The GABA network and the pathogenesis of IDDM

Esposti, Mauro Degli; Mackay, Ian R.

doi:10.1007/s001250050687

Cited by 17 publications

(9 citation statements)

References 51 publications

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“…In agreement with these results, it has been observed that primary cultures gradually lose their ability to produce insulin and this inability is accompanied by the loss of GAD65 expression [28]. It is therefore possible that GAD65 expression is related to the capability of beta cells to secrete insulin [30]. Nearly 70 % of the insulin-secreting cells are GAD65-positive.…”

Section: Discussionsupporting

confidence: 66%

Heterogeneity in glutamic acid decarboxylase expression among single rat pancreatic beta cells

et al. 1999

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Pancreatic beta cells contain the enzyme glutamic acid decarboxylase (GAD) that catalyses the biosynthesis of the neurotransmitter g-aminobutyric acid (GABA) [1,2]. Two non-allelic genes probably derived from a common ancestral gene encode GAD. The two GAD isoforms, named GAD65 and GAD67 according to their approximate molecular weight in kDa, share a similar structure, except in the first 95 amino acids [3]. Despite their homology, there are structural and functional differences between them that are reflected by their intracellular compartmentalization and the degree of saturation with the coenzyme pyridoxal phosphate (PLP) [2±4].Although the physiological significance of GAD and GABA in beta-cell function is not entirely clear, the presence of antibodies directed against GAD65 have been implicated in the pathogenesis of Type I (insulin-dependent) diabetes mellitus and Stiff-Man Abstract Aims/hypothesis. An isoform of glutamic acid decarboxylase, (GAD)65 has been identified as a pancreatic beta-cell autoantigen in Type I (insulin dependent) diabetes mellitus. We investigated the expression of GAD isoforms among single rat beta cells in culture, under different conditions and the correlation between GAD65 expression and insulin secretion-rate. Results. Independent of culture conditions, 100 % of fresh and cultured beta cells express GAD67. In contrast, considerable heterogeneity in GAD65 expression among single beta cells was observed. After 2 days in culture in 2.6 mmol/l glucose, only 24 % of the beta cells express GAD65. This percentage increases to 39 % in 5.6 mmol/l glucose and to 54 % and 56 % in 11.6 mmol/l and 20.6 mmol/l glucose, respectively. Moreover, reducing glucose concentration from 11.6 to 2.5 mmol/l for 2 days, reduces GAD65 expression by nearly 30 %. After 11 days in culture with 11.6 mmol/l glucose, 50 % of beta cells continue expressing GAD65, this percentage is further increased to nearly 75 % by including either nerve growth factor or dibutyryl cyclic AMP or both in the culture medium. When beta cells are challenged for 1 h with 20.6 mmol/l glucose, 67 % respond forming insulin-immunoplaques. More than two-thirds of insulin-secretors are GAD65-positive, in contrast to only 11 % of the non-secreting cells. Moreover, 87 % of beta cells that have a high insulin secretory rate express GAD65. Conclusion/interpretation. These results show that the most active beta cells, which secrete more insulin, also express GAD65 and that manipulating extracellular glucose may modify the expression of the enzyme and possibly the autoimmune attack in Type I diabetes. [Diabetologia (1999

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Section: Discussionsupporting

confidence: 66%

Heterogeneity in glutamic acid decarboxylase expression among single rat pancreatic beta cells

et al. 1999

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“…Identification of GAD (1), a family of tyrosine phosphatase-like proteins variously designated islet cell antigen 512 (ICA512)/IA-2/IA-2 (2,3), and insulin (4) as autoantigens in type 1 diabetes has led to the proposal of several mechanisms for the initiation and progression of islet autoimmunity. These include molecular mimicry between GAD and coxsackievirus B (5) or between ICA512 and rotavirus (6), hyperexpression of GAD in response to metabolic stress (7), and lack of tolerance to (pro)insulin as a consequence of genetic variation of proinsulin expression levels in the thymus (8,9). The multifactorial nature of type 1 diabetes and the association of numerous environmental agents with the disease (10) suggest that there may be multiple pathways leading to -cell autoimm u n i t y.…”

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confidence: 99%

Sex-determining region Y-related protein SOX13 is a diabetes autoantigen expressed in pancreatic islets.

et al. 2000

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The SOX (sex-determining region [SRY]-type high mobility group [HMG] box) family of transcription factors play key roles in determining cell fate during organ development. In this study, we have identified a new human SOX gene, S O X 1 3, as encoding the type 1 diabetes autoantigen, islet cell antigen 12 (ICA12). Sequence analysis showed that SOX13 belongs to the class D subgroup of SOX transcription factors, which contain a leucine zipper motif and a region rich in glutamine. SOX13 autoantibodies occurred at a significantly higher frequency among 188 people with type 1 diabetes (18%) than among 88 with type 2 diabetes (6%) or 175 healthy control subjects (4%). Deletion mapping of the antibody epitopes showed that the autoantibodies were primarily directed against an epitope requiring the majority of the protein. S O X 1 3 R N A was detected in most human tissues, with the highest levels in the pancreas, placenta, and kidney. Immunohistochemistry on sections of human pancreas identified SOX13 in the islets of Langerhans, where staining was mostly cytoplasmic. In mouse pancreas, Sox13 was present in the nucleus and cytoplasm of -cells as well as other islet cell types. Recombinant SOX13 protein bound to the SOX consensus DNA motif AACAAT, and binding was inhibited by homodimer formation. These observations-along with the known molecular interactions of the closely related protein, rainbow trout Sox23-suggest that SOX13 may be activated for nuclear import and DNA binding through heterodimer formation. In conclusion, we have identified ICA12 as the putative transcription factor SOX13 and demonstrated an increased frequency of autoantibody reactivity in sera from type 1 diabetic subjects compared with type 2 diabetic and healthy control subjects. T ype 1 diabetes results from the destruction of pancreatic islet -cells by an autoimmune response to -cell constituents, which is initiated by an unknown environmental agent acting on a susceptible genetic background. Identification of GAD (1), a family of tyrosine phosphatase-like proteins variously designated islet cell antigen 512 (ICA512)/IA-2/IA-2 (2,3), and insulin (4) as autoantigens in type 1 diabetes has led to the proposal of several mechanisms for the initiation and progression of islet autoimmunity. These include molecular mimicry between GAD and coxsackievirus B (5) or between ICA512 and rotavirus (6), hyperexpression of GAD in response to metabolic stress (7), and lack of tolerance to (pro)insulin as a consequence of genetic variation of proinsulin expression levels in the thymus (8,9). The multifactorial nature of type 1 diabetes and the association of numerous environmental agents with the disease (10) suggest that there may be multiple pathways leading to -cell autoimm u n i t y. To attain a better understanding of the pathogenesis of type 1 diabetes, the autoimmune response to islet -c e l l s needs to be fully characterized.In a search for novel diabetes-associated autoantigens, the screen of an islet cDNA expression library with type 1 diabetes sera tha...

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“…However, the molecular mechanisms underlying this effect are largely unknown. Degli et al suggested that accumulation of glutamate upon perturbation of GABA network, produced by nutrient or environmental stress, could up-regulate expression of GAD [17]. High glucose concentrations were also shown to increase GAD expression in cultured islets [18][19][20].…”

Section: Introductionmentioning

confidence: 99%