title: Linagliptin treatment improves cerebrovascular function and remodeling and restores reduced cerebral perfusion in Type 2 diabetes.
abstract: The antihyperglycemic 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 rats were treated with linagliptin for 4 wk, and blood glucose and DPP-IV plasma levels were assessed. Cerebral perfusion was assessed after treatment using laser-Doppler imaging, and dose response to insulin (10(-13) M-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 hippocampus-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 as 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.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, Georgia; and.
authors.forename: Trevor
authors.initials: T
authors.lastname: Hardigan
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, Georgia; and.
authors.forename: Abdul
authors.initials: A
authors.lastname: Yasir
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia; Department of Physiology, Medical College of Georgia, Augusta, Georgia; and.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abdelsaid
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia; Department of Physiology, Medical College of Georgia, Augusta, Georgia; and.
authors.forename: Maha
authors.initials: M
authors.lastname: Coucha
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta, Georgia; and.
authors.forename: Sally
authors.initials: S
authors.lastname: El-Shaffey
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia; Department of Physiology, Medical College of Georgia, Augusta, Georgia; and.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Biostatistics, The Graduate School at Augusta University, Augusta, Georgia.
authors.forename: Maribeth H
authors.initials: MH
authors.lastname: Johnson
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia; Department of Physiology, Medical College of Georgia, Augusta, Georgia; and aergul@augusta.edu.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D003071:Cognition / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000069476:Linagliptin / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D016896:Treatment Outcome; D066253:Vascular Remodeling
chemical_list: D007004:Hypoglycemic Agents; D000069476:Linagliptin
keywords: cerebrovascular; cognitive impairment; diabetes; dipeptidyl peptidase-4; linagliptin