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Review
. 2023 Apr 20:14:1151389.
doi: 10.3389/fphys.2023.1151389. eCollection 2023.

Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology

Rachel M Handy  1 , Graham P Holloway  1
Affiliations
Review

Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology

Rachel M Handy et al. Front Physiol. .

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.

Keywords: bioenergetics; insulin resistance; metabolism; mitochondria; skeletal muscle.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Altered peripheral tissue lipid metabolism initiates skeletal muscle reactive lipid accretion and ROS emission, a mechanism linked to peripheral insulin resistance. Obesity is associated with increased lipid availability (from both an impaired ability to regulate adipose tissue lipolysis, and increased hepatic de novo lipogenesis) resulting in increased flux of fatty acids through plasma membrane CD36 in skeletal muscle and the accumulation of various fatty acid species. While some excess fatty acids are converted to TAG for neutral storage, others support the accumulation of reactive lipids (DAG and ceramide). Accumulation of reactive lipids potentiate mitochondrial ROS emission due to increased CPT-I dependent fatty acid transport into the mitochondria, which directly attenuates ADP transport at the level of ANT. Importantly physical inactivity can exacerbate the induction of peripheral insulin resistance, while physical activity can mediate many of the outlined perturbations (created with BioRender.com). Abbreviations: Adenine nucleotide translocase (ANT), adenosine diphosphate (ADP), adenosine triphosphate (ATP), carnitineacylcarnitine translocase (CACT), carnitine palmitoyltransferase-I, -II (CPT-I, -II), cytochrome C (Cyt C), diacylglycerol (DAG), electron (e−), electron transport chain complexes I—IV (I—IV), electron transfer flavoprotein (ETF), fatty acid translocase (CD36), flavin adenine dinucleotide (FADH2), glucose transporter 4 (GLUT4), inner mitochondrial membrane (IMM), nicotinamide adenine dinucleotide (NADH), non-esterified fatty acid (NEFA), outer mitochondrial membrane (OMM), reactive oxygen species (ROS), triacylglycerol (TAG), tricarboxylic acid cycle (TCA), voltage-dependent anion channel (VDAC).
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Grants and funding

GPH holds a Natural Sciences and Engineering Research Council (NSERC) of Canada Grant (400362).

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