Strengthening monocarboxylate transporters by adiponectin receptor agonist ameliorates diabetic peripheral neuropathy

Disruption of energy support to peripheral nerves leads to dysfunction and degeneration of both neuronal axons and Schwann cells (SCs). We evaluated the effects of the adiponectin receptor (AdipoR) agonist, AdipoRon on diabetic peripheral neuropathy (DPN) using db/db mice, murine ND7/23 cells, and human SCs. AdipoRon improved sensorimotor function and restored nerve phenotypes in the sciatic nerve and paw skin of db/db mice by reducing systemic oxidative stress and insulin resistance. AdipoRon restored impaired oxidative stress response, apoptosis, and autophagy activity through increased AdipoR1/R2-intracellular Ca++-CaMKKβ expression as well as LKB1/AMPK-PPARα/PGC-1α/Nrf2 phosphorylation. It also decreased mTOR phosphorylation, which is related to the preservation of mitochondria in axons and SCs, and improved MCT1/2/4 expression and lactate and ATP/AMP levels in the sciatic nerve of db/db mice. In ND7/23 cells and SCs, AdipoRon decreased oxidative stress and apoptosis while increasing autophagy by suppressing high glucose- and palmitate-induced cellular and mitochondrial oxidative stress, activating the same signaling as in the sciatic nerve. These protective changes were induced by providing energy substrate, lactate and ATP, through the increased expression of MCT1/2/4, facilitating metabolic communication between neurons and SCs. AdipoRon may play an important role in preventing DPN by ameliorating oxidative stress, apoptosis, and autophagy, strengthening metabolic support for neurons and SCs under diabetic conditions.