The genotype frequencies were almost identical in all three Finnish populations of different ages, with no gender differences, and did not differ from corresponding figures for the Finnish blood donors. However, the PRNP codon 129 genotype distribution in Finland differed significantly from that of the British and the Irish blood donors and the previously published blood donor data on other Western Europeans and Americans.

SUMMARY Rotavirus, the most common cause of childhood gastroenteritis, has been implicated as one of the viral triggers of diabetes‐associated autoimmunity. To study the possible association between rotavirus infections and the development of diabetes‐associated autoantibodies, we measured the prevalence of rotavirus antibodies in serum samples collected at 3–6‐month intervals up to the age of 2 years from 177 children selected from consecutive newborns because they carried HLA‐DQB1 alleles associated with increased risk for type 1 diabetes. Twenty‐nine of the children developed at least two of four diabetes‐associated autoantibodies (ICA, IAA, GADA or IA‐2A) during the first 2 years of life (the cases), whereas 148 children remained autoantibody‐negative matched with the cases for date of birth, gender, living region and HLA‐DQB1 alleles. The temporal association between the development of the first‐appearing diabetes‐associated autoantibody and rotavirus infections was studied by analysing whether the cases had a diagnostic increase in rotavirus antibody titre more often during the 6‐month period that preceded seroconversion to autoantibody positivity than the controls. By the age of 12 months one of the 13 case children (7%), who had a serum sample drawn at that age and who had developed at least one type of diabetes‐associated autoantibodies, had experienced a rotavirus infection, while 12 of the 61 (20%) autoantibody‐negative control children had had a rotavirus infection. By 18 months, four of the 22 autoantibody‐positive cases (18%) and 18 of the 89 controls (20%) had rotavirus antibodies, and by the age of 24 months the respective numbers were five of the 27 cases (19%) and 32 of the 113 (28%) controls. A rotavirus infection occurred during the 6 months preceding the sample which was positive for an autoantibody in four of the 25 periods (16%) for which both necessary samples were available, while the controls had a rotavirus infection during 55 of the 370‐such periods (15%). Accordingly, our data suggest that rotavirus infections are unlikely triggers of beta‐cell autoimmunity in young children with genetic susceptibility to type 1 diabetes.

Timing of onset of autoimmunity is a prerequisite for unmasking triggers and pathogenesis of type 1 diabetes. We followed 4,590 consecutive newborns with 8 or 3% HLA-DQB1 conferred risk for type 1 diabetes at 3-, 6-, or 12-month intervals up to 5.5 years of age. Islet cell autoantibodies (ICAs) and, in the 137 children with ICAs, insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and IA-2 protein autoantibodies (IA2As) were measured. Children with high genetic risk developed ICAs more often than those with moderate risk (log-rank P ‫؍‬ 0.0015); 85 and 91% remained ICA negative by 5 years of age, respectively. The time of appearance of biochemical autoantibodies was then compared with the appearance of ICAs. IAAs and GADAs emerged usually before ICAs (means ؊1.8 and ؊1.5 months, respectively) and IA-2As after ICAs (mean 2.0 months). Ninety-five percent of all IAAs, GADAs, and IA-2As seroconversions occurred in a cluster (؊12 to 8 months) around the ICA seroconversion. We conclude that diabetes-associated autoantibodies emerged in children with predisposing HLA-DQB1 alleles after 3 months of age at a constant tempo, determined by the genetic risk level, usually in the order of IAA, GADA, ICA, and IA-2A. Seroconversion to multiple autoantibody positivity usually occurred tightly clustered in time. Diabetes 51:646 -651, 2002

Aims/hypothesis. A reduced first-phase insulin response to intravenous glucose is perceived as a sign of far-advanced deterioration of beta-cell function during the development of Type I (insulin-dependent) diabetes mellitus, but data on insulin responses at the onset of diabetes-related autoimmunity are lacking. We studied the first-phase insulin responses of small children soon after observed seroconversion to autoantibody positivity. Methods. In the Type I Diabetes Prediction and Prevention Study newborn infants are screened for HLA-DQB1-associated genetic risk for Type I diabetes and those with increased risk are followed-up for the emergence of islet-cell antibodies. If antibodies are detected, autoantibodies to three other antigens (insulin, GAD65 and IA-2) are also measured. To measure first-phase insulin responses, intravenous glucose tolerance tests were carried out in 52 (1 to 5-year-old) children who had recently seroconverted to islet-cell antibody positivity.Results. The first-phase insulin response was subnormal (<38 mU/l, the 5 th percentile of insulin responses of 20 islet-cell antibody negative healthy children at this age) in 22 of the 52 children (42%). Stepwise multiregression analysis showed that islet-cell antibody greater than 20 JDFU (p=0.0005), insulin autoantibodies (p=0.0009) and an increasing number of positive autoantibodies (p=0.0011) were independent predictors of low first-phase insulin response. Conclusion/interpretation. A decreased first-phase insulin response could be an early phenomenon in the course of prediabetes in young children, implying a rapid autoimmune destruction or loss of function of beta cells as well as possible metabolic compensation mechanisms, since 11 out of the 22 high risk children remain nondiabetic for a considerable period of time despite low insulin responses. [Diabetologia (2002[Diabetologia ( ) 45:1639[Diabetologia ( -1648 Keywords Autoantibodies, HLA risk markers, insulin secretion, prediabetic state, Type I diabetes. Corresponding author: Dr. P. Keskinen, The JDRF Center for Prevention of Type I Diabetes in Finland. E-mail: paivi.keskinen@uta.fi Abbreviations: DIPP, Type I Diabetes Prediction and Prevention project; FPIR, first-phase insulin response; GAD65, 65 kilodalton isoform of glutamic acid decarboxylase; GADA, antibodies to GAD65; IAA, insulin autoantibodies; IA-2A, antibodies to the protein tyrosine phosphatase related IA-2