Effects of hyperglycemia on angiotensin II receptor type 1 expression and insulin secretion in an INS-1E pancreatic beta-cell line.

CONTEXT: A local pancreatic islet renin-angiotensin 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 activation-mediated 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 activation-mediated 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.