Background: The disorders of glucolipid metabolism are prevalent in patients with type-2 diabetes mellitus (T2DM). Palmitic-Acid-Hydroxy-Stearic Acid (PAHSA) had been reported to benefit glucolipid metabolism in diabetic mice. Given the importance of autophagy in T2DM, the aim of the present study was to investigate whether S-9-PAHSA has specific therapeutic effects on diabetics, particularly with regards to autophagy.Methods: 19-week-old male C57BL6 mice were fed with high-fat-diet for 4 months, and administered with 22.5 mg/kg/d or 5.5 mg/kg/d fatty acids or an equivalent volume of vehicle for 35 days. Glucose levels and weight were determined. Insulin, glycosylated serum protein (GSP), glucagon-like peptide-1(GLP-1) and oxidized modified low-density lipoprotein (ox-LDL) were assessed by ELISA kit. Autophagy-related proteins P62 and Beclin-1in cerebral cortex were detected by western blot. SH-SY 5Y cells were incubated under diabetic environment (glucose 100mmol/L, fatty acid 200μmol/L), and then treated with S-9-PAHSA, R-9-PAHSA and 9-PAHSA. Cell viability, cell proliferation, lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) production were detected by respective kits. Apoptosis was assessed by the TUNEL assay. The protein levels of apoptosis (Cleaved caspase-3, BAX/Bcl-2), autophagy (Beclin1, p62 and LC3II/I) and PI3K/AKT pathway were determined by western blot. Results: Although S-9-PAHSA did not alter glucose levels, weight, GLP-1 and GSP in mice, high-does S-9-PAHSA improved insulin resistance and lowered ox-LDL. Compared with control group, the up-regulated expression of P62 and down-regulated expression of Beclin1 in diabetic mice were found, and the S-9-PAHSA administration reduced P62. In vitro, S-9-PAHSA increased cell viability and proliferation while reduced LDH release and ROS production, which were better than R-9-PAHSA and 9-PAHSA. S-9-PAHSA could lower the levels of Cleaved caspase-3 and percentage of TUNEL-positive cells. S-9-PAHSA enhanced the expression of LC3II/I under high glucose and fatty acid stimulation. PI3K and p-AKT/AKT ratio under diabetic environment had a downward trend, and S-9-PAHSA might enhance their expression, but there was no statistical difference. Conclusions: S-9-PAHSA could regulate glycolipid metabolism in HFD-induced T2DM mice through autophagy-associated protein, and exerted protective effects on diabetes by the regulation of autophagy, reducing oxidative stress, partially activating PI3K/AKT signaling pathway.

The disorders of glucolipid metabolism are prevalent in patients with type 2 diabetes mellitus (T2DM). Since the effects of Palmitic-Acid-Hydroxy-Stearic Acid (PAHSA) on T2DM were not fully understood, the study aimed to investigate the role of S-9- PAHSA in diabetes and the possible mechanisms. Male C57BL6 mice were fed with a high-fat diet (HFD) and injected with streptozotocin (STZ) to establish the diabetic mice model, and then administered with low- or high-dose S-9-PAHSA. Insulin, glycosylated serum protein (GSP), glucagon-like peptide-1 (GLP-1), and oxidized lowdensity lipoprotein (ox-LDL) were assessed by ELISA. SH-SY 5Y cells were incubated in a diabetic environment and treated with S-9-PAHSA, R-9-PAHSA, or 9-PAHSA. Cell viability, cell proliferation, apoptosis, lactate dehydrogenase (LDH), and reactive oxygen species (ROS) were measured by corresponding kits. Protein expressions were determined by western blot. The results showed high-does S-9-PAHSA improved insulin resistance and lowered ox-LDL. Compared with the control group, the significantly up-regulated expression of p62 and down-regulated expression of beclin 1 were found in diabetic mice and could be reversed by S-9-PAHSA. In vitro, S-9- PAHSA increased cell viability and proliferation while reducing LDH and ROS. S-9- PAHSA could reduce the expression of cleaved caspase-3 and TUNEL-positive cells, and increase the ratio of LC3II/I after high glucose and fatty acid stimulation in vitro. Downward trends were observed in PI3K and the phosphorylation of AKT in diabetic environments, which could be slightly restored by S-9-PAHSA. In conclusion, S-9- PAHSA could regulate glycolipid metabolism both in vivo and in vitro, indicating the vital role of S-9-PAHSA in T2DM.

The disorders of glucolipid metabolism are prevalent in patients with type 2 diabetes mellitus (T2DM). Since the effects of Palmitic-Acid-Hydroxy-Stearic Acid (PAHSA) on T2DM were not fully understood, the study aimed to investigate the role of S-9- PAHSA in diabetes and the possible mechanisms. Male C57BL6 mice were fed with a high-fat diet (HFD) and injected with streptozotocin (STZ) to establish the diabetic mice model, and then administered with low- or high-dose S-9-PAHSA. Insulin, glycosylated serum protein (GSP), glucagon-like peptide-1 (GLP-1), and oxidized lowdensity lipoprotein (ox-LDL) were assessed by ELISA. SH-SY 5Y cells were incubated in a diabetic environment and treated with S-9-PAHSA, R-9-PAHSA, or 9-PAHSA. Cell viability, cell proliferation, apoptosis, lactate dehydrogenase (LDH), and reactive oxygen species (ROS) were measured by corresponding kits. Protein expressions were determined by western blot. The results showed high-does S-9-PAHSA improved insulin resistance and lowered ox-LDL. Compared with the control group, the significantly up-regulated expression of p62 and down-regulated expression of beclin 1 were found in diabetic mice and could be reversed by S-9-PAHSA. In vitro, S-9- PAHSA increased cell viability and proliferation while reducing LDH and ROS. S-9- PAHSA could reduce the expression of cleaved caspase-3 and TUNEL-positive cells, and increase the ratio of LC3II/I after high glucose and fatty acid stimulation in vitro. Downward trends were observed in PI3K and the phosphorylation of AKT in diabetic environments, which could be slightly restored by S-9-PAHSA. In conclusion, S-9- PAHSA could regulate glycolipid metabolism both in vivo and in vitro, indicating the vital role of S-9-PAHSA in T2DM.