Tracer metabolomics reveals the role of aldose reductase in glycosylation

Cell Rep Med. 2023 Jun 20;4(6):101056. doi: 10.1016/j.xcrm.2023.101056. Epub 2023 May 30.

Abstract

Abnormal polyol metabolism is predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has been implicated in phosphomannomutase 2 congenital disorder of glycosylation (PMM2-CDG) and an AR inhibitor, epalrestat, proposed as a potential therapy. Considering that the PMM2 enzyme is not directly involved in polyol metabolism, the increased polyol production and epalrestat's therapeutic mechanism in PMM2-CDG remained elusive. PMM2-CDG, caused by PMM2 deficiency, presents with depleted GDP-mannose and abnormal glycosylation. Here, we show that, apart from glycosylation abnormalities, PMM2 deficiency affects intracellular glucose flux, resulting in polyol increase. Targeting AR with epalrestat decreases polyols and increases GDP-mannose both in patient-derived fibroblasts and in pmm2 mutant zebrafish. Using tracer studies, we demonstrate that AR inhibition diverts glucose flux away from polyol production toward the synthesis of sugar nucleotides, and ultimately glycosylation. Finally, PMM2-CDG individuals treated with epalrestat show a clinical and biochemical improvement.

Keywords: aldose reductase; aldose reductase inhibition; congenital disorder of glycosylation; glycosylation; phoshomannomutase-2 deficiency; polyol metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Reductase* / genetics
  • Aldehyde Reductase* / metabolism
  • Animals
  • Glycosylation
  • Mannose / metabolism
  • Metabolomics
  • Zebrafish* / metabolism

Substances

  • epalrestat
  • Aldehyde Reductase
  • Mannose

Supplementary concepts

  • Congenital disorder of glycosylation type 1A