title: D-Glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective beta cell function via non-mitochondrial pathways.
abstract: D-Glyceraldehyde (D-GLYC) is usually considered to be a stimulator of insulin secretion but theoretically can also form reactive oxygen species (ROS), which can inhibit beta cell function. We examined the time- and concentration-dependent effects of D-GLYC on insulin secretion, insulin content, and formation of ROS. We observed that a 2-h exposure to 0.05-2 mM D-GLYC potentiated glucose-stimulated insulin secretion (GSIS) in isolated Wistar rat islets but that higher concentrations inhibited GSIS. A 24-h exposure to 2 mm D-GLYC inhibited GSIS, decreased insulin content, and increased intracellular peroxide levels (2.14 +/- 0.31-fold increase, n = 4, p < 0.05). N-Acetylcysteine (10 mM) prevented the increase in intracellular peroxides and the adverse effects of d-GLYC on GSIS. In the presence of 11.1 but not 3.0 mm glucose, koningic acid (10 microM), a specific glyceraldehyde-3-phosphate dehydrogenase inhibitor, increased intracellular peroxide levels (1.88 +/- 0.30-fold increase, n = 9, p < 0.01) and inhibited GSIS (control GSIS = p < 0.001; koningic acid GSIS, not significant). To determine whether oxidative phosphorylation was the source of ROS formation, we cultured rat islets with mitochondrial inhibitors. Neither rotenone or myxothiazol prevented D-GLYC-induced increases in islet ROS. Adenoviral overexpression of manganese superoxide dismutase also failed to prevent the effect of D-GLYC to increase ROS levels. These observations indicate that exposure to excess D-GLYC increases reactive oxygen species in the islet via non-mitochondrial pathways and suggest the hypothesis that the oxidative stress associated with elevated D-GLYC levels could be a mechanism for glucose toxicity in beta cells exposed chronically to high glucose concentrations.
authors.affiliation: Pacific Northwest Research Institute, Seattle, Washington 98122, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahashi
authors.forename: Phuong Oanh T
authors.initials: PO
authors.lastname: Tran
authors.forename: Eric
authors.initials: E
authors.lastname: LeRoy
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Harmon
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: R Paul
authors.initials: RP
authors.lastname: Robertson
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004579:Electron Transport; D005985:Glyceraldehyde / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010545:Peroxides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D010545:Peroxides; D005985:Glyceraldehyde; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D000111:Acetylcysteine