GPR40 Activation Abolishes Diabetes-Induced Painful Neuropathy by Suppressing VEGF-A Expression

Königs V, Pierre S, Schicht M, Welss J, Hahnefeld L, Rimola V, Lütjen-Drecoll E, Geisslinger G, Scholich K (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Diabetes American Diabetes Association

Book Volume: 71

Pages Range: 774-787

Journal Issue: 4

DOI: 10.2337/db21-0711

Abstract

G-protein-coupled receptor 40 (GPR40) is a promising target to support glucose-induced insulin release in patients with type 2 diabetes. We studied the role of GPR40 in the regulation of blood-nerve barrier integrity and its involvement in diabetes-induced neuropathies. Because GPR40 modulates insulin release, we used the streptozotocin model for type 1 diabetes, in which GPR40 functions can be investigated independently of its effects on insulin release. Diabetic wild-type mice exhibited increased vascular endothelial permeability and showed epineural microlesions in sciatic nerves, which were also observed in naïve GPR40-/- mice. Fittingly, expression of vascular endothelial growth factor-A (VEGF-A), an inducer of vascular permeability, was increased in diabetic wild-type and naïve GPR40-/- mice. GPR40 antagonists increased VEGF-A expression in murine and human endothelial cells as well as permeability of transendothelial barriers. In contrast, GPR40 agonists suppressed VEGF-A release and mRNA expression. The VEGF receptor inhibitor axitinib prevented diabetes-induced hypersensitivities and reduced endothelial and epineural permeability. Importantly, the GPR40 agonist GW9508 reverted established diabetes-induced hypersensitivity, an effect that was blocked by VEGF-A administration. Thus, GPR40 activation suppresses VEGF-A expression, thereby reducing diabetes-induced blood-nerve barrier permeability and reverting diabetes-induced hypersensitivities.

Authors with CRIS profile

Martin Schicht Lehrstuhl für Funktionelle und Klinische Anatomie Jessica Farger Lehrstuhl für Funktionelle und Klinische Anatomie Elke Lütjen-Drecoll Lehrstuhl für Funktionelle und Klinische Anatomie

Involved external institutions

Fraunhofer-Institut für Translationale Medizin und Pharmakologie (ITMP) / Fraunhofer Institute for Translational Medicine and Pharmacology DE Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) DE Germany (DE)

How to cite

APA:

Königs, V., Pierre, S., Schicht, M., Welss, J., Hahnefeld, L., Rimola, V.,... Scholich, K. (2022). GPR40 Activation Abolishes Diabetes-Induced Painful Neuropathy by Suppressing VEGF-A Expression. Diabetes, 71(4), 774-787. https://doi.org/10.2337/db21-0711

MLA:

Königs, Vanessa, et al. "GPR40 Activation Abolishes Diabetes-Induced Painful Neuropathy by Suppressing VEGF-A Expression." Diabetes 71.4 (2022): 774-787.

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