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But little does Kerney know that the truth may go back 30 years to the day when Spalding's son mysteriously disappeared. Find a copy online Links to this item torontoon. Show all links. Allow this favorite library to be seen by others Keep this favorite library private. J Diabetes, doi, HLA-DQ haplotypes differ by ethnicity in pa tients with childhood-onset diabetes.

Pediatr Diabetes, 12 4 Pt 2 , Update on islet transplantation. Seasonality of birth in patients with childhood Type I diabe tes in 19 European regions. Incidence and prevalence of childhood diabetes in Slovakia Diabetes Care, 18 3 , Improvements in the life expectancy of type 1 diabetes: The Pittsburgh Epidemiology of Diabetes Complications Study cohort.

Diabetes, Jul 30, Epub ahead of print. Seasonal variation of diagnosis of Type 1 diabetes mellitus in children worldwide. Diabet Med, 26 7 , Seasonality of type 1 diabetes mellitus in children and its modification by weekends and holidays: retrospective observational study. Arch Dis Child, 89 10 , Insights into type 1 diabetes provided by genetic analyses.

Curr Opin Endocrinol Diabetes Obes, 19 4 , New insights into the epidemiology of type 1 diabetes in Mediter ranean countries. Diabetes Metab Res Rev, 15 2 , Diabetes Care, 15 10 , A functional framework for interpretation of genetic associations in T1D. Curr Opin Immunol, Jul 25, Epub ahead of print. Rising incidence of type 1 diabetes in Germany: 12year trend analysis in children years of age.

Diabetes Care, 24 4 , Seasonality of birth in children years with diabetes mellitus type 1 in Baden-Wuerttemberg, Germany. J Pediatr Endocrinol Met ab, 13 8 , Tissue Antigens, 78 5 , Risk of developing insulin-dependent diabe tes mellitus IDDM before 35 years of age: indications of climatological determinants for age at onset. Int J Epidemiol, 21 2 , Worldwide increase in incidence of Type I diabetes--the analysis of the data on published incidence trends.

Diabetologia, 42 12 , Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J Exp Med, 13 , Gender differences and temporal variation in the incidence of type 1 diabetes: results of cases in the nationwide Diabetes Inci dence Study in Sweden J Intern Med, 4 , Seasonal variation in the incidence of Type 1 diabetes mellitus during to in the countries around the Baltic Sea.

Diabet Med, 16 9 , The rising incidence of type 1 diabetes in the northeastern part of Thailand. J Med Assoc Thai, 94 12 , Incidence trends for childhood type 1 diabetes in Europe during and predicted new cases a multicentre prospective registration study.

Epidemiology of type 1 diabetes mellitus in Bydgoszcz region in the years Insulin eine Erfolgsgeschichte der modernen Medizin. BioFokus Forschung fr Leben Increasing incidence of childhood type 1 diabetes in Montenegro from to Seasonal variation in the diagnosis of type 1 diabetes in south-east Sweden.

Diabetes Res Clin Pract, 76 1 , Incidence rate and spatio-temporal clustering of type 1 diabetes in Santiago, Chile, from to Rev Saude Publica, 35 1 , Type 1 diabetes in the Maltese Islands.

Multiple complications and frequent severe hy poglycaemia in 'elderly' and 'old' patients with Type 1 diabetes. Diabet Med, 29 8 , ee Kuwait Study Group of Diabetes in Childhood.

Diabetes Care, 18 7 , Being born in Sweden increases the risk for type 1 diabetes - a study of migration of children to Sweden as a natural experiment. Acta Paediatr, 1 , Diabetes in the young: a paediatric and epidemiological perspec tive.

Diabetologia, 46 4 , Worldwide childhood type 1 diabetes inci dence--what can we learn from epidemiology? Pediatr Diabetes, 8 Suppl 6 , Incidence and trends of childhood Type 1 diabetes in Croatia from to Diabetes Res Clin Pract 80 1 , Early childhood risk factors associated with type 1 diabetes is gender important?

Eur J Epidemiol, 20 5 , Long-term trends in the incidence of type 1 diabetes in Denmark: the seasonal variation changes over time. Pediatr Dia betes 10 4 , Incidence of type 1 diabetes mellitus in chil dren in Tuzla Canton between and Eur J Pediatr, 5 , The rising incidence of childhood type 1 dia betes in New South Wales, Med J Aust, 5 , Increasing incidence of childhood-onset type 1 diabetes mellitus among Estonian children in Time trend analysis Pediatr Diabetes 11 2 , Seasonality of birth in children and young adults years with type 1 diabetes in Ukraine.

Diabetologia, 50 1 , The changing epidemiology of type 1 diabetes: why is it going through the roof? Diabetes Metab Res Rev, 27 1 , Increasing incidence of type 1 diabetes in 0- to year-old Colorado youth.

Diabetes Care, 30 3 , Three- and four-digit ICD is not a reliable classification system in primary care. Scand J Prim Health Care, 27 3 , Lack of seasonality in the month of onset of childhood IDDM 0. J Pediatr Endocrinol Metab, 11 3 , Epidemiology of type 1 diabetes in Lower Silesia in the years Pediatr Endocrinol Diabetes Metab, 16 1 , It is caused by a selective destruction of insulin-producing cells in the pancreas. The disease has two subtypes: 1A, which includes the common, immune-mediated forms of the disease; and 1B, which includes nonimmune forms.

In this review, we focus on subtype 1A, which for simplicity will be referred to as type 1 diabetes. An increasing incidence rate of T1D has been observed for the last few decades especially in young individuals less than five years old []. The cause of T1D is still unknown. Several factors interact and lead to the development of the disease. An inflammatory islet infiltrate insulitis can be observed at the symptomatic onset of T1D, and reflects the immune response to -cells [45].

T1D is an autoimmune disease, which implies a role of immune response effectors in the pathogenic processes and a failure of tolerance to wards -cell antigens.

The susceptibility to T1D is influenced by genetic factors. Another contribution to the pathogen esis of the disease could rely on epigenetic modifications such as DNA methylation and parent-of-origin effects [11]. Genetic modifications in the population cannot explain the rap idly increased incidence of T1D in most populations. Altogether, the incidence variation from one season to another, the relationship between immigration and disease develop ment, and the differences in incidence in different parts of the world in neighboring popula tions with similar genetic profiles, suggest that the disease is a result of interaction of genetic and environmental factors [94].

Interplay between immune response, genetic and environmental factors such as nutriments, drugs, toxin and viruses play a role in the pathogenesis of the disease. Several teams paid attention to the relationship between viruses and type 1 diabetes, and their role in the patho genesis of the disease.

A novel subtype of type 1 diabetes called fulminant type 1 diabetes, without evidence of autoimmunity has been observed [61]. In that disease the role of viruses is strongly suspected as well, but is out of the scope of this chapter. The relationship between type 1 diabetes in human beings and animals and various viruses belonging to different families has been investigated. Enteroviruses are among the viruses most able to be involved in the pathogenesis of autoimmune type 1diabetes.

After a presentation of the role of various viruses in the disease we will focus on enteroviruses, and then the clinical studies that were conducted to assess the relationship between enterovi ruses and autoimmune T1D will be detailled. Thereafter the results of experimental investiga tions aimed to elucidate the link between these viruses and the disease will be analyzed. Various viruses have been associated with the development of type 1 diabetes The role of viral infections in the pathogenesis of T1D has long been suspected and several viruses have been associated with T1D in various studies [, ].

In humans, observa tions of acute diabetes succeeding to destruction of -cells by cytopathic effect of viral infec tion remain exceptional.

Some viruses, as mumps, influenza B virus or human herpes virus 6 have already been reported in cases of acute T1D. Nevertheless, the fact that T1D devel oped after the infection by such commun viruses suggest that factors within the host play more important roles than virus itself in the etiology of T1D [27, 59, ].

The relationship between viral infection and T1D is mainly based on epidemiological argu ments. The incidence of many allergic and autoimmune diseases has increased in developed countries North-South gradient over the past three decades, particularly in young chil dren. Concomitantly, there was a clear decrease in the incidence of many infectious diseases in these countries, probably explained by the introduction of antibiotics, vaccination, and an improved hygiene and better socioeconomic conditions [6, ].

Interestingly, viruses have been reported to be associated with T1D occurrence in animals. Experimental animal models, as BioBreeding BB -rat, nonobese diabetic NOD mouse or specific transgenic mouse strains, were used to investigate the mechanism by which viruses can modulate diabetogenesis.

Viruses and human type 1 diabetes 2. The serum levels of antibodies against measles, mumps, and rubella MMR and autoanti bodies against pancreas islet cells ICA , islet cell surface, glutamic acid decarboxylase auto antibodies GADA , and insulin were determined in school children between 11 and 13 years of age, before and 3 months after vaccination with combined MMR vaccine.

It has been shown that children with rubella antibodies before vaccination had higher levels of ICA than seronegative children [98]. However, a study conducted in showed inconsis tent results: in fact, no signs of -cells autoimmunity ie detection of ICA, insulin autoanti bodies IAA , antibodies to the tyrosine phosphatase related IA-2 molecule IA-2 A and glutamic acid decarboxylase GADA were detected in 37 subjects with congenital rubella syndrome or exposed to rubella virus during fetal life [].

The role of rubella in the trig gering of T1D has been determined in hamsters. This study revealed that an autoimmune process and diabetes developed after rubella virus infection in neonatal hamsters [].

Some authors suggested the molecular mimicry as a mechanism for rubella virus causing T1D, on the basis of co-recognition of -cell protein determinants, such as GAD, and various rubella peptides by T-cells []. Recently, a clinical study has confirmed a significant asso ciation between type 1 diabetes incidence and rubella in children in Italia [].

Rotavirus Rotavirus RV , the most common cause of childhood gastroenteritis, has been suspected to trigger or exacerbate T1D in a few studies. Honeyman et al. In all children, 24 children had been classified as high-risk children because they developed diabetes or had at least 2 islet antibodies or 1 islet antibody detected on at least 2 occasions within the study period. In , Coulson et al demonstrated that rotavirus could infect pancreas in vivo [35].

In this study, nonobese diabetic NOD mice were shown to be susceptible to rhesus rotavirus in fection. Pancreatic islets from NOD mice, nonobese diabetes-resistant mice, fetal pigs, and macaque monkeys supported various degrees of rotavirus growth. Human rotaviruses that were propagated in African green monkey kidney epithelial MA cells in the presence of trypsin as previously described [] replicated in monkey islets only [35].

The de gree of diabetes acceleration was related to the serum antibody titer to RV. Thus, rotavirus infection aggravated insulitis and exacerbated diabetes, after -cell autoimmunity was es tablished [60].

Furthermore, rotavirus was also suspected to contain peptide sequences, in VP7 viral protein 7 , highly similar to T-cell epitopes in the islet autoantigens GAD and ty rosine phosphatase IA-2, suggesting that T-cells directed against RV could induce or ampli fy islet autoimmunity by molecular mimicry, in children with genetic susceptibility.

The proliferative responses of T-cells to. Altogether, these observations suggested that RV infection could trigger or exacerbate islet autoimmunity by molecular mimicry. Mumps In , Parkkonen et al showed that mumps virus was able to infect -cells, leading to a minor decrease in insulin secretion in human fetal islet cultures []. The infection was in variably associated with an increase in the expression of human leucocyte antigen HLA class I molecules, mediated by soluble factors secreted by infected T cells, which could exag gerate the autoimmune process in pre-diabetic individuals by increasing the activity of au toreactive cytotoxic T cells [].

Moreover, ICA have been observed in 14 out of 30 sera of children with mumps. In most children, the ICA persisted for no more than months, al though 2 children have been positive for 15 months. Nevertheless, no ICA-positive child ac quired diabetic glucose metabolism, apart from one child who had persistent ICA and acquired diabetes mellitus three weeks after mumps infection [62].

Since the introduction of vaccination against MMR in most of occidental countries, several studies have reported on the relation between vaccination at childhood and the development of T1D [41, 78, 79]. Hyo ty et al. However, the incidence of T1D continued to rise after the plateau. Other studies hypothesized that childhood vaccination would rather promote the development of T1D. No evidence has been found for the triggering effect of childhood vaccination on the development of T1D later in life [41, 78].

Hyoty et al. In some medical conditions, HERVs genes could be transcripted, expressed in protein and could be responsible of the development of autoantibodies that might react against host pro teins. As a result, these mechanisms could lead to autoimmune diseases, such as T1D.

HERVs may also dysregulate the immune response by being moved and inserted next to certain genes involved in immune regulation whose expression would be consequentially altered. HERV-K18 transcription and SAg function in cells capable of efficient presentation are induced by proinflammatory stimuli and may trig ger progression of disease to insulitis or from insulitis to overt diabetes [].

The HERV-. Rubella virus, rotavirus, mumps virus and endogenous retroviruses are RNA viruses whose role in type 1 diabetes has been suspected. In addition to RNA viruses, it has been reported that DNA viruses as well could be involved in the development of the disease as described in the following paragraphs. Cytomegalovirus In , Numazaki et al showed that cytomegalovirus CMV was able to infect tissue mon olayer cultures of human fetal islets []. CMV infection apparently did not cause direct destruction of -cells but was leading to changes in production of insulin [].

Hille brands et al. In , Smelt et al demonstrated that RCMV induced a low, persistent infection in rat -cells, as sociated with an increasing -cell immunogenicity, which might be an essential step in cells destruction and in the development or the acceleration of the onset of T1D []. In , Aarnisalo et al analysed specific anti-CMV IgG antibodies in serum sam ples from children who had developed the first T1D-associated autoantibody by the age of 2 years, and, in parallel, in serum control from healthy children [1].

This study con cluded that perinatal CMV infections were not particularly associated with early serological signs of beta cell autoimmunity or progression to T1D in children with diabetes risk-asso ciated HLA genotype [1]. However, serological, immunological, histological signs of auto immunity and allograft rejection appeared concomitantly with early CMV infections in one type 1 diabetic patient receiving pancreas allograft.

This observation suggests that persis tent CMV infections might be relevant to the pathogenesis of type 1 diabetes []. Parvovirus B19 Several cases of autoimmune disease occurrence after an acute infection with parvovirus B19 have been reported. Kasuga et al. The authors noted homology in amino acid sequences between B19 and the extracellular domain of IA-2 [88, ].

Some authors attempted to explain these observations. Parvovirus B19 is known to promote a T-cell-mediated lymphoproliferative response, through the presenta tion by HLA class II antigen to CD4 cells and thus could theoretically generate T-cell-medi ated autoimmunity [].

Vigeant et al suggested that parvovirus B19 infection may lead to chronic modulation of the autoimmune response in predisposed individuals []. Although correlations between T1D and the occurrence of a viral infection that precedes the development of the autoimmune disease have been recognized, mechanisms by which vi ruses activate diabetogenic processes are still elusive and difficult to prove in humans.

Stud ies of animal virus-induced T1D provide a lot of information concerning the possible role of virus infections in the induction of TID.

Viruses and animal type 1 diabetes 2. Encephalomyocarditis virus A number of studies provide clear evidence that encephalomyocarditis virus EMCV , be longing to the Cardiovirus genus of the Picornaviridae family, is able to induce very rapid onset of diabetes in mice. Nucleotide sequence analy sis showed that EMC-D virus bases differs from EMC-B virus bases by only 14 nucleotides: two deletions of 5 nucleotides, 1 base insertion, and 8 point mutations.

Further studies revealed that only the th amino acid, alanine Ala , of the EMC virus poly protein, located at position of the major capsid protein VP1, is common to all diabeto genic variants. In contrast, threonine in this position Thr is common to all nondiabetogenic variants []. A single point mutation at nucleotide position or of the recombinant EMC viral genome, resulting in an amino acid change Ala in Thr , leads to the gain or loss of viral diabetogenicity [84].

A three-dimensional molecu lar modeling of the binding site of the EMC viral capsid protein VP1 revealed that the sur face areas surrounding alanine or glycine at position of the VP1 was more accessible, thus increasing the availability of the binding sites for attachment to -cell receptors, result ing in viral infection and the development of diabetes [85].

Baek et al. Recently, Mc Cartney et al. Mice lacking just 1 copy. Thus, in the case of EMCV-D which infects and damages directly the pancreatic cells, optimal functioning of viral sensors and type 1 IFN responses are required to prevent diabetes []. Kilham rat virus Ellerman et al. Chung et al. As it had been previ ously shown, KRV did not directly infect -cells.

Thus, Choung et al. Thus, KRV might be responsible for the activation of autoreactive T cells that are cytotoxic to beta cells, resulting in T cell-mediated autoimmune diabetes. Zipris et al. The disease was associated with accumulation of non proliferating Treg in pancreatic lymph nodes.

Together these data suggest a virus- and rat strain- specific mechanism of KRV-induced diabetes in genetically susceptible rats as BBDR rats, through an alteration of T cell regulation. It ap pears that Treg are no longer able to inhibit autoreactive T cells activation []. Using appropriate inhibitors of TLRsignaling pathways, Zipris et al. Finally, ad ministration of chloroquine to virus-infected BBDR rats decreased the incidence of diabetes. These data indicates that the TLR9 -signaling path way is implicated in the KRV-induced innate immune activation and participates to the de velopment of autoimmune diabetes in the BBDR rat [, 13].

The role of these viruses in the human T1D has not been reported, however, the Ljungan virus is another rodent virus that has been suspect ed to be involved in human type 1diabetes.

Ljungan virus and human parechoviruses The Ljungan virus LV is a RNA virus discovered in Sweden in the mids in rodents Myodes glareolus; formerly Clethrionomys glareolus called bank vole.

This virus be longs to the Parechovirus genus within the Picornaviridae family. Niklasson et al. The disease was correlated with LV antibodies. Moreover, LV antigen was detected by immunocytochemistry in the is lets of diabetic bank voles. In parallel, two groups of new onset diabetic children were stud ied: the first group represented a total of 53 children which were diagnosed with T1D between and , and the second group was composed of children with newly di agnosed T1D between and The study showed increased levels of LV antibodies in newly diagnosed T1D children indicating a possible zoonotic relationship between LV infec tion and human T1D [].

In addtion to type 1 diabetes, viruses could be involved in the development of type 2 diabe tes. Indeed, Niklasson et al.

Pregnant CD-1 mice were infected with LV and kept under not stressful conditions. After weaning, puberty male mice were kept under stress all males in the same cage or not animals in individual cage. Only animals infected in utero and kept under stress devel oped diabetes.

Thus, in these animals, viral infection in utero, in combination with stress in adult life could induce diabetes in males []. In , Blixt et al. Human parechoviruses, like LV, belong to the Parechovirus genus; they have also been im plicated in the development of T1D in humans. In a recent nested case-control study, the. Environmental Triggers of Type 1 Diabetes: The MIDIA study, stool samples from 27 chil dren who developed islet autoimmunity repeatedly positive for two or three autoantibod ies and 53 children matched for age and community of residence control group were analyzed for human parechovirus using a semi-quantitative real-time polymerase chain re action every month from the 3rd to the 35th month.

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