ArticleMolecular metabolism2015
Metabolic modeling of muscle metabolism identifies key reactions linked to insulin resistance phenotypes.
Article in Molecular metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- Association between the triglyceride glucose index and diabetic retinopathy in type 2 diabetes: a meta-analysis.Frontiers in endocrinology · 2023Pooled it
- An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells.Nature communications · 2025Article
- An integrative profiling of metabolome and transcriptome in the plasma and skeletal muscle following an exercise intervention in diet-induced obese mice.Journal of molecular cell biology · 2023Article
- A holistic view of muscle metabolic reprogramming through personalized metabolic modeling in newly diagnosed diabetic patients.PloS one · 2023Article
- The mitochondrial pyruvate carrier at the crossroads of intermediary metabolism.American journal of physiology. Endocrinology and metabolism · 2022Review
- Simulating Metabolic Flexibility in Low Energy Expenditure Conditions Using Genome-Scale Metabolic Models.Metabolites · 2021Article
- Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism.Cell communication and signaling : CCS · 2021Article
- A Distance-Based Framework for the Characterization of Metabolic Heterogeneity in Large Sets of Genome-Scale Metabolic Models.Patterns (New York, N.Y.) · 2020Article
- Unraveling the molecular heterogeneity in type 2 diabetes: a potential subtype discovery followed by metabolic modeling.BMC medical genomics · 2020Article
- CMap analysis identifies Atractyloside as a potential drug candidate for type 2 diabetes based on integration of metabolomics and transcriptomics.Journal of cellular and molecular medicine · 2020Article
- Article
- SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms.JCI insight · 2019Article
- GSH levels affect weight loss in individuals with metabolic syndrome and obesity following dietary therapy.Experimental and therapeutic medicine · 2018Article
- Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease.Endocrine reviews · 2018Review
- Squeezing Flux Out of Fat.Trends in endocrinology and metabolism: TEM · 2018Article
- Integrating Extracellular Flux Measurements and Genome-Scale Modeling Reveals Differences between Brown and White Adipocytes.Cell reports · 2017Article
- Modelling the molecular mechanisms of aging.Bioscience reports · 2017Review
- Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome.JCI insight · 2016Article
- Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.Molecular metabolism · 2016Article
- What Have Metabolomics Approaches Taught Us About Type 2 Diabetes?Current diabetes reports · 2016Review
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
objectiveDysregulated 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.
methodsWe 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.
resultsWhile 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.
conclusionsOur 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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