Elisabeth Björk

GAD autoantibodies in IDDM, stiff-man syndrome, and autoimmune polyendocrine syndrome type I recognize different epitopes

Glutamic acid decarboxylase (GAD) is a major islet cell autoantigen in insulin-dependent diabetes mellitus (IDDM), and autoantibodies are found in high frequencies in patients with recent-onset IDDM, stiff-man syndrome (SMS), and autoimmune polyendocrine syndrome type I (APS I). Antigens in autoimmune disorders are often enzymes, and autoantibody binding frequently inhibit their activity. In this study, we examined the reactivity of anti-GAD–containing sera from 7 patients with IDDM, 4 patients with SMS, and 5 patients with APS I. All sera immunoprecipitated GAD from [35S]methionine-labeled rat islet lysates and the sera from patients with SMS and APS I, but none of the IDDM patients’ sera, identified the GAD protein in Western blots. Two of four SMS patients’ sera and 5 of 5 APS I patients’ sera, in contrast to 0 of 7 IDDM patients’ sera, inhibited the enzymatic activity of GAD. When the various sera were tested with the GAD65 and GAD67 isoforms, produced separately by transient expression in COS cells, the enzymatic activity of GAD65 was inhibited by sera from patients with SMS and APS I, whereas no effect on the GAD67 activity was observed. Taken together, the results demonstrate that the GAD autoantibodies in these three disorders display marked differences in epitope recognition and indicate that, during the development of the diseases, the autoantigen is being presented to the immune system through separate pathogenetic mechanisms.

Diazoxide Treatment at Onset Preserves Residual Insulin Secretion in Adults with Autoimmune Diabetes

Twenty islet cell antibody (ICA)-positive patients, aged 19–38 years, with IDDM were randomized at onset to treatment with either diazoxide, a K+ channel opener that inhibits the release of insulin, or placebo for 3 months, in addition to multiple insulin injection therapy. The patients who were given diazoxide displayed higher residual insulin secretion than the placebo group after 1 year (basal C-peptide level, 0.40 ± 0.04 vs. 0.25 ± 0.04 [mean ± SE] nmol/l; P < 0.021) and at an 18-month follow-up (0.37 ± 0.06 vs. 0.20 ± 0.01 nmol/l, P < 0.033). Metabolic control did not differ between the two groups. During the course of the study, no differences in islet cell or GAD autoantibodies were detected between the two groups. The results of this study warrant further trials to explore the potential of inducing target cell rest in order to halt the loss of insulin-producing cells during the early course of the disease.

High-Glucose Stimulation of 64,000-Mr Islet Cell Autoantigen Expression

This study examined the effect of various extracellular glucose concentrations on the expression of a previously described 64,000-Mr islet cell autoantigen associated with insulin-dependent diabetes mellitus. The protein was precipitated from patient serums incubated with Triton X-100 lysates of [35S]methioninelabeled rat pancreatic islets that had been cultured in 5, 11, or 28 mM glucose for 6 h or 3 days. In both types of experiment, 28 mM glucose was the most efficient stimulator of 64,000-Mr autoantigen production. In contrast, the class I antigens of the major histocompatibility complex, precipitated by a rabbit polyclonal antiserum, were not influenced by differences in glucose concentrations. Our data indicate that expression of islet cell antigens may be increased during the course of hyperglycemia and suggest that the functional activity of islet cells influences their antigenicity.

Expression of the 64 kDa/glutamic acid decarboxylase rat islet cell autoantigen is influenced by the rate of insulin secretion

SummaryThis study examined the relationship between insulin secretion and expression of the 64 kDa/glutamic acid decarboxylase autoantigen in pancreatic islets. Islets isolated from Wistar rats were cultured for 3 days under different conditions: in 5.5 mmol/l glucose with or without a-ketoisocaproic acid or glipizide and in 28 mmol/l glucose with or without diazoxide. The 64 kDa/glutamic acid decarboxylase autoantigen was precipitated from lysates of [35S]-methionine-labelled islets with sera from patients with Type 1 (insulin-dependent) diabetes mellitus and identified by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and fluorography. In parallel, insulin contents of the islets and the media were determined as well as the rates of glucose-stimulated (pro)insulin biosynthesis. α-Ketoisocaproic acid and glipi zide were found to stimulate the expression of the 64 kDa/glutamic acid decarboxylase autoantigen and also the rate of insulin secretion. Diazoxide on the other hand reduced the rate of the 64 kDa/glutamic acid decarboxylase autoantigen synthesis in parallel with an inhibition of glucose-stimulated insulin release. Under most of the conditions employed, (pro)insulin biosynthesis was not affected. The correlation found between the rate of insulin release and expression of the 64 kDa/glutamic acid decarboxylase auto-antigen might provide an explanation for the earlier observed relationship between the functional demands on the Beta cells and their rate of destruction which may result in diabetes.

Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds

Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes.

Islet antibodies and remaining beta-cell function 8 years after diagnosis of diabetes in young adults : a prospective follow-up of the nationwide Diabetes Incidence Study in Sweden.

Objectives.  To establish the prevalence of remaining β‐cell function 8 years after diagnosis of diabetes in young adults and relate the findings to islet antibodies at diagnosis and 8 years later.

CRP and IL-6 concentrations are associated with poor glycemic control despite preserved beta-cell function during the first year after diagnosis of type 1 diabetes.

The role of non‐specific inflammation in β‐cell loss in type 1 diabetes is unclear. In the present study, inflammatory markers were determined in patients with newly diagnosed disease and related to β‐cell function, glycemic control and autoimmunity.

Factors predicting clinical remission in adult patients with type 1 diabetes

Objectives. To describe the course of clinical remission in adult patients (16–50 years of age) with type 1 diabetes and to identify factors predictive of the occurrence and length of remission.

Normal weight promotes remission and low number of islet antibodies prolong the duration of remission in Type 1 diabetes

Aim  To identify clinical, immunological and biochemical factors that predict remission, and its duration in a large cohort of young adults with Type 1 diabetes mellitus (DM).

Blood glucose in acute stroke, different therapeutic targets for diabetic and non-diabetic patients?

Objectives –  To study the impact of blood glucose concentrations on early stroke mortality in diabetic and non‐diabetic stroke patients, and to identify the optimal blood glucose concentration for each patient category.