Effects of Hyperglycemia on Angiotensin II Receptor Type 1 Expression and Insulin Secretion in an INS-1E Pancreatic Beta-Cell Line

Kwan Keung Leung, Po Sing Leung

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Abstract

system has been identified and found to be upregulated in type 2 diabetes mellitus. Inhibition of this system improves beta-cell function and structure. The effects of hyperglycemia, a condition observed in diabetes, on angiotensin II type 1 receptor (AT1R) expression and beta-cell secretory function have yet to be explored. Objective This study investigated the effects of chronic hyperglycemia (glucotoxicity) on the expression of AT1Rs, and possibly thereby on oxidative stress-induced insulin release, in an INS-1E beta-cell line. Settings INS-1E beta-cells cultured and incubated in different glucose concentrations with a varying time course. Main outcome measures Immunocytochemistry was employed for the precise localization of AT1Rs in INS-1E cells. The effects of hyperglycemia-induced AT1R expression changes in gene and protein levels were examined by real-time RT-PCR and Western blot analysis, respectively. AT1R activationmediated oxidative stress was assessed by changes in NADPH oxidase expression, and the level of superoxide production was determined by nitroblue tetrazolium (NBT) assay. Glucotoxicity-induced AT1R activationmediated secretory dysfunction was also assessed by insulin release from INS-1E cells. Results AT1R immunoreactivity was found to be localized specifically on the cell membrane. Chronic hyperglycemia resulted in dose-dependent upregulation of AT1R gene and protein expression accompanied by concomitantly-enhanced oxidative stress. Glucose-stimulated insulin secretion via AT1R activation was impaired by hyperglycemia. Conclusion These data indicate that hyperglycemia-induced AT1R activation impairs insulin secretion; this impairment may be mediated via AT1R-dependent oxidative stress.

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