GPR40 Activation Abolishes Diabetes-Induced Painful Neuropathy by Suppressing VEGF-A Expression
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posted on 2022-01-21, 16:52 authored by Vanessa Königs, Sandra Pierre, Martin Schicht, Jessica Welss, Lisa Hahnefeld, Vittoria Rimola, Elke Lütjen-Drecoll, Gerd Geisslinger, Klaus ScholichG-protein
coupled receptor 40 (GPR40) is a promising target to support glucose-induced
insulin release in patients with diabetes type 2. Here, we studied the role of
GPR40 in the regulation of the blood-nerve-barrier integrity and its involvement in diabetes-induced
neuropathies. Since GPR40 modulates insulin release, we used the
streptozotocin-model for type 1 diabetes, since here GPR40 functions can be
investigated independently of its effects on insulin release. Diabetic wildtype
mice exhibited increased vascular endothelial permeability and showed epineural
microlesions in sciatic nerves, which were also observed in naïve GPR40-/-
mice. Fittingly, expression of VEGF-A, an inducer of vascular permeability, was
increased in diabetic wildtype 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 which 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.