Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible individuals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children. Diabetes 49:1319-1324, 2000 T ype 1 diabetes is an autoimmune disease that results from the destruction of pancreatic islet ␤-cells in genetically predisposed individuals. A large proportion of the lifetime risk of type 1 diabetes is attributed to environmental agents (1,2), but the only virus shown unequivocally to be responsible for clinical disease is rubella following infection in utero of infants bearing the HLA haplotype B8-(DR3-DQ2) (3). Circulating insulin autoantibodies (IAA), GAD65 antibodies (GADAb), and tyrosine phosphatase IA-2 autoantibodies (IA-2Ab) are markers of islet autoimmunity that predict the T-cell-mediated destruction of ␤-cells (4-6). Peptides in these islet autoantigens that are recognized by T-cells may provide clues to environmental agents that trigger or exacerbate islet autoimmunity through the mechanism of molecular mimicry (7,8).Recently, we identified T-cell epitope peptides in tyrosine phosphatase IA-2 (IA-2) restricted by HLA-DR4 in individuals at risk for type 1 diabetes (9,10). The dominant epitope (amino acid [aa] 805-820) contains a core 9-aa sequence in which 5 aa are identical and 4 aa are homologous with a 9-aa sequence (aa 41-49) within virus protein (VP)7 of rotavirus (RV) serotype G3 and to a lesser extent in the G1 and G2 serotypes. Because the T-cell contact residues in these similar IA-2 and RV VP7 sequences appear to be identical (9), the potential exists for molecular mimicry. Furthermore, just NH 2 -terminal of this region in VP7 is a 12-aa sequence (11) strongly similar to a sequence in GAD65 (aa 117-128) (9) that is a T-cell epitope in HLA-DR4 transgenic mice (12) and DR4-DQ8 homozygous at-risk humans (13). All human RV serotypes in the GenBank database contain the GAD-related sequence. VP7, the major outer capsid protein of RV, is an important determinant of virulence and induces virus-neutralizing antibodies (14). However, elimination of RV infection is predominantly due to T-cells (15). The CD4 T-cell epitopes in VP7 are unknown, but in C57/Bl 6 and BALB/c mice, CD8 T-cell epitopes (15,16) map adjacent to the IA-2-and GAD-like sequences, confirming that this signal sequenc...

BackgroundGestational diabetes rates have increased dramatically in the past two decades and this pattern of increase appears to relate primarily to the obesity epidemic, older maternal age and migration from world areas of high GDM risk. Women from disadvantaged and migrant backgrounds are most at risk of developing and of mismanaging this condition. The aim of the study was to explore the factors that facilitated or inhibited gestational diabetes self-management among women in a socially deprived area.MethodsFifteen pregnant women, with a diagnosis of gestational diabetes, were purposively recruited for this study. Qualitative semi structured interviews and 1 focus group were conducted when participants were approximately 28–38 weeks gestation. The study’s theoretical framework was based on interpretative phenomenology and data was analysed using a thematic analysis approach.ResultsWomen in this study identified a number of factors that complicated their task of GDM self-management. Barriers included: (1) time pressures; (2) physical constraints; (3) social constraints; (4) limited comprehension of requirements, and (5) insulin as an easier option. Factors facilitating GDM self-management included: thinking about the baby and psychological support from partners and families.ConclusionWomen from low socio economic and migrant backgrounds often struggle to comprehend GDM self-management requirements. To improve adherence to management plans, these women require educational and supportive services that are culturally appropriate and aimed at a low level of literacy.

OBJECTIVE -Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate ␤-cell destruction, and could induce immune effects consistent with mucosal tolerance. RESEARCH DESIGN AND METHODS-A total of 38 individuals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was ␤-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly; the secondary outcome was immunity to islet antigens, measured monthly for 12 months.RESULTS -No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible ␤-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as ␤-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin. CONCLUSIONS -Results from this pilot study suggest that intranasal insulin does not accelerate loss of ␤-cell function in individuals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes. Diabetes Care 27:2348 -2355, 2004T ype 1 diabetes is an autoimmune disease in which T-cells mediate destruction of insulin-secreting ␤-cells in the pancreatic islets. Asymptomatic individuals with preclinical type 1 diabetes can be identified by the presence of circulating antibodies (Abs) to insulin, GAD 65-kDa isoform, and tyrosine phosphatase-like insulinoma antigen 2 (IA2) (1-3). Insulin is the only self-antigen specific for ␤-cells, and several lines of evidence indicate that it may play a major role in driving autoimmune ␤-cell destruction (4 -7). In experimental rodent models, administration of self-antigens to mucosa-associated lymphoid tissues can induce immune tolerance and prevent autoimmune disease (8,9). In the nonobese diabetic (NOD) mouse, a spontaneous model of autoimmune type 1 diabetes, oral (10) or naso-respiratory (11) insulin induces regulatory, diabetes-protective Tcells. After naso-respiratory insulin, there was a decrease in T-cell and an increase in Ab responses to insulin (11), conforming to the shift from T-helper (Th)-1 cellular immunity to Th2 humoral immunity that is associated with protection against diabetes in this rodent model (12). In human volunteers, oral (13)...