The paradox of fatty-acid β-oxidation in muscle insulin resistance: Metabolic control and muscle heterogeneity

The skeletal muscle is a metabolically heterogeneous tissue that plays a key role in maintaining whole-body glucose homeostasis. It is well known that muscle insulin resistance (IR) precedes the development of type 2 diabetes. There is a consensus that the accumulation of specific lipid species in the tissue can drive IR. However, the role of the mitochondrial fatty-acid β-oxidation in IR and, consequently, in the control of glucose uptake remains paradoxical: interventions that either inhibit or activate fatty-acid β-oxidation have been shown to prevent IR. We here discuss the current theories and evidence for the interplay between β-oxidation and glucose uptake in IR. To address the underlying intricacies, we (1) dive into the control of glucose uptake fluxes into muscle tissues using the framework of Metabolic Control Analysis, and (2) disentangle concepts of flux and catalytic capacities taking into account skeletal muscle heterogeneity. Finally, we speculate about hitherto unexplored mechanisms that could bring contrasting evidence together. Elucidating how β-oxidation is connected to muscle IR and the underlying role of muscle heterogeneity enhances disease understanding and paves the way for new treatments for type 2 diabetes.