How do reducing equivalents increase insulin secretion?

Attie, Alan D.

doi:10.1172/jci84011

Cited by 9 publications

(6 citation statements)

References 21 publications

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“…Alternatively, alterations in the balance between reduced (glutathione [GSH]) and oxidized (glutathione disulfide [GSSG]) glutathione due to hypoxic depletion of nicotinamide adenine dinucleotide phosphate (NADPH) could contribute to oxidative inactivation of SENPs. In line with this idea, recent work has connected SENP1 activity to the cellular GSSG/GSH balance (Attie, 2015;Ferdaoussi et al, 2015).…”

Section: Discussionmentioning

confidence: 88%

SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases

et al. 2016

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Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1α. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.

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Section: Discussionmentioning

confidence: 88%

SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases

et al. 2016

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“…Previous studies have focused special attention on NADPH as crucial for GSIS amplification [ 65 , 66 , 67 ]. For instance, the intracellular addition of NADPH into β-cells enhanced insulin exocytosis [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the intracellular addition of NADPH into β-cells enhanced insulin exocytosis [ 65 ]. The precise mechanisms involved are not completely understood but might involve the NADPH-dependent activation of sentrin/SUMO-specific protease-1 (SENP1), involved in the amplification of insulin exocytosis [ 67 , 68 ]. Thus, in WT islets exposed to cytokines, the NOX2-derived ROS and the consequent NAD(P)H depletion observed here might play a role in the secretory impairment.…”

Section: Discussionmentioning

confidence: 99%

Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival

et al. 2021

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In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination. We show that cytokines increase O2•− production after 2 h in WT and NOX1 KO but not in NOX2 KO islets. Using transgenic mice constitutively expressing a genetically encoded compartment specific H2O2 sensor, we show, for the first time, a transient increase of cytosolic/nuclear H2O2 in islet cells between 4 and 5 h during cytokine exposure. The H2O2 increase coincides with the intracellular NAD(P)H decrease and is absent in NOX2 KO islets. NOX2 KO confers better glucose tolerance and protects against cytokine-induced islet secretory dysfunction and death. However, NOX2 absence does not counteract the cytokine effects in ER Ca2+ depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H2O2 production. As early NOX2-driven ROS production impacts β-cells’ function and survival during insulitis, NOX2 might be a potential target for designing therapies against early β-cell dysfunction in the context of T1D onset.

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“…The conversion of L-arginine to NO and increased insulin secretion in cell-free preparations of HIT-T15 cells appear to be due to the activity of cNOS, as the Ca 2+ ionophore A23187, which induces insulin secretion (Conaway et al, 1976[ 19 ]), also induces NO release from HIT-T15 cells (Schmidt et al, 1992[ 110 ]). In addition, insulin secretion is correlated with the intracellular concentration of NADPH (Attie, 2015[ 7 ]), Ca 2+ (Conaway et al, 1976[ 19 ]), and calmodulin (Dadi et al, 2014[ 23 ]) which all are necessary for cNOS activation. Low concentrations of NO elevate ATP production and cause K ATP channel closure, while high concentrations of NO are associated with a decrease in ATP production, independent of cGMP (Sunouchi et al, 2008[ 123 ]).…”

Section: Controversy About the Role Of No In Insulin Secretionmentioning

confidence: 99%