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DPP-4 Inhibitor and Sulfonylurea Differentially Reverse Type 2 Diabetes–Induced Blood–Brain Barrier Leakage and Normalize Capillary Pericyte Coverage

Elabi, Osama F. LU ; Karampatsi, Dimitra ; Vercalsteren, Ellen ; Lietzau, Grazyna ; Nyström, Thomas ; Klein, Thomas ; Darsalia, Vladimer LU ; Patrone, Cesare and Paul, Gesine LU (2023) In Diabetes 72(3). p.405-414
Abstract

Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). Although accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl pep-tidase-4 inhibitor linagliptin and the sulfonylurea glimepiride, which restore T2D-induced brain vascular pathology. Micro-vascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3... (More)

Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). Although accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl pep-tidase-4 inhibitor linagliptin and the sulfonylurea glimepiride, which restore T2D-induced brain vascular pathology. Micro-vascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months be-fore sacrifice. We demonstrate that T2D caused leakage of the blood–brain barrier (BBB), induced angiogenesis, and reduced pericyte coverage of microvessels. However, linaglip-tin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalized T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial acti-vation, increased microglial–vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage, which may contribute to antidiabetic neurorestorative effects.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
72
issue
3
pages
10 pages
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:36448982
  • scopus:85148677898
ISSN
0012-1797
DOI
10.2337/db22-0674
language
English
LU publication?
yes
id
62bfa8e7-a20a-4125-ba13-c9ca18b208a5
date added to LUP
2023-03-15 12:33:46
date last changed
2024-06-12 08:22:53
@article{62bfa8e7-a20a-4125-ba13-c9ca18b208a5,
  abstract     = {{<p>Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). Although accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl pep-tidase-4 inhibitor linagliptin and the sulfonylurea glimepiride, which restore T2D-induced brain vascular pathology. Micro-vascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months be-fore sacrifice. We demonstrate that T2D caused leakage of the blood–brain barrier (BBB), induced angiogenesis, and reduced pericyte coverage of microvessels. However, linaglip-tin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalized T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial acti-vation, increased microglial–vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage, which may contribute to antidiabetic neurorestorative effects.</p>}},
  author       = {{Elabi, Osama F. and Karampatsi, Dimitra and Vercalsteren, Ellen and Lietzau, Grazyna and Nyström, Thomas and Klein, Thomas and Darsalia, Vladimer and Patrone, Cesare and Paul, Gesine}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{405--414}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{DPP-4 Inhibitor and Sulfonylurea Differentially Reverse Type 2 Diabetes–Induced Blood–Brain Barrier Leakage and Normalize Capillary Pericyte Coverage}},
  url          = {{http://dx.doi.org/10.2337/db22-0674}},
  doi          = {{10.2337/db22-0674}},
  volume       = {{72}},
  year         = {{2023}},
}