Fig. 8: Chronically hyperglycemic Mfsd2b−/− mice are resistant to HbA1c elevation and lipid peroxidation and feature increased metabolic flux through PPP with unchanged glycolysis.
A Glucose tolerance test in Mfd2b+/+ and Mfsd2b−/− mice either on a normal chow diet or on a DIO diet for 8 weeks. Inset shows area under the curve (n = 5). B HbA1c (n = 5 each) and (C) TBARS levels (n = 4/3) in the same mice as determined by MDA measurements. D 13C2 PRPP relative exchange rate in metabolic flux experiments using 1,2,3-13C3-D-glucose (20 min incubation); n = 6/8 Mfd2b+/+ and 4/4 Mfsd2b–/–. E 13C3 lactate/13C2 lactate ratio in the same experiment (n = 5/9 Mfd2b+/+ and 4/4 Mfsd2b–/–). F 13C3 2,3-BGP relative exchange rate from the same experiment (n = 7/9 Mfd2b+/+ and 4/4 Mfsd2b–/–). Data are presented as mean ± sd and tested with one-way ANOVA (A) and ordinary two-way ANOVA followed by Tukey’s (B–F); p* < 0.05; p** < 0.01; p**** < 0.0001. G Schematic of putative S1P functions in RBC: Blood glucose and sphingosine entry regulate Sphk1 activity and S1P production, whereas MFSD2B exports S1P, resulting in dynamic modulation of S1P levels in RBC. S1P associates with the catalytic PP2a subunit and activates the enzyme to reduce GLUT phosphorylation, cell surface localization and glucose uptake. The full arrow indicates dephosphorylation-dependent and the dotted arrow dephosphorylation-independent PP2A-mediated GLUT internalization, respectively. Acute S1P elevation activates glycolysis to compensate for lower glucose entry at the expense of the pentose phosphate pathway (PPP), whereas chronically high S1P RBC levels as in Mfsd2b–/– RBC retain normal glycolysis but increase PPP metabolic fluxes to produce reducing equivalents for protection against hyperglycemia-induced lipid peroxidation.
