Abstract 051: Oral Antihyperglycemic Therapy With a SGLT2 Inhibitor Reverses Cognitive Impairments in Elderly Diabetics

Abstract

Diabetes mellitus is a leading risk factor for aging-related dementia, but the underlying mechanisms by which long-standing hyperglycemia accelerates the loss of cognitive function are not fully elucidated. In the present study, we examined whether normalizing blood glucose and HbA1C levels with Luseogliflozin (20 mg/kg/day in drinking water for 4 months) can reverse cognitive impairments in old diabetic rats (18-month), and explored if this is related to the amelioration of cerebral vascular dysfunction seen in these rats. Plasma glucose and glycated hemoglobin levels fell from 392 ± 18 to 148 ± 7 mg/dL and 12 ± 0.2 vs. 6 ± 0.4% in old diabetic rats (n=12) after 4-month treatment with Luseogliflozin. Oral antihyperglycemic therapy did not alter body weight, blood pressure and protein excretion in these rats. We identified that impaired myogenic response in middle cerebral arteries (MCAs) observed in old diabetic rats was normalized after reducing plasma glucose levels with the SGLT2 inhibitor. Forced dilatation occurred at pressures > 140 mmHg in MCAs of elderly diabetic rats was rescued by normalization of plasma glucose. Cortical blood flow measured by laser Doppler flowmetry rose by 122 ± 19%, 41 ± 10%, 36 ± 4%, respectively, in old diabetic, SGLT2 inhibitor treated diabetic and non-diabetic rats when blood pressure was increased from 100 to 180 mmHg. Autoregulation of CBF was shifted to lower pressures in elderly diabetic rats and they exhibited breakthrough at pressures > 140 mmHg, while CBF autoregulation curve was shifted to the right after Luseogliflozin treatment in these rats. Normalization of plasma glucose with Luseogliflozin decreased reactive oxygen species (ROS) production in cerebral vessels by 50% to the same level as age-matched non-diabetic rats, improved endothelial function and rescued the impaired neurovascular coupling (NVC), blood-brain barrier (BBB) leakage and cognitive disabilities in old diabetic rats. These results provide the first evidence demonstrating that normalization of hyperglycemia with a SGLT2 inhibitor can reverse cerebrovascular dysfunction and cognitive impairments in the elderly with long-standing diabetes.