Glucose-fatty acid cycle (Randle cycle) (Randle cycle)

The glucose-fatty acid cycle, commonly known as the Randle cycle, is a fundamental metabolic regulatory mechanism that describes the reciprocal competition between glucose and fatty acids for oxidative fuel selection in animal tissues (Randle et al., 1963). This cycle plays a crucial role in maintaining energy homeostasis, where the utilization of one fuel source inhibits the use of the other through allosteric regulation of key enzymes like pyruvate dehydrogenase and phosphofructokinase (Hue & Taegtmeyer, 2009). Specifically, high rates of fatty acid oxidation increase the ratios of acetyl-CoA/CoA and NADH/NAD+, which inhibit the pyruvate dehydrogenase complex, thereby reducing glucose oxidation. In pathological conditions such as type 2 diabetes and obesity, elevated plasma fatty acids lead to an over-activation of this cycle, contributing significantly to insulin resistance and impaired glucose tolerance (StatPearls, 2023). Therapeutically, the cycle is targeted by drugs that shift cardiac or skeletal muscle metabolism away from fatty acid oxidation toward more oxygen-efficient glucose oxidation. This metabolic shift is a proven strategy used to treat chronic angina and myocardial ischemia, as seen with drugs like ranolazine and trimetazidine (DrugBank, 2024). While the cycle itself is a pathway rather than a single protein, the individual enzymes and transporters governing its flux are major focal points for metabolic drug development.

Other names

Randle cycleGlucose-fatty acid competitionRandle mechanism

Reciprocal inhibition of glucose and fatty acid oxidation via allosteric regulation of pyruvate dehydrogenase and phosphofructokinase by fatty acid metabolites like acetyl-CoA and citrate.