Mangiferin, a natural C-
glucoside xanthone, is one of the major bioactive ingredients derived from the dry rhizome of Anemarrhenae rhizome, which has been reported to exhibit various pharmacological effects, including
anti-oxidant, anti-inflammatory, anti-
fatty liver, anti-
metabolic syndrome, and anti-diabetic. However, the precise molecular mechanisms underlying its impact on
phospholipid metabolism in the erythrocyte membrane of
type 2 diabetes mellitus (T2DM) remain unclear. The present research aimed to evaluate the effects of
mangiferin on
glucose and lipid metabolism in T2DM model rats and discuss the relationship between
lipid metabolites and potential targets involved in the
hypoglycemic effects by integrating lipidomics and network pharmacology method. After 8 consecutive weeks of treatment with
mangiferin, the T2DM model rats exhibited significant improvements in several biochemical indices and
cytokines, including fasting
blood glucose (FBG) levels after 12 h of fasting, fasting
insulin level (FINS), total
cholesterol (T-CHO),
triacylglycerols (TG),
high-density lipoprotein cholesterol (HDL-C),
low-density lipoprotein cholesterol (
LDL-C), homeostasis model assessment of
insulin resistance (HMOA-IR), TNF-α and
IL-6. A total of 22 differential
lipid metabolites were selected from erythrocyte membrane
phospholipids, which were closely associated with the processes of T2DM. These metabolites mainly belonged to
glycerophospholipid metabolism and
sphingolipid metabolism. Based on network pharmacology analysis, 22 genes were recognized as the potential targets of
mangiferin against diabetes. Moreover, molecular docking analysis revealed that the targets of TNF,
CASP3,
PTGS2, MMP9, RELA, PLA2G2A, PPARA, and NOS3 could be involved in the modulation of inflammatory signaling pathways and
arachidonic acid (AA) metabolism to improve IR and
hyperglycemia. The combination of immunohistochemical staining and PCR showed that
mangiferin could treat T2DM by regulating the expression of PPARγ
protein and NF-κB
mRNA expression to impact
glycerophospholipids (GPs) and AA metabolism. The present study showed that
mangiferin might alleviate IR and
hyperglycemia of T2DM model rats via multiple targets and multiple pathways to adjust their
phospholipid metabolism, which may be the underlying mechanism for
mangiferin in the treatment of T2DM.