diabetes Prediction and Prevention Project) (60), and NOBADIA (Norwegian Babies against Diabetes) (61) studies. In such a strategy, treatment (e.g. vaccination) would be only of susceptible individuals.

Understanding What Type Diabetes Is and Isnt

T1DM, simply stated, is an autoimmune disease. Immunity is what protects you from foreign invaders like bacteria and viruses. In autoimmunity, your body mistakenly acts against your own tissues. In T1DM, the immune cells and proteins react against the cells that make insulin, destroying them. (Insulin is the chemical or hormone that controls the blood glucose glucose is sugar that provides instant energy.)

Recent Developments

1 The association of coeliac disease and diabetes, as well as their common genetic predisposition, has long been recognized. Several important epidemiological studies have appeared recently. If a temporal relationship between the appearances of the two diseases could be established, a firmer opinion about screening might emerge. Recent evidence is conflicting, with a French study5 suggesting that coeliac disease generally preceded the diagnosis of diabetes, while in a large Italian series6 the reverse seemed to hold true. The latter study also suggested that female gender, the presence of thyroid autoimmunity and earlier age of diabetes onset were all associated with increased risk of coeliac disease. Adults with type 1 diabetes have a lower prevalence of undiagnosed coeliac disease than do children, amounting to around 2.5 .7

Hyperthyroidism and hypothyroidism

Thyroid disorders based on autoimmunity such as hyperthyroidism (an overactive thyroid) and hypothyroidism (an underactive thyroid) occur more frequently in people with T1DM. Both conditions are the result of autoimmune thyroiditis, which is usually missed because it causes no symptoms most of the time. In a study of 58 people enrolled in the Diabetes Control and Complications Trials published in Diabetes Care in April 2003, 18 patients had hypothyroidism and one had hyperthyroidism.

Clinical Trials of Human Islet Allotransplantation

The demonstration that prolonged insulin independence could be achieved after transplantation of allogeneic islets was made in 1990, with the Pittsburgh trial reporting nine patients who underwent upper abdominal exenteration, including pancreatoduodenectomy, for malignancy and received a combined liver-islet transplant. Six patients who survived the extensive surgery became insulin independent (48), a consistency of results that was previously only achieved with islet autotransplantation (26,47). This unusual success rate could be attributed to the absence of autoimmunity, but the common identity of islets and liver from a same donor led to the intriguing notion that the islet survival was facilitated by a modification of antigen-driven immunity in a syngeneic environment. In addition, the islets were transplanted immediately after isolation and the recipients were treated with a FK506-based, steroid-free immunosuppression. Our experience in Miami with islet allotransplantation in...

Tcell Receptor Characteristics And Susceptibility To

Autoimmunity is thought to result from an imbalance between the two functionally opposite processes, tolerance induction and immune responsiveness, each dependent on the presence of class I and class II molecules with appropriate structures (dictated by the genes encoding them) that are able to present critical antigenic peptides. In genetically susceptible individuals, certain class II molecules may ineffectively present self peptides, thereby leading to inadequate negative selection of T-cell populations that could later become activated to manifest an autoimmune response. Nepom and Kwok explain the molecular basis of HLA-DQ associations with T1DM exactly on this basis (142). Paradoxically, some self peptides that normally negatively select T-cells are likely to lead to positive selection when the MHC molecule is, for example, the HLA-DQ3.2.

Prevention of Type Diabetes Mellitus

The best characterized loci, IDDM1 (HLA) and IDDM2 (INS-VNTR), encode true susceptibility genes. Yet, there is also clear evidence that certain alleles provide genetic resistance from the development of diabetes. In particular, genetic protection from Type 1 diabetes is associated with specific alleles at the IDDM1 (6) and IDDM2 loci (7,8). For example, the HLA molecule DQA1 *0102-DQB1 *0602 (also known as DQ6). There usually is dominance of protection over susceptibility for genes encoded at these loci. It is a fair speculation that IDDM1 may be involved in antigen presentation and control immune responsiveness to one or more islet cell antigens, while IDDM2 may control insulin gene expression in the thymus and in turn selectively influence immune responsiveness to insulin. These two susceptibility loci may influence the specificity of the autoimmune response rather than a generic predisposition to autoimmunity. A recent study examined the frequency of various islet cell antibodies...

First Trimester Weeks

Coincident thyroid disease is very common in type 1 diabetes, up to 40 (26). In addition, women who are euthyroid but have thyroid autoimmunity (TAI) are at risk of developing hypothyroidism during pregnancy and should be monitored. The thyroxine dose often will require increased dosing of 30-50 by 4-6 weeks of gestation. Women who do not require increased amounts of replacement in the first trimester may still require increased dosing later in gestation, and therefore a serum TSH should be measured every 30-40 days. The TSH goal is less than 2.5 mLU L if hypothyroidism is diagnosed prior to pregnancy in the first trimester and 3.0 mLU L in the second and third trimesters (27).

Overview of Diabetes Management Combined Treatment and Therapeutic Additions

It is the frontier of immunological therapy in diabetes mellitus and is directed to express regulatory cytokines (such as IL-4, IL-10 and TGF-P) or autoantigens in the thymus (selection of T cells in the thymus results in deletion of cells that cause autoimmunity), thus preventing or delaying type 1 diabetes. In overt clinical diabetes, both immunoregulatory and immunosuppressive therapy are unsuccessful. However, it is useful to identify the appearance of antibodies already in the preclinical period in order to preventively treat susceptible people (who will develop type 1 diabetes).

Investigating the causes of type diabetes

Type 1 diabetes is an autoimmune disease, meaning that your body is unkind enough to react against and, in this case, destroy a vital part of itself, namely the insulin-producing beta (B) cells of the pancreas. One way that doctors discovered that type 1 diabetes is an autoimmune disease is by measuring proteins in the blood, called antibodies, which are literally substances directed against your body and, in particular, against your islet cells. (These specific antibodies are called islet cell antibodies and GAD antibodies.) Doctors find islet cell antibodies and GAD antibodies in relatives of people who have type 1 diabetes and in the people with diabetes themselves for a few years before the disease begins. Another clue that type 1 diabetes is an autoimmune disease is that drugs that reduce autoimmunity, also delay the onset of type 1 diabetes. Also, type 1 diabetes tends to occur in people who have other known autoimmune diseases.

How Common Is Diabetes

Full-blown adult-onset diabetes affects an estimated 15 million Americans, about half of whom have not been officially diagnosed with the disease. (Juvenile-onset diabetes is an autoimmune disease that is rarely reversible.) However, as many as 70 million Americans have some degree of insulin resistance or Syndrome X. Syndrome X refers to a cluster of insulin resistance, high blood pressure, abdominal obesity, and elevated cholesterol and triglycerides. (For more information see my previous book Syndrome X.) Basically, anyone eating the typical American diet is consuming foods that increase the risk of insulin resistance, Syndrome X, and diabetes.

Type Diabetes Insulindependent Diabetes

This autoimmune disease is the result of genetic environmental triggers. These patients demonstrate CD8-cell infiltration of the islet cells that likely are involved with subsequent P-cell destruction. A long prodrome is usually present from genetic predisposition to onset of disease. These patients may demonstrate various antibodies to islet antigens including insulin, glutamic acid decarboxylase, and tyrosine phosphotase 1A-2. Thus, a combination of markers rather than a single test should be used for predictive and diagnostic testing to enhance sensitivity without losing specificity.

Michael J Haller MDa Mark A Atkinson PhDb Desmond Schatz MDc

Type 1 diabetes mellitus (T1D) is a heterogeneous disorder characterized by autoimmune-mediated destruction of pancreatic beta cells that culminates in absolute insulin deficiency. T1D is most commonly diagnosed in children and adolescents, usually presents with symptomatic hyperglycemia, and imparts the immediate need for exogenous insulin replacement. Approximately one fourth of patients with T1D are diagnosed as adults and often are labeled as having latent autoimmune disease of adults, however. Approximately 5 to 10 of adults diagnosed with type 2 diabetes actually may have T1D. Terms such as ''juvenile diabetes'' and ''insulin-dependent diabetes'' have been replaced because they no longer adequately reflect our understanding of the natural history and patho-physiology of T1D. This article provides an in-depth review regarding our current understanding of the epidemiology, etiology, presentation, and management of T1D as it relates to childhood and adolescence.

Pathophysiology of Type diabetes

Type 1A DM is therefore an autoimmune disease. It usually occurs during childhood and adolescence (which is why in previous classifications it was called juvenile diabetes mellitus), but can present during adult life as well. According to current estimates, autoimmune Type 1A DM represents 5-10 percent of the cases of DM that occur in adults. Adults that manifest this type of DM are (arithmetically) equal to the children that manifest Type 1 DM. When someone suffers from Type 1A DM, both themselves and their relatives are at increased risk of developing other autoimmune diseases as well. Coeliac disease, hypothyroidism, hyperthyroidism, Addison's disease and atrophic gastritis (megaloblastic anaemia) are some of the most common autoimmune diseases that develop in these people. The role of viruses in the development of Type 1 DM was mainly based on two types of observations i) on the description of sporadic patient cases and ii) on the development of DM in children whose mothers had...

Preventing type diabetes

The most prevalent methods of secondary prevention for type 1 diabetes attempt to block the autoimmune disease from destroying all of your pancreas's beta cells. The following list shows some of the more promising secondary prevention trials and techniques Most people with type 2 diabetes are over the age of forty. Your chances of getting type 2 diabetes increase as you get older. Because the symptoms are so mild at first, you may not notice them. You may ignore these symptoms for years before they become bothersome enough to consult your doctor. So type 2 diabetes is a disease of gradual onset rather than the severe emergency that can herald type 1 diabetes. No autoimmunity is involved in type 2 diabetes, so no antibodies are found. Doctors believe that no virus is involved in the onset of type 2 diabetes.

Association with the HLA locus

MHC class II proteins function as peptide-binding proteins. MHC class II molecules are assembled in the endoplasmic reticulum and then transported through the Golgi apparatus to the cytosol, where they take up peptide fragments of degraded protein. The molecules are then transported to the cell surface, where they present the peptides as antigen to CD4+ T cells, including autoreactive T cells involved in autoimmune disease as well as those involved in adaptive immune responses to infectious microorganisms. Polymorphisms within MHC molecules affect which antigenic peptides are bound and presented. Pancreatic p-cells do not express class II MHC proteins therefore, presentation to CD4+ T cells of autoantigens derived from p-cells is likely to occur on professional antigen-presenting cells such as dendritic cells.

Maternal Complications

Thyroid disease is autoimmune disease colinked with diabetes. Physiological stress from pregnancy brings out the tendency toward thyroid disease in diabetic women. Hypothyroidism may lead to gestational hypertension, which, in turn, causes increased incidence of pre-eclampsia and low birth weight (29). Controlling maternal hypothyroidism should be a concern during pregnancy. A study by Haddow and colleagues (30) indicates that hypothyroidism in the mother can impair the intellectual development of

Costimulatory Blockade

Many efforts have focused on costimulatory blockade, because it was demonstrated that delivery of signal 1 in the absence of signal 2 could lead to T-cell clonal anergy and thus could be a way of inducing donor-specific tolerance (129-131). Interestingly, costimulatory blockade was shown to prevent or delay the occurrence of autoimmunity in various animal models (132-135), enhancing the appeal of this strategy for its application to islet transplantation.

Obstacles to Success of Islet Allotransplantation

Finally, islet grafts are prone to destruction by recurrence of autoimmunity in addition to allorejection. There has not been a clear indication so far that islets are more susceptible to allorejection than whole-pancreas transplants. However, as discussed earlier, there is growing evidence that ischemia-reperfusion injury, similar to the early inflammatory events peculiar to the islet transplant situation, may upregulate specific immune mechanisms. Recurrence of islet-directed autoimmunity has been clearly demonstrated by recurrence of insulitis in recipients of segmental pancreatic grafts from an identical twin. However, the process was not observed when such recipients received full-dose immunosuppression and is rarely observed in recipients of pancreatic allografts (113). Although, immune rejection and recurrence of autoimmunity are exceedingly difficult to distinguish, there is strong evidence that the latter is a significant mechanism of islet graft loss despite adequate...

Therapies For Microvascular Insufficiency

Protein kinase C (PKC) and diacylglycerol (DAG) are intracellular signaling molecules that regulate vasculature by endothelial permeability and vasodilation. The PKC isozymes are a family of 12 related serine threonine kinases (25) whose normal function is the activation of essential proteins and lipids in cells essential for cell survival. PKC-P is expressed in the vasculature (26,27) and belived to be involved in cell proliferation, differentiation, and apoptosis. PKC is activated by oxidative and osmolar stress, both of which are a consequence of the dysmetabolism of diabetes. Increased polyol pathway activity and pro-oxidants bind to the catalytic domain of PKC and it is disin-hibited. PKC-p overactivation is induced by hyperglycemia or fatty acids through receptor-mediated activation by phospholipase C. It is hypothesized that AGEs and oxidants produced by nonenzymatic glycation and the polyol pathway, respectively, increase the production of DAG (28). Increased DAG and calcium...

Gastroduodenal Dysfunction The Gastroparesis Syndrome

Ballondilatation Pylorus

Another possible connection between diabetes mellitus and the GI tract can be infrequent autoimmune disease associated with type 1 diabetes mellitus, such as celiac disease, autoimmune chronic pancreatitis, and autoimmune gastropathy (2). Indeed, about 15-20 of patients with type 1 diabetes mellitus exhibit parietal cell antibodies (26), but on the other hand no clear-cut relationship has been found between parietal cell antibody titers and delayed gastric emptying (26). Finally, the finding of gastroparesis associated with autonomic neuropathy in a diabetic should not preclude the possibility of coexistent mechanical factors contributing to the apparent motor abnormality (27). First assessing the possibility of mechanical obstruction remains a key premise to diagnosing a gut motor disorder under any circumstances.

In How Many Ways Can the pCells Get Killed Killing by Virus

Since Yoon et al. (131) isolated coxsackie B4 virus from the pancreas of a patient with type 1 diabetes, various viruses have been studied to examine their diabetogenic potential and to what extent viruses represent an environmental factor that contributes to the disease. The viral infection seems to be able to indirectly activate autoreactive T-cells that, in turn, can generate initial pancreatic tissue damage. Damaged P-cells release previously ignored self antigens that may activate an autoimmune process, rapidly promoting the generation of insulitis and, eventually, overt diabetes by immune-mediated P-cell killing. Viral infections could trigger type 1 diabetes through several mechanisms for example, (1) sequence similarities between islet-cell GAD65 and coxsackie virus could cause immune attack against coxsackie virus to also target the beta cells, (2) enteroviral infections could sustain autoimmunity until a final hit results in P-cell destruction following lysis of the cells,...

Pathogenesis Of Dpn And

Although the exact etiology of DPN and DAN is unknown, the Diabetes Control and Complications Trial (DCCT) confirmed the long-held concept that DPN and DAN are the result of sustained hyperglycemia in type 1 patients and not insulin deficiency and or autoimmunity alone (7). The mechanisms underlying the metabolic and vascular changes that occur in complication-prone tissues in the presence of acute and chronic hyperglycemia are an active area of research. Multiple etiologies have been proposed to underlie the development of DPN and DAN. These include altered polyol metabolism, abnormal lipid or amino acid metabolism, protein glycation (i.e., formation of advanced glycation end productions AGE ), blunted nitric oxide production, altered neurotrophism, and autoimmune mechanisms (8). More recently, the idea has emerged that these alterations in cellular metabolism occur in concert and as a consequence of glucose-mediated oxidative stress (8). Recent interest has emerged about the role of...

Concluding Remarks

It is noteworthy acknowledging that familial association of different autoimmune diseases in the same pedigree (172), association of different autoimmune disorders including T1DM in the same individual (186,187), and common clinical parameters of different autoimmune diseases (6,188) might share similar pathophysiologic mechanisms leading to autoimmunity. Colocalization and overlapping of candidate loci in autoimmune disease, such as T1DM, imply that common biological pathways may be involved in the immunopathogenesis of at least a subgroup of autoimmune diabetes and other clinically diversified autoimmune disorders. The latter example may resemble what occurs as a result of mutations of the autoimmune regulator gene (AIRE) (189-191), which forms the basis for genetic dysregulation in autoimmune polyen-docrine syndrome type 1 (APS-I), a non-MHC-linked disorder that is also associated with autoimmune impairment of pancreatic -cells.

Pathophysiology

Genetics and Autoimmunity T1D is a cell-mediated autoimmune disease with destruction of P-cells that are located in the pancreatic islets of Langerhans. Several islet cell autoantibodies have been isolated glutamic acid decarboxylase (GAD) and tyrosine phosphatases IA-2 and IA-2P. The majority of type 1 diabetic patients (75-95 ) have positive autoantibodies at the time of manifestation. In addition, observations in families have shown an association with the HLA complex, especially the class 2 molecules, suggesting a predominant role in aberrances in T-cell-mediated responses via cytotoxic and helper T cells (6). T1D is strongly associated with HLA DQA and DQB genes, but this can differ among various populations throughout the world. In contrast, twin studies show a low concordant prevalence of T1D of only 30-55 . Associated Autoimmune Diseases Diabetes mellitus type 1 may be sporadic or associated with other autoimmune diseases within patients or within families. The latter has been...

Genetic Syndromes

Are thought to be responsible for this syndrome, which is found in greatest frequency among Iranian Jews, Sardinians, and Finns (55). Although T1DM is relatively uncommon in APS Typel (approximately 1 of affected probands), a publication on a series of Finnish patients with APECED reported a 12-fold higher prevalence of diabetes compared to the general population (56). The association between diabetes and both autoimmune adrenal insufficiency and thyroiditis is considerably greater in patients with APS type 2, also known as Schmidt syndrome (57), or Carpenter syndrome, so called when all the three conditions are present (58). Autoimmune diabetes is present in 20 to 50 of subjects with the APS type 2, and usually presents at an earlier age than either Addison's disease or thyroid disorders (59,60). As with classical type 1A diabetes, and similar to what is seen in other isolated autoimmune disorders, there is clear evidence of both humoral and cellular autoimmunity as manifested by the...

Clinical Picture

Although rare, adrenal insufficiency (AI) is about 50 times more common in patients with type 1 diabetes (0.12-0.5 ) than in the general population (93-117 per million) (103,104). Antibodies to adrenal cortex (AA) or 21-hydroxylase (21-OHA) are present in 0.2-2.3 of type 1 diabetic patients (7,67,84,86,105-108). In a study on 8840 adult patients with organ-specific autoimmune disease, 50 of patients with AA progressed to impaired adrenal function (decreased response to intravenous ACTH) (107). It is not clear whether the predictive value of the antibodies is associated with the age of the subject. Fewer adult (36 ) than juvenile (90 ) patients developed impaired adrenal function, but no distinction was made between APS-1 and APS-2 (106,107). In most cases, the diagnosis of IDDM preceded that of AI (66,109) the latency time from the AA-positive test may be as long as 7 yr (107). Development of Type 1 Diabetes in Patients with Other Autoimmune Diseases Islet cell antigens were...

Type Diabetes

The relevance of further sub-classifying type 1 diabetes may appear less immediately apparent than for type 2. After all, once total beta-cell destruction has occurred then insulin replacement therapy will have to be used irrespective of the cause. However, certain genetic sub-types may be at much higher risk of other autoimmune diseases or complications, for example, and the identification of these at an early stage would be highly relevant. The real importance of sub-phenotyping in type 1 diabetes will be in the research effort to identify at risk and presymptomatic individuals and to intervene in their autoimmune

The CTLA Locus

Activation of T lymphocytes by the TCR complex after antigen recognition requires the costimulation by CD28 (59). The protein encoded by CTLA4 transmits inhibitory signals to attenuate T-cell activation by competing for the B7 ligands with its homologue CD28 (60, 61). In addition, CTLA-4 can inhibit TCR signaling by direct interaction with the TCR complex (62). Blocking CTLA-4 by anti-CTLA-4 mAb can increase IL-2 mRNA expression and IL-2 secretion (63) and promote T-cell proliferation (63, 64). Therefore, it is conceivable that genetic variations associated with decreased CTLA4 expression might increase the risk of autoimmune diseases because of the deficit of inhibiting T-cell activity.

Other Loci

The discovery of these DM1 genes greatly expands the understanding of the etiology of DM1. The genetic susceptibility from the variation of the INS gene, which encodes the primary autoantigen that initiates the T-cell autoimmune destruction of the pancreatic b cells, is specific for the development of DM1. Other DM1-associated genes are involved in the activation of autoreactive CD4+ T cell and or the maintaining of immune homeostasis and may be involved in other autoimmune diseases. These genetic findings will help in disease prediction and identification of potential therapeutic targets for drug development.

Preclinical diabetes

Onset of P-cell autoimmunity Islet autoantibodies can be detected in early childhood and are presumed to be a guide to when p-cell autoimmunity begins. When autoantibodies were measured from birth in children of parents with type 1 diabetes, 11 were positive by 2 years of age for an islet autoantibody on at least one occasion,41 and 2.8 were persistently positive for two or more antibodies.42 Importantly, the latter group had a higher frequency of the 'at-risk' HLA DR4 and DR3 alleles.43 When present, maternal autoantibodies were not detected in infants after 6-9 months of age, and autoantibodies began to develop after 18 months. How accurately this indicates the time of onset of autoimmune disorder within the pancreas is unknown. Most commonly, but not always, IAA are the first autoantibody detected. These studies continue in several countries to follow children through to the development of clinical diabetes. Another study reported that approximately 13 of children of first-degree...

Classification

Type 1 diabetes, accounting for 5-10 of cases of diabetes in populations of European origin, is associated with primary beta cell failure, commonly a result of autoimmune-associated destruction. In its initial stages, type 1 diabetes can be identified by the presence of circulating anti-glutamic acid dehydrogenase antibodies, islet cell autoantibodies, or insulin autoantibodies. In some subjects, particularly non-Caucasians with this clinical form of the disease, no evidence of an autoimmune disorder is demonstrable, and the causes of beta cell destruction remain obscure. Once the disease is established, patients with type 1 diabetes require insulin to prevent spontaneous ketosis and to permit survival.

Other Specific Types

Markers of immune destruction, including ICA, and or IAA, autoantibodies to GAD and IICA 512 are present in 85-90 of individuals when fasting hyperglycemia is initially detected, and often many years before (28). The peak incidence of this form of Type 1 diabetes occurs in childhood and adolescence but the onset may occur at any age ranging from childhood to the ninth decade of life (29). Patients are rarely obese when they present with this type of diabetes. However, the presence of obesity is not incompatible with the diagnosis. Other autoimmune disorders such as Grave's disease, Hashimoto's thyroiditis and Addison's disease may be associated with Type 1 diabetes mellitus (30). b. Idiopathic There are some forms of Type 1 diabetes which have no known etiologies. Some of these patients have permanent insulinopenia and are prone to ketoacidosis, but have no evidence of autoimmunity (31). This form is more common among individuals of African and Asian origin (32). In another form found...

Risk Identification

The identification of individuals at risk of type 1 diabetes, the ability to predict disease development, is crucial for studies of disease prevention. In family members, testing for autoantibodies (i.e. identification at stage 2) is usually used, and in this circumstance genetic testing is of limited value. On the other hand, genetic testing may be useful for identifying individuals in the general population or in infant relatives for prospective follow-up for the appearance of autoantibodies or for recruitment into trials aimed at prevention of initiation of autoimmunity. Indeed, there are several studies underway involving screening of newborns or infants for genetic markers22-26 with the goal of following these subjects (with or without intervention) for the appearance of autoimmunity. In addition, there are studies following offspring of diabetic parents for the appearance of autoimmunity27.

Primary Prevention

Some studies, however, have found no association of cow's milk exposure and P-cell autoimmunity, the precursor to clinical type 1 diabetes. The Diabetes Autoimmunity Study in the Young (DAISY) from Denver, Colorado screened 253 children with a first-degree relative with type 1 diabetes for evidence of P-cell autoimmunity, defined as elevated levels of insulin, GAD, or ICA512 (IA-2) autoantibodies. There was no association between the early exposure of cow's milk protein or other dietary protein (cereal, fruit, vegetable, or meat) and the development of P-cell autoimmunity (68). These results were later independently confirmed with the Australian BabyDIAB trial of 317 infants with a first-degree relative with type 1 diabetes and the German BabyDIAB trial. The study prospectively examined infants from birth to 29 mo of age for the effect of both breast-feeding and the introduction of cow's milk protein on the development of P-cell autoimmunity. Analyses were performed on cohorts based...

Summary

Type 1A diabetes is characterized by the loss of insulin secretion due to autoimmune destruction of pancreatic beta cells, often presenting with diabetic ketoacidosis, and usually requiring insulin replacement for survival. Genetic, environmental, and possibly other unknown factors contribute to disease susceptibility. The DR3 DR4 alleles in the MHC (HLA) complex have clearly been implicated in disease risk. Mechanisms of both central and peripheral tolerance appear to play a role in the development of autoimmunity and may

Islet Autoantibodies

Somewhat higher than that among whites. A more recent analysis of islet cell autoimmunity among young insulin-treated patients, testing for ICA on both human and rat pancreas substrates, demonstrated that 11.6 of 43 African American patients compared with just 4.1 of 394 non-Hispanic white patients were negative for all four major kinds of ICA tested. (53) Specific antibodies to glutamic acid decarboxy-lase (GAD) have been associated with pancreatic autoimmunity in more recent years (54,55). Like other kinds of ICA, they are found in 75-80 of newly-diagnosed patients, and very rarely in non-diabetics. The presence of GAD antibodies is predictive of the development of Type 1 diabetes in high-risk groups and population samples (56), and have been reported in subsets of Type 2 diabetic patients as well. Ethnic differences in GAD antibody prevalence have also been demonstrated (57). Among 125 Pima Indian children diagnosed at ages 5 -19 with Type 2 diabetes, GAD antibodies were detected...

Tolerance Mechanisms

Central (based in the thymus) and peripheral (based in lymph nodes and the circulation) tolerance mechanisms are essential in ensuring that mature lymphocytes can differentiate between pathogens and self-antigen. Disruption of these tolerance mechanisms can lead to autoimmunity to various organs and cells, and result in chronic autoimmune The MHC-antigen complex is an essential component of the thymic selection (or deletion) of lymphocytes and their eventual maturation into CD4+ or CD8+ T cells. Both the expression of coreceptors, CD4 and CD8, and costimulatory molecules such as CD80 86 and CD40L, appear to be important in the selection of regulatory T cells and the deletion of potentially autoreactive lymphocytes. Another important mechanism in the determination of central tolerance is the expression and presentation of autoantigens in the thymic cortex and medulla. Animal studies have clearly shown that specialized cells, called medullary thymic epithelial cells (mTECs) and...

Immunology

Exceptions to this uncertainty of antibody role are some antibodies against membrane receptors, like the a-chain of the acetylcholine receptor in myasthenia gravis and the thyrotropin receptor in AITD. Antibodies to thyrotropin receptor can act as either agonists causing Graves' hyperthyroidism or blockers causing hypothyroidism. The net effect depends on their relative activities. Other important thyroid autoantigens are microsomal thyroid peroxidase and thyroglobulin. Thyroid autoimmunity, defined by the presence of any thyroid antibody, is much more common than clinical AITD and does not always herald the development of hypothyroidism. Part of this difference may be a result of the slowness of the destructive process. Agents inhibiting thyroid hormone synthesis, such as lithium and amiodarone, may turn subclinical hypothyroidism into manifest disease.

Blockade of Signal

Blockade of the first signal of T-cell activation can be obtained by treatment with anti-CD45RB MAbs. CD45 (also known as leukocyte common antigen) is a transmembrane protein tyrosine phosphatase critically involved in the coupling of signals from the T-cell receptor (TCR) to the proximal signaling apparatus (see Fig. 1A, B). Engagement of the TCR by the MHC peptide complex triggers activation of protein tyrosine kinases, which leads to phosphorylation of chains of the CD3 TCR complex, and, in turn, of critical downstream signaling intermediates. CD45 plays a critical role in T-cell activation by regulating reversible dephosphorylation of regulatory tyrosine residues. The CD45 molecule exists in multiple isoforms obtained by alternative splicing of three exons termed A, B, and C. In mice, T-cells can be roughly divided in two populations with regard to their level of expression of exon B. CD45RBHl CD4 T-cells preferentially secrete IL-2, whereas CD45RBLo CD4 T-cells preferentially...

Kidney Disease

Damage from autoantibodies An article in August 2005 in Diabetes Care showed that autoantibodies to autonomic nerves (see below) are present in patients with diabetes long before they suffer from autonomic neuropathy involving the heart and the peripheral autonomic nervous system. Autoimmunity may be yet another mechanism by which diabetes causes long-term complications.

Viral Infection

On the other hand, there is evidence that maternal viral infection during pregnancy is a risk factor for childhood-onset Type 1 diabetes. As many as 10-12 of children with congenital rubella develop Type 1 diabetes (23,24). The patients who develop Type 1 diabetes have the typical genetic background, and manifest the usual immunologic abnormalities (25). Congenital cyto-megalovirus infection has also been implicated in Type 1 diabetes (26). Careful studies from Sweden and Finland, using maternal cord blood, have found that maternal enteroviral infection during pregnancy, especially Coxsackie-B virus infection (but also echo virus), is a risk factor for Type 1 diabetes (27,28,29). Thus, children of mothers who expressed viral antibodies at delivery are at increased risk for developing childhood onset Type 1 diabetes. A fetal viral infection may initiate autoimmunity or cause persistent infection that may lead to progressive beta-cell destruction.

Problem

Preventing or curing type 1 diabetes is one of the holy grails for those who research autoimmune disease or treat patients with diabetes. The disease typically presents in childhood, currently necessitates lifelong use of insulin injections and exposes the indi Atlas Medical Publishing Ltd, 2006 2 Autoimmunity directed at insulin epitopes is one of the critical driving forces in the pathogenesis of type 1 diabetes. In animal models, exposure to mucosal insulin induces tolerance and thus decreases risk of diabetes. This mechanism is of particular interest because of the recent developments of insulin formulations which are active after oral or nasal administration. The Diabetes Prevention Trial-Type 1 reported recently.9 In this trial, a large number of first- and second-degree relatives of patients with diabetes were screened for pre-diabetes. Those found to be positive were ran- Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity...

Celiac disease

Celiac disease is an inherited autoimmune disease present in as many as 2 to 3 percent of patients with T1DM. A person who has celiac disease, also known as celiac sprue, can't eat foods that contain gluten, including wheat, barley, and rye, because gluten damages the wall of the gastrointestinal tract. Patients with celiac disease (both adults and children) complain about these symptoms

Tcell Studies

Type 1 diabetes is a T-cell-mediated autoimmune disease. Over the last few years, our group has developed T-cell assays to measure reactivity to islet antigens in human type 1 diabetes one such assay called cellular immunoblotting uses proteins from human islets separated into 18 different molecular weight regions using SDS-PAGE. An excellent sensitivity and specificity was demonstrated by this assay in arecent, National Institutes of Health-Immune Tolerance Network Workshop (58). The cellular immunoblotting assay has been used to describe the T-cell reactivity of recently diagnosed type 1 diabetic patients to multiple different molecular weight islet proteins (59), to describe the antigen spreading that occurs during the prediabetic (type 1 diabetes) period (60), and to compare T-cell responses of type 1 diabetes with LADA (61). T cells from both type 1 diabetes and LADA commonly respond to four or more different molecular weight blot sections of islet proteins, whereas normal...

Disease Process

The Type 1 diabetes disease process is one of selective destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans (53, 54). The current concept is that islet beta-cells are destroyed by an immune response mediated by T-lymphocytes that react specifically to one or more beta-cell proteins (autoantigens). The exact mechanisms have not yet been clearly defined, as there appear to be complex regulatory interactions amongst various elements of the immune response, and it is unclear which elements of the immune circuitry are responsible for beta-cell destruction and which are responsible for beta-cell protection. The prevalent view is that islet cell destruction is enhanced by CD8+ cytotoxic T-lymphocytes stimulated by T-helper-1 (Th1) subset of CD4+ T-lymphocytes, with inhibition of islet destruction by T-helper-2 (Th2) subset of CD4+ T-lymphocytes and CD876 suppressor T-lymphocytes. Thus, the pathogenetic sequence potentially could be altered either by...

The ILRA Locus

What makes the IL2RA association interesting is the increased awareness of the importance of regulatory T cells in recent years. CD4+ CD25+ T cells, naturally occurring in the thymus, are a population of regulatory T cells, which are anergic to TCR signals and potently suppress activated T cells in a contact-dependent and cytokine-independent fashion (102). This active immune suppression mechanism plays an important role in maintaining immune homeostasis and inhibiting autoimmune disease (103). As direct evidence of the protective effect of CD4+ CD25+ T cells in DM1, the transfer of CD4+ CD25+ T cells can prevent diabetes in recipient NOD mice (104). CD4+ CD25+ T cells depend on interleukin-2 (IL-2) for their growth and survival, and the IL-2 signaling effect is mainly mediated by IL2Ra (105, 106). Adult IL2Ra-deficient mice develop massive enlargement of peripheral lymphoid organs from impaired T-cell death after activation, and older IL2Ra-deficient mice develop autoimmune...

Blood Flow

Autoimmune destruction might be prevented by purposely implanting islets whose tissue-typing antigens do not match those of the recipient's islets. But many investigators are taking a less chancy approach to circumventing both autoimmunity and rejection they are exploring ways to encapsulate donor islets in a semipermeable plastic membrane. When the pore size is ideal, such membranes permit glucose to reach the encased islets and allow insulin made by the islets to escape, but the membranes bar lymphocytes and antibody molecules which are much larger than glucose and insulin from crossing to the islets.

Etiology

Over the past 30 years, the ability to predict the development of T1D has improved dramatically with the combined use of genetic, autoantibody, and metabolic markers. The most often cited model of the natural history of T1D suggests that genetically susceptible individuals with a fixed number of beta cells are exposed to a putative environmental trigger that induces beta cell autoimmunity 11 . The development of islet reactive autoantibodies is a marker of ongoing autoimmune disease, but it is predominantly activated autoreactive T cells that destroy beta cells, which results in a progressive and predicable loss in insulin secretory function. Because clinical T1D typically does not present until approximately 80 to 90 of the beta cells have been destroyed, there is a marked gap between the onset of autoimmunity and the onset of diabetes (Fig. 1). Recently, some aspects of the classic model have been challenged. For example, data suggest that pancreatic beta cells have considerable...

Clinical examination

Skin infections (boils, cellulitis, ulcers, fungi) are common. Less common signs include diabetic dermopathy, necrobiosis lipoidica diabeticorum (p. 134), and granuloma annulare. Some patients have vitiligo as a marker of autoimmune disease. A jaundiced patient may have a pancreatic malignancy. Sweating may be reduced in autonomic neuropathy.

Genetic Risk

Data from Colorado suggest that the incidence has increased to 25 100,000 (17,18). The etiology of the increasing incidence is not defined, but it suggests environmental change (either decreasing protective factors or increasing triggering factors). First-degree relatives of patients with type 1A diabetes have a risk of approx 5 , including siblings, offspring, and parents. The risk of type 1A diabetes of an offspring of a mother with diabetes is less than for a father with type 1A diabetes (19), and siblings appear to have a risk for early childhood anti-islet autoimmunity and diabetes approximately twice that of offspring (20). Dizygotic twins have a risk similar to siblings, and monozygotic twins have a lifetime risk of approx 50 (21). As illustrated in Fig. 2, initially discordant monozygotic twins of patients with type 1A diabetes can progress to diabetes decades after the onset of diabetes in their proband twin. In addition, there appears to be genetic heterogeneity in eventual...

Jay S Skyler

This chapter will review evidence concerning interventions designed to interdict the type 1 diabetes disease process. To facilitate the discussion, the evolution of the disease can be divided into a number of stages, depicted in Figure 4.1, through which individuals progress. Interruption of the sequence at any stage is likely to be important13. The stages are (1) genetic susceptibility, modulated by genetic protection, identified by finding of susceptibility genes without dominant protective genes (2) initiation of autoimmunity, presumably by an environmental trigger, with a cellular immune response leading to immune-mediated islet infiltration (insulitis), with the stage identified by the presence of circulating autoantibodies (3) impairment of B-cell function resulting in loss of first-phase insulin response (FPIR) during an intravenous

Environmental

Many factors suggest that environmental factors are important determinants of Type 1 diabetes. It has already been noted that environmental factors are implicated by the discordance rate in monozygotic twins and the higher prevalence of autoimmunity in non-diabetic twins than in other first-degree relatives. Other indicators that environmental factors are involved include the seasonal variation in disease onset (15) and the rising incidence of Type 1 diabetes in Europe and many other parts of the world over the past 20-30 years (16,17). Although in most areas, there has been an overall increase in incidence rates, in two studies one in Finland and one in England there has been a marked increase amongst children aged under 5 years (18,19).

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