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. 2022 May 6;36(13-15):920–952. doi: 10.1089/ars.2021.0113

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© Petr Ježek et al., 2022; Published by Mary Ann Liebert, Inc.

This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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FIG. 6. — Hypothetical reverse and forward mode of nicotinamide nucleotide translocase at low and high glucose, respectively. (A) Low glucose conditions: hypothetical reverse NNT mode is depicted, when NNT acts as a proton pump, using the energy of NADPH and NAD⁺, converting them to NADP⁺ and NADH, respectively. It would be possible, since under low glucose conditions in pancreatic β-cells, a lower Δp would allow the proton pumping against that Δp. Possible NADPH sources could be the matrix IDH2 providing oxidative decarboxylation and ME3. (B) High glucose conditions: forward NNT mode is possible (193) when NNT uses Δp to translocate H⁺ into the matrix and drives NADPH formation from NADP⁺ with the simultaneous conversion of NADH to NAD⁺. This mode is highly probable upon GSIS since a high Δp is established, thus driving the H⁺ influx via NNT. Also, since the pyruvate/isocitrate shuttle is activated upon GSIS, it switches the IDH2 reaction direction to reductive carboxylation and NADP⁺ production. ME3, malic enzyme 3; NNT, nicotinamide nucleotide transhydrogenase.