TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE
IMAGE: RAPID AND EXTENSIVE SCHWANN CELL DEATH UNDER HIGH-GLUCOSE PYRUVATE-DEPLETED CONDITIONS CAN BE EVOKED BY THE FOLLOWING SEQUENTIAL METABOLIC ALTERATIONS; 1) DIMINISHED TCA CYCLE INTERMEDIATES AND MITOCHONDRIAL ATP PRODUCTION, 2) REDUCED GAPDH ACTIVITY AND INHIBITION OF GLYCOLYTIC FLUX THROUGH THE ACTIVATION OF PARP, 3) ESCALATION OF THE POLYOL AND OTHER COLLATERAL GLYCOLYSIS PATHWAYS, 4) IMPAIRED HEXOKINASE (HK) ACTIVITY AND GLUCOSE UTILIZATION IN THE GLYCOLYTIC PATHWAY, AND 5) FURTHER ESCALATION OF THE POLYOL PATHWAY FLUX.
CREDIT: TMIMS
Endogenous pyruvate is an end-product in glycolysis and a key molecule for ATP production under aerobic and anaerobic conditions, whereas exogenous pyruvate is transferred to cells via monocarboxylate transporters (MCTs) and predominantly acts as an antioxidant. Pyruvate supplementation has been shown to ameliorate hyperglycemia, retinopathy, and nephropathy in experimental diabetic animals; however, neither the significance of pyruvate as an antioxidant or a glucose metabolism promoter at the cellular level under hyperglycemic conditions nor its efficacy for the prevention and restoration of diabetic peripheral neuropathy remains obscure.
We observed rapid and massive cell death of peripheral sensory neurons and Schwann cells under high-glucose pyruvate-starved conditions in culture. Rucaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, prevented decreases in cell viability, GAPDH activity, and glycolytic flux. Further analyses using Schwann cells indicated that the pyruvate starvation-induced cell death under high-glucose milieu may result from the following sequential metabolic disturbances; 1) reduced TCA cycle intermediates and mitochondrial ATP production, 2) inhibition of GAPDH activity and glycolytic flux through the activation of PARP, 3) escalation of the polyol and other collateral glycolysis pathways, 4) inhibition of hexokinase activity and glucose utilization in the glycolytic pathway, and 5) further escalation of the polyol pathway flux. In other words, exogenous pyruvate may play a pivotal role in maintaining glycolysis–TCA cycle flux under high-glucose conditions by suppressing PARP activity.
While these findings contribute to further our understanding of cellular metabolism under hyperglycemic conditions, the efficacy of pyruvate therapy toward diabetic neuropathy awaits future analyses on experimental diabetic animals and patients with diabetic neuropathy.
This study was performed in collaboration with Tokyo Metropolitan Institute of Medical Science, and Aichi Gakuin University, School of Pharmacy.
About the Tokyo Metropolitan Institute of Medical Science and Diabetic Neuropathy Project
The Tokyo Metropolitan Institute of Medical Science (TMIMS) is dedicated to promoting the basic and medical research to improve human health and quality of life. Diabetic Neuropathy Project in TMIMS is studying diabetes-related neurodegeneration in the central and peripheral nervous systems. The objectives of the project are to establish effective pathogenesis-based remedies for diabetic peripheral neuropathy and elucidate mechanistic links between metabolic dysfunction and neurodegenerative diseases.
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