Glucose-fatty acid cycle (Randle cycle)

The glucose-fatty acid cycle, also known as the Randle cycle, is a fundamental metabolic mechanism describing the reciprocal competition between glucose and fatty acids for oxidation in oxidative tissues like the heart and skeletal muscle (Randle et al., 1963, Lancet). The cycle operates through the inhibition of the pyruvate dehydrogenase (PDH) complex by the end-products of fatty acid oxidation, specifically acetyl-CoA and NADH, which leads to a reduction in glucose uptake and utilization (Hue & Taegtmeyer, 2009, Am J Physiol Endocrinol Metab). This regulatory mechanism is crucial for maintaining energy homeostasis but becomes maladaptive in chronic conditions such as type 2 diabetes and heart failure, where excessive fatty acid oxidation suppresses glucose utilization, contributing to insulin resistance and decreased cardiac efficiency (Stanley et al., 2005, Nat Clin Pract Cardiovasc Med). Therapeutic strategies targeting this cycle aim to shift the metabolic balance back toward glucose oxidation—which requires less oxygen per unit of ATP produced—using agents like trimetazidine or ranolazine (Kantor et al., 2000, Circ Res). While beneficial for treating ischemia, modulating this cycle requires careful management to avoid side effects such as lactic acid accumulation or unintended lipid deposition in non-adipose tissues (Lopaschuk et al., 2010, Physiol Rev).

Other names

Randle cycleGlucose-fatty acid cycleFatty acid-glucose cycleSubstrate competition cycle

Modulation of the cycle typically involves inhibiting fatty acid oxidation (e.g., via CPT1 or 3-KAT inhibition) to shift the metabolic balance toward glucose oxidation, or directly activating the pyruvate dehydrogenase complex to enhance glucose utilization.