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Insulin resistance significantly interferes with autophagy, and this has significant implications for cellular health and disease prevention.
How Insulin Resistance Disrupts Autophagy
“Autophagy was suppressed in the livers of mice with insulin resistance and hyperinsulinemia… Importantly, autophagy of mitochondria (mitophagy) in cultured cells was suppressed by insulin in the presence of insulin resistance.”
– Liu et al., Journal of Biological Chemistry, 2009
Autophagy is normally suppressed by insulin and activated during fasting states. However, in insulin resistance, this regulatory system becomes dysfunctional:
Chronic mTOR activation:
Elevated insulin levels continuously activate mTOR (mechanistic target of rapamycin), which is autophagy’s master inhibitor and this means autophagy is stopped. Persistently high insulin keeps mTOR activated even during fasting periods when autophagy should be occurring.
Rapamycin’s main action is inhibiting mTOR (mechanistic target of rapamycin), a key protein that regulates:
Cell growth and proliferation
Protein synthesis
Autophagy (cellular cleanup)
Metabolism
Aging processes
Impaired AMPK signalling: Insulin resistance reduces AMPK (AMP-activated protein kinase) activity, which normally promotes autophagy during energy stress. This means the cellular “switch” that should turn on autophagy becomes less responsive.
Defective autophagosome (is a double-membrane structure that forms around cellular waste materials) formation: The elevated insulin and inflammatory signalling in insulin resistance directly impair the formation and maturation of autophagosomes – the cellular structures that engulf and recycle damaged components.
This creates a vicious cycle: impaired autophagy leads to accumulation of damaged mitochondria and proteins, which worsens insulin resistance, which further suppresses autophagy.
Key Research Studies
1. Insulin resistance impairs hepatic autophagy – Yang et al. (2010) in Autophagy demonstrated that high-fat diet-induced insulin resistance in mice suppressed hepatic autophagy through sustained mTORC1 activation. When they restored autophagy, insulin sensitivity improved, showing the bidirectional relationship.
2. Autophagy deficiency promotes insulin resistance – Liu et al. (2009) in Journal of Biological Chemistry found that genetic deletion of essential autophagy genes (Atg7) in mice led to insulin resistance, glucose intolerance, and reduced insulin signaling in liver and adipose tissue.
3. Hyperinsulinemia suppresses autophagy in humans – Minnaard et al. (2017) in *Obesity* showed that acute hyperinsulinemia in overweight men suppressed skeletal muscle autophagy markers, and this suppression was more pronounced in insulin-resistant individuals.
4. Autophagy restoration improves metabolic health – He et al. (2012) in Nature Medicine* demonstrated that enhancing autophagy in obese mice improved glucose tolerance and insulin sensitivity, while also reducing hepatic steatosis.
Clinical Implications for Program Clients
People with elevated insulin and insulin resistance are indeed not experiencing the full benefits of autophagy, even when they fast or practice intermittent fasting.
This means:
– Reduced cellular cleanup and repair
– Accumulation of damaged mitochondria (contributing to further metabolic dysfunction)
– Impaired clearance of misfolded proteins
– Decreased anti-aging benefits
– Reduced neuro-protective effects
This is why the integrative remission method combining GAPS, intermittent fasting and metabolic rebalancing are so powerful – you’re not just implementing fasting, but actually restoring the cellular machinery that makes fasting therapeutically effective. As insulin sensitivity improves through you can regain the full autophagy response, creating radiant metabolic health.
Intermittent Fasting Is Still Essential for High IR
Yes, your autophagy is impaired at with HOMA-IR levels over 2.0, but fasting still works – it’s actually how you FIX it. Think of autophagy like a dimmer switch, not an on/off switch. Right now your autophagy is at 30% capacity. Every week of fasting and metabolic improvement turns that dimmer up. By the time you hit HOMA-IR 2.5, you’re at 70% capacity. Under 2.0, you’re at 90%+.