Jianjun Deng

BACKGROUND AND PURPOSE: Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the underlying mechanism is unclear. The present study aimed to investigate the effects of nuciferine on lipid and glucose metabolism in a murine model of Type 2 diabetes mellitus (T2DM) and to determine the underlying mechanisms of these effects. EXPERIMENTAL APPROACH: A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with nuciferine in their food. The underlying mechanism of the anti-steatotic effect of nuciferine was further explored in HepG2 hepatocytes cultured with palmitic acid. Major signalling profiles involved in fatty acid oxidation were then evaluated, using Western blot, RT-qPCR and si-RNA techniques, along with immunohistochemistry. KEY RESULTS: Nuciferine restored impaired glucose tolerance and insulin resistance in diabetic mice. Hepatic levels of total cholesterol, triglycerides and LDL were decreased, as were the number of lipid droplets, by nuciferine treatment. Furthermore, nuciferine up-regulated β-oxidation related genes in livers of diabetic mice. Luciferase reporter cell assay showed that nuciferine directly reversed palmitic acid-induced inhibition of PPARα transcriptional activity. Silencing PPARγ coactivator-1α (PGC1α) expression in HepG2 cells abolished the effects of nuciferine in accelerating β-oxidation. CONCLUSIONS AND IMPLICATIONS: Nuciferine improved lipid profile and attenuated hepatic steatosis in HFD/STZ-induced diabetic mice by activating the PPARα/PGC1α pathway. Nuciferine may be a potentially important candidate in improving hepatic steatosis and the management of T2DM.

Ginsenoside Rk3 (G-Rk3) is a main active ingredient of ginsenosides. Several recent studies demonstrated that ginsenosides have potential anti-type 2 diabetes mellitus (T2DM) properties. To evaluate the anti-T2DM effect of G-Rk3 and verify its potential mechanism, a high-fat-diet/streptozocin (HFD/STZ) induced model of T2DM in C57BL/6 mice and a high glucose induced insulin resistance model of HepG2 cells were applied in this research. Our analysis indicated that G-Rk3 reduced HFD/STZ induced hyperglycemia, and serum insulin and inflammation levels, and ameliorated glucose tolerance and insulin resistance, and prevented liver histological changes. Furthermore, it also significantly reduced lipid accumulation as shown by lower TG, LDL-C and TC serum concentrations and Oil Red O staining in liver tissues. The hypoglycemic effect of G-Rk3 seemed to be partially mediated via the inhibition of hepatic gluconeogenesis, which was supported by the activated p-Akt, p-FoxO1 and GLUT2 and inhibited FoxO1, PEPCK and G6pase protein expressions in the liver as well as increased glucose uptake in high glucose induced HepG2 cells. The gene expressions of hepatic gluconeogenesis were also down-regulated by G-Rk3 in HFD/STZ induced T2DM mice. In addition, G-Rk3 suppressed HFD/STZ induced lipid accumulation by regulating related gene and protein expressions such as p-ACC, FAS and SREBP-1, which are the downstream targets of AMPK. AMPK and Akt inhibitors significantly reversed G-Rk3 mediated hepatic gluconeogenesis and lipid accumulation. Thus, our study is the first to illustrate that G-Rk3 mediates hepatic gluconeogenesis and lipid accumulation via activating the AMPK/Akt signaling pathway in HFD/STZ induced T2DM mice.

Procyanidins, commonly found in plant natural sources, are polymerized forms of flavanols, which are a subclass of flavonoids. They have been reported to exhibit broad benefits to human health and used in the prevention of cancers, cardiovascular diseases, diabetes, etc. Bioactivities of procyanidins depend on many factors including the structures of procyanidins. Differences in composition of the monomers and degree of polymerization (DP) contribute to the variation in procyanidins. The basic structures and natural sources of procyanidins have been summarized in detail. Importantly, the structure-activity relationships of procyanidins, especially the relationship between degrees of polymerization and their antioxidant, anticancer, antidiabetic, anti-obesity, and cardioprotective effects as well as their potential mechanisms have been reviewed in detail. Additionally, current challenges in the studies of procyanidins have been discussed. Procyanidins are structurally diverse compounds and can be classified as monomeric, oligomeric, or polymeric variants depending on the DP, which plays a role in manifesting various effects that are associated with human health. The diversity and complexity of these chemical compounds and the difficulties encountered in the isolation of plant procyanidins continue to be major challenges. A better understanding of this information may promote the use of procyanidins in improving human health.