The enduring relevance of the Randle cycle

Abstract

In people with diabetes mellitus, the heart is metabolically characterized by the excessive use of fatty acids and diminished oxidation of glucose. These changes are implicated in decreased cardiac efficiency, vulnerability to ischaemic insults and an increased risk of heart failure. Interestingly, these alterations have been observed even in the absence of any impairments in cardiac insulin signalling, which suggests a role for direct substrate competition — a concept that was first described by Philip Randle and colleagues in a 1963 Lancet paper. The principle of reciprocal substrate competition between fatty acids and glucose for ATP generation laid out in this landmark publication formed the basis for our present understanding of cardiac metabolism in physiology and in response to metabolic stress.

Randle et al. showed that provision of exogenous fatty acids to isolated heart and diaphragm preparations or the presence of increased circulating levels of nonesterified fatty acids following adipose tissue lipolysis promotes fatty acid oxidation (FAO) and inhibits glucose utilization independent of hormonal control. The authors proposed that inhibition of pyruvate dehydrogenase (PDH; the mitochondrial enzyme that catalyses the conversion of pyruvate to acetyl-CoA) by acetyl-CoA derived from FAO is the primary mechanism by which fatty acids inhibit glucose utilization. By contrast, when glucose is abundant, utilization of glucose in adipose tissue inhibits lipolysis and the release of nonesterified fatty acids, which results in reduced fatty acid utilization by oxidative tissues and hence completes a ‘glucose–fatty acid cycle’ (now better known as the Randle cycle).