Evolution of Nrf2 Gene Expression in HIT-T15 β-Cells During Chronic Oxidative Stress and Glucose Toxicity

CONTEXT: Chronic exposure of pancreatic islets to elevated glucose levels causes progressive declines in beta cell Pdx-1 and insulin gene expression, and glucose-induced insulin secretion. This has been shown to be associated with excessive islet reactive oxygen species and consequent damage to beta cell function, a process termed glucose toxicity. In short-term rodent in vivo studies, Nrf2 (Kelch-like ECH-associated protein 1:nuclear factor erythroid-derived-2 related factor complex) has been shown to play a central role in defending beta cells from oxidative damage via activation of antioxidant gene expression. OBJECTIVE: The current studies were primarily designed to examine the behavior of Nrf2 gene expression during longer term exposure of beta cells to glucose toxicity. METHODS AND RESULTS: We provide evidence that gene expression of Nrf2 in HIT-T15 cells, an insulin-secreting beta-cell line, undergoes a biphasic response characterized by an initial decrease followed by increased expression during prolonged culturing of these cells in a physiologic (0.8 mM) but not a supraphysiologic (16.0 mM) glucose concentration. This was associated with a slight rise in HO-1 gene expression. Pdx-1 and insulin mRNA levels also decreased but then stabilized in late passages of cells that had been cultured in low glucose concentrations. CONCLUSION: These complex events support the concept that Nrf2 gene expression plays an important regulatory role in defending beta cells during prolonged exposure to oxidative stress.