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

Abstract

G-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<sup>-/-</sup> mice. Fittingly, expression of VEGF-A, an inducer of vascular permeability, was increased in diabetic wildtype and naïve GPR40<sup>-/- </sup>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.