Mediation of Glucoregulation at Rest and During Exercise by the Glucose-Fatty Acid Cycle: In Vivo and In Vitro Studies

Abstract

Himsworth (1934) demonstrated that increased fat consumption leads to decreased glucose tolerance due to decreased insulin sensitivity. Randle and colleagues (1964) named this interplay between fat and carbohydrate metabolism the glucose-fatty acid cycle (GFAC) and proposed a series of feedback mechanisms by which elevated levels of free fatty acids (FFAs) impair glucose uptake and oxidation in rat heart and diaphragm muscle. Numerous investigators have extended these studies to clarify the existence of GFAC and provide insight into the mechanisms and conditions under which it occurs. This paper reviews the literature and highlights other indirect means by which FFAs affect carbohydrate metabolism. Numerous in vitro studies are reviewed, emphasizing the importance of FFA concentration, carbon length, and degree of saturation. This article addresses evidence that the interplay between fat and carbohydrate metabolism is not a function of FFA concentration but a result of the impact that FFA levels have on insulin. Key words: glucose-fatty acid cycle, Randle cycle, carbohydrate metabolism, lipid metabolism, glucose uptake, glucose oxidation, fat oxidation