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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.

Qingsong Wang,1 Xiu-ling Zhou,2 Guang-hai Mei,3 Jiantao Wang,1 Zhongyu Yu,1 Yue Hu,1 Xinyu Guo,1 Hanyu Zhang,1 Xiaodie Xu,4 Chengfeng He,4 Jingchun Guo,4 Yinghong Tao,5 Houguang Zhou1 1Department of Geriatrics, Huashan Hospital, National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, 200040, People’s Republic of China; 2Department of Ultrasonics, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 3Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 4National Key Laboratory of Medical Neurobiology, Institute of Brain Science, Fudan University, Shanghai, 200030, People’s Republic of China; 5Department of Medical Examination Center, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Houguang ZhouDepartment of Geriatrics of Huashan Hospital, National Clinical Research Center for Aging and Medicine, Fudan University, No. 24 Ward, Building 6, No.12 Middle WuLuMuQi Road, JingAn District, Shanghai, 200040, People’s Republic of ChinaTel +86-21-52887246Email zhouhouguang@huashan.org.cnYinghong TaoDepartment of Medical Examination Center of Huashan Hospital, Fudan University, Building 4, No. 12 Middle WuLuMuQi Road, JingAn District, Shanghai, 200040, People’s Republic of ChinaTel +86-21-52889087Email taoyinghong@huashan.org.cnAim: Metabolic inflammation syndrome (MIS) can lead to a series of complications, but its exact inflammatory mechanism is still unclear. The aim of this study was to explore the correlation between heparanase (HPA) and MIS, and the close relationship between HPA and other chronic low-grade inflammation index, such as C-reactive protein (CRP) and interleukin-6 (IL-6).Methods: A total of 105 patients with MIS in the physical examination population of Huashan Hospital affiliated to Fudan University from May to June 2018 were selected as the MIS group, and 52 patients who were relatively healthy during the same period were used as the control group. The basic clinical data of the selected candidates were collected, the levels of serum HPA, CRP and IL-6 were measured by ELISA, and the levels of blood glucose and blood lipids were also detected.Results: Compared with the control group, the levels of HPA, CRP, IL-6, FBG, HbA1C, and TG of MIS group were all significantly elevated (all P< 0.05), and HDL-C levels were considerably reduced (P< 0.05). Correlation analysis showed that there was a noticeably positive correlation between serum HPA level and CRP, IL-6 levels (P< 0.05).Conclusion: Higher HPA levels might play a certain role in the occurrence and development of MIS. There was a certain close correlation between serum HPA level and CRP and IL-6 levels, and which indicated that HPA was involved in the chronic low-grade inflammatory reaction process of MIS.Keywords: metabolic inflammatory syndrome, MIS, heparanase, HPA, C-reactive protein, CRP, interleukin-6, IL-6, chronic low-grade inflammation, CLGI