title: Peroxiredoxin 4 improves insulin biosynthesis and glucose-induced insulin secretion in insulin-secreting INS-1E cells.
abstract: Oxidative folding of (pro)insulin is crucial for its assembly and biological function. This process takes place in the endoplasmic reticulum (ER) and is accomplished by protein disulfide isomerase and ER oxidoreductin 1β, generating stoichiometric amounts of hydrogen peroxide (H2O2) as byproduct. During insulin resistance in the prediabetic state, increased insulin biosynthesis can overwhelm the ER antioxidative and folding capacity, causing an imbalance in the ER redox homeostasis and oxidative stress. Peroxiredoxin 4 (Prdx4), an ER-specific antioxidative peroxidase can utilize luminal H2O2 as driving force for reoxidizing protein disulfide isomerase family members, thus efficiently contributing to disulfide bond formation. Here, we examined the functional significance of Prdx4 on β-cell function with emphasis on insulin content and secretion during stimulation with nutrient secretagogues. Overexpression of Prdx4 in glucose-responsive insulin-secreting INS-1E cells significantly metabolized luminal H2O2 and improved the glucose-induced insulin secretion, which was accompanied by the enhanced proinsulin mRNA transcription and insulin content. This β-cell beneficial effect was also observed upon stimulation with the nutrient insulin secretagogue combination of leucine plus glutamine, indicating that the effect is not restricted to glucose. However, knockdown of Prdx4 had no impact on H2O2 metabolism or β-cell function due to the fact that Prdx4 expression is negligibly low in pancreatic β-cells. Moreover, we provide evidence that the constitutively low expression of Prdx4 is highly susceptible to hyperoxidation in the presence of high glucose. Overall, these data suggest an important role of Prdx4 in maintaining insulin levels and improving the ER folding capacity also under conditions of a high insulin requirement.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany.
authors.forename: Ilir
authors.initials: I
authors.lastname: Mehmeti
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lortz
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Elsner
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany. Electronic address: lenzen.sigurd@mh-hannover.de.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
mesh_terms: D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D054464:Peroxiredoxins / Q000096:biosynthesis* / Q000235:genetics; D017510:Protein Folding / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013549:Sweetening Agents / Q000378:metabolism / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D013549:Sweetening Agents; D006861:Hydrogen Peroxide; C515980:PRDX4 protein, human; D054464:Peroxiredoxins; D005947:Glucose
keywords: Beta Cell (B-cell); ER Redox Homeostasis; Endoplasmic Reticulum (ER); Insulin Secretion; Insulin Synthesis; Peroxiredoxin