Metabolic modeling of muscle metabolism identifies key reactions linked to insulin resistance phenotypes
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OBJECTIVE: Dysregulated muscle metabolism is a cardinal feature of human insulin resistance (IR) and associated diseases, including type 2 diabetes (T2D). However, specific reactions contributing to abnormal energetics and metabolic inflexibility in IR are unknown. METHODS: We utilize flux balance computational modeling to develop the first systems-level analysis of IR metabolism in fasted and fed states, and varying nutrient conditions. We systematically perturb the metabolic network to identify reactions that reproduce key features of IR-linked metabolism. RESULTS: While reduced glucose uptake is a major hallmark of IR, model-based reductions in either extracellular glucose availability or uptake do not alter metabolic flexibility, and thus are not sufficient to fully recapitulate IR-linked metabolism. Moreover, experimentally-reduced flux through single reactions does not reproduce key features of IR-linked metabolism. However, dual knockdowns of pyruvate dehydrogenase (PDH), in combination with reduced lipid uptake or lipid/amino acid oxidation (ETFDH), does reduce ATP synthesis, TCA cycle flux, and metabolic flexibility. Experimental validation demonstrates robust impact of dual knockdowns in PDH/ETFDH on cellular energetics and TCA cycle flux in cultured myocytes. Parallel analysis of transcriptomic and metabolomics data in humans with IR and T2D demonstrates downregulation of PDH subunits and upregulation of its inhibitory kinase PDK4, both of which would be predicted to decrease PDH flux, concordant with the model. CONCLUSIONS: Our results indicate that complex interactions between multiple biochemical reactions contribute to metabolic perturbations observed in human IR, and that the PDH complex plays a key role in these metabolic phenotypes.
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Flux balance computational modeling of muscle metabolism during the fasted to fed state transition showed that key metabolic phenotypes characteristic of human insulin resistance can be recapitulated by decreasing flux through the PDH complex.
“At the organ level, flux balance computational modeling of muscle metabolism during the fasted to fed state transition showed that key metabolic phenotypes characteristic of human insulin resistance can be recapitulated by decreasing flux through the PDH complex”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [313]
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Interactions Among mTORC, AMPK and SIRT A Computational Model for Cell Energy Balance and MetabolismPreprint
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- Authors
- Nogiec, C., Burkart, A., Dreyfuss, J. M., Lerin, C., Kasif, S., & Patti, M.-E.
- Affiliations
- Boston University (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Patti, Mary-Elizabeth
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 4
- Issue
- 3
- Pages
- 151-163
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC4338313
- OpenAlex
- W2141612278
- Cited by
- 34
- References
- 73
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 5 · 2015: 2
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Diabetes Association (Grant no. 7-12-MN-66)
- Harold Whitworth Pierce Charitable Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin resistance, muscle metabolism, type 2 diabetes, pyruvate dehydrogenase, PDK4, metabolic flexibility, TCA cycle, lipid oxidation, glucose uptake, flux balance analysis, muscle cells, ATP production
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