Hydrogen peroxide alters mitochondrial activation and insulin secretion inpancreatic beta cells

The effects of a transient exposure to hydrogen peroxide (10 min at 200 mu M H2O2) On pancreatic beta cell signal transduction and insulin secretion h ave been evaluated, In rat islets, insulin secretion evoked by glucose (16. 7 mM) or by the mitochondrial substrate methyl succinate (5 mM) was markedl y blunted following exposure to H2O2. In contrast, the secretory response i nduced by plasma membrane depolarization (20 mM KCl) was not significantly affected. Similar results were obtained in insulinoma INS-1 cells using glu cose (12.8 mM) as secretagogue. After H2O2 treatment, glucose no longer dep olarized the membrane potential (Delta Psi) of INS-1 cells or increased cyt osolic Ca2+. Both Delta Psi and Ca2+ responses were still observed with 30 mM KCl despite an elevated baseline of cytosolic Ca2+ appearing similar to 10 min after exposure to H2O2. The mitochondrial Delta Psi of INS-1 cells w as depolarized by H2O2 abolishing the hyperpolarizing action of glucose. Th ese Delta Psi changes correlated with altered mitochondrial morphology; the latter was not preserved by the overexpression of the antiapoptotic protei n Bcl-2, Mitochondrial Ca2+ was increased following exposure to H2O2 up to the micromolar range. No further augmentation occurred after glucose additi on, which normally raises this parameter. Nevertheless, KCl was still effic ient in enhancing mitochondrial Ca2+. Cytosolic ATP was markedly reduced by H2O2 treatment, probably explaining the decreased endoplasmic reticulum Ca 2+. Taken together, these data point to the mitochondria as primary targets for H2O2 damage, which will eventually interrupt the transduction of signa ls normally coupling glucose metabolism to insulin secretion.