Bioenergetics in diabetic neuropathy: what we need to know

Abstract

Progress in developing treatments for diabetic neuropathy is slowed by our limited understanding of how disturbances in metabolic substrates - glucose and fatty acids - produce nerve injury. In this review, we present the current oxidative stress hypothesis and experimental data that support it. We identify weaknesses in our understanding of diabetes-disordered metabolism in the neurovascular unit, that is, in critical cell types of the microvascular endothelium, peripheral sensory neurons, and supporting Schwann cells. Greater understanding of peripheral nervous system bioenergetics may provide insight into new drug therapies or improvements in dietary interventions in diabetes or even pre-diabetes.

Figure 1

Prevailing view that excessive glycolytic metabolism is responsible for the generation of harmful reactive oxygen species (ROS), mitochondrial injury, and diabetic neuropathy. White boxes, experimental evidence derived from neuronal tissue and cells; black boxes, associations based on hypotheses derived from multiple, non-neuronal tissue and cell types.

Figure 2

Proposed relationship between diabetes, ROS and the TCA cycle. In a state of oxidative stress and/or decreased glycolysis, aconitase is inhibited. α-KGDH remains sufficiently active to permit truncated TCA cycling and delivery of electron donors to the electron transport chain, but further contributes to the production of ROS. α-KGDH, alpha-ketoglutarate dehydrogenase; ROS, reactive oxygen species.