Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology
Open accessAbstract
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.
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Excess intramyocellular lipids are associated with impaired muscle function in Type 2 diabetes and obesity.
“excess IMCLs, largely in the form of lipid droplets (LDs), are associated with impaired muscle function in conditions such as Type 2 diabetes and obesity”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [59]
Exercise and nutrition affect the supply and demand aspects of metabolism and have been shown to influence intramyocellular lipid levels in aging and obesity.
“they affect the supply and demand aspects of metabolism, respectively, and have been shown to influence IMCL levels in both aging and obesity [59, 97, 99, 101, 102].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [59]
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Self-citation
Flagged first, then by citations
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Mechanisms of endurance and resistance exercise in type 2 diabetes mellitus: A Narrative review
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- Authors
- Handy, R. M., & Holloway, G. P.
- Affiliations
- University of Guelph (CA)
- Corresponding author
- Handy, Rachel M.
- Holloway, Graham P.
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2023-04-20
- Volume
- 14
- Pages
- 1151389-1151389
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC10157178
- OpenAlex
- W4366549977
- Cited by
- 38
- References
- 219
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 11 · 2023: 3
- FWCI
- 1.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Sciences and Engineering Research Council of Canada (400362)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- insulin resistance, type 2 diabetes, physical inactivity, lipid metabolism, mitochondrial biology, insulin signaling, mitochondrial reactive oxygen species, lipid accumulation, mitochondrial biogenesis, exercise training, protein synthesis
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