Ethnopharmacological relevance:Diabetic peripheral neuropathy (DPN) in traditional Chinese medicine is called Xiaoke, and can be attributed to collateral disease.Tang Luo Ning recipe (TLN), derived from Huangqi Guizhi Wuwu decoction, has been shown to be effective in DPN patients.But the mechanism of TLN in treating DPN needs to be further studies.Endoplasmic reticulum (ER) stress is involved in the development of DPN in recent years, but whether the prevention of DPN by TLN associated with ER stress is not clear;the purpose of this study is to investigate the effects of TLN on IRE1 pathway of ER stress in DPN rats.Materials and methods: Rats were induced by high-carbohydrate/high-fat diet for 4 weeks followed with intraperitoneal inject streptozotocin (STZ, 35mg/kg), homeostasis model of assessment for insulin resistance index (HOMA-IR) was measured by radioimmunoassay kits, neurological function were determined by thermal perception threshold test (TPT), motor and sensory nerve conduction velocity (MNCV and SNCV) and protein gene product 9.5 (PGP9.5).Neurological morphology was determined by electron microscope and Luxol fast blue staining.Glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP-1), ER degradation-enhancing-mannosidase-like protein (EDEM), CATT/EBP homologous protein (CHOP), B-cell lymphoma 2 (Bcl-2), Bcl-2 Associated X Protein (Bax) and eukaryotic translation initiation factor 2α phosphorylation (P-eIF2α) were measured by Western blot analysis.Inositol-requiring enzyme1α phosphorylation (P-IRE1α), IRE1α, growth-arrest and DNA damage-inducible gene 34 (GADD34) and endoplasmic oxidoreductin-1-like (Ero1α) were measured by immunofluorescence.Results: TLN improved the neurological function and morphology effectively.Moreover, TLN increased the expression of GRP78, EDEM, Bcl-2 and P-eIF2α, as well as decreased the expression of P-IRE 1α, XBP-1, CHOP, GADD34, Bax and Ero1α significantly.Conclusions: TLN can improve neurological function and morphology to prevent DPN by attenuating ER stress through regulating IRE 1 pathway.