Phenolipid JE improves metabolic profile and inhibits gluconeogenesis via modulating AKT-mediated insulin signaling in STZ-induced diabetic mice

• Published in: Pharmacological research 2023-01, Vol.187, p.106569-106569, Article 106569
• Main Authors: Wang, Guihua, Xu, Jialin, Ma, Hang, Mu, Yu, Xu, Wen, Yan, Na, Liu, Wei, Zheng, Dan, Huang, Xueshi, Li, Liya
• Format: Article
• Language: English
• Subjects: AKT/FoxO1; Animals; Diabetes mellitus; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 1 - drug therapy; Gluconeogenesis; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin - metabolism; Insulin Resistance; Jambone E; Liver; Metabolome; Mice; Nontargeted metabolomics; Phenolipid; Phytochemicals - pharmacology; Phytochemicals - therapeutic use; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Streptozocin; Syzygium; Syzygium - chemistry
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2022.106569

Phenolipids are characteristic phytochemicals of Syzygium genus. However, the antidiabetic potential and underlying molecular mechanism of these components are not fully elucidated. Herein, we studied the anti-diabetic effects of jambone E (JE), a phenolipid from S. cumini, with in vitro and in vivo models. Data from current study showed that JE enhanced glucose consumption and uptake, promoted glycogen synthesis, and suppressed gluconeogenesis in insulin resistant (IR)-HepG2 cells and primary mouse hepatocytes. JE also attenuated streptozotocin-induced hyperglycemia and hyperlipidemia in type 1 diabetic (T1D) mice. Eleven metabolites (e.g. trimethylamine n-oxide, 4-pyridoxic acid, phosphatidylinositol 39:4, phenaceturic acid, and hippuric acid) were identified as potential serum biomarkers for JE’s antidiabetic effects by an untargeted metabolomics approach. The further molecular mechanistic study revealed that JE up-regulated phosphorylation levels of protein kinase B (AKT), glycogen synthase kinase 3 beta, and forkhead box O1 (FoxO1), promoted nuclear exclusion of FoxO1 whilst decreased gene expression levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase in IR-HepG2 cells and T1D mice. Our data suggested that JE might be a potent activator for AKT-mediated insulin signaling pathway, which was confirmed by the usage of AKT inhibitor and AKT-target siRNA interference, as well as the cellular thermal shift assay. Findings from the current study shed light on the anti-diabetic effects of phenolipids in the Syzygium species, which supports the use of medicinal plants in the Syzygium genus for potential pharmaceutical applications. [Display omitted] •Phenolipid JE ameliorated impaired hepatic gluconeogenesis in vitro and in vivo.•JE improved glucose and lipid metabolism in STZ-induced T1D mice.•JE attenuated metabolic disturbance in T1D mice at the metabolite level.•JE displayed potential in treating diabetes-induced kidney injury.•JE promoted AKT-mediated insulin signaling transduction.