The anti-hyperglycemic agent linagliptin, a dipeptidyl peptidase-4 (DPP-IV) inhibitor, has been shown to reduce inflammation and improve endothelial cell function. In this study, we hypothesized that DPP-IV inhibition with linagliptin would improve impaired cerebral perfusion in diabetic rats as well as improve insulin-induced cerebrovascular relaxation and reverse pathological cerebrovascular remodeling. We further postulated that these changes would lead to a subsequent improvement of cognitive function. Male type-2 diabetic and nondiabetic Goto-Kakizaki (GK) rats were treated with linagliptin for four weeks, and blood glucose and DPP-IV plasma levels were assessed. Cerebral perfusion was assessed post-treatment using laser Doppler imaging, and dose response to insulin (10-13- 10-6 M) in middle cerebral arteries was tested on a pressurized arteriograph. The impact of DPP-IV inhibition on diabetic cerebrovascular remodeling was assessed over a physiologically relevant pressure range, and changes in short-term hippocampal-dependent learning were observed using a novel object recognition test. Linagliptin lowered DPP-IV activity but did not change blood glucose or insulin levels in diabetes. Insulin-mediated vascular relaxation and cerebral perfusion were improved in the diabetic rats with linagliptin treatment. Indices of diabetic vascular remodeling such increased cross-sectional area, media thickness, and wall to lumen ratio were also ameliorated, however improvements in short-term hippocampal-dependent learning were not observed. The present study provides evidence that linagliptin treatment improves cerebrovascular dysfunction and remodeling in a type-2 model of diabetes independent of glycemic control. This has important implications in diabetic patients who are predisposed to the development of cerebrovascular complications such as stroke and cognitive impairment.
- Cognitive Impairment
- Copyright © 2016, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology