OBJECTIVE:To observe the therapeutic effect of Shenzhu Tiaopi granule(参术调脾颗粒,STG)on in-sulin resistance(IR)in the liver of diabetic Go-to-Kakizaki(GK)rat and investigate underlying mechanisms.METHODS:Ten 12-week-old male Wistar rats were assigned as normal control(NC)group,while 40 12-week-old male specific-pathogen-free GK rats were randomly divided into four experimental groups,10 diabetic rats each.Animals were fed with a normal diet.Fasting blood glucose(FBG),wa-ter intake,and body weight were recorded during 6 weeks of daily single-dose treatment:STG low-dose group,4.5 g/kg(STG-L);STG high-dose group,9 g/kg(STG-H);metformin group,0.1 g/kg(MET);model control(MC)and NC groups,equal volume of 0.9％NaCl solution.The serum fasting in-sulin(FINS),C-Peptide and IR index(HOMA-IR)were detected every 2 weeks during treatment and glu-cose tolerance was measured in the 3rd day before the material was taken.After the 6-week STG treat-ment,Liver tissues were processed for hematoxy-lin-eosin staining to perform light microscopy anal-ysis and for assessing expression and distribution of insulin receptor substrates(IRS-1)and glucose transporter(GLUT-4)by immunohistochemistry analysis.Expression levels of liver kinase B1(LKB1)/adenosine 5’-monophosphate-activated protein ki-nase(AMPK)/mammalian target of rapamycin(mTOR)pathway proteins,including LKB1,phos-pho-AMPK(p-AMPK)/AMPK,phospho-mTOR(p-mTOR)/mTOR,and ribosomal protein S6 kinase polypeptide 1(S6K1),were detected by Western blotting.RESULTS:STG significantly reduced the FBG level and liver fat deposition in diabetic GK rats.After STG treatment completion,FINS,HOMA-IR,C-Pep-tide and area under blood glucose curve(AUC)were lower in STG groups than in the MC group,in-dicating that IR was reduced and liver fat lesions were resolved.In liver tissues,STG groups dis-played significantly higher IRS-1 and GLUT-4 expres-sion than the MC group,along with increasedLKB1 and p-AMPK/AMPK expression and decreased p-mTOR/mTOR and phospho-S6K1 expression,sug-gesting that STG stimulatedLKB1 activation of AMPK and suppressed them TOR/S6K1 down-stream pathway.CONCLUSION:Growing GK rats developed hepatic IR,but STG treatment significantly improved hyper-glycemia and IR and resolved hepatic fatty lesions.Interestingly,STG treatment stimulated the expres-sion of IRS-1 and GLUT-4 in the liver of diabetic GK rats,indicating a potential involvement in the regu-lation of theLKB1/AMPK/mTOR signaling pathway.