Objective To study the effects of Dendrobium nobile Lindl. alkaloids (DNLA) on insulin resistancein diabetic rats with non-alcoholic fatty liver disease (NAFLD). Methods Sprague-Dawley (SD) rats were fed a high-fat,high-sugar diet for 4 weeks, and intraperitoneally injected with 40 mg/ kg streptozotocin to establish a diabetic rat modelwith NAFLD. Rats were then randomly divided into the model group, DNLA 20 mg/ kg group, DNLA 40 mg/ kg group,DNLA 80 mg/ kg group, and metformin 100 mg/ kg group (n = 10 rats per group). Ten normal SD rats were used ascontrols. Four weeks after intragastric administration of the drugs, fasting blood glucose (FPG) and fasting insulin (FINS)levels were measured, the insulin resistance index (HOMA-IR) was calculated, histological changes of the liver andpancreas were observed using hematoxylin and eosin staining, and islet insulin levels were detected byimmunohistochemistry. Results FPG, FINS, and HOMA-IR were significantly increased in the model rats compared withcontrols ( P < 0. 05), and FPG, FINS, and HOMA-IR were significantly decreased in the DNLA 40 mg/ kg and DNLA 80mg/ kg groups compared with controls ( P < 0. 05). Compared with the model group, the degree of fatty degeneration of theliver and the number of islet cells were reduced in diabetic rats. The expression of insulin in the islets of diabetic rats withNAFLD was significantly decreased. Compared with the model group, DNLA 40 mg/ kg and DNLA 80 mg/ kg groups showeda reduced extent of fatty degeneration of the liver and more islet cells. Insulin expression increased by varying degrees in theislets of the 40 mg/ kg and 80 mg/ kg DNLA groups. Conclusions DNLA reduces blood glucose and liver steatosis in diabetic rats with NAFLD. The mechanism may be related to the improvement of insulin resistance.