Alpha-Lipoic Acid Treatment Reverses 2-Deoxy-D-ribose-Induced Oxidative Damage and Suppression of Insulin Expression in Pancreatic Beta-Cells

Abstract

We investigated whether α-lipoic acid (LA) could prevent 2-deoxy-D-ribose (dRib)-induced oxidative damage and suppression of insulin expression in pancreatic β-cells. Stimulation with 50 mM dRib elevated cytotoxicity, apoptosis and intracellular reactive oxygen species (ROS) levels in HIT-T15 cells, but pretreatment with LA significantly reversed the dRib-induced changes. LA directly scavenged hydroxyl radicals generated by a Fenton reaction. Intracellular reduced glutathione (GSH) and oxidized glutathione (GSSG) were depleted by stimulation with dRib but levels were restored by addition of LA to HIT-T15 cells. However, the GSH/GSSG ratio was unchanged by LA treatment. In rat islets, stimulation with 10 mM dRib for 6 h suppressed expression of insulin and pancreatic and duodenal homeobox 1 mRNA and decreased insulin content, but these were dose-dependently reversed when LA was added. Treatment with L-buthioninesulfoximine, an inhibitor of intracellular glutathione biosynthesis, completely abolished the protective effects of LA on dRib-mediated glutathione depletion and cytotoxicity in HIT-T15 cells. In summary, LA reversed the dRib-induced oxidative damage and suppression of insulin expression in β-cells. Enhanced intracellular total glutathione production, rather than the scavenging of ROS, is possibly the mechanism for the protective effect of LA.

Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential

“…This last evidence was observed and confirmed with acute and chronic treatment of LA. Another interesting study showed a protective effect of LA on 2-deoxy-D-ribose that caused oxidative damage and insulin expression in cell culture [35]. This protective activity seems to be correlated to an enhanced intracellular GSH level.…”

Inhibitory effects of indole α‐lipoic acid derivatives on nitric oxide production in LPS/IFNγ activated RAW 264.7 macrophages

“…18 Alpha-lipoic acid has the capability to repair the oxidative damage that arises from the oxidation of some amino acid residues like tryptophan, histidine and tyrosine in the proteins. [16][17][18] It has also been shown that indole α-lipoic acid derivatives inhibited lipid peroxidation significantly. 19 Alpha-lipoic acid has also been investigated for its antiinflammatory activity, and it was shown that α-lipoic acid and its positively charged amide analogue exhibited antiinflammatory effects and inhibited nitric oxide production in RAW 264.7 macrophages.…”

“…Lipoic acid has been shown to reverse oxidative damage in β‐cells by enhancing total glutathione production, to decrease oxidative stress in brain by restoring glutathione and α ‐tocopherol levelsand to prevent oxidative stress in aged rat brain by decreasing mitochondrial ROS (reactive oxygen species) production …”

“…Alpha‐lipoic acid has the capability to repair the oxidative damage that arises from the oxidation of some amino acid residues like tryptophan, histidine and tyrosine in the proteins . It has also been shown that indole α ‐lipoic acid derivatives inhibited lipid peroxidation significantly …”

“…Because of interaction with other antioxidants, α-lipoic acid can regenerate several antioxidant molecules such as glutathione, 12 tocopherols, 13 ascorbic acid 14 and vitamin E. 15 Lipoic acid has been shown to reverse oxidative damage in β-cells by enhancing total glutathione production, 16 to decrease oxidative stress in brain by restoring glutathione and α-tocopherol levels 17 and to prevent oxidative stress in aged rat brain by decreasing mitochondrial ROS (reactive oxygen species) production. 18 Alpha-lipoic acid has the capability to repair the oxidative damage that arises from the oxidation of some amino acid residues like tryptophan, histidine and tyrosine in the proteins.…”