Linagliptin treatment improves cerebrovascular function and remodeling and restores reduced cerebral perfusion in Type 2 diabetes

Trevor Hardigan, Abdul Yasir, Mohammed Abdelsaid, Maha Coucha, Sally El-Shaffey, Weiguo Li, Maribeth H. Johnson, Adviye Ergul

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14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)R466-R477
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume311
Issue number3
DOIs
Publication statusPublished - Jan 1 2016

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Keywords

  • Cerebrovascular
  • Cognitive impairment
  • Diabetes
  • Dipeptidyl peptidase-4
  • Linagliptin

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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