VII International "Onnela" Workshop: gut immune system and type 1 diabetes mellitus held in Janakkala, Finland, June 25-26, 1998.
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Diabetes Mellitus, Type 1↗
Biomedical subjects
M Knip
Publications and source records attributed to M Knip.
Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group.
The relationships between genetic markers and disease-associated autoantibodies were studied in an unselected population of 701 siblings of children with type 1 diabetes, and the predictive characteristics of these markers over a period of 9 years were determined. Increased prevalences of all the antibodies were closely associated with HLA identity to the index case, the DR4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 genotype. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*02 alleles. Siblings carrying the protective DR2 and DQB1*0602-3 alleles were characterized by lower frequencies of islet cell antibodies (ICA), antibodies to IA-2 (IA-2A), and GADA. Higher levels of ICA were related to HLA identity, the DR4 and DQB1*0302 alleles, and the susceptible DQB1 genotypes, while no significant differences were observed in the levels of IA-2A, GADA, or insulin autoantibodies among siblings with different HLA risk markers. The DR2 or DQB1*0602-3 alleles were not related to the levels of any antibody specificity. A combination of the genetic markers and autoantibodies increased the positive predictive values of all autoantibodies substantially, which may have clinical implications when evaluating the risk of developing type 1 diabetes at the individual level or when recruiting high-risk individuals for intervention trials. However, because such combinations also resulted in reduced sensitivity, autoantibodies alone rather than in combination with genetic markers are recommended as the first-line screening in siblings. Finally, not all siblings with a broad humoral autoimmune response or high-risk genetic markers present with type 1 diabetes, while some with a low genetic risk and weak initial signs of humoral autoimmunity may progress to disease.
Alleles↗
Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group.
Type 1 diabetes is considered to be a T-cell-mediated autoimmune disease in which insulin-producing beta-cells are destroyed. Immunity to insulin has been suggested to be one of the primary autoimmune mechanisms leading to islet cell destruction. We have previously shown that the first immunization to insulin occurs by exposure to bovine insulin (BI) in cow's milk (CM) formula. In this study, we analyzed the development of insulin-specific T-cell responses by proliferation test, emergence of insulin-binding antibodies by enzyme immunoassay, and insulin autoantibodies by radioimmunoassay in relation to CM exposure and family history of type 1 diabetes in infants with a first-degree relative with type 1 diabetes and increased genetic risk for the disease. The infants were randomized to receive either an adapted CM-based formula or a hydrolyzed casein (HC)-based formula after breast-feeding for the first 6-8 months of life. At the age of 3 months, both cellular and humoral responses to BI were higher in infants exposed to CM formula than in infants fully breast-fed (P = 0.015 and P = 0.007). IgG antibodies to BI were higher in infants who received CM formula than in infants who received HC formula at 3 months of age (P = 0.01), but no difference in T-cell responses was seen between the groups. T-cell responses to BI at 9 months of age (P = 0.05) and to human insulin at 12 (P = 0.014) and 24 months of age (P = 0.009) as well as IgG antibodies to BI at 24 months of age (P = 0.05) were lower in children with a diabetic mother than in children with a diabetic father or a sibling, suggesting possible tolerization to insulin by maternal insulin therapy. The priming of insulin-specific humoral and T-cell immunity occurs in early infancy by dietary insulin, and this phenomenon is influenced by maternal type 1 diabetes.
Animals↗
Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B.
Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)- and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association.
Adolescent↗
Cow's milk consumption, HLA-DQB1 genotype, and type 1 diabetes: a nested case-control study of siblings of children with diabetes. Childhood diabetes in Finland study group.
The evidence for the putative role of cow's milk in the development of type 1 diabetes is controversial. We studied infant feeding patterns and childhood diet by structured questionnaire (n = 725) and HLA-DQB1 genotype by a polymerase chain reaction-based method (n = 556) in siblings of affected children and followed them for clinical type 1 diabetes. In a nested case-control design in a population who had both dietary and genetic data available, we selected as cases those siblings who progressed to clinical diabetes during the follow-up period (n = 33). For each case, we chose as matched control subjects siblings who fulfilled the following criteria: same sex, age within 1 year, not from the same family, the start of the follow-up within 6 months of that of the respective case, and being at risk for type 1 diabetes at the time the case presented with that disease (n = 254). The median follow-up time was 9.7 years (range 0.2-11.3). Early age at introduction of cow's milk supplements was not significantly associated with progression to clinical type 1 diabetes (relative risk adjusted for matching factors, maternal education, maternal and child's ages, childhood milk consumption, and genetic susceptibility markers was 1.60 [95% CI 0.5-5.1]). The estimated relative risk of childhood milk consumption for progression to type 1 diabetes was 5.37 (1.6-18.4) when adjusted for the matching and aforementioned sociodemographic factors, age at introduction of supplementary milk feeding, as well as for genetic susceptibility markers. In conclusion, our results provide support for the hypothesis that high consumption of cow's milk during childhood can be diabetogenic in siblings of children with type 1 diabetes. However, further studies are needed to assess the possible interaction between genetic disease susceptibility and dietary exposures in the development of this disease.
Adolescent↗
Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study.
Previous studies suggest that enterovirus infections may initiate and accelerate beta-cell damage years before the clinical manifestation of type 1 diabetes. We have now analyzed the role of enterovirus infections in the initiation of autoimmunity in children who have tested positive for diabetes-associated autoantibodies in a prospective study starting at birth (the Finnish Diabetes Prediction and Prevention Study). The frequency of enterovirus infections was studied using both serology and testing for the presence of enterovirus RNA in the sera of 21 children who developed and retained autoantibodies and in 104 control subjects chosen from the same study cohort and matched for the time of birth, sex, and HLA alleles determining genetic diabetes susceptibility. Sample intervals were taken as basic units of follow-up, to which the observed number of infections was adjusted. Enterovirus infections were detected in 26% of sample intervals in the case subjects and in 18% of the sample intervals in the control children (P = 0.03). A temporal relationship between enterovirus infections and the induction of autoimmunity was found; enterovirus infections were detected in 57% of the case subjects during a 6-month follow-up period preceding the first appearance of autoantibodies compared with 31% of the matched control children in the same age-group (odds ratio 3.7, 95% CI 1.2-11.4). The frequency of adenovirus infections did not differ between the patient and control groups. Our data imply that enterovirus infections are associated with the development of beta-cell autoimmunity and provide evidence for the role of enteroviruses in the initiation of beta-cell destruction.
Alleles↗
Obesity, increased linear growth, and risk of type 1 diabetes in children.
OBJECTIVE: The purpose of the present study was to evaluate the effect of obesity and linear growth on the risk of developing type 1 diabetes in children. RESEARCH DESIGN AND METHODS: The study population consists of all diabetic children <15 years of age diagnosed from September 1986 to April 1989 in Finland and their birth date- and sex-matched population-based control subjects. Growth data were obtained from well-baby clinics and school health care units for 586 diabetic and 571 control subjects, resulting in a total of 18,823 paired weight-height observations. RESULTS: Both boys and girls who developed type 1 diabetes were heavier and taller throughout childhood than control children. A 10% unit increment in relative weight was associated with a 50-60% increase in the risk of type 1 diabetes before 3 years of age and a 20-40% increase from 3 to 10 years of age. The increase in risk of type 1 diabetes for 1 SD score increment in relative height was 20-30%. Obesity (relative weight > 120%) after 3 years of age was associated with a more than twofold risk of developing type 1 diabetes. CONCLUSIONS: The present observation that obesity and rapid linear growth are risk factors for type 1 diabetes in children indicates that the increase in the prevalence of obesity and secular growth that has occurred in most industrialized countries over the last decades may be involved in the increase in type 1 diabetes incidence simultaneously observed in many countries.
Aging↗
Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes.
OBJECTIVE: To assess whether there are any differences in genetic, autoimmune, or clinical features between type 1 diabetes presenting in childhood and that diagnosed later. RESEARCH DESIGN AND METHODS: We studied 352 individuals (252 children and adolescents <20 years of age and 100 adults > or =20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years at a university hospital in northern Finland with a primary catchment area population of approximately 300,000. The patients were analyzed for susceptible and protective HLA-DQB1 alleles (*02, *0302, *0301, *0602, *0603, and *0604), islet cell antibodies (ICA), insulin autoantibodies, and antibodies to GAD and IA-2 (IA-2A). Their clinical symptoms and signs were recorded at diagnosis. RESULTS: The adult patients carried the high-risk DQB1*02/0302 genotype less frequently than the children and more often had protective genotypes. They also had a decreased frequency of all 4 single autoantibody specificities and of multiple (> or =3) autoantibodies. The proportion of patients testing negative for all autoantibodies was lower among the children than among the adults. IA-2A were associated with the DQB1*0302/x genotype in both the children and adults, and the same held true for ICA among the adults. The adults were characterized by a higher proportion of males, a longer duration of symptoms, and a lower frequency of infections during the preceding 3 months. In addition, they had a higher relative body weight on admission and milder signs of metabolic decompensation (higher pH, base excess, and bicarbonate concentrations) and a lower glycated hemoglobin level at diagnosis than the children. CONCLUSIONS: Clinical manifestation of type 1 diabetes before the age of 20 years is associated with a strong HLA-defined genetic disease susceptibility, an intensive humoral immune response to various beta-cell antigens, a higher frequency of preceding infections, and a shorter duration of symptoms and more severe metabolic decompensation at diagnosis. Taken together, these observations suggest that the age at clinical onset of type 1 diabetes is determined by the intensity of the beta-cell-destructive process, which is modulated by both genetic and environmental factors.
Adolescent↗
Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group.
Recent prospective studies have documented serologically an increased frequency of enterovirus infections in prediabetic children, indicating that these infections may initiate and accelerate the beta-cell damaging process several years before the clinical manifestation of type 1 diabetes. The aim of the present study was to establish whether these serological findings would be supported by the detection of enterovirus RNA in a unique prospective series of sera collected from prediabetic children 0-10 years before the manifestation of clinical type 1 diabetes. Reverse transcription followed by polymerase chain reaction employing highly conserved primers among enteroviruses were used to amplify enteroviral sequences. Viral RNA was found in 22% (11/49) of follow-up samples from prediabetic children but in only 2% (2/105) of those from controls (OR 14.9, P < 0.001). Persisting RNA positivity was not observed in any of these children. The presence of enterovirus RNA was associated with concomitant increases in the levels of autoantibodies against islet cells (OR 21.7, P < 0.01) and glutamic acid decarboxylase (OR 15.4, P < 0.05), but not in the levels of antibodies against insulin or the tyrosine phosphatase-like IA-2 protein. In contrast to the prediabetic children, those with newly diagnosed type 1 diabetes were negative for enterovirus RNA. The results thus complement previous serological data, suggesting that enterovirus infections are an important risk factor underlying type 1 diabetes and associated with the induction of beta-cell autoimmunity even years before symptoms appear.
Adolescent↗
Valproate-induced hyperandrogenism during pubertal maturation in girls with epilepsy.
Valproate is effective for treatment of a variety of seizure types both in adults and in children with epilepsy, but it induces obesity and polycystic ovaries in a considerable proportion of adult women, particularly when the medication is started before the age of 20. In the present study we evaluated reproductive endocrine function in 41 girls, 8 to 18 years old, taking valproate for epilepsy and in 54 healthy control girls. Among the girls taking valproate, 16 were prepubertal, 11 were pubertal, and 14 were postpubertal, and the corresponding numbers were 20, 13, and 21 in the control group. The mean serum testosterone concentrations of prepubertal, pubertal, and postpubertal girls taking valproate were significantly higher than those of the control girls at the same pubertal stage. Hyperandrogenism, defined as serum testosterone levels higher than the mean + 2SD in the control girls at the same pubertal stage, was seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls taking valproate. In addition, postpubertal girls taking valproate were more obese than the controls and the mean serum insulin-like growth factor binding protein-1 concentration of pubertal and postpubertal hyperandrogenic girls taking valproate was lower than in valproate-treated girls without hyperandrogenism. Valproate may induce hyperandrogenism in girls with epilepsy during the sensitive period of pubertal maturation, and the frequency of hyperandrogenism increases with pubertal development. This emphasizes the importance of careful endocrine observation of girls taking valproate for epilepsy.
Adolescent↗
Progression to type 1 diabetes is associated with a change in the immunoglobulin isotype profile of autoantibodies to glutamic acid decarboxylase (GAD65). Childhood Diabetes in Finland Study Group.
To investigate whether type 1 diabetes in man is associated with a preferential Th1/Th2 response, and whether autoantibodies to one of the main autoantigens would reflect such a response, we characterized the immunoglobulin isotype profile to the 65-kDa isoform of glutamic acid decarboxylase (GAD65) in siblings to IDDM patients. Samples obtained from affected subjects before and at clinical onset of IDDM, from unaffected individuals at high risk and at low risk and from healthy controls were studied. The immunoglobulin isotype profile in the siblings at low risk reflected a more immature, i.e., IgM and Th2 like, i.e., IgE response compared to the progressors and siblings at high risk, with significantly higher median levels of IgM and IgE. The rank order of anti-GAD65 immunoglobulin isotypes was similar in the siblings before and at clinical onset of IDDM, IgG1 > IgG4 > IgM > IgE > IgA > IgG3 > IgG2, but markedly different in the individuals at low risk, IgG1 > IgM > IgE > IgG4 > IgG3 > IgA > IgG2. Based on these observations, we suggest that progression to clinical onset of IDDM is associated with a maturation and a decrease in the Th2 immune response against GAD65; findings which could have implications for future intervention and prediction strategies.
Adolescent↗
T cell responses to enterovirus antigens and to beta-cell autoantigens in unaffected children positive for IDDM-associated autoantibodies.
Enterovirus infections have been implicated in the pathogenesis of IDDM in a number of studies. The aim of the present study was to evaluate whether the cellular immune response to enterovirus antigens is abnormal in children who test positive for IDDM-associated autoantibodies. Lymphocyte proliferation responses were analysed to enterovirus antigens and to a panel of beta-cell autoantigen preparations in 31 non-diabetic ICA and/or GAD65 antibody-positive children and in 19 ICA/GAD65-negative control children. The responses to highly purified enteroviruses did not differ between autoantibody (AA)-positive and -negative subjects. However, proliferation responses to coxsackievirus-infected cell lysate, which also included non-structural proteins of the virus, were higher in AA-positive than in AA-negative subjects (P<0.05). This difference was most marked in children carrying the HLA-DQB1*02 allele (P=0.01). AA-positive subjects also had higher responses to one of the three GAD65 antigen preparations compared to AA-negative subjects (P<0.05). Proliferation responses to the adenovirus hexon protein did not differ between the groups. These results show that the increased responses to virus infected cell lysates are associated with early phases of beta-cell autoimmunity.
Adolescent↗
Cystatin C as a marker for glomerular filtration rate in pediatric patients.
Cystatin C is a non-glycated 13-kilodalton basic protein produced by all nucleated cells. The low molecular mass and the basic nature of cystatin C, in combination with its stable production rate, suggest that the glomerular filtration rate (GFR) is the major determinant of cystatin C concentration in the peripheral circulation. Recently published studies have shown that cystatin C correlates more strongly than creatinine with GFR measured using the 51Cr-EDTA clearance. The aim of this study was to evaluate serum cystatin C as a marker for GFR in children. GFR was determined on medical indications using the 51Cr-EDTA technique in pediatric patients (2-16 years) in our renal unit. Simultaneously their cystatin C and creatinine concentrations were also measured. Of our 52 patients, 19 had a reduced renal function (<GFR 89 ml/min per 1.73 m2) based on the 51Cr-EDTA clearance. The correlation of cystatin C with the isotopic measurement of GFR tended to be stronger (r=0.89, P=0.073) than that of creatinine (r=0.80). Receiver operating characteristic analysis showed that the diagnostic accuracy of cystatin C was better (P=0.037) than that of creatinine in discriminating between subjects with normal renal function and those with reduced GFR. This study demonstrates that serum cystatin C has an increased diagnostic accuracy for reduced GFR when compared with serum creatinine. Hence, cystatin C seems to be an attractive alternative for the estimation of GFR in children.
Adolescent↗
Absence of glutamic acid decarboxylase antibodies in childhood epilepsies.
Glutamic acid decarboxylase antibodies are present in some patients with therapy-resistant epilepsy. The authors measured glutamic acid decarboxylase antibodies in an unselected population of 114 children with different types of epilepsy. Three children with temporal lobe epilepsy and six children with various other types of epilepsy had intractable epilepsy. None of the children tested positive for glutamic acid decarboxylase antibodies. The study suggests that glutamic acid decarboxylase antibody testing cannot be recommended in unselected cases of childhood epilepsy.
Antibodies↗
Relation between T-cell responses to glutamate decarboxylase and coxsackievirus B4 in patients with insulin-dependent diabetes mellitus.
BACKGROUND: the role of enteroviruses has been implicated in the etiology of insulin-dependent diabetes mellitus (IDDM). A possible connection between glutamate decarboxylase (GAD) autoimmunity and enterovirus infections in IDDM has been suggested to be based on a homology region between GAD and the non-structural protein 2C of coxsackievirus B4 (CVB4). OBJECTIVES: the aims of the study were to measure the occurrence of cellular immunity to GAD and CVB4 in Finnish patients with newly diagnosed IDDM, and to study the relation between these two responses. T-cell responses to GAD and CVB4 were analyzed in relation to HLA DQB1 risk alleles for IDDM and antibodies to GAD and CVB4. STUDY DESIGN: T-cell and antibody responses to GAD65 and purified CVB4 were measured in patients with newly diagnosed IDDM and in healthy children. The purified CVB4 did not contain the non-structural protein 2C thus lacking the reported homology region with GAD. RESULTS: high proliferative responses of PBMC to both GAD and CVB4 were more frequent in IDDM patients than in the control children (40 vs. 16%, 27 vs. 10%; P = 0.03 and 0.04, respectively; Fisher's exact test), when the cut-off for positivity was three multiples of the median SI in the healthy children. Median SI to GAD was higher in the patients with IDDM than in the control subjects (3.10 vs. 1.55; P = 0.03, Mann-Whitney U-test). T-cell responses to GAD and CVB4 showed a positive correlation in the patients (r = 0.62, P = 0.001), but not in the control children (r = 0.23; P = 0.38). CONCLUSIONS: enhanced T-cell responsiveness to CVB4 in patients with newly diagnosed IDDM support the involvement of enteroviral infections in the development of IDDM. The observed correlation between T-cell reactivity to GAD and CVB4, lacking the crossreactive protein 2C, in patients with IDDM suggests that CBV4 reactivity is associated with GAD autoimmunity in IDDM but does not reflect immunization to GAD.
Adolescent↗
Disease-associated autoantibodies and HLA-DQB1 genotypes in children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). The Childhood Diabetes in Finland Study Group.
The possible relation between HLA-DQ genotypes and both frequencies and levels of autoantibodies associated with IDDM was assessed by examining HLA-DQB1 alleles and antibodies to islet cells (ICA), insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase-related IA-2 molecule (IA-2A) in 631 newly diagnosed diabetic children under the age of 15 years. ICA were found in 530 children (84.0%), while close to half of the subjects (n = 307; 48.7%) tested positive for IAA. GADA were detected in 461 index cases (73.1%), with a higher frequency in those older than 10 years (78.9% versus 69.2% in the younger ones; P = 0.006). More than 85% of the children (n = 541; 85.7%) tested positive for IA-2A. Altogether there were only 11 children (1.7%) who had no detectable autoantibodies at diagnosis. There were no differences in the prevalence of ICA or GADA between four groups formed according to their HLA-DQB1 genotype (DQB1*0302/02, *0302/X (X = other than *02), *02/Y (Y = other than *0302) and other DQB1 genotypes). The children with the *0302/X genotype had a higher frequency of IA-2A and IAA than those carrying the *02/Y genotype (93.8% versus 67.3%, P < 0.001; and 49.0% versus 33.6%, P = 0.002, respectively). The children with the *02/Y genotype had the highest GADA levels (median 36.2 relative units (RU) versus 14.9 RU in those with *0302/X; P = 0.005). Serum levels of IA-2A and IAA were increased among subjects carrying the *0302/X genotype (median 76.1 RU versus 1.6 RU, P = 0.001; and 50 nU/ml versus 36 nU/ml, P = 0.004) compared with those positive for *02/Y. Only three out of 11 subjects homozygous for *02 (27.3%) tested positive for IA-2A, and they had particularly low IA-2A (median 0.23 RU versus 47.6 RU in the other subjects; P < 0.001). The distribution of HLA-DQB1 genotypes among autoantibody-negative children was similar to that in the other patients. These results show that DQB1*0302, the most important single IDDM susceptibility allele, is associated with a strong antibody response to IA-2 and insulin, while GAD-specific humoral autoimmunity is linked to the *02 allele, in common with a series of other autoimmune diseases as well as IDDM. We suggest that IA-2A may represent beta cell-specific autoimmunity, while GADA may represent a propensity to general autoimmunity.
Adolescent↗
Population-based genetic screening for the estimation of Type 1 diabetes mellitus risk in Finland: selective genotyping of markers in the HLA-DQB1, HLA-DQA1 and HLA-DRB1 loci.
AIMS: To improve sensitivity and specificity of the diabetes risk assessment of the population-based genetic screening used in the Finnish Diabetes Prediction and Prevention (DIPP) trial. METHODS: One thousand consecutive newborns enrolled in the DIPP were compared with 316 samples from children with Type 1 diabetes mellitus. A modification of the previously described technique based on hybridization of relevant PCR products with five lanthanide-labelled probes detected by time-resolved fluorometry (TRF) was used. A new probe was designed and allowed discrimination between DQB1*0602 and 0603 alleles, in addition to DQB1*02, *0301 or *0302, each of which required specific probes. A new, added screening strategy was developed for individuals carrying low-risk genotypes through specific typing of DQA1 *05 and *0201 alleles in DQB1*02 positive, and DRB1 typing for DR4 subtypes in DQB1*0302 positive subjects, with a new specifically designed high-resolution TRF-based DR4 subtyping technique. RESULTS: This two-step screening approach enhanced the sensitivity of the detection of genetic risk for Type 1 diabetes mellitus in this cohort up to 85.4%. In the general population cohort, 24.4% were identified for prospective follow-up, 2.6% of these are expected to develop Type 1 diabetes mellitus before the age of 15 years. Exclusive typing for HLA-DQB1 locus as an alternative screening strategy had sensitivities of 26.3-77.2% with general population cohorts of 2.3-23.1% identified for follow-up. CONCLUSIONS: The described strategy for genetic prediction of Type 1 diabetes mellitus relies on the convenient genotyping procedure and could be applied in large scale screening projects such as DIPP.
Biomarkers↗
Environmental factors in the pathogenesis of type 1 diabetes mellitus.
Type 1 diabetes mellitus is perceived as a chronic autoimmune disease with a subclinical prodrome characterized by selective loss of insulin producing beta cells in the pancreatic islets in genetically predisposed subjects. Less than 10% of those with increased genetic susceptibility progress to clinical disease suggesting a strong environmental modification of the prediabetic process. Various exogenous triggers, such as certain dietary factors and viruses, are thought to induce the autoimmune process leading in some individuals to extensive beta-cell destruction and ultimately to the clinical manifestation of type 1 diabetes. In addition to their role as triggers, environmental factors are also likely affecting the outcome of the process and the rate of progression to clinical disease in those who do develop Type 1 diabetes. The present review focuses on relatively recent data on environmental factors potentially involved in the pathogenesis of Type 1 diabetes with an emphasis on dietary factors, and cow's milk (CM) proteins in particular. The CM hypothesis has remained controversial for a decade, and therefore an intervention trial should be performed to settle the issue. Recent prospective studies have indicated that enterovirus infections may induce beta-cell autoimmunity and potentiate the humoral immune response to beta-cell antigens in subjects with an ongoing process. There are also very preliminary data suggesting a similar role for rotavirus infections. Although there may be a single trigger of beta-cell autoimmunity in a given individual, it is highly unlikely that there is only one exogenous determinant of Type 1 diabetes. Rather we have a complicated interaction between a series of environmental factors and between environmental factors and genetic disease predisposition resulting in progression to clinical Type 1 diabetes in those genetically susceptible individuals who experience an unfortunate timing and/or clustering of diabetogenic exogenous culprits and/or a lack of protective environmental modifiers. Ongoing prospective studies starting from birth provide an optimal setting for the identification of environmental factors affecting the risk of progression to clinical Type 1 diabetes.
Animals↗