Fig. 2.

The glucose-fatty acid cycle hypothesis in insulin resistance. Randle et al. [52] proposed that lipid-induced insulin resistance in skeletal muscle is attributed to limited insulin-stimulated glucose utilization caused by increased fatty acid oxidation. Fatty acid oxidation might increase mitochondrial acetyl-CoA levels and subsequently inactivate pyruvate dehydrogenase (PDH), which in turn, would increase intracellular citrate levels and inhibit phosphofructokinase 1 (PFK-1), and lead to the accumulation of intramyocellular glucose-6-phosphate (G6-P), which inhibits hexokinase activity and causes the accumulation of intramyocellular glucose and reduced glucose uptake. FFA, free fatty acid; GLUT4, glucose transporter type 4; GSV, GLUT4 storage vesicle; ATP, adenosine triphosphate; CPT1, carnitine palmitoyltransferase 1; NADH, reduced nicotinamide adenine dinucleotide; TCA, trichloroacetic acid.