Islet autoantibodies, nationality and gender: a multinational screening study in first-degree relatives of patients with Type I diabetes

Williams, A. J. K.; Bingley, Polly J.; Moore, W.; Gale, E. A. M.

doi:10.1007/s00125-001-0749-6

Cited by 55 publications

(25 citation statements)

References 18 publications

(21 reference statements)

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“…Error bars represent SE sembling that of early childhood, while adolescent females tend to have a more adult profile, with higher GAD antibody levels. A similar excess of IAA was observed in male relatives of patients with Type 1 diabetes over the age of 10 in a recent screening study [2]. These observations would be consistent with continued expansion of islet autoimmunity in adolescent males and/or down-regulation of islet autoimmunity in females with puberty.…”

Section: Discussionsupporting

confidence: 82%

“…The lower prevalence of IAA in adolescent females implies sex-specific modulation of the autoimmune process during puberty. [Diabetologia (2003) In a recent multinational screening study of firstdegree relatives, we found a higher prevalence of islet autoimmunity in males than females during adolescence [2]. Strikingly, the prevalence of IAA did not vary up to 20 years of age in islet cell antibody (ICA) positive male relatives, whereas in female relatives the prevalence fell sharply between the ages of 10 and 20 years.…”

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confidence: 79%

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The prevalence of insulin autoantibodies at the onset of Type 1 diabetes is higher in males than females during adolescence

et al. 2003

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Aims/hypothesis. The incidence of Type 1 diabetes shows little sex bias up to age 15 years, but more males are diagnosed in early adult life. Humoral responses to the beta cell antigen insulin could help to reveal the mechanism underlying this difference. We therefore determined the influence of sex on the prevalence of insulin autoantibodies (IAA) at diagnosis. Methods. IAA were measured by radiobinding assay in 598 patients with newly diagnosed Type 1 diabetes (aged 10.5, range 0.8-20.7 years, 333 male), and analysed according to age, sex and HLA class II genotype. Results. Overall, 74% of males and 65% of females had IAA above the 97.5 th centile of 2860 schoolchildren (p=0.028). IAA prevalence was similar in males and females under the age of 15 (0-4 yr, 95% vs 88%; 5-9 yr, 76% vs 73%; 10-14 yr, 67% vs 58%), but male excess was seen between 15 and 21 years (66% vs. 32%, p corr =0.016). HLA class II genotype was available for 426 patients. IAA prevalence in DR4 homozygous patients was 87%, in DR4 heterozygous patients 72% and in DR4 negative patients 55% (p<0.001). Multivariate analysis showed independent association of IAA with age (p<0.001), number of DR4 alleles (p<0.001) and male sex (p=0.002). Conclusions/interpretation. The prevalence of IAA in patients with newly diagnosed Type 1 diabetes is higher in males than females between 15 and 21 years of age. The lower prevalence of IAA in adolescent females implies sex-specific modulation of the autoimmune process during puberty. [Diabetologia (2003) In a recent multinational screening study of firstdegree relatives, we found a higher prevalence of islet autoimmunity in males than females during adolescence [2]. Strikingly, the prevalence of IAA did not vary up to 20 years of age in islet cell antibody (ICA) positive male relatives, whereas in female relatives the prevalence fell sharply between the ages of 10 and 20 years.We wanted to know whether the sex difference in the prevalence of IAA observed in relatives is also seen in patients at diagnosis of Type 1 diabetes, and therefore examined the influence of sex on the prevalence and levels of IAA according to age at onset. Since there are associations between IAA and HLA class II haplotypes [3,4], we also considered the impact of genetic factors on the prevalence of IAA in this cohort.The pattern of onset of Type 1 diabetes differs between the sexes, with earlier peak incidence in girls than boys, and a higher incidence of disease in males than females after 15 years of age [1]. The reason for this is unknown, but differences in the prevalence of the various islet autoantibodies before and after diagnosis could provide indirect clues as to the mechanisms underlying this sex difference.

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Section: Discussionsupporting

confidence: 82%

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confidence: 79%

The prevalence of insulin autoantibodies at the onset of Type 1 diabetes is higher in males than females during adolescence

et al. 2003

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“…Not all individuals that carry autoantibodies towards the beta cells ultimately develop clinical diabetes, and the signs of autoimmunity may disappear [11][12][13]. Autoantibody prevalence is similar among relatives of type 1 diabetic patients in different countries, despite a wide variation in diabetes incidence [14]. Many authors thus agree that, once autoimmunity has been triggered, the progressive decrease in beta cell function may be caused by subsequent exposure events [7,15,16].…”

Section: Introductionmentioning

confidence: 99%

Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis

2005

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“…ICA determination in the central laboratory was performed by indirect immunofluorescence [7]. Briefly, sera were incubated on sections of human pancreas for 30 min at room temperature.…”

Section: Islet Cell Antibodiesmentioning

confidence: 99%

Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT)

Gale

Inte²

2003

Diabetologia

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Aims/hypothesis To set up a clinical trial to establish whether nicotinamide can prevent or delay clinical onset of Type 1 diabetes.Method The European Nicotinamide Diabetes Intervention Trial is a randomised, double-blind, placebo-controlled intervention trial undertaken in 18 European countries, Canada and the USA.Entry criteria were a first-degree family history of Type 1 diabetes, age 3-40 years, confirmed islet cell antibody (ICA) levels greater than or equal to 20 JDF units, and a non-diabetic OGTT; the study group was further characterised by intravenous glucose tolerance testing, measurement of antibodies to GAD, IA-2 and insulin and HLA class II genotyping.Results ICA screening was carried out in approximately 30,000 first-degree relatives. A total of 1004 individuals fulfilled ICA criteria for eligibility, and 552 (288 male) were randomised to treatment. Of these, 331 were aged less than 20 years (87% siblings and 13% offspring of the proband with diabetes) and 221 were 20 years of age or more (76% parents, 21% siblings and 3% offspring). Oral glucose tolerance was normal in 500 and impaired in 52 (9.4%), and first phase 1 insulin response in the IVGTT was below the 10 th centile in 34%. Additional islet autoantibodies were identified in 354 trial entrants. Diabetes-associated HLA class II haplotypes were found in 84% of the younger age group and 80% of the older group. The protective haplotype HLA-DQA1*0102-DQB1*0602 was found in 10% overall.Conclusions/interpretation ENDIT has shown that a trial of an intervention designed to halt or delay progression to Type 1 diabetes can be carried out on a multinational collaborative basis, as and when potentially safe and effective forms of intervention become available. Primary screening with biochemically defined autoantibodies will substantially reduce the number of lower risk individuals to be included in future intervention trials Europe includes countries with the highest incidence of Type 1 (insulin-dependent) diabetes mellitus in the world. These rates continue to rise rapidly, and the EURODIAB TIGER Concerted Action has shown an annual 3 to 4% increase in the incidence of childhood diabetes across our continent [1]. In Finland, it is estimated that childhood diabetes is now four times as common as 2 it was in the 1950s [2]. There is currently no means of preventing or curing this disorder. Type 1 diabetes can, however, be predicted by screening for islet autoantibodies, and both animal and human pilot studies suggest that prevention is possible. The US Diabetes Prevention Trial-Type 1 (DPT-1) has recently reported experience with parenteral insulin therapy in high risk relatives of an individual with Type 1 diabetes [3]. Here we show baseline data from a trial of high-dose oral nicotinamide, and demonstrate that a candidate preventive measure can be tested successfully on a multinational collaborative basis. MethodsStudy Design ENDIT is a randomised, double-blind, placebo controlled trial designed to test whether daily oral administration of hi...

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Islet autoantibodies, nationality and gender: a multinational screening study in first-degree relatives of patients with Type I diabetes

Cited by 55 publications

References 18 publications

The prevalence of insulin autoantibodies at the onset of Type 1 diabetes is higher in males than females during adolescence

The prevalence of insulin autoantibodies at the onset of Type 1 diabetes is higher in males than females during adolescence

Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis

Intervening before the onset of Type 1 diabetes: baseline data from the European Nicotinamide Diabetes Intervention Trial (ENDIT)

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