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 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: Vanessa Königs, Sandra Pierre, Martin Schicht, Jessica Welss, Lisa Hahnefeld, Vittoria Rimola, Elke Lütjen-Drecoll, Gerd Geisslinger, Klaus Scholich
• Journal: Diabetes (Diabetes) Vol. 71 Issue 4 Pg. 774-787 (04 01 2022) ISSN: 1939-327X [Electronic] United States
• PMID: 35061031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by the American Diabetes Association.

Chemical References

• FFAR1 protein, human
• Ffar1 protein, mouse
• Insulin
• Receptors, G-Protein-Coupled
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse

Topics

• Animals
• Diabetes Mellitus, Type 2 (complications, metabolism)
• Diabetic Neuropathies (metabolism)
• Endothelial Cells (metabolism)
• Humans
• Hypersensitivity
• Insulin (metabolism)
• Mice
• Receptors, G-Protein-Coupled (metabolism)
• Vascular Endothelial Growth Factor A (genetics)