Reducing monocarboxylate transporter MCT1 worsens experimental diabetic peripheral neuropathy

Mithilesh Kumar Jha, Xanthe H. Ament, Fang Yang, Ying Liu, Michael J. Polydefkis, Luc Pellerin, Brett M. Morrison

Research output: Contribution to journalArticlepeer-review

Abstract

Diabetic peripheral neuropathy (DPN) is one of the most common complications in diabetic patients. Though the exact mechanism for DPN is unknown, it clearly involves metabolic dysfunction and energy failure in multiple cells within the peripheral nervous system. Lactate is an alternate source of metabolic energy that is increasingly recognized for its role in supporting neurons. The primary transporter for lactate in the nervous system, monocarboxylate transporter-1 (MCT1), has been shown to be critical for peripheral nerve regeneration and metabolic support to neurons/axons. In this study, MCT1 was reduced in both sciatic nerve and dorsal root ganglia in wild-type mice treated with streptozotocin (STZ), a common model of type-1 diabetes. Heterozygous MCT1 null mice that developed hyperglycemia following STZ treatment developed a more severe DPN compared to wild-type mice, as measured by greater axonal demyelination, decreased peripheral nerve function, and increased numbness to innocuous low-threshold mechanical stimulation. Given that MCT1 inhibitors are being developed as both immunosuppressive and chemotherapeutic medications, our results suggest that clinical development in patients with diabetes should proceed with caution. Collectively, our findings uncover an important role for MCT1 in DPN and provide a potential lead toward developing novel treatments for this currently untreatable disease.

Original languageEnglish (US)
Article number113415
JournalExperimental Neurology
Volume333
DOIs
StatePublished - Nov 2020

Keywords

  • Diabetic peripheral neuropathy
  • Dorsal root ganglion
  • Metabolism
  • Monocarboxylate transporter
  • Peripheral nerve

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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