Combined metformin and insulin therapy improves neurocognitive dysfunction in type 2 diabetic rat model via anti-inflammatory and antioxidant mechanisms

Introduction: Improper glycemic control is associated with diabetic cognitive dysfunction. Several studies have confirmed the neuroprotective effects of metformin and insulin. This study aimed to investigate the effects of metformin and/or insulin therapy on neurocognitive functions in a type 2 diabetes mellitus (T2DM) rat model. Methods: Fifty adult male Wistar rats were used in this study and had free access to water and a normal chow diet. After an acclimatization period, 10 rats were kept on a normal chow diet and considered as the control group. T2DM was induced in the other 40 rats by a high-fat diet and low-dose streptozotocin method. Then, diabetic rats were randomly allocated into 4 equal groups: Non-treated diabetic group; Metformin-treated diabetic group (treated with metformin 250 mg/kg/day for 6 weeks); Insulin-treated diabetic group (treated with NPH insulin 40 U/kg for 6 weeks); and Metformin and insulin-treated diabetic group. Neurocognitive functions were assessed by footprint assay, Y-maze, open field test, and Morris water maze. Glycaemic profile, serum levels of amyloid A, interleukin-18, and nuclear factor-kappa B were analyzed. Brain malondialdehyde and total antioxidant capacity were measured. A histopathological examination of the frontal lobe was performed. Results: Treatment with metformin and/or insulin significantly improved the impaired neurocognitive dysfunction, brain oxidative stress, changes in biochemical parameters, and the associated histopathological changes in the frontal cortex of diabetic rats. The combined therapy showed a better effect than either monotherapy alone. Conclusion: Metformin and insulin therapy may be valuable for the prevention of neurocognitive dysfunction in T2DM.