DPP-4 inhibitor and sulfonylurea differentially reverse type 2 diabetes-induced blood-brain barrier leakage and normalise capillary pericyte coverage

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). While accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. </p> <p>Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, restore T2D-induced brain vascular pathology. Microvascular 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 before the sacrifice. </p> <p>We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalised 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 activation, increased microglial-vascular interaction, and increased collagen IV density. </p> <p>This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage which may contribute to the antidiabetic neurorestorative effects. </p>