2.3 OCD List

Ketones Without Losing Metabolic Flexibility

Context

The following actions assume transient, physiologic ketosis—typically hours within a day—not prolonged or continuous ketosis. Rather than long-term ketogenic diets or chronic ketone supplementation, the goal is metabolic flexibility, the ability to move smoothly between fuels, not permanent fuel exclusion.

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1. Treat Ketosis as a State That Opens and Closes Daily

ACTION

• Allow ketones to appear only during defined windows, typically:
  • overnight
  • early morning
  • between the first and second meal
• Require a deliberate return to mixed-fuel metabolism later in the day.

Endogenous ketones are produced when:

• insulin levels fall
• hepatic glycogen is depleted
• fatty acid flux to the liver increases

This occurs naturally during fasting and overnight periods.

From an evolutionary perspective:

• ketones likely appeared intermittently
• they bridged short gaps in food availability
• they were followed by re-feeding and insulin reactivation

There is no evidence that humans generally evolved to:

• suppress insulin indefinitely
• remain in a fat-dominant state continuously

Key takeaway:
Ketones are a phase, not a destination.

2. Do Not Reinforce Ketosis From Multiple Directions

ACTION

• Choose one method to enter ketosis:
  • meal timing
  • carbohydrate restriction
  • exogenous ketones
• Do not stack strategies.

Reinforced Ketosis, the Randle Cycle, and Glucose Deconditioning

The Randle cycle (substrate competition) describes how high availability of fatty acids and ketones suppresses glucose oxidation.

Mechanistically:

• ↑ fatty acid and ketone oxidation → ↑ acetyl-CoA, ↑ NADH
• pyruvate dehydrogenase (PDH) is inhibited
• glycolysis and glucose oxidation are downregulated

This is adaptive in the short term.

When prolonged:

• glucose-handling pathways are underused
• re-entry into glucose metabolism becomes slower
• post-prandial glucose excursions may worsen

This phenomenon explains why:

• long-term ketogenic individuals may appear metabolically “stable”
• yet show exaggerated glucose responses when carbohydrates return

Becoming excellent at fat oxidation does not guarantee preserved glucose flexibility.

3. Plan Your Re-Entry Into Glucose Oxidation

ACTION

• Eat one mixed-fuel meal daily:
  • protein
  • fat
  • carbohydrate
• Pair with walking or soleus pump activation.

Metabolic Flexibility Is Use-Dependent

Metabolic flexibility refers to the ability to:

• oxidize fat and ketones during fasting
• rapidly switch to glucose oxidation when insulin rises

Glucose oxidation pathways:

• require regular activation
• are downregulated when unused

Avoiding glucose entirely:

• does not “rest” the system
• it deconditions it

Key takeaway:
Avoiding glucose ≠ repairing glucose handling.

4. Keep Protein Fixed to Protect Muscle and GLUT4 Function

ACTION

• Maintain protein intake regardless of ketone use.
• Do not lower protein to deepen ketosis.

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5. Do Not Add Fat Beyond Satiety

ACTION

• Use fat to:
  • cook food
  • maintain satiety
• Do not add fat just to “support” ketosis.

Fat Flux, Triglycerides, and Hepatic Stress

Excess dietary fat:

• increases fatty acid delivery to liver and muscle
• raises triglyceride production in susceptible individuals
• can worsen hepatic insulin resistance

In reinforced ketosis:

• glucose signals are muted
• lipid signals become dominant

Early warning signs:

• rising fasting triglycerides
• increasing liver fat markers

These indicate metabolic narrowing, not adaptation.

6. Aim for Physiologic Ketosis

ACTION

• Physiologic ketosis (from timing): no fixed limit.
• Reinforced ketosis (dietary or supplemental): ≤14 days continuous use; for prolonged use, do so under medical guidance.

Why Cycling Matters

Reinforced ketosis can:

• suppress glucose oxidation pathways
• delay insulin responsiveness
• mask insulin resistance

Cycling restores:

• enzymatic readiness
• insulin oscillation
• fuel flexibility

Ketosis should train flexibility, not replace it.

7. Monitor for Masking, Not Just “Good Numbers”

Re-feeding unmasks the problem

When carbohydrates are reintroduced after prolonged ketosis:

• glucose spikes may be exaggerated
• insulin response may be delayed or excessive
• CGM curves show slow recovery

This shows that glucose-handling pathways have been deconditioned.

That is reduced metabolic flexibility.

Important Distinction

This critique applies to reinforced, chronic ketosis, not to:

• overnight ketosis
• early-morning ketone availability
• intermittent fasting–induced ketones
• transient ketosis within a mixed-fuel life

Those patterns preserve oscillation.

Chronic ketosis eliminates oscillation.

ACTION

Track:

• fasting insulin (when available)
• fasting triglycerides
• glucose recovery after meals

Do not rely solely on:

• fasting glucose
• HbA1c

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8. Use Glucose Recovery as the Functional Readout

ACTION (CGM or labs)

Assess:

• post-meal glucose peak
• time to return to baseline

Recovery Speed = Flexibility

• Fast recovery → flexible metabolism
• Slow recovery → impaired disposal

Ketone levels tell you what fuel is present, not whether metabolism is working well.

9. Adjust Ketone Strategy Based on Ethnic Risk Profile

ACTION

Use extra caution with reinforced/prolonged ketosis if you have:

• East Asian ancestry
• Black / African ancestry
• South Asian ancestry

Prefer:

• brief ketone windows
• daily mixed-fuel re-entry
• explicit carbohydrate testing with movement

Ethnic Differences in Insulin Physiology (Kodama et al.)

Population studies demonstrate distinct metabolic phenotypes:

Population	Insulin Sensitivity	Insulin Secretion	Dominant Risk
East Asian	High	Low	Early β-cell failure
Black	Low	High	Hyperinsulinemia precedes dysglycemia
South Asian	Low–moderate	Inadequate for IR	Early diabetes at lower BMI
European	Intermediate	Intermediate	Mixed phenotype

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Summary of implications for ketosis:

• East Asians: risk of β-cell stress on refeeding
• Black populations: risk of masking hyperinsulinemia
• South Asians: risk of hepatic lipid overload

This explains why ketogenic success stories:

• cluster in certain populations
• fail to generalize universally

10. Exit Ketone Use Cleanly and Test the Result

ACTION

• Reintroduce carbohydrates:
  • at one meal
  • with protein
  • followed by movement
• No tapering, no rebound days.

Why the Exit Matters

The exit reveals whether:

• metabolic flexibility improved
• or ketones were compensating

If glucose handling worsens after exit, the intervention failed.

11. Reassess Before Repeating

ACTION

Within 3–5 days, reassess:

• hunger regulation
• energy stability
• glucose recovery
• lipid trends

If baseline is worse → do not blindly repeat. This means you need to adjust what you’ve been doing. Tracking everything carefully will allow you to look at the data and tweak a variable.

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Bottom Line

The goal is not ketosis.
The goal is effortless movement between fuels.

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References

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Again, if this is too much, go back to the Life is Short List. Doing a few things well and consistently is better than trying to do everything and then giving up after a week.