Ebselen Treatment Prevents Islet Apoptosis, Maintains Intranuclear Pdx-1 and MafA Levels, and Preserves β-Cell Mass and Function in ZDF Rats

Abstract

We reported earlier that β-cell–specific overexpression of glutathione peroxidase (GPx)-1 significantly ameliorated hyperglycemia in diabetic db/db mice and prevented glucotoxicity-induced deterioration of β-cell mass and function. We have now ascertained whether early treatment of Zucker diabetic fatty (ZDF) rats with ebselen, an oral GPx mimetic, will prevent β-cell deterioration. No other antihyperglycemic treatment was given. Ebselen ameliorated fasting hyperglycemia, sustained nonfasting insulin levels, lowered nonfasting glucose levels, and lowered HbA1c levels with no effects on body weight. Ebselen doubled β-cell mass, prevented apoptosis, prevented expression of oxidative stress markers, and enhanced intranuclear localization of pancreatic and duodenal homeobox (Pdx)-1 and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), two critical insulin transcription factors. Minimal β-cell replication was observed in both groups. These findings indicate that prevention of oxidative stress is the mechanism whereby ebselen prevents apoptosis and preserves intranuclear Pdx-1 and MafA, which, in turn, is a likely explanation for the beneficial effects of ebselen on β-cell mass and function. Since ebselen is an oral antioxidant currently used in clinical trials, it is a novel therapeutic candidate to ameliorate fasting hyperglycemia and further deterioration of β-cell mass and function in humans undergoing the onset of type 2 diabetes.

Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stress

“…Several reports involving mouse models of diabetes appeared midway through our study and supported this possibility (6,(37)(38)(39). Our current work used Zucker diabetic fatty rats (ZDF rats) that are known to develop severe hyperglycemia and oxidative stress when fed a HFD (40). The design involved an initial baseline period of a regular chow (17% fat) diet followed by exposure to a HFD (48% fat) for increasing lengths of time, and then an intervention period during which the HFD was removed and the regular chow diet was resumed.…”

“…As separate assessments of the KEAP-1/Nrf2/antioxidant pathway, we examined islets from hyperglycemic male ZDF rats and hyperglycemic male db/ db mice in which we have previously shown to have increased cytoplasmic levels of 8-OH-dG and 4HNE (27,40). These experiments revealed that the hyperglycemic male ZDF rats that were fed a HFD demonstrated substantial staining for Nrf2 ( Figure 6A), both cytosolic and nuclear, whereas simultaneously feeding these animals the antioxidant Ebselen, while on a HFD, prevented the appearance of Nrf2-specific immunoreactivity ( Figure 6B).…”

Rpl13a small nucleolar RNAs regulate systemic glucose metabolism

“…In vivo dynamic testing was carried out following a 4-hour fast using standard procedures of the NIH-sponsored National Mouse Metabolic Phenotyping Centers Morphometry. Morphometric analysis of pancreases from 8-week-old mice was performed as previously reported (56). For measurement of β cell mass, every 40th pancreatic section was immunostained with guinea pig anti-insulin antibody (1:100, Invitrogen) and counterstained with hematoxylin.…”

Pancreatic β-cell failure in type 2 diabetes mellitus

“…[3][4][5][6][7][8][9][10][11][12] Furthermore, antioxidant treatment protects β-cells from glucose toxicity in various diabetic model animals; β-cell mass and insulin content are preserved by antioxidant treatment. [13,14] In addition, expression levels of MafA and PDX-1 are decreased by oxidative stress and those expression levels are preserved by antioxidant treatment. These data suggest that oxidative stress and reduction of insulin gene transcription factors such as MafA and PDX-1 are involved in β-cell glucose toxicity found in type 2 diabetes.…”