The Randle cycle revisited: a new head for an old hat

Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E578-91. doi: 10.1152/ajpendo.00093.2009. Epub 2009 Jun 16.


In 1963, Lancet published a paper by Randle et al. that proposed a "glucose-fatty acid cycle" to describe fuel flux between and fuel selection by tissues. The original biochemical mechanism explained the inhibition of glucose oxidation by fatty acids. Since then, the principle has been confirmed by many investigators. At the same time, many new mechanisms controlling the utilization of glucose and fatty acids have been discovered. Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.

Publication types

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

MeSH terms

  • Animals
  • Energy Metabolism / physiology*
  • Fatty Acids / metabolism*
  • Glucose / metabolism*
  • Humans
  • Insulin Resistance / physiology
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Models, Biological
  • Stress, Physiological / physiology
  • Substrate Cycling / physiology


  • Fatty Acids
  • Glucose