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OBJECTIVE--We examined maximal graded exercise test (GXT) results in 5,783 overweight/obese men and women, aged 45-76 years, with type 2 diabetes, who were entering the Look AHEAD (Action for Health [...]

OBJECTIVE--To study how tolerance to GAD65 affects the development of autoimmunity to other β-cell autoantigens (β-CAAs) in GAD654ransgenic (GAD-tg) NOD mice. RESEARCH DESIGN AND METHODS--We used ELISPOT to characterize the frequency and functional phenotype of T-cell responses to GAD65 and other β-CAAs at different ages in GAD-tg mice and their NOD mouse littermates. RESULTS--In young GAD-tg mice, Th1 responses to GAD65's dominant determinants were 13-18% of those in young NOD mice. This coincided with a great reduction in Th1 responses to other β-CAAs. Evidently, GAD65-reactive T-cells are important for activating and/or expanding early autoreactivities in NOD mice. As GAD-tg mice aged, their T-cell responses to GAD65 remained low, but they developed supernormal splenic and pancreatic lymph node T-cell autoimmunity to other β-CAAs. Apparently, the elimination/impairment of many GAD65-reactive T-cells allowed other β-CAA-reactive T-cells to eventually expand to a greater extent, perhaps by reducing competition for antigen-presenting cells, or homeostatic proliferation in the target tissue, which may explain the GAD-tg mouse's usual disease incidence. CONCLUSIONS--Transgenically induced reduction of GAD65 autoreactivity curtailed the development of early T-cell responses to other β-CAAs. However, later in life, β-CAA-reactive T-cells expanded to supernormal levels. These data suggest that early p-cell autoreactivities are mutually dependent for support to activate and expand, while later in the disease process, autoantigen-specific T-cell pools can expand autonomously. These findings have implications for understanding type 1 diabetes immunopathogenesis and for designing antigen-based immunotherapeutics., The role of T-cell autoreactivity to the 65-kDa form of GAD (GAD65) in the etiology of type 1 diabetes in nonobese diabetic (NOD) mice has been much debated, in large [...]

Whether autoimmunity results primarily from a defect of the immune system, target organ dysfunction, or both remains an open issue in most human autoimmune diseases. The highly multigenic background on which diabetes develops in the NOD mouse and in the human suggests that numerous gene variants associate in contributing to activation of autoimmunity to [beta]-cells. Both immune genes and islet-related genes are involved. The presence of [beta]-cells is required for initiation of diabetes autoimmunity to proceed. Available experiments in the NOD mouse and epidemiological evidence in the human point to proinsulin as a key autoantigen in diabetes. The functional importance of insulin, the high number of autoantigens characterized at different stages of diabetes, and their clustering within [beta]-cell subparticles point to the islet as a starting point in the initiation phase of the disease. Genes that direct the autoimmune reaction toward the [beta]-cell target, autoantigens that are recognized by autoreactive B- and T-cells along the autoimmune process, the importance of [beta]-cells in the activation of autoreactive lymphocytes, and the expression level of key [beta]-cell molecules along diabetes development are successively considered in this review. Diabetes, Type 1 diabetes is the result of an autoimmune reaction that develops against pancreatic [beta]-cells. Indirect evidence for autoimmunity in human type 1 diabetes relies on the detection of insulitis, [...]

GAD is a pancreatic β-cell autoantigen in humans and nonobese diabetic (NOD) mice. Modulation of GAD expression in pancreatic β-cells has been suggested to be associated with the development of autoimmune diabetes. Hormonal changes through environmental stimuli are considered to influence the expression of the disease. We determined whether steroid hormones would modulate the expression of GAD in pancreatic β-cells. We treated NOD mouse beta-cells (MIN6N8a cells) with various steroids, including testosterone, estradiol, progesterone, and cortisol, and examined the expression of GAD67 mRNA. We found that only cortisol enhanced the expression of GAD67, whereas the other steroid hormones had no effect. When we treated MIN6N8a cells with a synthetic glucocorticoid, dexamethasone, we found that GAD67 mRNA expression was stimulated in a dose- and time-dependent manner. Cells treated with 100 nmol/l dexamethasone for 6 h showed a 10-fold increase in the expression of GAD67 mRNA and an increase in GAD67 protein. The upregulation of GAD67 expression in β-cells by dexamethasone was found to be due to the transcriptional activation of the GAD67 promoter. We then examined whether dexamethasone would influence the development of diabetes in NOD mice. Injection of dexamethasone into neonatal NOD mice resulted in a significant increase in the expression of GAD67 mRNA in pancreatic β-cells and the development of insulitis and diabetes. We conclude that glucocorticoid hormones can modulate GAD expression by the transcriptional activation of the GAD promoter and may influence the development of autoimmune diabetes in NOD mice., GAD is an enzyme that catalyzes the formation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) from glutamic acid. The two isoforms of GAD, GAD65 and GAD67, are encoded by two [...]

Administration of antigens via mucosal routes, such as orally or intranasally, can induce specific immunological tolerance and has been used as a rational basis for the treatment of autoimmune diseases, [...]

IDDM is a T-cell-mediated autoimmune disease in which the insulin-producing Β-cells are destroyed. The disease process is complex, involving the recognition of several Β-cell autoantigens. One of these, GAD65, appears [...]

A single injection of syngeneic islet cells into the thymus of 4-week-old NOD/Lt female mice strongly retards diabetogenesis. The present study used the intrathymic route of antigen administration to compare [...]

A peptide of the human 60-kDa heat-shock protein (hsp60), designated p277, was found to be useful as a therapeutic agent to arrest the autoimmune process responsible for diabetes in nonobese [...]

Prevention of type 1 diabetes in NOD mice by 1,25-dihydroxyvitamin [D.sub.3] [1[Alpha],25[(OH).sub.2][D.sub.3]] is accompanied by a T-helper (Th) 1/Th2 cytokine shift in the pancreas. The aim of this study was [...]

Coxsackievirus infections have been proposed as an environmental trigger for the development of T-cell--mediated autoimmune (type 1) diabetes by either providing a molecular mimic of the candidate pancreatic Β-cell autoantigen [...]

The 65KD isoform of GAD is considered to be a major target autoantigen in many humans with autoimmune prediabetes or diabetes. The major histocompatibility complex class II allele DQA1*0301, DQB1*0302, [...]