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

• Published in: Journal of the Endocrine Society 2023-03, Vol.7 (3)
• Main Authors: Abebe, Tsehay, Bogachus, Lindsey, Vegaraju, Adithya Krishna, Robertson, R. Paul
• Format: Article
• Language: English
• Subjects: Analysis; Antioxidants; Dextrose; Gene expression; Genes; Glucose; Insulin; Messenger RNA; Oxidative stress; Type 2 diabetes
• ISSN: 2472-1972; 2472-1972
• DOI: 10.1210/jendso/bvac178

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 ECHassociated 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. Key Words: Nrf2 gene expression, beta cells, oxidative stress Abbreviations: HFD, high-fat diet; HO-1, hemoxygenase-1; KEAP1, Kelch-like ECH- associated protein 1; Nrf2, nuclear factor erythroid-derived-2 related factor; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; ROS, reactive oxygen species.