AUTHOR=Handy Rachel M. , Holloway Graham P. TITLE=Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology JOURNAL=Frontiers in Physiology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1151389 DOI=10.3389/fphys.2023.1151389 ISSN=1664-042X ABSTRACT=

While impairments in peripheral tissue insulin signalling have a well-characterized role in the development of insulin resistance and type 2 diabetes (T2D), the specific mechanisms that contribute to these impairments remain debatable. Nonetheless, a prominent hypothesis implicates the presence of a high-lipid environment, resulting in both reactive lipid accumulation and increased mitochondrial reactive oxygen species (ROS) production in the induction of peripheral tissue insulin resistance. While the etiology of insulin resistance in a high lipid environment is rapid and well documented, physical inactivity promotes insulin resistance in the absence of redox stress/lipid-mediated mechanisms, suggesting alternative mechanisms-of-action. One possible mechanism is a reduction in protein synthesis and the resultant decrease in key metabolic proteins, including canonical insulin signaling and mitochondrial proteins. While reductions in mitochondrial content associated with physical inactivity are not required for the induction of insulin resistance, this could predispose individuals to the detrimental effects of a high-lipid environment. Conversely, exercise-training induced mitochondrial biogenesis has been implicated in the protective effects of exercise. Given mitochondrial biology may represent a point of convergence linking impaired insulin sensitivity in both scenarios of chronic overfeeding and physical inactivity, this review aims to describe the interaction between mitochondrial biology, physical (in)activity and lipid metabolism within the context of insulin signalling.