Comparative effects of selective and non-selective sodium–glucose cotransporter inhibition on cognitive dysfunction in a rat model of type 2 diabetes

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for cognitive decline and Alzheimer’s disease (AD), yet the therapeutic potential of antidiabetic agents on diabetes-associated neurodegeneration remains incompletely understood. In this study, we investigated the effects of the non-selective sodium–glucose cotransporter (SGLT) inhibitor phlorizin and the selective SGLT2 inhibitor dapagliflozin on metabolic parameters and cognitive performance in a rat model of T2DM-related cognitive dysfunction (T2DM-CD). Male Sprague–Dawley rats were fed a high-fat diet and administered low-dose streptozotocin to induce a diabetic phenotype accompanied by cognitive impairment. Animals were treated for four weeks with dapagliflozin, phlorizin, metformin, or rivastigmine. Blood glucose levels, body weight, locomotor activity, and recognition memory were assessed using standardized metabolic and behavioural tests. The T2DM-CD model exhibited sustained hyperglycaemia and significant impairment in recognition memory without alterations in locomotor activity. Treatment with dapagliflozin and phlorizin significantly reduced blood glucose levels and markedly improved recognition memory compared with untreated animals. Rivastigmine also improved cognitive performance without affecting glycaemic control, whereas metformin produced only modest cognitive benefits. None of the treatments significantly altered body weight. These findings demonstrate that SGLT inhibition ameliorates cognitive deficits in a T2DM-CD model, suggesting that SGLT inhibitors may exert beneficial effects on diabetes-associated cognitive dysfunction through combined metabolic and central mechanisms.