What happens when your body gets stuck burning fat and can't switch back to glucose?
In Part 2, Zane breaks down metabolic inflexibility and explains why being locked into fat-dominant metabolism is not the same as being metabolically healthy.
You'll learn how this pattern affects the muscle, heart, and liver — and how elevated fatty acids can impair glucose oxidation, disrupt insulin signaling, and contribute to insulin resistance, fatty liver disease, and heart failure.
Start with Part 1 first for the ATP and glucose-efficiency breakdown.
- 01:00 The metabolic signature of insulin resistance
- 03:30 Why your body should switch between fat and glucose
- 06:00 The 3 tissues that reveal metabolic inflexibility
- 08:30 Why Zane changed his mind about low carb
- 13:30 The real definition of metabolic inflexibility
- 15:00 Why elevated blood sugar can happen on keto or carnivore
- 20:00 Heart failure and metabolic disease
- 22:00 Why failing hearts become more dependent on fat
- 25:00 Why glucose is not the problem
- 29:00 The liver and fatty liver disease
- 33:00 Fatty liver is a metabolic inflexibility problem
- 34:00 Why the liver starts producing more glucose
- 40:00 How liver disease progresses
- 41:00 The muscle, heart, and liver connection
- 46:00 How to restore glucose oxidation
- 47:00 Why high-fat, low-carb can mimic metabolic disease
Kelley, D.E. (2005) "Skeletal muscle fat oxidation: timing and flexibility are everything" Journal of Clinical Investigation — JCI25758 / PMC1159159 Used for: Definition of metabolic inflexibility; experimental elevation of plasma FFAs recreating T2D metabolic signature in skeletal muscle; blunted insulin-stimulated glucose oxidation; impaired suppression of lipid oxidation
Ukropcova, B. et al. (2005) "Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor" Journal of Clinical Investigation — JCI24332 Used for: Formal definition of metabolic inflexibility — insulin-resistant muscle characterized by lower fasting lipid utilization and failure to switch to carbohydrate oxidation in response to insulin
Sun, Q., Lopaschuk, G.D. et al. (2024) "Mitochondrial fatty acid oxidation is the major source of cardiac ATP production in heart failure with preserved ejection fraction" Cardiovascular Research, Volume 120 — PMID 38193548 Used for: Direct radiolabeled substrate measurements in HFpEF; suppressed insulin-stimulated glucose oxidation; increased FAO; decreased PDH phosphorylation confirmed in human heart samples; disrupted glucose/fat ATP balance
Sun, Q., Karwi, Q.G., Wong, N., Lopaschuk, G.D. (2024) "Advances in myocardial energy metabolism: metabolic remodelling in heart failure and beyond" Cardiovascular Research — PMC11646102 Used for: Comprehensive synthesis — decreased glucose oxidation as universal defect across HFpEF, HFrEF, and diabetic cardiomyopathy; uncoupling of glycolysis from glucose oxidation; FAO increases in HFpEF and diabetic cardiomyopathies
Lopaschuk, G.D., Ussher, J.R., Folmes, C.D.L., Jaswal, J.S., Stanley, W.C. (2010) "Myocardial Fatty Acid Metabolism in Health and Disease" Physiological Reviews — PMC3976623 Used for: Fat oxidation dominance in HF, ischemia, and diabetes; uncoupling of glycolysis from glucose oxidation; therapeutic case for reducing FAO and increasing glucose oxidation (quotes carried over from Video 1 for context)
Fillmore, N., Jaswal, J.S., Lopaschuk, G.D. (2011) "Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure" Journal of Molecular and Cellular Cardiology — ScienceDirect Used for: Pharmacological shifting from fat to glucose oxidation improving ATP efficiency; cardiac ischemia and heart failure therapeutic mechanism (context reference from Video 1)
Satapati, S. et al. (2011) "Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease" Cell Metabolism — PMC3658280 Used for: 50% higher lipolysis in NAFLD; 30% higher gluconeogenesis; 2-fold increase in TCA cycle flux correlated with intrahepatic triglyceride content; increased FFA delivery and oxidation driving gluconeogenesis and oxidative stress
Donnelly, K.L., Smith, C.I., Schwarzenberg, S.J., Jessurun, J., Boldt, M.D., Parks, E.J. (2005) "Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease" Journal of Clinical Investigation — JCI23621 Used for: Fat source breakdown in NAFLD — ~60% from plasma NEFA/adipose lipolysis, ~26% from de novo lipogenesis, ~15% dietary fat; stable isotope methodology confirming adipose lipolysis as primary driver
Kolwicz, S.C. Jr. (2021) "Ketone Body Metabolism in the Ischemic Heart" Frontiers in Cardiovascular Medicine — DOI 10.3389/fcvm.2021.789458 Used for: Supporting context on cardiac metabolic flexibility; KD association with worse ischemic outcomes in some models; ketone-glucose suppression dynamic in the ischemic heart
