To investigate the effects of hesperidin on improving hepatic glucose metabolism disorder in type 2 diabetes model db/db mice and its underlying molecular mechanisms.

A total of 40 mice were divided into a normal control group, a db/db model group, and hesperidin low-dose [50 mg/(kg·d)] and high-dose[100 mg/(kg·d)] intervention groups, which were administered orally for 6 consecutive weeks.

Compared with the model group, hesperidin intervention could dose-dependently reduce fasting blood glucose, improve weight loss, alleviate hepatic steatosis and histopathological damage, significantly reduce serum total cholesterol, triglycerides and low-density lipoprotein cholesterol, increase high-density lipoprotein cholesterol, and decrease pro-inflammatory factors (interleukin-6, interleukin-1β and tumor necrosis factor-α) (P<0.01). Western blot results indicated that hesperidin significantly downregulated the expression of forkhead box protein O1 (FOXO1) and glucose-6-phosphatase catalytic subunit (G6PC) in the liver, while upregulating the expression of hexokinase 2(HK2) (P<0.01).

Hesperidin can effectively improve hepatic glucose and lipid metabolism disorders and inflammation in type 2 diabetes mellitus mice, and its mechanism may be related to regulating the hepatic FOXO1/HK2/G6PC signaling pathway, inhibiting excessive gluconeogenesis, and promoting glucose utilization. This study provides new experimental evidence for hesperidin as a potential adjuvant therapeutic strategy for diabetes.