Metabolic Flexibility & Insulin Sensitivity — References

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Parent Topic: Metabolic Flexibility & Insulin Sensitivity | References Hub: 01 - Foundations References MOC

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Primary Literature & Landmark Studies

Goodpaster & Sparks (2017)

• Citation: Goodpaster, B. H., & Sparks, L. M. (2017). Metabolic flexibility in health and disease. Cell Metabolism, 25(5), 1027–1036.
• Identifiers: DOI: 10.1016/j.cmet.2017.04.015 (DOI · SciDB · Scholar) | PMID: 28467922 (PubMed · Europe PMC)
• Study Design: Comprehensive mechanistic and clinical synthesis of human indirect calorimetry, hyperinsulinemic-euglycemic clamp studies, and skeletal muscle biopsy trials.
• Key Quantitative Outcomes:
  • Defined quantitative thresholds of metabolic flexibility via changes in Respiratory Exchange Ratio ($\Delta \text{RER}$ or $\Delta \text{RQ}$) from fasting to insulin-stimulated states: metabolically healthy endurance-trained individuals shift from fasting $\text{RQ}\approx 0.74$ to clamped $\text{RQ}\approx 0.95$ ($\Delta \text{RQ}>0.20$), whereas insulin-resistant individuals display elevated fasting RQ ($\sim 0.85$) and blunted clamped response ($\Delta \text{RQ}<0.07$).

Petersen & Shulman (2018)

• Citation: Petersen, M. C., & Shulman, G. I. (2018). Mechanisms of insulin action and insulin resistance. Physiological Reviews, 98(4), 2133–2223.
• Identifiers: DOI: 10.1152/physrev.00063.2017 (DOI · SciDB · Scholar) | PMID: 30067154 (PubMed · Europe PMC)
• Study Design: Landmark physiological review integrating magnetic resonance spectroscopy (${}^{13}\text{C}{/}^{31}\text{P}{/}^1\text{H}$ MRS) human studies and molecular signaling experiments.
• Key Quantitative Outcomes:
  • Demonstrated that impaired skeletal muscle glycogen synthesis accounts for >75% of whole-body insulin resistance in early metabolic disease, driven by plasma membrane sn-1,2-diacylglycerol (DAG) activation of $\text{PKC}\theta$ (muscle) and $\text{PKC}ϵ$ (liver), which inhibits insulin receptor Thr1160/IRS-1 signaling and blocks GLUT4 translocation.

Buffey et al. (2022)

• Citation: Buffey, A. J., Herring, M. P., Langley, C. K., Donnelly, A. E., & Carson, B. P. (2022). The acute effects of interrupting prolonged sitting time in adults with standing and light-intensity walking on biomarkers of cardiometabolic health in adults: A systematic review and meta-analysis. Sports Medicine, 52(8), 1765–1787.
• Identifiers: DOI: 10.1007/s40279-022-01649-4 (DOI · SciDB · Scholar) | PMID: 35147898 (PubMed · Europe PMC)
• Study Design: Systematic review and meta-analysis of 7 randomized crossover trials evaluating postprandial glucose and insulin responses.
• Key Quantitative Outcomes:
  • Light-intensity postprandial walking interruptions significantly attenuated postprandial glucose AUC by 17.01% (Cohen’s $d=-0.54,95\%\text{CI}[-0.70,-0.37],p<0.001$) and postprandial insulin AUC by 15.6% ($d=-0.37,p<0.001$) compared to uninterrupted sitting.

Knowler et al. (2002)

• Citation: Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A., & Nathan, D. M. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine, 346(6), 393–403.
• Identifiers: DOI: 10.1056/NEJMoa012512 (DOI · SciDB · Scholar) | PMID: 11832527 (PubMed · Europe PMC)
• Study Design: Multi-center randomized controlled trial (Diabetes Prevention Program, $N=3,234$ adults with impaired glucose tolerance followed for 2.8 years).
• Key Quantitative Outcomes:
  • Intensive lifestyle modification ($\ge 150\text{min/week}$ moderate physical activity + 7% weight reduction) reduced the incidence of Type 2 diabetes by 58% (95% CI, 48–66%), significantly outperforming metformin 850 mg BID (31% reduction; 95% CI, 17–43%).