Nrf2 Activation Protects Mouse Beta Cells from Glucolipotoxicity by Restoring Mitochondrial Function and Physiological Redox Balance

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.

Beta Cell Physiological Dynamics and Dysfunctional Transitions in Response to Islet Inflammation in Obesity and Diabetes

“…Maintaining optimal beta cell physiology for insulin biosynthesis and secretion requires efficiently functioning unfolded protein response (UPR) machinery [57]. In beta cells, nuclear factor erythroid 2p45-related factor 2 (Nrf2) regulates many antioxidant defense factors [62]. ROS are necessary for beta cell signaling but excessive ROS induces oxidative stress.…”

“…ROS are necessary for beta cell signaling but excessive ROS induces oxidative stress. Physiologically, in response to Nrf2 activators, GSIS was impaired with altered ROS handling [62]. Nrf2 activators may shield beta cells from glucolipotoxicity, through the preservation of mitochondrial function and redox balance, to maintain GSIS [62].…”

VMAT2 Safeguards β-Cells Against Dopamine Cytotoxicity Under High-Fat Diet–Induced Stress

“…Since ROS are mainly produced during mitochondrial respiration, we then assessed the proportion of MAO-mediated ROS generation, by treating islets with oltipraz, an antioxidant that exerts mitochondrial protective effects in β-cells ( 35 ). We found that approximately one-half of the H 2 O 2 generated was reduced by oltipraz treatment in control islets ( Fig.…”

Potential Benefits of Nrf2/Keap1 Targeting in Pancreatic Islet Cell Transplantation

“…Interestingly, and conveniently, DMF has demonstrated to be most efficacious under stressful conditions. In a study performed by Schultheis et al, islet cells from adult mice were cultured for 12-16 h in DMF, and then for 2 or 48 h under control or glucolipotoxic conditions (25 mmol/L glucose and 100 µmol/L palmitate) [44]. Compared to controls, cells in the glucolipotoxic medium had a decrease in oxidized status, superior insulin secretion, and a higher mitochondrial membrane potential (50 vs. 10 µmol/L) at 48 h [44].…”

“…In a study performed by Schultheis et al, islet cells from adult mice were cultured for 12-16 h in DMF, and then for 2 or 48 h under control or glucolipotoxic conditions (25 mmol/L glucose and 100 µmol/L palmitate) [44]. Compared to controls, cells in the glucolipotoxic medium had a decrease in oxidized status, superior insulin secretion, and a higher mitochondrial membrane potential (50 vs. 10 µmol/L) at 48 h [44]. While the benefits of DMF in the treatment of inflammatory conditions have been shown to be due to a sundry of anti-inflammatory responses [45][46][47][48], the specific mechanism behind Nrf2-activation necessitates further investigation.…”