Islet cell and insulin autoantibodies in subjects at high risk for development of Type 1 (insulin-dependent) diabetes mellitus: the Lyon family study

Summary Genetic determination as well as prospective analysis of islet cell autoantibodies and autoantibodies to insulin were conducted in a population of 479 first degree relatives of 174 Type 1 (insulin-dependent) diabetic patients. Analysis of HLA haplotypes within families illustrated the high frequency of DR3 and DR4 alleles with preferential transmission from parent to both affected and unaffected offspring. DR4 was preferentially associated with DQw3.2 (TA10^–) in 60/73 (82.2%) patients and 101/127 (79.5%) relatives. Relatives have been followed for a period of 800 subject-years. Twenty-two out of 430 relatives (5.1%) were found islet cell antibodies (ICA-IgG) positive. Seven sera with low titres became negative 6 months later at two different determinations. Fifteen sera ICA-IgG and ICA-protein A positive with high titres remained positive thereafter. Half of the ICA positive relatives were also found insulin autoantibodies (IAA) positive. All but 3 ICA negative relatives did not have IAA in their sera. Analysis of IAA specificity with competition experiments indicated that most antibodies recognised epitopes shared between human and pork insulins while four were specific for human insulin determinants. Analysis of class I and class II HLA antigen distribution indicated no particular allelic restriction in antibody positive individuals. Metabolic status of antibody positive relatives was determined with oral and intravenous charge of glucose. Two haplo-identical DR3-DQw2 brothers became diabetic during the study. One child and one mother both with DR4-DQw3.2 became intolerant to glucose. Each of these relatives had high titre ICA prior to metabolic deterioration. Taken together, these data indicated that ICA and IAA may be present in first degree relatives of diabetic patients. Individualisation of markers of the ongoing autoimmune process and accurate evaluation of the residual B-cell mass are necessary steps before further immune interventions in the early phases of the disease.     

Proinsulin autoantibodies are more closely associated with Type 1 (insulin-dependent) diabetes mellitus than insulin autoantibodies

Summary The disease association of autoantibodies to proinsulin and insulin was compared in patients with Type 1 (insulin-dependent) diabetes mellitus and first-degree relatives. Following the recommendation of the Fourth International Workshop on the Standardization of insulin autoantibodies, autoantibodies were determined by fluid-phase radioimmunoassay using equimolar concentrations of mono¹²⁵I-A14-insulin or -proinsulin to detect insulin or proinsulin autoantibodies, respectively. A higher prevalence of proinsulin autoantibodies vs insulin autoantibodies was found in 97 patients with Type 1 diabetes prior to insulin treatment (34.0 % vs 22.7 %, p< 0.05) and in 16 islet cell antibody-positive relatives (43.8% vs 31.3%, NS). There was only one serum positive for insulin and proinsulin autoantibodies in 110 islet cell antibody-negative first degree relatives (0.9 %). None of 88 normal sera contained proinsulin autoantibodies or insulin autoantibodies. There was a close correlation of proinsulin autoantibody and insulin autoantibody titres in individual sera (r=0.95, p< 0.01) due to crossreaction of all insulin autoantibodies with proinsulin. However, some proinsulin autoantibodies did not crossreact with insulin. Background binding in normal sera was lower for proinsulin autoantibodies. We conclude that proinsulin autoantibodies have a higher association to acute Type 1 diabetes than insulin autoantibodies.Part of this work was presented at the 26th Annual Meeting of the EASD in Copenhagen, 10^th–13^th September 1990     

Autoantibodies to the insulin receptor are infrequent findings in Type 1 (insulin-dependent) diabetes mellitus of recent onset

Summary To determine whether autoantibodies to the insulin receptor may represent markers of Type 1 (insulin-dependent) diabetes, the prevalence of such antibodies was investigated in sera of 60 newly diagnosed untreated Type 1 diabetic patients. A sensitive assay, based on enzyme linked immunosorbent assay has been set up which detects antibodies to the insulin receptor irrespective of their potentially inhibiting effect on insulin binding. Moreover, this method allows easy determination of the immunoglobulin class involved in the anti-receptor activity. Among the 60 sera examined, only one was found to contain anti-insulin receptor autoantibodies (IgG class). In view of our data, we conclude that autoantibodies to the insulin receptor are infrequent findings in Type 1 diabetes of recent onset.     

Autoantibodies to Glutamic Acid Decarboxylase and Insulin in Islet Cell Antibody Positive Presymptomatic Type 1 Diabetes Mellitus: Frequency and Segregation by Age and Gender

The frequency of antibodies to glutamic acid decarboxylase (GAD) and insulin (IAA) in presymptomatic Type 1 diabetes mellitus with a positive test for antibodies to islet cell antigen (ICA) was examined. Thirty-two persons positive for ICA (> 10 JDF units) were tested 2 to 48 months before their ascertained onset of Type 1 diabetes. ICA was quantitated by immunofluorescence as JDF units, anti-GAD by radioimmunoprecipitation and anti-insulin by radioimmunoassay. There was a positive test for anti-GAD in 25 (78%), and for IAA in 23 (72%), of the 32 prediabetic ICA-positive subjects. Stratification according to age at the onset of diabetes showed differing frequencies of anti-GAD and IAA in the prediabetic stage. Thus the positivity rate for anti-GAD for 18 subjects older than 10 years at onset of diabetes was 83%, and for 14 aged 10 or younger at onset was 71%; conversely, the rate for IAA for 18 subjects older than 10 at onset was 56% and for 14 aged 10 or less at time of onset was 93% (p = 0.01). The frequency of anti-GAD was higher in females (88%) than males (71%) whereas the frequency of IAA was higher in males (82%) than in females (60%). Since autoantibodies to GAD and insulin occur in presymptomatic Type 1 diabetes with differences in frequencies by age and gender, the stimuli to autoimmunity may operate differently at different ages, and may also be gender-related.     

Insulin autoantibodies are associated with islet cell antibodies; their relation to insulin antibodies and B-cell function in diabetic children

Summary Blood was drawn from 74 children, 3–16 years old, at diagnosis of Type 1 (insulin-dependent) diabetes and before the first insulin injection. Insulin autoantibodies were detected with a polyethylen-glycol-method in 27/74 (36.4%) and with an immuno-electrophoretic method in 6/74 (8.1%). Islet cell cytoplasmic antibodies detected by indirect immuno-fluorescence were found in 49/74 patients (66.2%), who included as many as 23 of the 27 patients with insulin autoantibodies determined with the polyethylen-glycol-method (p<0.01). The proportion of insulin autoantibody-positive patients who developed insulin antibodies during the first 9 months of insulin treatment was not significantly greater (51.8%) than that of insulin autoantibody-negative patients (44.6%), but patients with both islet cell antibodies and insulin autoantibodies at diagnosis produced more insulin antibodies during the first 9 months (p<0.05). There was no difference in fasting or meal stimulated serum C-peptide after 3, 9 or 18 months as related to occurrence of insulin autoantibodies and/or islet cell antibodies. The correlation between insulin autoantibodies and islet cell antibodies indicates that both types of autoantibodies reflect the same immunological process, although the lack of correlation to C-peptide may indicate that they play a minor causal role. In addition, the results show that patients with an active autoimmune process evidently tend to produce more insulin antibodies during the first months of insulin treatment, but the islet cell antibodies and insulin autoantibodies-positive patients had at least as good residual B-cell function as patients without autoantibodies at diagnosis. If insulin antibodies produced as a response to exogenous insulin do have a negative effect on B-cell function our present results suggest that such mechanisms are of minor importance.     

Endocrine autoimmunity in families with type 1 diabetes: frequent appearance of thyroid autoimmunity during late childhood and adolescence

Aims/hypothesis  Thyroid autoimmunity clusters with other endocrine and non-endocrine forms of autoimmunity. The aim of this study was to determine the chronological appearance of thyroid autoantibodies in relation to other forms of autoimmunity in at-risk children. Methods  The BABYDIAB study follows children of parents with type 1 diabetes. Children born in Germany between 1989 and 2000 were recruited at birth and followed up at 9 months and at 2, 5, 8, 11, 14 and 17 years. Antibodies to thyroid peroxidase were measured in samples taken at the last study visit in 1,489 children and in all previous samples in children who tested positive. Islet antibodies and antibodies to 21-hydroxylase and transglutaminase were also measured in all children. Median follow-up was 8 years. Results  The cumulative risk for developing antibodies to thyroid peroxidase was 20.3% (95% CI 12.3–28.3) by age 14 years. The risk was increased in girls (adjusted HR 2.0; 95% CI 1.2–3.4; p = 0.008), in children who had multiple first-degree family history of type 1 diabetes (adjusted HR 3.3; 95% CI 1.4–8.0; p = 0.006) and in children who also had antibodies to GAD (adjusted HR 3.0; 95% CI 1.5–5.9; p = 0.001). Thyroid peroxidase antibody appearance was most common from age 8 years and was often the last autoantibody to develop in children with other autoantibodies. Conclusions/interpretation  Among children of patients with type 1 diabetes, the appearance of thyroid autoantibodies is frequent, is not synchronous to the appearance of other autoantibodies and is most common in late childhood and adolescence.     

Detection of autoantibodies against islet amyloid polypeptide in human serum. Lack of association with Type 1 (insulin-dependent) diabetes mellitus,or with conditions favouring amyloid deposition in islets

Summary A radiobinding assay for the detection of autoantibodies against islet amyloid polypeptide was developed, analytically validated, and -in parallel with a similar assay for the detection of autoantibodies against insulin — applied to sera from recent-onset Type 1 (insulin-dependent) diabetic patients and from age- and sex-matched control subjects. There was no difference in islet amyloid polypeptide autoantibody titres between patient groups and matched control subjects, nor within subject groups according to age. At onset of Type 1 diabetes, elevated islet amyloid polypeptide-autoantibody levels (> 97th percentile of control subjects) were only detected in 1 of 30 patients aged 0–19 years and in 2 of 35 patients aged 20–39 years. By contrast, insulin autoantibodies were frequently demonstrated, in particular at onset of diabetes under age 20 (0–19 years: 18 of 30 patients; 20–39 years: 10 of 35 patients; p < 0.01 vs matched control subjects). Islet amyloid polypeptide autoantibodies were not detectable in 3 insulinoma patients nor in 37 patients (aged 33–70 years) with Type 2 diabetes (vs 1 of 40 in matched control subjects). In positive serum, adsorption onto protein A-Sepharose removed islet amyloid polypeptide binding activity, hereby confirming its antibody nature. In conclusion, Type 1 diabetes is associated with an age-dependent autoantibody reaction against insulin but not against islet amyloid polypeptide. Conditions associated with amyloid deposition in islets (Type 2 diabetes, insulinoma and ageing) do not favour the formation of autoantibodies against islet amyloid polypeptide.     

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

Summary Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type 1 diabetic patients. Relatives were prospectively followed for 2 304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas others remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common. Despite current knowledge and available genetic and immune markers, early identification of the relatives progressing to clinical diabetes is still difficult and does not allow at the present time aggressive immunointervention at the prediabetic stage.Members of the Lyons' family study also include Prs F.BerthezèneMembers of the Lyons' family study also include Prs F.Berthezène     

Islet cell and insulin autoantibodies in organ-specific autoimmune patients. Their behaviour and predictive value for the development of Type 1 (insulin-dependent) diabetes mellitus. A 10-year follow-up study

Summary To evaluate the behaviour and predictive value of islet cell and insulin autoantibodies in patients with organspecific autoimmune diseases, we followed 21 non-diabetic subjects for a mean period of 84±27 months. Ten patients were persistently seropositive for complement-fixing islet cell antibodies and high titres of immunoglobulin G islet cell antibodies ( 18). The prevalence of persistent insulin autoantibodies in this group was 67%. Seven patients (70%) developed Type 1 (insulin-dependent) diabetes mellitus after a latency period of 2–60 months. The predictive value of complement-fixing islet cell antibodies was 65%, and in the presence of both complement-fixing islet cell and insulin autoantibodies the predictive value rose to 76%. Eleven patients were seronegative for complement-fixing islet cell antibodies and had low immunoglobulin G islet cell antibodies titres (< 18) that were either persistent or transient, or that fluctuated during follow-up. The prevalence of persistent insulin autoantibodies in this group was 45%; only one subject developed Type 1 diabetes. The predictive value of persistent islet cell antibodies (complement-fixing positive/negative) was 54%, and it rose to 70% when both islet cell and insulin autoantibodies were present. Individuals with only insulin autoantibodies or immunoglobulin G islet cell antibodies did not develop diabetes mellitus. A high frequency of HLA-DR3 and/or DR4 was found in patients who developed diabetes mellitus. Thus, the presence of both islet cell and insulin autoantibodies in patients with organ-specific autoimmune disease appears to confer the highest risk of progression toward Type 1 diabetes.Deceased 29 June 1986     

Immunogenetic heterogeneity in Type 1 (insulin-dependent) diabetes among Japanese — HLA antigens and organ-specific autoantibodies

Summary HLA phenotypes and haplotypes in relation to organ-specific autoantibody responses were studied in 82 Japanese patients with Type 1 (insulin-dependent) diabetes. HLA-DRw9 antigen and HLA phenotype of DRw9/X (X: not DR4) were increased in patients with organ-specific autoantibodies other than islet cell antibody (CP<0.02, RR=4.02 and p<0.05, RR=2.30, respectively); whereas HLA-DR4 antigen and HLA phenotype of DR4/X (X: not DRw9) were increased in those without the autoantibodies (CP<0.001, RR=3.95 and p<0.01, RR=2.46, respectively). HLA haplotype of Bw61-DRw9 was increased in patients with the autoantibodies (p<0.005, RR=4.94), and HLA haplotype of Bw54-DR4 was increased in those without the autoantibodies (p<0.001, RR=5.52). The relative risk of HLA-DR4/DRw9 was the highest among all HLA-DR phenotypes or genotypes in patients either with or without the autoantibodies. No association was, however, found between the incidence of islet cell antibody and HLA-DR phenotypes. These findings suggest that Type 1 diabetes among Japanese is immunogenetically heterogeneous as is Type 1 diabetes among Caucasians; and the differences in HLA-association of Type 1 diabetes among ethnic groups might give a clue to understanding of a role of HLA-antigens in the development of Type 1 diabetes.     

Antibodies to a Mr-64000 islet cell protein in Swedish children with newly diagnosed Type 1 (insulin-dependent) diabetes

Summary Sera from 40 Swedish children diagnosed as having Type 1 (insulin-dependent) diabetes mellitus during a one year period along with 40 age and geographically matched control subjects were tested for antibodies to a M_r-64000 islet protein by immunoprecipitation of ³⁵S-methionine-labelled rat islet amphiphilic proteins. Of the 40 diabetic patients, 29 (73%) were found to be positive whereas all 40 control subjects were negative. Samples were also tested for titres of islet cell cytoplasmic antibodies by indirect immunofluorescence on frozen sections of human pancreas. In the diabetic group, 30 of the 40 patients (75%) were positive for islet cell cytoplasmic antibodies compared with 2 of the 40 control subjects (5%). A comparison of levels of antibodies to the M_r-64000 protein with islet cell cytoplasmic antibodies revealed a weak (r _s=0.46), but significant (p<0.01) correlation between the two tests. There was no effect of age or sex on levels of antibodies to the M_r-64000 protein. These results in population-based diabetic children and control subjects demonstrate a high frequency of antibodies to the M_r-64000 protein at the time of clinical onset.     

The Swedish childhood diabetes study — results from a nine year case register and a one year case-referent study indicating that Type 1 (insulin-dependent) diabetes mellitus is associated with both Type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders

Summary From July 1, 1977 to July 1, 1986, 3,503 incident cases of Type 1 (insulin-dependent) diabetes mellitus were registered in the Swedish childhood diabetes study. Using data from this register and from a case-referent study, including all incident Type 1 diabetic children in Sweden during one year and, for each patient, two referent children matched according to age, sex and county, we have studied the associations between Type 1 diabetes and familial Type 1 and Type 2 (non-insulin-dependent) diabetes, thyroid, adrenal, allergic, rheumatic, heart and bowel disease. The mean annual incidence per 100,000 during the nine year period was 25.1 for boys and 23.5 for girls. In 8.5% of the patients, one parent had Type 1 diabetes, 73% of whom were fathers. Fifty-six of the patients (1.7%) had a parent with Type 2 diabetes. The prevalence of parental Type 1 diabetes tended to be higher in patients with younger age at onset; whereas, the opposite was found for patients with parental Type 2 diabetes. In the case-referent study, the age-adjusted odds ratio for Type 1 diabetes when a first and/or second degree relative had Type 1 diabetes was 5.5 (95% confidence limits 4.0–7.7), and in accordance with the findings of the case register, the odds ratio tended to be highest in patients with the youngest age at onset. Season at onset of the patients was not associated with parental Type 1 diabetes. The odds ratio for Type 1 diabetes was significantly increased 3.3 (95% confidence limits: 2.3–4.6) when Type 2 diabetes was reported in relatives (three generations). Odds ratios were also significantly increased (p(0.05) when thyroid or rheumatic diseases were reported among relatives.It is concluded that although the majority of incident Type 1 diabetic children lack family history, parental Type 1 diabetes may influence the age at onset of the disease but has no effect on sex distribution of these children. An increased risk for Type 1 diabetes in children is also indicated when Type 2 diabetes, (non-insulin-treated) thyroid or rheumatic disease is reported in relatives.     

Prospective analysis of islet cell antibodies in children with Type 1 (insulin-dependent) diabetes

Summary The prevalence of islet cell antibodies in children with Type 1 (insulin-dependent) diabetes was determined in a cohort of 678 children. The natural course of islet cell antibodies was followed in 375 children at 1 year, 252 and 135 children after 2 and 3 years respectively. Islet cell antibodies were determined by indirect immunofluorescence on cryostat sections of human pancreas. At diagnosis of diabetes 85% of the children had detectable islet cell antibodies (mean titre 10.4). After 3 years 62% of the children were still islet cell antibody positive (mean titre 2.9) indicating a greater persistence of islet cell antibodies than described in earlier studies. In this large cohort a significant correlation between islet cell antibody prevalence or persistence and sex, age or HLA-DR type was not observed except for a faster loss of islet cell antibodies in very young boys and in patients lacking HLA-DR types 3 and 4. Complement fixing islet cell antibodies correlated with high titre islet cell antibodies. Greater persistence of islet cell antibodies was seen for cases with high antibody titre and in children with diagnosis of diabetes during the first half of the year.     

Lack of association of the insulin gene region with Type 1 (insulin-dependent) diabetes mellitus in Japanese subjects

Summary Although the insulin gene region is implicated in susceptibility to Type 1 (insulin-dependent) diabetes mellitus in Caucasians, significance of this region to Type 1 diabetes in Japanese remains unclear because the class 1 alleles (shorter insertion) of the variable number of tandem repeat in the 5′ region of the insulin gene are predominant in both diabetic and non-diabetic subjects. The 5′ insulin gene polymorphism was analysed in 75 Japanese patients and 69 control subjects with a precise method using PvuII and a polymorphism specific probe, which enabled us to divide class 1 alleles into four subclasses. Allelic frequencies were not significantly different between Type 1 diabetic patients and control subjects. The polymorphism in the 3′ untranslated region of the insulin gene (1127/ PstI) was also analysed and found to be tightly linked to the 5′ insulin gene polymorphism, and thus was not associated with diabetes. Interaction between HLA-DR and the insulin gene region, which was reported in the French study, was not observed in Japanese. These results suggest that the insulin gene region is not a valuable genetic risk factor for Type 1 diabetes in Japanese. [Diabetologia (1994) 37: 210–213] Received: 3 May 1993 and in revised form: 31 August 1993     

The significance of the concordance rate for Type 1 (insulin-dependent) diabetes in identical twins

Summary We studied prospectively 49 non-diabetic identical twins of recently-diagnosed Type 1 (insulin-dependent) diabetic patients for up to 24 years (median 9 years). During this time 15 developed Type 1 diabetes. Actuarial analysis indicates that by 12 years 34% of the twins will have developed Type 1 diabetes and that thereafter only another 2% will do so. Inevitable bias in ascertainment of the twins makes it likely that the true figure is less. We conclude that factors which are not genetically determined must be important in the pathogenesis of the disease. The rates of developing Type 1 diabetes in the co-twins declines sharply in the years after diagnosis of the index twin, which suggests that the initiation of the process leading to Type 1 diabetes occurs within a finite, and not a prolonged, period.     

Insulin autoantibodies at the clinical manifestation of Type 1 (insulin-dependent) diabetes — a poor predictor of clinical course and antibody response to exogenous insulin

Summary To study the possible clinical significance of the appearance of insulin autoantibodies prior to the diagnosis of Type 1 (insulin-dependent) diabetes, and their value in predicting the antibody response to exogenous insulin, we observed 46 newly diagnosed diabetic children and adolescents over the year following diagnosis for the occurrence and duration of clinical remission, daily insulin dose, metabolic control, residual B-cell function, insulin-binding antibodies and conventional as well as complement-fixing islet cell antibodies. Insulin-binding antibodies were determined using both monoiodinated human and porcine insulin. Sixteen children (34.7%) were positive for insulin autoantibodies upon diagnosis of Type 1 diabetes. These subjects were significantly younger (6.2±1.0 versus 10.8±0.8 years; mean±SEM, p<0.001), and their haemoglobin A₁ levels were lower (14.1±0.6 versus 16.0±0.8%, p<0.05) at diagnosis than in the insulin autoantibody negative group. There were no significant differences in the occurrence and duration of clinical remission between insulin autoantibody-positive and -negative test groups. Daily insulin dose, haemoglobin A₁ and serum C-peptide concentrations were of the same magnitude in both groups after the diagnosis, and no association could be found between the presence of insulin autoantibodies at diagnosis and persistently positive islet cell antibodies. In tests conducted 3 months after diagnosis, the group of patients with insulin autoantibodies showed significantly higher levels (p<0.05) of antibodies binding human insulin than the group negative for insulin autoantibodies, but no significant differences could be found between the insulin binding titres of the two groups in subsequent analyses. Those who were still positive for conventional islet cell antibodies one year after diagnosis had significantly higher levels of antibodies binding human insulin (34.6±6.1 versus 12.9±1.7%, p<0.05) as well as antibodies binding porcine insulin (33.0±5.9 versus 12.7±2.9%, p<0.05) than the other subjects. Our observations suggest that insulin autoantibodies developing before the diagnosis of Type 1 diabetes have no influence on the clinical course of the disease over the first year following diagnosis, and they appear to serve as a poor predictor of the antibody response to insulin treatment.     

Immunoglobulin heavy chain switch region polymorphisms are not associated with type 1 diabetes

In order to ascertain whether the immunoglobulin heavy chain genes are important in the aetiology of Type 1 diabetes, we have used restriction fragment length polymorphism (RFLP) analysis of genomic DNA to study 148 Caucasoid subjects with Type 1 diabetes and 146 normal Caucasoid subjects. A DNA probe homologous to the switch regions for the IgM (S mu) and IgA1 (S alpha 1) genes when used in conjunction with the restriction endonuclease Sst I detects RFLPs at both these loci. There were no significant differences in phenotype or gene frequencies for the alleles of S mu or S alpha 1 in the patients when compared with control subjects; nor were there significant associations of S mu or S alpha 1 with HLA-DR type or gender.     

Effect of oral insulin on insulin autoantibody levels in the Diabetes Prevention Trial Type 1 oral insulin study

Aims/hypothesis Our aim was to evaluate insulin autoantibody (IAA) levels over time in the Diabetes Prevention Trial Type 1 (DPT-1) oral insulin study to determine the effect of oral insulin compared with placebo on IAA levels. Subjects and methods The DPT-1 trial randomised 372 relatives of subjects with type 1 diabetes, positive for IAA and with normal IVGTTs and OGTTs, to oral insulin 7.5 mg daily or placebo. Subjects were followed with IVGTTs, OGTTs and serial IAA measurements. The change in IAA level over time was modelled statistically using mixed model longitudinal data analysis with spatial exponential law for unevenly spaced data. In a separate analysis, subjects were divided into four groups by treatment and diabetes status at the end of the study. IAA levels were compared amongst the groups at randomisation, last sampling and at the maximum level. Results Longitudinal data analysis showed that treatment did not affect levels of IAA over time. After controlling for age, the IAA levels at randomisation and the last visit and the maximum values were different in the four groups. Significantly higher levels were noted in groups that developed diabetes compared with those that did not, with no significant difference by treatment group. Conclusions/interpretation This suggests that IAA levels over time were not influenced by oral insulin in subjects already positive for IAA at the start of treatment. ClinicalTrials.gov ID no.: NCT00004984. Electronic supplementary material The online version of this article (doi:) contains supplementary material, including a list of the members of the DPT-1 Study Group. This is available to authorised users.     

The incidence of Type 1 (insulin-dependent) diabetes mellitus in subjects aged 0–19 years in Luxembourg: a retrospective study from 1977 to 1986

Summary A decrease in the incidence of Type 1 (insulin-dependent) diabetes mellitus in the age group 0–14 years has been observed from north to south over north-western Europe. To evaluate whether this trend could be found in Luxembourg (a small country between the Netherlands and France) we performed a retrospective study over a period of 10 years. Information concerning all Type 1 diabetic patients (aged 0–19 years at diagnosis), diagnosed between January 1, 1977 and December 31, 1986 was obtained through paediatricians, internists, general practitioners and the Luxembourg Diabetes Association (LDA). The LDA was used as the ascertainment group (to estimate the real number and incidence of Type 1 diabetes mellitus). During the study period 91 Type 1 diabetic patients aged between 0–19 years were diagnosed. An incidence of 11.2 was found in boys (0–19 years). Girls in the same age group showed a considerably lower incidence of 8.8. Standardised incidence (using as standard the world population) revealed an almost similar incidence in the Netherlands and Luxembourg (respectively 10.3 and 10.2) for the age group aged 0–14 years. In France a considerably lower incidence is found (3.6). To what extent different methodology contributes to the differences remains to be clarified. Further prospective studies are necessary to investigate the role of environmental and genetic factors.     

Relationship between serum insulin autoantibodies,islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies at the clinical manifestation of Type 1 (insulin-dependent) diabetes

Summary In order to elucidate the possible relationship between insulin autoantibodies (IAA), conventional (ICA-IgG) and complement-fixing (CF-ICA) islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies (IgG, IgM and IgA classes), we studied 194 children and adolescents with newly diagnosed Type 1 (insulin-dependent) diabetes. Sixty-one (31.4%) of the subjects were IAA-positive at diagnosis and 73.8% (45/61) of these also had ICA-IgG compared to 51.1% (68/113, p<0.01) of IAA-negative children. CF-ICA showed no significant association with IAA. The levels of IAA were significantly higher in the patients with ICA-IgG compared to those without [5.9±1.6% (SEM) vs 2.5±0.3%, p<0.01]. The patients positive for IAA were younger at diagnosis than the IAA-negative ones; (7.1±0.5 vs 9.3±0.3 years, p<0.001) and this was also true for ICA-IgG-positive children (8.1±0.4 vs 9.4±0.5 years, p<0.05) in comparison to ICA-IgG-negative subjects. No significant associations were found between IAA or ICA on the one hand and a positive family history of Type 1 diabetes or metabolic derangements at diagnosis on the other. Subjects negative for ICA were more frequently positive for mumps virus specific IgG antibodies than the ICA-positive patients (50/80 vs 53/111, p<0.05), and Coxsackie-B4 virus-specific IgA antibodies were more common in the CF-ICA-negative than the CF-ICA-positive children (53/111 vs 29/80, p<0.05). There was no association between the IAA levels and Coxsackie-B4 or mumps virus specific antibodies. However, patients with serological evidence of a recent mumps infection (n=13) had higher IAA levels than the other children (4.4±7.7% vs 2.8±1.4%, p<0.02). Our data suggest a positive association between IAA and ICA-IgG, supporting the view that IAA are like ICA serological markers of autoimmune B cell damage. The inverse associations between autoantibodies and age and between ICA and viral antibodies support the hypothesis that autoimmune mechanisms may play a more crucial role in younger patients contracting Type 1 diabetes while environmental factors may be more important in older ones.