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. Author manuscript; available in PMC: 2017 Sep 27.
Published in final edited form as: Nat Chem Biol. 2017 Mar 27;13(6):624–632. doi: 10.1038/nchembio.2344

Figure 5. Compd. 23 increases liver cell insulin signaling, is orally bioavailable and reverses diabetes in obese mice.

Figure 5

(a–b) HepG2 hepatocytes were incubated overnight with 10 μM compound (Compd.) or dimethylsulfoxide (DMSO) and stimulated with 10 nM insulin for 5 min or left unstimulated (Unst.). Insulin receptor (IR) tyrosine phosphorylation was assessed by (a) Western blotting of anti-IR immunoprecipitations (representative of 2 independent experiments) and (b) phosphoIR (pIR) ELISA (data from 5 independent experiments, Compd. 23: p=0.0079, Compd. 28: p=0.1667). (c–g) Diet-induced obese (DIO) male B6 mice were treated with 0.05% w/w Compd. 23 in high-fat diet (HFD) or HFD alone for 2 weeks. (c) Body weight during treatment (HFD, n=17; Compd. 23, n=13). (d) Intraperitoneal glucose tolerance test (IPGTT), p=0.0162 (HFD, n=8; Compd. 23, n=6). (e) Fasting plasma insulin levels, relative to littermates fed HFD, p=0.0235 (HFD, n=4; Compd. 23, n=4). (f–g) Mice were injected intraperitoneally with insulin and livers harvested after 10 min. (f) Liver IR tyrosine phosphorylation, p=0.0002 (HFD, n=7; Compd. 23, n=6). (g) Western blot of liver homogenates (HFD, n=3; Compd. 23, n=3). (h–i) DIO liver-specific LMPTP KO mice were treated with Compd. 23 (HFD, n=6; Compd. 23, n=6) as in (c–g). (h) IPGTT, p=0.6120. (i) Liver IR tyrosine phosphorylation, p=0.2791. (b–f,h–i) Mean±SEM. *, p<0.05; NS, non-significant (p≥0.05): (b) Kolmogorov-Smirnov test, (d,h) Two-Way ANOVA, (e) two-tailed unpaired t-test with Welch’s correction, (f,i) one-tailed unpaired t-test with Welch’s correction. (a,c) Full gels are shown in Supplementary Figure 18