© 2022 Elsevier LtdType 2 diabetes mellitus (T2DM) is a widely prevalent chronic disease and risk factor for several other diseases, such as cardiovascular diseases, neuropathy, nephropathy, and retinopathy. Apoptosis is a homeostatic mechanism to maintain cell numbers at a certain level in tissues. Chronic high blood glucose levels might lead to mitochondrial dysfunction and trigger undesirable apoptosis in T2DM. The pineal hormone melatonin has been shown to regulate apoptosis. The aim of this study was to investigate the impact of the melatonin MT2 receptor in the role of melatonin to prevent undesirable apotosis in different tissues of diabetic rats. Male Sprague Dawley rats were randomly divided into 4 groups; 1. Control group (only vehicle), 2. Diabetic group (streptozotozin/nicotinamide treated), 3. Diabetic group treated with melatonin (500μg/kg/day), and 4. Diabetic group treated with melatonin (500 μg/kg/day for 6 weeks) and the selective MT2 receptor antagonist luzindole (0.25 g/kg/day for 6 weeks). Various tissue samples (kidney, liver, adipose tissue, pancreas) were removed after 6 weeks for immunohistochemistry and western blot analysis. Our results demonstrated an increased rate of apoptosis in different tissues of diabetic rats compared to controls with melatonin reducing the apoptotic rate in the tissues of rats with T2DM. Furthermore, the anti-apoptotic effects of melatonin were partly mediated by the melatonin MT2 receptor.