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Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal
Root Ganglion Drives Painful Diabetic Neuropathy
#MMPMID26769971
Rahman MH
; Jha MK
; Kim JH
; Nam Y
; Lee MG
; Go Y
; Harris RA
; Park DH
; Kook H
; Lee IK
; Suk K
J Biol Chem
2016[Mar]; 291
(11
): 6011-6025
PMID26769971
show ga
The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic
neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or
lower ambient oxygen tension that leads to aberrant metabolic functions.
Metabolic dysfunctions have been documented to play a crucial role in the
pathogenesis of diverse pain hypersensitivities. However, the contribution of
diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful
diabetic neuropathy remains ill-explored. In this study, we report that pyruvate
dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose
metabolism, mediate glycolytic metabolic shift in the DRG leading to painful
diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the
expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2
and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity.
Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge,
expression of pain-related ion channels, activation of satellite glial cells, and
infiltration of macrophages in the DRG, in addition to reducing central
sensitization and neuroinflammation hallmarks in the spinal cord, which probably
accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were
partly resistant to the diabetes-induced loss of peripheral nerve structure and
function. Furthermore, in the experiments using DRG neuron cultures, lactic acid
treatment enhanced the expression of the ion channels and compromised cell
viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid
production substantially attenuated diabetes-induced pain hypersensitivity. Taken
together, PDK2/4 induction and the subsequent lactate surge induce the metabolic
shift in the diabetic DRG, thereby contributing to the pathogenesis of painful
diabetic neuropathy.
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