Phytol/Phytanic acid and insulin resistance: potential role of phytanic acid proven by docking simulation and modulation of biochemical alterations.

Since activation of PPARγ is the main target for the antidiabetic effect of TZDs, especially when it heterodimerizes with RXR, we aimed to test the potential antidiabetic effect of phytol (250 mg/kg), the natural precursor of phytanic acid, a RXR ligand and/or pioglitazone (5 mg/kg) to diabetic insulin-resistant rats. Regarding the molecular docking simulation on PPARγ, phytanic acid, rather than phytol, showed a binding mode that mimics the crystal orientation of rosiglitazone and pioglitazone, forming H bonds with the same amino acids (S289, H 323, H 449 and Y 473), and the least energy level, which emphasizes their importance for PPARγ molecular recognition, activation, hence antidiabetic activity. In addition, docking on the RXRα/PPARγ heterodimer, revealed that phytanic acid has higher binding affinity and lesser energy score on RXRα, compared to the original ligand, retinoic acid. Phytanic acid binds by 3H bonds and shares retinoic acid in arginine (R 316). These results were further supported biochemically, where oral phytol and/or pioglitazone (5 mg/kg) improved significantly glucose homeostasis, lipid panel, raised serum adiponectin level and lowered TNF-α, reaching in most cases the effect of the 10 mg/kg pioglitazone. The study concluded that the insulin sensitizing/anti-diabetic effect of phytol is mediated by partly from activation of nuclear receptors and heterodimerization of RXR with PPARγ by phytanic acid

Effect of diabetes (DV) and different oral drug regimens on the serum lipid profile.

<p>Effect of diabetes (DV) and different oral drug regimens, viz., phytol (DP_h, 250 mg/kg); pioglitazone (DP₅, 5 mg/kg); pioglitazone (DP₁₀, 10 mg/kg); phytol and pioglitazone (DP_hP₅); on serum levels of triglycerides, total cholesterol, LDL-C, HDL-C, ALT and TC/HDL ratio (mean of 7 animals ± S.D). As compared with non-diabetic [ND] (*) and diabetic [DV] (#) groups using one way ANOVA followed by Tukey post hoc test, <i>P</i><0.05. (^Ο) Significant interaction when P_h and P₅ were combined using Factorial Design.</p

Effect of diabetes (DV) and different oral drug regimens on glucose homeostasis indicators.

<p>Effect of diabetes (DV) and different oral drug regimens, viz., phytol (DP_h, 250 mg/kg); pioglitazone (DP₅, 5 mg/kg); pioglitazone (DP₁₀, 10 mg/kg); phytol and pioglitazone (DP_hP₅); on serum levels of glucose, insulin, fructosamine, TNF-α, adiponectin and insulin resistance (HOMA-ratio) (mean of 7 animals ± S.D). As compared with non-diabetic [ND] (*) and diabetic [DV] (#) groups using one way ANOVA followed by Tukey post hoc test, <i>P</i><0.05. (^Ο) Significant interaction when P_h and P₅ were combined using Factorial Design.</p

Correlation coefficient (<i>r</i>) between serum glucose, insulin and HOMA-R with TNF-α, adiponectin, ALT and visceral fat weight/body weight ratio.

<p>Correlation was carried out in untreated and treated hyperglycemic animals only.</p