Novel Regulation And Signaling Of Pancreatic Islet Function By Intracellular Redox Homeostasis

The insulin secretion of pancreatic islet β-cell is strictly regulated by intracellular redoxstatus. Being a “privilege” of aerobic organisms, redox regulation is implicated inglucose-stimulated insulin secretion（GSIS）of pancreatic islet β-cells. Thus, the relatively lowexpression of antioxidant enzymes in islets（containing only2%Gpx1and29%SOD1activities compared with liver）may not only render them susceptible to oxidative insults, butalso provide a necessary metabolic condition for their sensitive responses to reactive oxygenspecies（ROS）-mediated signaling in GSIS. Most likely, evolution has selected uniquesignaling pathways for different antioxidant enzymes or compounds to precisely controlinsulin secretion in response to complicated metabolic conditions. Actually, variousantioxidant enzyme knockout or overexpress animal models developed different phenotypesin the pathogenesis process of Diabetes, which implicated different regulation mechanisms forblood glucose homeostasis in response to various stress situations. While overexpression ofSOD1enhanced mouse resistance to streptozotocin-induced diabetes, the same manipulationof Gpx1induced type2diabetes-like phenotypes. Overexpression of Gpx1increased insulincontent, mitochondrial membrane potential, and GSIS, whereas Gpx1knockou（tGKO）causedopposite effects in mice islets. Although the overt phenotypes of GSIS impairments in theGKO, SOD1knockou（tSKO）, and their double knockou（tdKO）mice were similar, the rescueeffects and activated signaling pathways of Gpx mimic Ebselen, SOD mimic CuDIPs, andselenium as essential micronutrient presented in the active center of Gpx1were distinctlydifferent. Evidence showed strong relations between malondialdehyde（MDA）levels anddifferent pathological stages of diabetes. Traditionally, MDA has been recognized by itsnon-specific chemical reactivity. However, as a small, stable, uncharged and freely diffusiblemolecule, MDA arguably meets the important criteria for a signaling messenger. Herein, wesought to investigate the effect and unique pathways of different antioxidant enzymes andstress inducers on GSIS process.The GSIS rescue tests, genomic promoter prediction, bioinformatics analysis, Q-PCRscreening, and RNA interference methods promoted the studies to a new level. Ebselenactually enhanced insulin secretion at both basal（2.8mM glucose）and stimulated（16.7mM glucose）levels crossing all four（WT, GKO, SKO, and dKO）genotypes, which is differentwith the effects induced by CuDIPs and selenium. An in vivo study for the GSIS of theEbselen injected GKO mice indicated an elevation of the plasma insulin at0min（baseline）by95%,15min by1.2-fold, and30min by91%after the glucose challenge. Consequently,glucose clearance was improved by17%,18%, and21%（p <0.05）at15,30, and60min,respectively. This rescue effect is mainly through the regulation of four key GSIS regulators（GLUT2, GK, PDX1, and UCP2）by activating the PGC-1α mediated ARE and/or GRsignaling. The MDA treatment exerted a dose-dependent impact on GSIS of islets. WhileMDA at low concentrations（0.1and1μM）showed no effect, moderately high concentrationsat5and10μM MDA elevated（p <0.01）islet GSIS by69%and1.1-fold, respectively.However, further increasing the MDA concentration to50μM suppressed（p <0.05）isletGSIS by24%. And this MDA regulated GSIS is mainly through the TCF7L2-dependent Wntsignaling pathway. Therefore, our research clarified the different antioxidant enzyme（sor theirmimics）and stress inducers have their specific impacts on insulin secretion and activatedunique signaling pathways in islets. Clinically, more specific targeting medicines should beadministrated based on the stress inducers and pathway genes profile. And new clinicalstrategies should focus on rebalancing the islet redox equilibrium and signaling pathways forinsulin secretion disorders.