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M Knip

Publications and source records attributed to M Knip.

At least 73 records · Page 4Linked to original sources
PubMed2001

The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish Type 1 Diabetes Prediction and Prevention Study.

Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of beta-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of beta-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of beta-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.

Autoantibodies↗
PubMed2001

Disease-associated autoantibodies as predictive markers of type 1 diabetes mellitus in siblings of affected children.

The long latent preclinical period of type 1 diabetes mellitus (DM) makes it possible to identify individuals at increased risk for clinical DM before the beta-cell destructive process has reached the point of no return. A series of reports on the predictive value of DM-associated autoantibodies are available in first-degree relatives of patients with type 1 DM, but only a few of these studies target exclusively siblings and young siblings of affected children. When planning screening of siblings for DM risk, their age needs to be considered, as predictive characteristics of autoantibodies seem to vary in different age groups. Autoimmunity may be initiated early in life and therefore early screening for signs of beta-cell autoimmunity is crucial to avoid missing young children en route to overt DM and to be able to start intervention, when clinically applicable preventive modalities become available, before the disease process has advanced too far. Young age, positivity for at least two autoantibodies, high levels of autoantibodies and low first phase insulin response are highly predictive for progression to clinical disease in initially unaffected siblings of children with type 1 DM.

Aging↗
PubMed2001

Dynamic pattern of disease-associated autoantibodies in siblings of children with type 1 diabetes: a population-based study.

To study the dynamics of disease-associated humoral immune responses, we analyzed autoantibodies to the IA-2 protein (IA-2A), glutamic acid decarboxylase (GADA), and insulin (IAA) and also islet cell antibodies (ICA) in a population-based, prospective, representative series of 710 siblings (<20 years of age) of children with type 1 diabetes. Positivity for single autoantibodies was observed in 8-13% of these siblings during an average follow-up of 4 years. The overall incidence rates per 1,000 years (number of cases/person-years in parentheses) for positive seroconversion of IA-2A were nine (19/2,123), followed by six (12/2,049) for GADA, 19 (40/2,111) for IAA, and 16 (31/1965) for ICA. Positive seroconversions seemed to be associated with a young age of the sibling, HLA DR3/DR4 heterozygosity, HLA identity, and a high initial number of detectable autoantibodies. The overall incidence rates per 1,000 years (number of cases/person-years in parentheses) for inverse seroconversion of IA-2A were 76 (12/157), followed by 42 (10/237) for GADA, 460 (32/70) for IAA, and 27 (9/331) for ICA. No consistent risk factor for inverse seroconversions was present, although seroconversions were most frequent in siblings with older age, male sex, HLA phenotypes other than DR3/DR4, a small family size, and no other autoantibodies detectable at seroconversion. Altogether, these observations indicate that beta-cell autoimmunity may be induced at any age in childhood and adolescence. HLA-conferred genetic disease susceptibility is a strong determinant of persistent beta-cell autoimmunity, but environmental factors may also contribute to such autoimmunity.

Adolescent↗
PubMed2001

Peripheral nerve function is increasingly impaired during puberty in adolescents with type 1 diabetes.

OBJECTIVE: To evaluate the impact of puberty on peripheral nerve function in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: Of 138 eligible patients with type 1 diabetes, 100 patients (age >9 years and diabetes duration >2 years) attending an outpatient diabetes clinic and 100 age- and sex-matched healthy control subjects took part in this cross-sectional study. Peripheral motor and sensory nerve conduction tests, cardiovascular reflex tests on the autonomic nervous system, and measurements of vibration-perception threshold (VPT) were performed. RESULTS: Nerve conduction velocity (NCV) in the distal motor and sensory nerves, the motor nerve distal latency, and the sensory nerve action potential (SNAP) amplitude were impaired in the adolescent patients with type 1 diabetes. The deterioration in motor NCV, H-reflex latency, and SNAP amplitude became more conspicuous in late puberty and postpuberty and was related to poor metabolic control. A total of 10 patients had distal diabetic polyneuropathy (DP) neurophysiologically, and these patients had significantly lower heart-rate variation in the deep breathing test than the other patients. Three of the patients with DP had peripheral neurological signs or symptoms. A slight difference in the VPT between the patients and control subjects was observed after puberty. CONCLUSIONS: Increasing subclinical motor nerve impairment can be detected during late puberty and after puberty, and sensory NCV and SNAP amplitude are reduced in adolescents with type 1 diabetes. Poor metabolic control during puberty appears to induce deteriorating peripheral neural function in young patients with type 1 diabetes.

Action Potentials↗
PubMed2000

Novel fusion proteins in the analysis of diabetes-associated autoantibodies to GAD65 and IA-2.

Assays to detect autoantibodies to glutamic acid decarboxylase (GAD65) and the protein tyrosine phosphatase-like molecule IA-2, which are both present in pancreatic islets, have been used in the diagnosis and prediction of type 1 diabetes. In this study a novel fusion protein combining the entire GAD65 molecule with the 40 kDa intracellular domain of IA-2 (GAD-IA-2) was constructed to detect autoantibodies to both antigens by one single assay. For the same purpose a truncated version of this fusion protein which contained the entire GAD65 linked to the 203 carboxy-terminal amino acids of IA-2 (GAD-dIA-2) was made. A panel of 34 diabetic sera which represented unequivocally positive or negative antibody responses to GAD65 and/or IA-2 as well as 20 serum samples from healthy controls were tested in a radioligand binding assay with the constructed fusion proteins as antigens. Nine of the samples from patients with type 1 diabetes reacted with GAD65 while being negative for IA-2. Six sera were positive for IA-2 only, 11 were double positive, and 8 negative for both antibodies using the standard in vitro transcription translation assay with single antigens. The full-length, as well as the truncated fusion protein detected all samples positive for antibodies either to GAD65 or IA-2 or both, except for one GAD65 antibody positive sample. All samples from healthy controls tested negative in all assays. We conclude that the principle of a combinatorial molecule where a fusion protein expresses both GAD65 and IA-2 epitopes is feasible, and such a fusion protein can be used instead of the single antigens to reduce time and costs of large-scale screening for clinical purposes.

Adolescent↗
PubMed2000

Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy.

BACKGROUND: Autoantibodies to glutamic acid decarboxylase (GAD-A) are present in type 1 diabetes and stiff man syndrome (SMS), and have also been reported in cerebellar ataxia. Epilepsy was present in 4 of 19 patients with SMS and GAD-A, implying that epilepsy sometimes is associated with anti-GAD autoimmunity. METHODS: The authors investigated the prevalence of GAD-A in patients with therapy-resistant localization-related epilepsy (n = 51) and generalized epilepsy (n = 49) by a radiobinding assay. The positive samples were confirmed by immunohistochemistry and immunoblotting of recombinant human GAD65. RESULTS: GAD-A were found in eight patients with localization-related epilepsy, whereas none of the patients with generalized epilepsy, other neurologic disorders (n = 38), or the control subjects (n = 48) had GAD-A. Two patients had high levels of GAD-A, similar to SMS, whereas six patients had significantly lower titers, characteristic of type 1 diabetes. The two patients with high levels of GAD-A had GAD-A both in serum and CSF by immunohistochemistry and immunoblotting. Both of them had longstanding therapy-resistant temporal lobe epilepsy but did not have diabetes. One had a history of autoimmune disease, whereas the other had serologic evidence of multiple autoantibodies without any clinical signs of autoimmune disease. CONCLUSIONS: GAD autoimmunity may be associated with refractory localization-related epilepsy.

Adolescent↗
PubMed2000

Epitope spreading and a varying but not disease-specific GAD65 antibody response in Type I diabetes. The Childhood Diabetes in Finland Study Group.

AIMS/HYPOTHESIS: The aim of this study was to analyse the conformational and linear epitope profiles of glutamic acid decarboxylase antibody (GAD65-ab)-positive sera to find disease-specific epitope profiles and to study, whether GAD65-ab epitope recognition changes or spreads during the prediabetic period and, thus, can provide markers to differentiate early from later stages of progression to diabetes. METHODS: Sera from subjects before (n = 21), at onset (n = 44), or at increased risk of Type I (insulin-dependent) diabetes mellitus (n = 20) and from patients with stiff-man syndrome (SMS, n = 18) or polyendocrine autoimmune syndrome (PAS, n = 21) were analysed for conformational and linear GAD65 epitope recognition by an immunohistochemical blocking test based on human monoclonal GAD65-ab (MICA 1-10) and western blotting of a GAD65 epitope-cDNA-library. RESULTS: A redundant reactivity of many GAD65-ab positive sera to three major conformational (EP-1, EP-2, EP-3) and two dominant linear epitope clusters (amino acid 1-124 and 535-585) was observed in diabetes, polyendocrine autoimmune syndrome and stiff-man syndrome and no disease-specific epitopes or epitope-profiles were detected. Epitope recognition broadened with higher titres and with the vulnerability of patients to acquire additional autoimmune diseases apart from diabetes. Low GAD65-ab serum titres (< 1200 arbitrary units) and EP-1 recognition in the absence of EP-2 binding characterised the early immune response. Changing epitope profiles combined stable recognition of EP-1 with gain or loss of reactivity to C-terminal epitopes during follow-up. CONCLUSION/INTERPRETATION: A maturing autoantibody response, which could spread from EP-1-recognition to other regions of GAD65, resulted in titre-related rather than disease-specific epitope profiles which were not sufficient to predict whether GAD65-ab positive subjects will progress to Type I diabetes, autoimmune polyendocrine syndrome or stiff-man syndrome.

Adolescent↗
PubMed2000

Stability of autoantibodies and their relation to genetic and metabolic markers of Type I diabetes in initially unaffected schoolchildren.

AIMS/HYPOTHESIS: To study temporal changes in positivity for autoantibodies associated with Type I (insulin-dependent) diabetes mellitus and the relations between these antibodies, HLA-DQB1-risk markers and first-phase insulin response (FPIR) in non-diabetic schoolchildren. METHODS: The stability of the antibody status over 2 years was assessed in 104 schoolchildren initially positive for islet cell antibodies (ICA) or antibodies to the 65,000 M(r) isoform of the glutamic acid decarboxylase (GADA) or both and in 104 antibody-negative control children matched for sex, age and place of residence. All children were also studied for their first-phase insulin response and HLA-DQB1 alleles on the second occasion. RESULTS: On the second occasion 3 of the 98 initially ICA-positive children, 3/13 of those positive for antibodies to the IA-2 protein (IA-2A), 1/17 GADA-positive and 2/7 of those positive for insulin autoantibodies (IAA) tested negative for these antibodies. Children with IA-2A, GADA, IAA and multiple (> or = 2) antibodies had significantly lower first-phase insulin responses than the control children. In contrast, these responses did not differ between subjects with and without specific HLA-DQB1-risk alleles or genotypes. Of the six subjects with a considerably reduced first-phase insulin response three had multiple antibodies on both occasions but none of them had a DQB1 genotype conferring increased diabetes risk. Two subjects progressed to Type I diabetes within 3.4 years of follow-up, both of them having multiple antibodies and a considerably reduced first-phase insulin response but neither of them having a DQB1-risk genotype. CONCLUSIONS/INTERPRETATION: Positivity for diabetes-associated autoantibodies is a relatively stable phenomenon in unaffected schoolchildren, although conversion to seronegativity can occur occasionally. Our observations also indicate that DQB1 alleles associated with decreased susceptibility to Type I diabetes do not protect from impaired beta-cell function or from progression to overt disease in initially unaffected schoolchildren.

Adolescent↗
PubMed2000

Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report.

AIMS/HYPOTHESIS: Neonatal diabetes mellitus is rare, and it has not been associated with beta-cell autoimmunity. Enteroviral infections during pregnancy have been implicated as a risk factor for the later development of Type I (insulin-dependent) diabetes mellitus. We now report of a baby girl who was born severely growth-retarded with neonatal insulin-deficient diabetes, and look for evidence of intrauterine enteroviral infections and beta-cell targeted autoimmunity. METHODS: Diabetes-associated autoimmunity was studied by measurement of several types of islet cell reactive autoantibodies. The infant's T-cell responses to insulin and enterovirus antigens were recorded and enterovirus antibodies were measured both from the mother and the child. RESULTS: Several types of diabetes-associated autoantibodies were detected postnatally, including insulin autoantibodies, conventional islet cell autoantibodies and glutamic acid decarboxylase antibodies, whereas no autoantibodies were observed in the mother. The infant's T-cells showed reactivity to insulin and purified enterovirus particles. Based on serological studies, the pathogenetic process could have been triggered by an echovirus 6 infection during pregnancy. The patient's diabetes has been permanent, although there were signs of endogenous insulin production for several months. Exocrine pancreatic insufficiency was diagnosed at the age of 1 year. CONCLUSION/INTERPRETATION: These observations suggests that enteroviral infections may induce beta-cell autoimmunity even in utero.

Autoimmunity↗
PubMed2000

Safety of high-dose nicotinamide: a review.

Nicotinamide, the amide derivative of nicotinic acid, has over the past forty years been given at high doses for a variety of therapeutic applications. It is currently in trial as a potential means of preventing the onset of Type I (insulin-dependent) diabetes mellitus in high-risk, first-degree relatives. Nicotinamide is for regulatory purposes classed as a food additive rather than a drug and has not therefore required the formal safety evaluation normally expected of a new therapy. Because the safety of treatment with megadoses of vitamins cannot be assumed, a full literature review has been undertaken. The therapeutic index of nicotinamide is wide but at very high doses reversible hepatotoxicity has been reported in animals and humans. Minor abnormalities of liver enzymes can infrequently occur at the doses used for diabetes prevention. There is no evidence of teratogenicity from animal studies and nicotinamide is not in itself oncogenic; at very high doses it does however potentiate islet tumour formation in rats treated with streptozotocin or alloxan. There is no evidence of oncogenicity in man. Growth inhibition can occur in rats but growth in children is unaffected. Studies of its effects on glucose kinetics and insulin sensitivity are inconsistent but minor degrees of insulin resistance have been reported. The drug is well tolerated, especially in recent studies which have used relatively pure preparations of the vitamin. Experience to date therefore suggests that the ratio of risk to benefit of long-term nicotinamide treatment would be highly favourable, should the drug prove efficacious in diabetes prevention. High-dose nicotinamide should still, however, be considered as a drug with toxic potential at adult doses in excess of 3 gm/day and unsupervised use should be discouraged.

Abnormalities, Drug-Induced↗
PubMed2000

Impaired insulin secretion in non-diabetic offspring of probands with latent autoimmune diabetes mellitus in adults.

AIMS/HYPOTHESIS: This study was undertaken to investigate metabolic and genetic characteristics of latent autoimmune diabetes in adults (LADA). METHODS: We evaluated insulin secretory capacity with oral and intravenous glucose tolerance tests (early insulin response) and hyperglycaemic clamp (insulin secretory capacity) and the rates of whole body glucose uptake with the euglycaemic clamp, HLA-DQB1 genotypes (time-resolved fluorescence) and islet cell antibodies (ICA) (immunofluorescence) and antibodies to glutamic acid decarboxylase (GAD) (radio-immunoprecipitation) in 36 non-diabetic offspring (LADA-offspring) of patients with Type II (non-insulin-dependent) diabetes mellitus who tested positive for ICA and/or GAD antibodies during the 10-year follow-up from the diagnosis and in 19 healthy control subjects without a family history of diabetes. RESULTS: The early insulin response during the first 10 min of an intravenous glucose tolerance test was about 40% lower in the LADA-offspring than in the control group (p = 0.008). Insulin secretory capacity in the hyperglycaemic clamp was also about 30% lower in the LADA-offspring (p = 0.048). The rates of whole body glucose uptake were similar in both groups. The frequency of low risk HLA-DQB1 genotypes was higher in the LADA-offspring than among Finnish healthy blood donors (p = 0.033). The risk conferring genotypes were associated with the lowest tertile of insulin secretory capacity in the LADA-offspring (p = 0.032). There were no associations between the autoantibodies and early insulin response or insulin secretory capacity within the study groups. CONCLUSION/INTERPRETATION: We conclude that LADA is a familial disease involving most likely gene defects leading to a slow progressive beta-cell destruction and insulin deficiency.

Adipose Tissue↗
PubMed2000

Geographical differences within Finland in the frequency of HLA-DQ genotypes associated with type 1 diabetes susceptibility. The Childhood Diabetes in Finland Study Group.

Geographical variations in the HLA-DQ genotypes associated with risk for type 1 diabetes were evaluated in Finland. Samples of 280 diabetic children diagnosed in Turku (south-west of the country) and 405 in Oulu (north of the country) were studied as well as a series of 14 096 and 10 016 newborns collected from the same hospitals. There were no major differences in the risk or protection conferred by various HLA-DQB1 genotypes between south-western and northern parts of the country when genotypes of children with type 1 diabetes from these two centres were compared with those of newborns, representing the background populations. However, the distribution of various genotypes was different, both in diabetic children and in newborns, when compared between the two regions (P < 0.0001, chi2 test). These differences reflected the allele frequencies in newborn cohorts in which HLA-DQB1*02 and DQB1*0301 were found more often in Turku and DQB1*0302 more often in Oulu (P < 0.0001 for all differences). Similar types of differences were detected when children who were diagnosed as having diabetes during the national 'Childhood Diabetes in Finland' (DiMe) study between the years 1986-1989 were compared according to their residence. The observed differences in genotype and allele frequencies demonstrate the heterogeneity for HLA alleles even in a population that is generally regarded as highly homogeneous. These differences also affect the sensitivity and efficiency of the screening programme used for identifying infants with genetic susceptibility to IDDM in the ongoing Finnish Diabetes Prediction and Prevention Study.

Adolescent↗
PubMed2000

Human surfactant protein--A gene locus for genetic studies in the Finnish population.

Lung surfactant lowers the surface tension but surfactant proteins also have other functions. Surfactant protein A (SP-A) has a well-defined role in innate immunity. The gene locus for human SP-A genes is in chromosome 10q21 through q24 and consists of two highly homologous functional SP-A genes (SP-A1 and SP-A2) and a pseudogene. Several alleles that differ by a single amino acid have been identified for both SP-A genes. The SP-A gene locus has been shown to be sufficiently polymorphic for genetic studies in the American population. In this study, we analysed the SP-A allele frequencies in a Finnish population (n = 790) and found them to differ from the frequencies observed in US. Furthermore, we describe several new alleles for both SP-A genes. The heterozygosity indices and polymorphism information content values ranged between 0.50--0.62 indicating that SP-A gene locus is polymorphic enough for studies associating the locus with pulmonary diseases.

Alleles↗
PubMed2000

Postnatal elimination of transplacentally acquired disease-associated antibodies in infants born to families with type 1 diabetes. The Finnish TRIGR Study Group. Trial to Reduce IDDM in the Genetically at Risk.

The elimination of maternally acquired, diabetes-associated antibodies from the peripheral circulation of infants was studied in a population of 47 mothers and their newborn infants from families in which at least 1 first degree relative had type 1 diabetes. Blood samples were taken from the placental cord; from the infant at follow-up visits at the ages of 3, 6, 9, 12, 18, and 24 months; and from the mother at the time of delivery. The samples were analyzed for cytoplasmic islet cell antibodies (ICA), insulin antibodies (IA), autoantibodies to the 65-kDa isoform of glutamic acid decarboxylase (GADA), and autoantibodies to the protein tyrosine phosphatase-related IA-2 antigen (IA-2A). The mean elimination times for ICA, IA, GADA, and IA-2A were 3.1, 3.1, 4.5, and 4.3 months (P = NS), respectively. The initial levels of IA, GADA, and IA-2A in the cord blood correlated closely with the elimination time (r(s) = 0:84-0.91; P < 0.001). The mean proportions of ICA, IA, GADA, and IA-2A still detectable were 18%, 21%, 30%, and 20%, respectively, at 3 months; 2.2%, 14%, 10%, and 6% at 6 months; and 0.3%, 15%, 2.3%, and 5.1% at 9 months. One infant still tested positive for GADA at the age of 12 months, whereas all of the other antibodies had been eliminated by that age. When observing the natural history of beta-cell autoimmunity or when screening for secondary prevention in young children, cross-sectional autoantibody analyses do not provide sufficient information. Repeated testing is to be recommended in young children. In infancy, increasing antibody levels most likely reflect de novo synthesis of diabetes-associated autoantibodies.

Aging↗
PubMed2000

ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.

Adolescent↗
PubMed2000

Disease-associated autoantibodies as surrogate markers of type 1 diabetes in young children at increased genetic risk. Childhood Diabetes in Finland Study Group.

To evaluate the emergence of diabetes-associated autoantibodies in young children and to assess whether such antibodies can be used as surrogate markers of type 1 diabetes in young subjects at increased genetic risk, we studied 180 initially unaffected siblings (92 boys and 88 girls) of children with newly diagnosed type 1 diabetes. All siblings were younger than 6 yr of age at the initial sampling, and they were monitored for the emergence of islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) up to the age of 6 yr and for progression to clinical type 1 diabetes up to the age of 10 yr. All 160 siblings with DNA samples available were typed for susceptible (DQB1*02 and *0302) and protective (DQB1*0301 and *0602-03) HLA DQB1 alleles. Twenty-two siblings (12.2%) tested positive for ICA in their first antibody-positive sample before the age of 6 yr, 13 (7.2%) tested positive for IAA, 15 (8.3%) tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There were 16 siblings (8.9%) who had 1 detectable autoantibody, 5 (2.8%) had 2, and 12 (6.7%) had 3 or more. In the group of 82 siblings with increased human leukocyte antigen-defined genetic susceptibility [DQB1*02/*0302, *0302/x (x = other than *02 or a protective allele), *02/y (y = other than *0302 or a protective allele)], 18 (22.0%) tested positive for ICA in their first antibody-positive sample, 10 (12.2%) tested positive for IAA, 14 (17.1%) tested positive for GADA, and 12 (14.6%) tested positive for IA-2A. One antibody was detectable in 6 siblings (7.3%), 2 were detectable in 5 (6.1%), and 3 or more were detectable in 12 (14.6%). Fifteen siblings (18.3%) presented with clinical type 1 diabetes before the age of 10 yr. All of the progressors showed increased human leukocyte antigen-defined genetic susceptibility. Thirteen of those 15 siblings, who presented with clinical type 1 diabetes before the age of 10 yr, had at least 2 antibodies detectable before the age of 6 yr (disease sensitivity, 87%; 95% confidence interval, 60-98%). Thirteen of the 17 siblings who tested positive for 2 or more autoantibodies before the age of 6 yr developed type 1 diabetes before the age of 10 yr (positive predictive value, 76%; 95% confidence interval, 50-93%). These observations suggest that disease-associated autoantibodies can well be used as surrogate markers of clinical type 1 diabetes in primary prevention trials targeting young subjects with increased genetic disease susceptibility.

Adolescent↗