Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic β-cells

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Abstract

IA-2, a member of the protein tyrosine phosphatase family, represents a major target autoantigen in type 1 diabetes. To study the regulation of IA-2 gene expression, we used INS-1 insulinoma cells to analyze β-cell signal transduction pathways as well as the effect of metabolic and hormonal factors involved in the regulation of insulin secretory pathway. Quantitative competitive reverse transcriptase-polymerase chain reaction revealed that an increase of cellular cAMP mediated by forskolin (10 μmol/l, 24 h) or 3- isobutyl-1-methylxanthine (100 μmol/l, 24 h) induced maximal stimulation of IA-2 mRNA levels (451 ± 85 and 338 ± 86% compared with basal conditions; P < 0.001). In contrast, activation of protein kinase C (PKC) by short-term treatment with phorbol 12-myristate 13-acetate (PMA) (1 μmol/l, 6 h) did not alter IA-2 expression, whereas depletion of PKC by prolonged culturing (24 h) exerted a significant inhibition (57 ± 24%; P < 0.05). cAMP-dependent upregulation was confirmed by the findings that glucagon (10 μmol/l, 24-48 h) increased levels of IA-2 mRNA (190 ± 35%; P < 0.05), whereas short-term incubation with high glucose concentration showed no effect. However, prolonged incubation in high glucose (21 mmol/l) induced a time- and dose- dependent increase of IA-2 mRNA expression, reaching maximal values after 144 h (285 ± 68%; P < 0.05). These studies demonstrate that stimuli of insulin secretion that operate by activation of adenylate cyclase generating cAMP significantly increase IA-2 gene expression. In contrast, activation of PKC by high glucose concentration or PMA exerted no effect, suggesting that IA-2 gene expression is not simply coupled to insulin secretion, but may be involved in the fine regulation of β-cell function. These findings may be important to clarify the function of IA-2 in β-cells and elucidate mechanisms involved in the induction of autoimmunity to IA-2.

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APA

Seissler, J., Nguyen, T. B. T., Aust, G., Steinbrenner, H., & Scherbaum, W. A. (2000). Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic β-cells. Diabetes, 49(7), 1137–1141. https://doi.org/10.2337/diabetes.49.7.1137

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