Objective: To investigate the molecular mechanisms of Jinlida on ameliorating insulin sensitivity in insulin resistant rats. Method: Fourty-eight SD rats were randomly divided into 2 groups: the control group (normal diet) and the high-fat-diet group (high-fat diet). After 6 weeks of high-fat diet

the insulin resistant model in rats was tested by the euglycemic hyperinsulinemic clamp. Then the high-fat-diet rats were randomly subdivided into 5 groups: the high-fat group (HF)

the low-

middle- and high-dose Jinlida groups (0.75

1.5

3.0 g·kg-1) and the metformin group (0.2 g·kg-1). After 8 weeks of treatment

hyperinsulin-euglycemic clamp and intraperitoneal glucose tolerance test were performed to evaluate the whole-body insulin sensitivity. Blood samples were collected and fasting blood glucose (FBG)

fasting plasma insulin (FINS)

glycosylated hemoglobin (HbA1c)

total cholesterol (TC)

triglycerides (TG)

high density lipoprotein cholesterol (HDL-C)

low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) were tested. The mRNA expressions of insulin signaling pathway molecules such as insulin receptor (INSR)

insulin receptor substrate-1 (IRS-1)

phosphatidylinositol3 kinase (PI3K)

protein kinase (AKT) and glucose transporter (GLUT2) were investigated by quantitative RT-PCR. The protein expressions of phosphorylation and total IRS-1

AKT were determined by Western blot. The phosphorylated Akt/total Akt (p-Akt/Akt) and phosphorylated IRS-1/total IRS-1(p-IRS-1/IRS-1) were evaluated. Result: Compared with the control group

glucose infusion rate (GIR) decreased

levels of FBG

FINS

HbA1c

TG

TC

LDL-C and VLDL-C increased

level of HDL-C decreased

mRNA expressions of INS

IRS-1

AKT and GLUT2 decreased in the HF group (P<0.05). Compared with the HF group

GIR decreased

levels of FBG

FINS

HbA1c

TG

TC and VLDL-C increased

mRNA expressions of INS

IRS-1

AKT and GLUT2 increased

the ratio of p-IRS-1/IRS-1 decreased

the ratio of p-AKT/AKT increased in the Ji Lida groups (P<0.05). However

there was no significant effect on the level of HDL-C and expression of PI3K in the Ji Lida groups. Conclusion: Jinlida could effectively reduce the insulin resistance and improve the glucose and lipid metabolic disorder in high-fat-diet rats. The possible molecular mechanism might be related to inhibiting the PI3K/AKT signaling pathway.