Phenolics from Phyllanthus emblica Linn. ameliorate glucose homeostasis and insulin resistance in high-fat diet/streptozotocin-induced type 2 diabetic mice.

Phyllanthus emblica Linn. contains abundant free phenolic (PEFP) and bound phenolic (PEBP), both of which have demonstrated potential antidiabetic activities. However, their comparative hypoglycemic effects and underlying mechanisms remain unclear. This study investigated the effects of PEFP and PEBP using insulin-resistant HepG2 (IR-HepG2) cells and a high-fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetes mellitus (T2DM) mouse model. PEFP and PEBP showed no cytotoxicity toward HepG2 cells and significantly enhanced glucose consumption, glycogen synthesis, and hexokinase and pyruvate kinase activities in IR-HepG2 cells. Treatment with 160 μg mL-1 PEFP and PEBP increased glucose consumption in IR-HepG2 cells to 7.13 ± 0.30 and 6.73 ± 0.37 mmol L-1, respectively, restoring levels comparable to control cells (7.23 ± 0.69 mmol L-1). In HFD/STZ-induced T2DM mice, PEFP and PEBP significantly improved glucose homeostasis, insulin sensitivity, dyslipidemia, oxidative stress, and inflammatory responses after 10 weeks of intervention. High-dose PEFP and PEBP reduced fasting blood glucose from 13.02 ± 1.19 mmol L-1 in diabetic mice to 7.47 ± 1.18 and 9.87 ± 0.93 mmol L-1, respectively. At the molecular level, both treatments were associated with upregulation of insulin signaling-related genes (Insr, Irs1, Pik3r1, Pik3ca, and Akt1) and suppression of gluconeogenic genes (Foxo1, Pck1, and G6pc) in the liver. Notably, distinct functional patterns were observed. PEFP, particularly at high doses, showed stronger associations with restoration of insulin signaling and inhibition of gluconeogenesis, whereas PEBP was more closely associated with glucose utilization and glycogen storage. In addition, PEFP and PEBP inhibited jejunal α-glucosidase and α-amylase activities and altered gut microbiota composition. These findings demonstrate that PEFP and PEBP exert multifaceted antidiabetic effects, which were closely associated with the modulation of hepatic insulin signaling-related gene expression, intestinal carbohydrate digestion, and gut microbiota composition, highlighting their potential as functional food ingredients for T2DM management.