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Biomedical subjects

A G Ziegler

Publications and source records attributed to A G Ziegler.

At least 19 recordsLinked to original sources
PubMed1999

Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study.

The temporal development of autoantibodies was studied in 1,353 offspring of parents with type 1 diabetes. Islet cell antibodies (ICAs) and autoantibodies to insulin (IAAs), glutamic acid decarboxylase, and IA-2 were measured at birth, 9 months, 2 years, and 5 years of age. At birth, no offspring had islet autoimmunity other than maternally acquired antibodies, which were shown to influence antibody prevalence up to age 6 months. Antibodies detected thereafter were likely to represent a true de novo production, since prevalences were the same for offspring from mothers and fathers with diabetes, antibodies detected at 9 months were almost always confirmed in the 2-year sample and were associated with an increased likelihood of having or developing other antibodies. By 2 years of age, autoantibodies appeared in 11% of offspring, 3.5% having more than one autoantibody. IAAs were detected most frequently, and few had autoantibodies in the absence of IAAs. In 23 offspring with multiple islet autoantibodies, IAAs preceded other antibodies in 10 cases and were first detected concurrently with other antibodies in 12 and after detection of other antibodies in 1. Development of additional antibodies and changes in levels, including decline of IAAs at older age, was frequent. Nine children, all with IAAs and ICAs, developed diabetes. Overall cumulative risk for disease by 5 years of age was 1.8% (95% CI 0.2-3.4) and was 50% (95% CI 19-81) for offspring with more than one autoantibody in their 2-year sample. Autoimmunity associated with childhood diabetes is an early event and a dynamic process. Presence of IAAs is a consistent feature of this autoimmunity, and IAA detection can identify children at risk.

Aging↗
PubMed1998

Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes.

Autoimmunity precedes clinical type 1 diabetes, and indicators of maturing autoimmune responses may be useful markers for disease prediction. To study this, epitope maturation of autoantibodies to the related protein tyrosine phosphatase (PTP)-like autoantigens IA-2 and IA-2beta was examined in sequential samples from birth in a cohort of 21 offspring developing multiple islet autoantibodies and a similar cohort of 48 relatives of patients with type 1 diabetes recruited at an older age. Initial reactivity in offspring was heterogeneous against the IA-2 juxtamembrane region (10/21) and PTP domains (13/21), and both specificity and extent of initial IA-2/IA-2beta autoantibodies were associated with HLA class II genotype. Intra-IA-2 epitope spreading and/or intermolecular spreading to IA-2beta epitopes were observed in seven offspring. In contrast, in older relatives, IA-2/IA-2beta Ab reactivity was stable and spreading rare. Development of diabetes in children was associated with the presence of Abs to the IA-2 juxtamembrane region (risk by age 5 yr, 52% vs 0% in those with PTP domain Abs only; p < 0.02), and 5 of 26 relatives who developed diabetes had IA-2 Abs only against the juxtamembrane region. The findings show that autoantibody reactivity to IA-2/IA-2beta is dynamic in the young, show that the juxtamembrane region of IA-2 is an early IA-2 autoantibody target, and suggest that these Abs are a risk factor for development of type 1 diabetes in infancy.

Adult↗
PubMed1998

Evidence for specific autoimmunity against sympathetic and parasympathetic nervous tissues in Type 1 diabetes mellitus and the relation to cardiac autonomic dysfunction.

There is growing evidence for the involvement of immunological factors in the pathogenesis of cardiac autonomic dysfunction in Type 1 diabetes mellitus (DM). To evaluate the presence of autoantibodies against autonomic nervous tissues and their relationship with tests of autonomic function, 64 newly diagnosed and 142 long duration Type 1 DM patients were investigated for sympathetic and parasympathetic ganglia (CF-SG and CF-PSG) autoantibodies with a complement-fixing indirect immunofluorescence technique. Five cardiac reflex tests were performed to assess autonomic function. Fifty-seven patients with neurological diseases other than diabetic neuropathy and 131 healthy control subjects were also tested for CF-SG and CF-PSG autoantibodies. CF-SG autoantibodies were observed in 47 (23%) and CF-PSG autoantibodies in 21 (10%) of 206 Type 1 DM patients (p < 0.001). In contrast, these autoantibodies were detected in 3 (5%) and 1 (2%) of patients with non-diabetic neurological diseases and 3 (2%) and 4 (3%) of control subjects (p < 0.01, p < 0.05, p < 0.0001, p < 0.05 vs Type 1 DM patients). All except two Type 1 DM patients with CF-PSG autoantibodies also presented with CF-SG autoantibodies. In diabetic patients with long duration, CF-SG autoantibodies were more frequent in patients with ECG-based cardiac autonomic neuropathy (CAN; > or =2 of 5 cardiac reflex tests abnormal) compared to patients without CAN although this did not reach statistical significance (29% vs 17%, p = 0.06). However, 4 (80%) of 5 newly diagnosed and 23 (32%) of 73 established Type 1 DM patients with abnormalities in heart rate variation during deep breathing and/or standing from lying presented with CF-SG autoantibodies compared to 12 (25%) of 58 newly diagnosed (p < 0.05) and 7 (11%) of 63 established Type 1 DM patients (p < 0.01), in whom both tests were normal. The results suggest that autoimmune factors contribute to the pathogenesis of cardiac autonomic dysfunction in Type 1 DM and that autoantibodies against sympathetic and parasympathetic nervous tissues are relatively specific for Type 1 DM.

Adult↗
PubMed1998

Course of islet autoantibody titers during Ig-immunoadsorption in a patient with newly diagnosed type 1 diabetes.

The purpose of this study was to determine whether and to what extent diabetes-specific autoantibodies can be removed from the plasma by Ig-immunoadsorption therapy. We followed the course of islet cell antibodies (ICA), insulin antibodies (I[A]A), glutamic acid decarboxylase antibodies (GADA) and antibodies to the protein tyrosine phosphatase IA-2 (IA2A) in a patient with newly diagnosed insulin-dependent diabetes mellitus (IDDM) under multiple immunoadsorption treatments over 6 months. Autoantibodies were not removed from the plasma as efficiently as expected when compared to the removal of total immunoglobulin (IgG). Whereas IgG levels were lowered by 70-90% through each immunoadsorption treatment, antibodies to insulin were reduced by an average of 83%, IA2A by 36% and GADA by only 9% directly after treatment. ICA were > 320 JDF U at diabetes onset and remained above this level. During the 6 months of multiple immunoadsorption therapies, I[A]A levels showed a 24-fold increase due to stimulation of insulin antibody production by exogenous insulin substitution, IA2A levels remained unchanged (average 6% increase), and GADA levels were reduced by an average of 39% compared to antibody titers at onset. All four antibodies were highly positive in the eluate from the immunoadsorption columns. We showed that antibodies to pancreatic islet cells can be reduced by immunoadsorption, but as for plasmapheresis the effect is incomplete and transient for most of the antibodies. If there is clinical benefit through immunoadsorption therapy--as has been shown for newly diagnosed IDDM patients treated with plasmapheresis--our data suggest that this may be due to factors other than the sufficient removal of antibodies.

Adult↗
PubMed1998

Delay of type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial.

The Schwabing Insulin Prophylaxis Trial is a randomised, controlled pilot study designed to examine whether insulin therapy can delay or prevent the clinical onset of Type I diabetes in high risk first degree relatives of people with the disease. First degree relatives of patients with Type I diabetes, who were aged 4 years or more, had an islet cell antibody (ICA) value more than 20 Juvenile Diabetes Foundation Units (JDF-U), a reduced first phase insulin response (FPI) to an i.v. glucose tolerance test less than the 5th centile, and a normal oral glucose tolerance test were eligible for the trial. Between January 1989 and October 1995, 1736 relatives of patients with Type I diabetes were screened for ICA. We identified 64 cases (3.7%) with ICA values more than 20 JDF-U. Of ICA positive relatives, 17 (27%) had a low FPI and were eligible for enrolment. Of these 14 agreed to participate, of whom 7 were randomised to the treatment group and 7 to the control group. In the treatment group, human insulin was administered i.v. by continuous infusion for 7 days, followed by daily s. c. injections for 6 months. Intravenous insulin infusions were repeated every 12 months. In the treatment group 3 of the 7 individuals (follow-up from time of eligibility: 2.3 to 7.1 years) and in the control group 6 of the 7 untreated individuals (1.7 to 7.1 years) developed clinical diabetes. Life table analysis showed that clinical onset of Type I diabetes was delayed in insulin-treated subjects compared with control subjects (means+/-SEM diabetes-free survival: 5.0+/-0.9 years vs 2.3+/-0.7 years, p < 0.03). Insulin levels after i.v. glucose increased in the first year of intervention therapy. Titres of ICA, and antibodies to glutamic acid decarboxylase, and tyrosine phosphatase-like protein IA2 remained unchanged. These data suggest that insulin prophylaxis can delay the onset of overt diabetes in high risk relatives. This is encouraging in view of 1) the continuing American Diabetes Prevention Trial, which is currently testing the effect of parenteral insulin in a large nation-wide study and 2) the initiation of pilot trials to determine whether new antigen-specific intervention is more effective in delaying the clinical onset of Type I diabetes.

Adolescent↗
PubMed1998

Comparison of a novel micro-assay for insulin autoantibodies with the conventional radiobinding assay.

Measurement of insulin autoantibodies (IAA) with a novel micro radiobinding assay which requires only 20 microl of serum was compared with that in a conventional radiobinding assay which uses 600 microl of serum. IAA were measured with both assays in samples from 94 new onset insulin-dependent diabetes mellitus (IDDM) patients, 97 control subjects. and 48 first degree relatives of IDDM patients selected for having IAA in the conventional radiobinding assay. Overall, 227 (95%) of 239 samples tested were concordant. and IAA levels correlated well (r2 = 0.7) between the two assays. Discordant results were obtained in 7 new onset patients, 4 control subjects, and 1 first degree relative, and these had low IAA levels in the respective assays. Sensitivity and specificity in the new onset IDDM patients and control subjects were 69% and 98% for the micro radiobinding assay and 72% and 98% for the conventional radiobinding assay. The use of the micro radiobinding assay should greatly facilitate islet related antibody screening, particularly in children.

Adolescent↗
PubMed1998

Humoral and cellular immune parameters before and during immunosuppressive therapy of a patient with stiff-man syndrome and insulin dependent diabetes mellitus.

OBJECTIVES: Humoral and cellular immune reactivity are reported for two neuroendocrine autoantigens-glutamic acid decarboxylase (GAD) and the protein tyrosine phosphatase IA-2-in a patient with the autoimmune type of stiff-man syndrome and insulin dependent diabetes (IDDM). METHODS: Antibodies and T cell proliferation against GAD and IA-2 and cytokine release of antigen stimulated T cells (IFN-gamma) were determined before and several times during immunosuppressive therapy with prednisolone. RESULTS: Raised GAD antibodies against full length GAD65 or chimeric constructs were detected before therapy and they remained at a high concentration despite a marked clinical improvement during cortisone treatment. Antibodies to IA-2 were undetectable, but weak T cell responses to both GAD and IA-2 were seen before therapy and once on reduction of high cortisone dosages when the patient showed signs of clinical deterioration. Cytokine profiles showed increased IFN-gamma production after stimulation with GAD or IA-2 suggesting increased activation of TH1 cells. CONCLUSION: Immunosuppressive therapy --even with extremely high doses of 500 mg a day--does not lead to the reduction of antibody concentrations in the periphery nor to a switch in epitope recognition of such antibodies despite clinical improvement. The amount of T cell reactivity to various antigens, however, may be a useful marker to monitor the effectiveness of immunotherapy.

Autoantibodies↗
PubMed1998

GADIA2-combi determination as first-line screening for improved prediction of type 1 diabetes in relatives.

A new radiobinding assay for the simultaneous detection of antibodies to GAD and the tyrosine phosphatase IA2 has been recently described in patients with newly diagnosed type 1 diabetes. Here we assessed sensitivity and predictive value of this GADIA2-combi test in first-degree relatives of type 1 diabetic patients compared with islet cell antibody (ICA) and insulin autoantibody (IAA) screening. Of 1,606 relatives, 77 (4.8%) had elevated GADIA2-combi titers above the 99th percentile of 105 nondiabetic control subjects, and results were confirmed by testing these samples for GAD antibody (GADA) and tyrosine phosphatase IA2 antibody (IA2A) in the single antibody test (29 GADA+/IA2A+, 44 GADA+/IA2A-, and 4 IA2A+/GADA-). A further 9 of 1,606 relatives had detectable ICA (1) or IAA (8), but they were negative in the GADIA2-combi assay as well as in the single test for GADA or IA2A. Twenty-four relatives progressed to IDDM within a median follow-up time of 5.6 years (range 0.5-8.2). The sensitivity of antibody determination in relatives with progression to IDDM was 92% for the GADIA2-combi assay, 96% for the combined testing of IAA and GADIA2-combi antibodies, and 83, 67, 67, and 79%, respectively, for GADA, IA2A, IAA, or ICA testing alone. The cumulative life-table risk of antibody-positive relatives was related to GADIA2-combi titers (5-year risk: >50 U, 51% [95% CI 30-73]; >10 to 50 U, 12% [1-24]; <10 U, 0.17% [0-0.5]; P=0.0001) and on the presence of IA2A in addition to GADA (5-year risk: GADA+/IA2A+, 47% [25-68]; GADA+/IA2A-, 15% [2-28]; P=0.006). In those with detectable antibodies, risk was not associated with age (<15 vs. >15 years) or relation to proband (offspring, sibling, parent). Relatives with GADIA2-combi antibodies >10 U and the additional presence of IAA had a slightly higher diabetes risk than relatives without IAA (5-year: IAA+, 46% [23-68]; IAA-, 19% [6-32]; P=0.07). Furthermore, low first-phase insulin release after intravenous glucose tolerance test was associated with risk in relatives with GADIA2-combi antibodies (P=0.01). These results indicate that the GADIA2-combi test is a valuable marker for first-line screening and risk assessment of type 1 diabetes in relatives. It can be used for venous as well as capillary blood samples.

Adolescent↗
PubMed1997

Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients.

Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class II-matched normal individuals. Our data reveal that (a) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; (b) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and (c) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected.

Alleles↗
PubMed1997

[Alström syndrome--a rare disease of diabetic association].

BACKGROUND: Alström's disease is a rare hereditary multiple-system illness, whereas a second-messenger defect can be assumed. CASE REPORT: We describe a case-the first in Germany of 15 known cases in the world literature-, who suffers from all clinical features, such as non-insulin-dependent diabetes mellitus, retinitis pigmentosa, pancochlear damage of the ears, hypogonadism, obesity and chronic nephropathy, with the exception of acanthosis nigricans. CONCLUSION: Because of the multiplicity of affected organs the diagnosis of Alström's disease is difficult.

Adult↗
PubMed1997

Antibodies to bovine serum albumin (BSA) in type 1 diabetes and other autoimmune disorders.

Clinical and experimental studies have delineated a link between dietary cow milk protein and the development of insulin-dependent diabetes mellitus (IDDM), and bovine serum albumin (BSA) was proposed as one candidate mediator of this effect. The demonstration of anti-BSA antibodies in new onset type 1-diabetic children from Finland initiated a controversial debate on the utility of BSA antibodies as a disease marker and on the role of BSA in IDDM. Here we analyzed BSA antibodies in newly diagnosed type 1-diabetic patients and their first degree relatives, patients with other autoimmune diseases, and children with Down's syndrome from Germany. Blinded serum samples (n = 308) were screened for IgG anti-BSA antibodies by particle concentration fluoroimmunoassay (PCFIA). The prevalence of elevated BSA antibodies in newly diagnosed type 1-diabetic patients was low (11%), although mean BSA antibody levels were significantly increased in diabetic patients as compared to controls (1.94 +/- 1.51 vs. 0.97 +/- 0.93 kFU, p < 0.0007). Mean BSA antibody levels were also increased in ICA+ and/or IAA+ first degree relatives (1.32 +/- 0.43, p < 0.002) and in children with Down's syndrome (3.01 +/- 1.93, p < 0.0007), but not in the other autoimmune disorders tested. The low prevalence of elevated anti-BSA levels in IDDM patients limits the clinical usefulness of this immune marker. We conclude that current anti-BSA assays do not substantially contribute to the prediction and diagnosis of IDDM.

Adolescent↗
PubMed1997

Prediction of type 1 diabetes postpartum in patients with gestational diabetes mellitus by combined islet cell autoantibody screening: a prospective multicenter study.

Women with gestational diabetes mellitus (GDM) have a considerable risk of developing diabetes later in life. To determine the predictive value of autoantibody markers in gestational diabetic pregnancy for the development of type 1 diabetes postpartum, we tested 437 patients with GDM (289 women treated with diet only [GDM-A] and 148 requiring insulin treatment during pregnancy [GDM-B]) for antibodies to islet cells (ICAs), GAD (GADAs), and tyrosine phosphatase ICA512/IA-2 (IA2As). We prospectively followed them with repeated oral glucose tolerance tests and antibody determinations for up to 7 years postpartum (mean, 1.6 years; range, 0-7.2 years). The cumulative risk of diabetes up to 5 years postpartum was 17% (95% CI 12-22%). The risk of type 1 diabetes was 3% (2-5%) by 9 months and 7% (4-9%) 2 years after delivery. At delivery, 8.5% of all patients were ICA+, 9.5% were GADA+, 6.2% were IA2A+, and 18.1% were positive for at least one antibody (12.6% for GDM-A vs. 30.4% for GDM-B, P < 0.0001). During follow-up, GADAs persisted in 75%, ICAs in 35%, and IA2As in 30% of the subjects positive for the respective marker at delivery. By 2 years postpartum, 29% (19-39%) of patients positive for at least one antibody developed type 1 diabetes, compared with 2% (1-4%) of antibody-negative patients (P < 0.0001). Thereby, the risk for type 1 diabetes 2 years postpartum increased with the number of antibodies present at delivery from 17% (6-28%) for one antibody, to 61% (30-91%) for two antibodies, and to 84% (55-100%) for 3 antibodies. Risk of progression to type 1 diabetes postpartum was also associated with the status of parity. Women with one or more pregnancies before the index pregnancy had a higher risk for type 1 diabetes 2 years after delivery (14.7% [4.9.-24.5%]) than women having their first (i.e., index) pregnancy (5% [2.9-7.1%]) (P < 0.006). A comparison of different prediction strategies showed that single antibody screening with GADA yielded the highest sensitivity of 63% (45-75%), compared with ICA (48% [31-65%]) and IA2A (34% [13-47%]). Combined screening with two autoantibodies increased sensitivity to 74% (58-90%) and 75% (60-92%) when using GADA plus ICA or GADA plus IA2A, respectively. Screening with all three markers improved sensitivity further to 82% (67-100%). Beta-cell autoantibodies determined at delivery in women with GDM are highly predictive for the development of type 1 diabetes postpartum. Autoantibody screening in pregnant women with GDM from populations at high risk for type 1 diabetes should therefore be considered to allow early diagnosis and appropriate therapy.

Adolescent↗
PubMed1997

Autoantibodies to sympathetic ganglia, GAD, or tyrosine phosphatase in long-term IDDM with and without ECG-based cardiac autonomic neuropathy.

OBJECTIVE: To evaluate the association of autoantibodies to complement-fixing sympathetic ganglia (CF-SG), and tyrosine phosphatase (IA-2) with electrocardiogram (ECG)-based cardiac autonomic neuropathy (CAN) in long-term IDDM. RESEARCH DESIGN AND METHODS: We examined the prevalence of autoantibodies to CF-SG (by complement-fixing indirect immunoflourescence), GAD, and IA-2 (by radioligand assay) and islet cells (by indirect immunofluorescence) in 96 long-term IDDM patients (41 with ECG-based CAN, > or = 2 of 5 cardiac reflex tests abnormal; 55 without ECG-based CAN). As a control group, 89 healthy nondiabetic subjects were investigated. RESULTS: CF-SG autoantibodies were observed more frequently in long-term IDDM patients than in the control group (25 vs. 4%, P = 0.0001). Of the IDDM patients, 14 (34%) with CAN and 10 (18%) without CAN presented with CF-SG autoantibodies (P = 0.06). GAD or IA-2 autoantibodies were detected in 14 (34%) and 17 (41%) IDDM patients with CAN, compared with 24 (44%) and 29 (53%) IDDM patients without CAN (P = 0.2, P = 0.2). Islet cell antibodies were observed in 6 (15%) IDDM patients with and in 9 (16%) IDDM patients without CAN (P = 0.5). CONCLUSIONS: In long-term IDDM, the role of CF-SG autoantibodies, which tend to be more frequent in patients with ECG-based CAN, requires further investigations. The persistence of GAD and IA-2 autoantibodies is not related to ECG-based CAN.

Adult↗
PubMed1997

Validity of screening for individuals at risk for type I diabetes by combined analysis of antibodies to recombinant proteins.

OBJECTIVE: To determine whether screening for the presence of multiple antibody markers for IDDM is effective at identifying individuals with high risk for disease development. RESEARCH DESIGN AND METHODS: Antibodies to GAD and the tyrosine phosphatase-like protein 1A-2 were determined in sequential serum samples from 44 first-degree relatives of IDDM patients, identified as possessing islet cell antibody (ICA) and/or insulin autoantibody (IAA), who were followed prospectively for IDDM development, ICA, IAA, and antibodies to GAD and 1A-2 were also determined in 93 cases of new-onset nonfamilial IDDM. RESULTS: The presence of two or more antibodies in addition to ICA or IAA conferred high risk (61%) for development of IDDM within 5 years of entry into the study and identified 89% of those who have developed IDDM on current follow-up. None of the relatives positive for ICA or IAA alone, in the absence of other antibody markers, have developed IDDM. Antibodies to islet antigens could both appear and disappear in follow-up samples obtained after entry into the study. The majority (60%) of young (< 16 years), sporadic cases of IDDM had multiple antibodies to islet antigens, but this proportion was lower in older patients (37%). CONCLUSIONS: A screening strategy based on the analysis of antibodies to multiple islet antigens can predict IDDM at high sensitivity and specificity in families, and such a strategy may also be applicable to identify young individuals in the general population with high disease risk. Since appearance of antibodies to different antigens occurs sequentially rather than simultaneously, accurate assessment of diabetes risk based on the presence of multiple antibodies will require follow-up over a number of years after the first evidence of islet autoimmunity.

Adolescent↗