OBJECTIVE:To observe the effect of Jiangtang Xiaoke (JTXK) granule on endoplasmic reticulum (ER) stress in high fat diet (HFD)-induced type 2 diabetes mellitus (T2DM) KK-Ay mice.METHODS:KK-Ay mice were fed with HFD to induce the T2DM model,while normal control C57BL/6J mice were given standard feed.Fasting blood glucose (FBG) in all mice was measured weekly and oral glucose tolerance tests (OGTTs) were performed at 4 and 10 weeks after start of treatment to determine glucose metabolism.Serum fasting insulin (FINS) and insulin sensitivity index (ISI) were measured to determine insulin sensitivity,mRNA expressions of eukaryotic initiation factor-2 alpha (eIF2α),glucose regulated protein 78 (GRP78),activating transcription factor 4 (ATF4),and C/EBP homology protein (CHOP) were assessed by reverse transcription polymerase chain reaction and the protein expressions of p-eIF2c,GRP78,and CHOP were assessed by West blotting.RESULTS:JTXK granule significantly reduced FBG and free fatty acid levels and improved OGTT at the 120 min of the 10-week treatment in T2DM KK-Ay mice.FINS and HbAIc levels were reduced and insulin sensitivities were increased in KK-Ay diabetic mice,which were improved with the treatment of JTXK granule,especially at the 7 and 3.5 g/kg doses.JTXK granule at the 3.5 g/kg dose was most effective in reducing both gene and protein expressions of eIF2α,GRP78,and CHOR.CONCLUSION:ER stress response is increased in T2DM KK-Ay mice.Treatment with JTXK granule attenuates glucose disorders,improves insulin sensitivity,and reduces serum FFA in T2DM KK-Ay mice.The mechanisms may be attributed to regulation of the signaling ER stress pathway via decreasing eIF2α phosphorylation and suppressing eIF2α-ATF4-CHOP activation.