ROS Production and ERK Activity Are Involved in the Effects of d-β-Hydroxybutyrate and Metformin in a Glucose Deficient Condition.
Hypoglycemia, a complication of insulin or sulfonylurea therapy in diabetic patients, leads to brain damage. Furthermore, glucose replenishment following hypoglycemic coma induces neuronal cell death. In this study, we investigated the molecular mechanism underlying glucose deficiency-induced cytotoxicity and the protective effect of d-β-hydroxybutyrate (D-BHB) using SH-SY5Y cells. The cytotoxic mechanism of metformin under glucose deficiency was also examined. Cell viability under 1 mM glucose (glucose deficiency) was significantly decreased which was accompanied by increased production of reactive oxygen species (ROS) and decreased phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase 3 (GSK3β). ROS inhibitor reversed the glucose deficiency-induced cytotoxicity and restored the reduced phosphorylation of ERK and GSK3β. While metformin did not alter cell viability in normal glucose media, it further increased cell death and ROS production under glucose deficiency. However, D-BHB reversed cytotoxicity, ROS production, and the decrease in phosphorylation of ERK and GSK3β induced by the glucose deficiency. ERK inhibitor reversed the D-BHB-induced increase in cell viability under glucose deficiency, whereas GSK3β inhibitor did not restore glucose deficiency-induced cytotoxicity. Finally, the protective effect of D-BHB against glucose deficiency was confirmed in primary neuronal cells. We demonstrate that glucose deficiency-induced cytotoxicity is mediated by ERK inhibition through ROS production, which is attenuated by D-BHB and intensified by metformin.
['Lamichhane|Santosh|S|', 'Bastola|Tonking|T|', 'Pariyar|Ramesh|R|', 'Lee|Eun-Sol|ES|', 'Lee|Ho-Sub|HS|', 'Lee|Dae Ho|DH|', 'Seo|Jungwon|J|']
D020155:3-Hydroxybutyric Acid D000818:Animals D045744:Cell Line, Tumor D002478:Cells, Cultured D048049:Extracellular Signal-Regulated MAP Kinases D005947:Glucose D000071679:Glycogen Synthase Kinase 3 beta D006801:Humans D008687:Metformin D051379:Mice D008813:Mice, Inbred ICR D009474:Neurons D018696:Neuroprotective Agents D017382:Reactive Oxygen Species
metformin hypoglycemia reactive oxygen species extracellular signal-regulated kinase ">d-β-hydroxybutyrate