| BackgroundThe incidence and prevalence of prediabetes and diabetes continued to rise globally and constituted a major public health problem.Hyperglycemia and insulin resistance were closely related to pancreatic dysfunction,and gut microbes have become one of the key targets for the prevention and treatment of diabetes.Nobiletin(NOB)has attracted much attention due to its superior hypoglycemic effect,but the mechanism was not yet elucidated.Exploring the hypoglycemic mechanism of NOB by improving pancreatic function and regulating intestinal microbial metabolic pathways probably provided an innovative scientific perspective.ObjectivesThis study explored the hypoglycemic mechanism of NOB by improving pancreatic function and regulating intestinal microbial metabolic pathways,providing a scientific support for hyperglycemia prevention.The hypoglycemic effect and pancreatic protective effect were investigated to explore the hypoglycemic effect of NOB.The conversion of gut microbial composition and the metabolites was detected to explore the effect of NOB on microbial composition and function.MethodsApoE-/-mice were fed with a long-term high fat to establish an obese hyperglycemia animal model.The fasting blood glucose,glucose tolerance and insulin resistance of the mice were recorded regularly.The serum glycosylated protein levels were detected after the animals were sacrificed.Fractional pancreatic tissues were performed with HE staining and observed under the microscope.Fractional pancreatic tissue was observed under transmission electron microscope.Mice colon contents were collected for 16s rRNA high-throughput sequencing,enriched flora was screened and bacterial function was predicted.Mice cecal contents were collected for non-target metabolomics detection,differential metabolites were screened and functional enrichment analysis was performed.Pearson correlation analysis was used to mine the association between microbiota and metabolites.Results1.High-dose NOB reduced body weight of hyperglycemic mice.NOB reduced fasting blood glucose,relieved glucose tolerance impairment and insulin resistance,and reduced serum glycosylated protein levels in mice.2.NOB alleviated the decrease of pancreatic acinar cell secretion caused by hyperglycemia,prevented islet atrophy,slowed down acinar cell nuclear shrinkage and endoplasmic reticulum disorder.3.The 16s rRNA sequencing samples satisfied the quality inspection.After NOB intervention,the gut microbial diversity and richness did not change,while the microbial composition altered significantly;LEfSe analysis has detected 39,27 and 21 dominant bacteria respectively in the control group,the model group and H-NOB group.PICRUSt function analysis revealed that differential flora genes mainly enriched in metabolic function(Model vs H-NOB).4.The non-target metabolomics prediction model performed high reliability.After NOB intervention,the gut metabolic profile was significantly changed.11 potential differential metabolites(Control vs Model)were screened out by the OPLS-DA model,and 5 metabolites Changed(Model vs H-NOB)after NOB intervention.VIP value analysis found out more than 30 differential metabolites(Model vs H-NOB).KEGG analysis showed that differential enrichment pathways include bile acid biosynthesis,naphthol family and tyrosine metabolism,etc.Topology analysis revealed 3 differential metabolic pathways including tyrosine metabolism,phenylpropane biosynthesis and sphingolipid metabolism.5.Pearson correlation analysis showed that the relative abundance of differential flora at the phylum and genus levels was positively/negatively correlated with differential metabolites.ConclusionNobiletin effectively lowered fasting blood glucose,relieved glucose tolerance impairment and insulin resistance,protected islet activity and integrity,improve gut microbial composition,regulated gut amino acid and lipid metabolism.Nobiletin probably regulated blood sugar by improving pancreatic function and regulating intestinal microbial metabolic pathways. |
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