D-glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective beta cell function via non-mitochondrial pathways

Hiroki Takahashi, Phuong Oanh T. Tran, Eric LeRoy, Jamie S. Harmon, Yoshito Tanaka, R. Paul Robertson

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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 HIM 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 μM), 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.

Original languageEnglish (US)
Pages (from-to)37316-37323
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number36
DOIs
StatePublished - Sep 3 2004

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