Abstract
Influencing the redox balance of pancreatic beta cells could be a promising strategy for the treatment of diabetes. Nuclear factor erythroid 2p45-related factor 2 (Nrf2) is present in beta cells and regulates numerous genes involved in antioxidant defense. As reactive oxygen species (ROS) are important for beta cell signaling but induce oxidative stress when present in excess, this study elucidates the influence of Nrf2-activating compounds on different kinds of ROS and correlates changes in redox balance to effects on mitochondrial function, insulin release, and cell viability. Acute glucose stimulation (15 mmol/L) of murine islet cells of C57Bl/6N mice affects ROS and redox status of the cells differently. Those ROS monitored by dihydroethidium, which detects superoxide radical anions, decrease. By contrast, oxidant status, monitored by dichlorodihydrofluorescein, as well as intracellular H2O2, increases. Glucolipotoxicity completely prevents these fast, glucose-mediated alterations and inhibits glucose-induced NAD(P)H production, mitochondrial hyperpolarization, and ATP synthesis. Oltipraz (10 μmol/L) or dimethyl fumarate (DMF, 50 μmol/L) leads to nuclear accumulation of Nrf2, restores mitochondrial activity and glucose-dependent ROS turnover, and antagonizes glucolipotoxicity-induced inhibition of insulin release and apoptosis. Importantly, these beneficial effects only occur when beta cells are challenged and damaged by high lipid and carbohydrate supply. At physiological conditions, insulin release is markedly reduced in response to both Nrf2 activators. This is not associated with severe impairment of glucose-induced mitochondrial hyperpolarization or a rise in apoptosis but coincides with altered ROS handling. In conclusion, Nrf2 activators protect beta cells against glucolipotoxicity by preserving mitochondrial function and redox balance. As our data show that this maintains glucose-stimulated insulin secretion, targeting Nrf2 might be suited to ameliorate progression of type 2 diabetes mellitus. By contrast, nonstressed beta cells do not benefit from Nrf2 activation, thus underlining the importance of physiological shifts in ROS homeostasis for the regulation of beta cell function.
Highlights
In early stages of type 2 diabetes mellitus, pancreatic beta cells try to compensate insulin resistance of fat, muscle, and liver by elevated hormone secretion
reactive oxygen species (ROS) determined by DHE oxidation to ethidium and 2-hydroxyethidium in the presence of the stimulatory glucose concentration were lower compared to the substimulatory glucose concentration (Figure 1(a) point “0”, continuous vs. dotted line)
We previously demonstrated that activation of Nuclear factor erythroid 2p45-related factor 2 (Nrf2) by oltipraz prevented the inhibitory effect of H2O2 on insulin release [28]
Summary
In early stages of type 2 diabetes mellitus, pancreatic beta cells try to compensate insulin resistance of fat, muscle, and liver by elevated hormone secretion. With the progression of diabetes, beta cells are severely damaged and fail to meet the increased demand. Therapeutic strategies making beta cells more resistant to cellular stress induced by continuing high carbohydrate and/or. Since the discovery of the comparatively low level of antioxidant enzymes in pancreatic beta cells in the late 1990s [1], mechanisms to reinforce antioxidant defense pathways are objects of research. Nuclear translocation of Nrf requires dissociation of its adaptor protein Keap in the cytosol. This is achieved by oxidants and electrophiles, e.g., via formation of covalent bonds with different cysteine residues of Keap. Known Nrf2-activating compounds are dimethyl fumarate (DMF), oltipraz, sulforaphane, tert-butylhydroquinone, and dihydro-CDDO-trifluorethyl-amide
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