How useful is autoantibody screening in adult-onset diabetes?
Explore the source record for details and available documents.
Journal Article↗
Biomedical subjects
Lisa K Gilliam
Publications and source records attributed to Lisa K Gilliam.
Capecitabine therapy for refractory metastatic thyroid carcinoma: a case series.
OBJECTIVE: There are few effective therapies for metastatic medullary (MTC) or radioiodine-resistant follicular thyroid carcinomas (FTC). We report a single institution's experience with capecitabine, a thymidylate synthase (TS) inhibitor, in the treatment of MTC and FTC. DESIGN: We retrospectively analyzed five cases of metastatic thyroid carcinoma, three MTCs and two radioiodine-resistant FTCs, treated with capecitabine alone or in combination with other chemotherapeutics. Patients were selected for treatment based on low tumor TS immunohistochemical staining (< or =5%). Staining for thymidylate phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) was also performed. Therapeutic response was assessed by imaging studies and serum tumor markers: calcitonin and carcinoembryonic antigen (MTC), and thyroglobulin (FTC). MAIN OUTCOME: Two of three patients with MTC had stable disease or disease regression on capecitabine. One of these patients had a 90% reduction in calcitonin and stabilization by imaging that lasted 4 years. Both patients with FTC initially had stable disease on capecitabine. One patient, who was treated with capecitabine in combination first with doxorubicin and then etoposide, had an initial decrease in tumor burden, followed by stable disease for 2.8 years. The second patient had stable disease, but capecitabine was discontinued after 11 months because of hand/foot syndrome. CONCLUSIONS: This series demonstrates promising results for the use of capecitabine in treatment of MTC and radioiodine-resistant FTC, for which there is a limited repertoire of therapeutic agents. Larger studies are needed to confirm these findings and to establish the role of fluoropyramidine metabolism markers in predicting response.
Adult↗
Evaluation of leptin levels in subjects at risk for type 1 diabetes.
Type 1 diabetes (T1DM) is increasing in incidence worldwide, particularly in young children. Studies have suggested that weight gain in early childhood may play a role in determining disease risk, with increased risk in children who have gained more weight. We hypothesized that leptin may be involved by promoting a Th1-type immune response in individuals at risk for the development of T1DM. Insulin, GAD65, and IA-2 autoantibodies and leptin levels were measured in relatives of T1DM patients and in control subjects. After adjusting for HLA risk and age, autoantibody-positive relatives were compared with sex- and BMI-matched autoantibody-negative control subjects. BMI-matched individuals had similar leptin levels, and the leptin levels increased with increasing BMI Z-score, as expected. However, we did not demonstrate higher leptin levels in autoantibody-positive relatives, compared with autoantibody-negative control subjects. Thus, elevations in leptin levels do not appear to be a major determinant of whether an individual develops autoimmunity. If elevated BMI and associated elevations in leptin levels are risk factors for the initiation and/or progression of autoimmunity, they may act more as permissive factors in this process, in the setting of a certain degree of genetic predisposition.
Adolescent↗
Autoimmunity and clinical course in children with type 1, type 2, and type 1.5 diabetes.
AIMS: Both type 1 (T1D) and type 2 diabetes (T2D) are increasing in incidence in children; often an admixture of T1D and T2D features are present at diagnosis. We examined the relationship between diabetes autoantibodies (DAA), human leukocyte antigen (HLA), and clinical course in subjects grouped by clinical diabetes type. METHODS: Subjects 8-18 years old with T1D, T2D, and mixed clinical features (T1.5D), were studied at diagnosis. DAA were measured in all subjects; a subset of subjects underwent HLA genotyping. Clinical course was followed in 84% of subjects for 47.9+8.7 months. RESULTS: Eighty-nine percent of T1.5D subjects were positive for at least one DAA; 88% of HLA-typed subjects had risk HLA genotypes. Two subjects initially treated with oral agents were subsequently treated with insulin (50%); one had risk HLA, and the other was DAA positive. Thirty-three percent of T2D subjects were DAA positive and 93% were treated with oral agents at diagnosis. Three subjects were subsequently treated with insulin (21%); of these, two were DAA positive, and one had risk HLA. No subject who remained on diet therapy or oral agents had a combination of DAA-positivity and risk HLA genotype. CONCLUSIONS: Children clinically classified with T1.5D or T2D have a high frequency of autoimmune markers and T1D-associated HLA alleles which appears to indicate a more aggressive diabetes disease process, as has been shown for DAA-positive adults with phenotypic T2D.
Adolescent↗
Autoantibodies in diabetes.
Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens-GAD65, IA-2, or insulin-signals an autoimmune pathogenesis of beta-cell killing. A beta-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to beta-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitope-specific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of type 1 diabetes. The complexity of the disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations when examined longitudinally.
Autoantibodies↗
Development of glutamic acid decarboxylase 65 (GAD65) autoantibody assay using biotin-GAD65 fusion protein.
We evaluated a biotin-glutamic acid decarboxylase 65 (GAD65)-based enzyme-linked immunosorbent assay (B-ELISA) to detect GAD65 autoantibodies (GAD65Ab) in 78 sera from individuals with newly diagnosed type 1 diabetes. The GAD65Ab index of patients with type 1 diabetes (mean value of GAD65Ab index of 1.891) was significantly higher than those in 50 sera from healthy control group (mean value of 0.068). The intra- and inter-assay coefficients of variation (CV) were calculated to be 1.042 and 10.703%, respectively. The specificity of the B-GAD65 ELISA was comparable to the standard radioimmunoassay (RIA) which is routinely used in the laboratory. We describe the optimal conditions of the binding kinetics from each assay-step for the detection of GAD65Ab using the WHO standard serum 97/550 as a model autoantibody serum. We concluded that incubation times of 15, 90, and 90 min for step 1 (pre-incubation of Biotin14-GAD65 with serum), step 2 (binding the Ab/Ag complex to NeutrAvidin plate), and step 3 (incubation with HRPO-anti-human IgG), respectively, along with human serum dilutions of 1:50, would provide an optimal assay signal within a relatively short timeframe.
Autoantigens↗
Epitope-restricted 65-kilodalton glutamic acid decarboxylase autoantibodies among new-onset Sardinian type 2 diabetes patients define phenotypes of autoimmune diabetes.
The 65-kDa glutamic acid decarboxylase (GAD65) autoantibodies (GAD65Abs), commonly found in type 1 diabetes mellitus (T1DM) patients, are also found at lower frequencies in type 2 diabetes mellitus (T2DM) patients. GAD65Abs in T1DM patients are epitope specific, in contrast to those found in other GAD65Ab-positive individuals, including T2DM patients. Our aim was to assess whether epitope-specific GAD65Abs, or the additional presence of islet antigen 2 (IA-2) autoantibodies, better define T1DM phenotypes among T2DM patients. GAD65 and IA-2 autoantibodies were analyzed in 1436 Sardinian subjects classified with T2DM and in 384 nondiabetic patient controls. Autoantibody binding specificity to the N-terminal, middle (M), and C-terminal (C) portions of the GAD65 molecule was evaluated. Among the T2DM patients, 5.1% had GAD65 (P < 0.001) and 2.4% had IA-2 autoantibodies, compared with 1.3 and 1.6%, respectively, among the controls. GAD65Ab-positive T2DM patients with M+C (epitope-specific) reactivity were found to have the lowest body mass index (P < 0.001), followed by GAD65Ab/IA-2Ab-positive patients (P < 0.01), and non-M+C-reactive (non-epitope-specific) patients (P < 0.02). In GAD65Ab-positive T2DM patients, c-peptide levels were lower in M+C-reactive compared with non-M+C-reactive patients. Sardinian T2DM patients with M+C-predominant GAD65Ab reactivity have clinical features more similar to those of T1DM patients. Thus, GAD65Ab epitope analysis may help to define T1DM phenotypes among newly diagnosed GAD65Ab-positive patients classified with T2DM.
Adult↗
BRCA2 monoclonal antibodies react with differentiating epithelium.
The BRCA2 gene has previously been suggested to play a role in proliferation and DNA repair. Germline mutations in the BRCA2 gene predispose individuals to early onset, hereditary breast cancer. To better understand the expression pattern and function of the BRCA2 gene product, we have developed immunological reagents specific for BRCA2. These reagents recognize full-length (384 kDa) recombinant human BRCA2 proteins in transfected cell lysates as well as multiple smaller recombinant BRCA2 polypeptides. Detection of native BRCA2 protein in most tissue types, including breast epithelium, requires sensitive techniques such as immunoprecipitation-Western blot analysis. However, we have demonstrated strong reactivity of our immunological reagents with differentiating epithelium, including epidermis, thymic epithelium, and squamous cell carcinoma. These data suggest that BRCA2 may play a role in processes associated with cellular differentiation, in addition to its previously suggested roles in proliferation and DNA repair.
Animals↗
Type 1 diabetes-related autoantibodies are rare in Alaska native populations.
OBJECTIVES: When clinical data were initially gathered from the Alaskan Eskimos in the 1950's, diabetes mellitus was noted to be quite rare. The prevalence of diabetes has increased significantly since that time, with rates of 10% reported recently in some Alaska native populations. Our goal was to understand the pathogenesis of diabetes among these groups, with the hypothesis that Alaskan Eskimos were predominantly affected by type 2 diabetes, not by latent autoimmune diabetes in adults (LADA). STUDY DESIGN: Population based case control study METHODS: We tested sera from subjects in two Eskimo villages for the presence of type 1 diabetes-related autoantibodies against glutamic acid decarboxylase (GAD65Ab) and tyrosine phosphatase-like islet antigen-2 (IA-2Ab). RESULTS: Among subjects from one Inupiat village (#1) and one SiberianYup'ik village (#2), there were 21 subjects with diabetes mellitus (DM), 17 with impaired glucose tolerance (IGT), and 226 healthy controls with normal glucose tolerance (NGT). In village 1, GAD65 antibodies were not present in either diabetic subjects or those with IGT. One of the healthy controls (1%; 1/97) was positive for GAD65Ab. Similarly, no subjects from this village with DM or IGT had positive IA-2Ab titers, and one healthy control (1%; 1/97) was positive for IA-2Ab. In village 2, no DM subject was GAD65Ab positive. One (10%; 1/10) of the IGT subjects and two (1.6%;2/129) of the healthy controls were positive for GAD65Ab. In this village, two of the DM subjects (12%;2/17), one of the IGT subjects (10%; 1/10), and one of the healthy controls (0.8%;1/129) were IA-2Ab positive. No individual was positive for both GAD65Ab and IA-2Ab. CONCLUSION: Alaskan Inupiat and Siberian Yup'ik Eskimos appear to be predominantly affected by type 2 diabetes, not LADA.
Adult↗