Fig. 7: Decreasing F-K1057/1079 restores insulin signaling.

a Phenylalaninol is structurally analogous to phenylalanine. The molecular formulae of phenylalanine and phenylalaninol are shown. b Phenylalaninol and phenylalanine may occupy the same binding site of FARSA. Computer simulations show that phenylalaninol fits the phenylalanine binding site of FARSA. c Phenylalaninol decreases F-K1057/1079 levels and activates insulin signaling. The F-K1057/1079 levels of IRβ and phosphorylation levels of components of insulin signaling were detected in HepG2 cells and IRβ^2K/F knock-in HepG2 cells in the presence of different levels of phenylalaninol. d Phenylalaninol activates glucose uptake. The 2-DG uptake of 3T3-L1 cells and insulin-stimulated 3T3-L1 cells was measured in the absence and presence of 2 mM phenylalaninol (n = 5). e, f Phenylalaninol decreases F-K1057/1079 levels and activates insulin signaling in hFARSA-transgenic and aspartame-fed mice. The liver F-K1057/1079 levels (left) and insulin signaling were quantified for male wild-type and hFARSA-transgenic mice that were fed with standard and phenylalaninol-supplemented chow (e) and for male wild-type mice that were fed with standard, aspartame-supplemented, and chow supplemented with both aspartame and phenylalaninol (f). All values were normalized to those of wild-type mice fed standard chow (n = 9). g–i Phenylalaninol chow relieves diabetic symptoms in hFARSA-transgenic mice. Male wild-type and hFARSA-transgenic C57 mice were fed standard or phenylalaninol-supplemented chow for 12 weeks (n = 9). Body weight (g), fat mass (h), and fasting blood glucose level (i) were measured. j–p Phenylalaninol decreases F-K1057/1079 levels and relieves diabetic symptoms in db/db mice. Male db/db mice were fed standard or phenylalaninol-supplemented chow for 12 weeks (n = 10). The F-K1057/1079 levels in mouse liver and muscle tissues (j), glucose tolerance (k), insulin tolerance (l), blood insulin (m), blood glucose levels (n), HOMA-IR values (o), and body weights (p) were measured. Significance was indicated as two-tailed, unpaired, t test for (d), (k–p), one-way ANOVA test for (e–i). Values are expressed as the mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.