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Citrus sinensis (L.) Osbeck is extensively cultivated worldwide and one of the most consumed fruits in the world. We evaluated the therapeutic properties of the methanol extract from Citrus sinensis fruit peel (CSMe) in high-fat diet-fed streptozotocin-induced insulin-resistant diabetic rats. Body weight, food intake, and water consumption were analysed. Biochemical and molecular biologic indices, and the expression of insulin receptor-induced signalling molecules were assessed to identify possible mechanisms. In addition, we conducted histology of pancreatic and adipose tissues. UHPLC-MS/MS analysis showed the presence of 17 dietary phenolics at substantial concentrations. High-fat diet-fed streptozotocin-induced diabetic rats administered CSMe (50 and 100 mg/kg) had reduced fasting blood glucose (56.1% and 55.7%, respectively) and plasma insulin levels (22.9% and 32.7%, respectively) compared with untreated diabetic control rats. CSMe reversed the biochemical abnormalities in diabetic rats, showed cytoprotective activity, and increased the intensity of the positive immunoreactions for insulin in pancreatic islets. CSMe treatment increased the expression of PPARγ in the adipose tissue and signalling molecules GLUT4 and insulin receptor. Our data suggest that CSMe could optimize glucose uptake of adipose tissues through the insulin-dependent signalling cascade mechanism and it should be investigated in the management of individuals with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]