Abstract

Fructose is not only something we eat — the body can also make its own fructose through the polyol pathway. In response to stressors such as high glucose, salt, dehydration, alcohol, or low oxygen, glucose is converted into sorbitol and then fructose.

This pathway serves important survival functions — helping conserve water, slow metabolism, and store fat under stress. But in the modern world, where these triggers are constant, the same pathway now drives chronic energy failure.

This paper explains how endogenous fructose production works, what triggers it, and why it creates a self-fulfilling cycle of weight gain and fragility.

1. Introduction

The ability to produce fructose internally reframes decades of debate. Carbohydrates, salt, alcohol, stress — once treated as separate culprits — are actually different triggers of the same pathway.

The polyol pathway converts glucose into fructose during stress. This once served clear survival purposes in times of drought, famine, or hypoxia. Today, however, these triggers are constant, and the pathway contributes to fragile, energy-starved cells.

2. The Polyol Pathway: From Glucose to Fructose

1. Glucose → Sorbitol
• Enzyme: aldose reductase
• Activated by high glucose or osmotic stress
• Uses NADPH
2. Sorbitol → Fructose
• Enzyme: sorbitol dehydrogenase (SDH)
• Produces fructose as the final step

This pathway is active in liver, kidney, brain, vasculature, and eyes.

(Figure suggestion: Glucose → Sorbitol → Fructose, with arrows showing triggers like salt, dehydration, alcohol, hypoxia, stress.)

3. Primary Triggers and Their Survival Functions

3.1 High Glucose (Spikes & Chronic Elevation)

• Trigger: Excess glucose activates aldose reductase, both after sharp spikes (post-meal) and during chronic hyperglycemia (prediabetes, diabetes, stress-induced elevation).
• Survival function: Diverting glucose into fructose helped reduce glucose toxicity, slowed metabolism, and promoted fat storage. Glycogen also stores water with glucose (≈3g water per 1g glycogen), so carbohydrate cravings under this pathway helped the body stock both energy and water.
• Modern cost: In today’s environment of frequent high glucose, the pathway runs continuously, producing fructose internally even in people who avoid dietary sugar.

3.2 Salt, Dehydration & Osmolality

• Trigger: High salt intake or dehydration both raise blood osmolality. Obesity compounds this, as obese individuals are often chronically dehydrated.
• Lay metaphor: Like reducing a pan sauce, whether by adding salt or letting water boil off, the liquid becomes more concentrated. The same principle applies to blood.
• Survival function: Fructose metabolism conserved water by lowering energy expenditure and generating metabolic water. It also stimulated cravings for carbohydrates, which, when stored as glycogen, carried water. Together, this strategy conserved and replenished water in times of drought.
• Modern cost: Chronic high salt intake, low hydration, and obesity-linked dehydration turn this function into a driver of obesity, hypertension, and cravings.

3.3 Alcohol

• Trigger: Ethanol metabolism shifts NADH/NAD⁺ balance, pushing glucose into sorbitol and fructose. Alcohol also dehydrates, further activating osmolality stress.
• Survival function: Alcohol from fermented fruit acted as a seasonal signal. Converting it into fat through fructose metabolism provided stored energy for survival when food was scarce.
• Modern cost: Today, alcohol compounds dehydration and fructose load, mirroring sugar in its metabolic harms (fatty liver, cravings, insulin resistance).

3.4 Hypoxia & Ischemia

• Trigger: Low oxygen (hypoxia) or restricted blood flow (ischemia) activates aldose reductase.
• Survival function: Shifting to fructose metabolism supported survival under low oxygen by reducing reliance on oxidative phosphorylation and conserving energy.
• Modern cost: In obesity and sleep apnea, nightly hypoxia chronically switches the pathway on. This creates a double burden: less oxygen for energy plus more fructose generation driving fat storage.

3.5 Stress Hormones

• Trigger: Cortisol and adrenaline elevate glucose and alter redox balance, fueling sorbitol → fructose conversion.
• Survival function: Under acute stress, conserving energy and storing fat supported recovery after exertion or trauma.
• Modern cost: Chronic psychological stress keeps this pathway activated daily, adding metabolic fragility and fueling cravings.

4. Taste and Survival Signals

The most attractive tastes — sweet, salty, and savory (umami) — are each connected to triggers of the fructose pathway.

• Sweet: signals carbohydrate availability, fueling glucose spikes that activate the pathway.
• Salty: signals sodium, which raises osmolality and stimulates fructose production.
• Umami: signals purine-rich foods (meat, seafood, organ meats), which elevate uric acid. Since uric acid both results from and amplifies fructose metabolism, umami flavors encourage intake of foods that reinforced this survival pathway.

By contrast, bitter and sour tastes often signal toxins or spoilage and act as deterrents.

Together, these taste preferences reflect survival functions: encouraging activation of conservation pathways when needed, while protecting from unnecessary risks. In modern life, constant stimulation of sweet, salty, and umami cues keeps the pathway active when conservation is no longer required.

5. The Self-Fulfilling Cycle

Endogenous fructose production helps explain why weight gain reinforces itself:

• Obesity → chronic dehydration and hypoxia (sleep apnea, poor circulation).
• These states activate the polyol pathway → more fructose → more ATP depletion and fat storage.
• Fructose also stimulates carbohydrate cravings, reinforcing intake that restores glycogen-bound water but deepens the energy deficit.

Key point: The body interprets obesity as a stress state — dehydration, oxygen shortage, excess glucose — and flips the conservation switch. The more weight gained, the stronger the triggers that keep the pathway active.

6. Beyond Diabetes: A Broader Role

Once thought relevant only to diabetes complications (neuropathy, retinopathy), the pathway is now recognized as broadly active:

• Kidney: salt-triggered fructose contributes to hypertension and renal injury.
• Brain: endogenous fructose linked to memory loss and Alzheimer’s.
• Liver: fructose generated internally contributes to fatty liver.
• Eye: sorbitol accumulation drives cataracts.

It is increasingly seen as a general survival program that has become maladaptive in the modern environment.

7. Why This Matters

• Not just about sugar: Even without dietary fructose, the body can make its own.
• Explains contradictions: Carbs, salt, alcohol, stress, hypoxia — all triggers of the same pathway.
• Survival purpose respected: What once ensured survival now traps us in conservation mode.
• Intervention must target the full loop:
1. Inputs: sugar, salt, hydration, oxygen, stress, alcohol, purine-rich foods.
2. The pathway itself: inhibiting fructokinase to prevent ATP loss.
3. Downstream burden: lowering uric acid to reduce oxidative stress and restore nitric oxide.

Only by addressing all three can we reset metabolism from chronic conservation back to vitality.

8. Conclusion

Endogenous fructose production is a survival pathway. When blood is too salty, too concentrated, too oxygen-poor, or too glucose-rich, the body converts glucose into fructose — conserving water, slowing metabolism, and storing fat. Alcohol, stress, and purine-rich foods amplify the same program through uric acid.

This was once protective. But today, with constant salt intake, chronic dehydration, obesity, sleep apnea, alcohol, stress, and high glucose, the switch stays on.

The result is a self-fulfilling cycle: obesity creates dehydration, hypoxia, and hyperglycemia — which trigger more fructose — which deepens energy failure and fat storage.

To break this cycle, we must target the entire pathway — from lifestyle triggers to fructose metabolism to uric acid itself. Only then can we release the body from unnecessary conservation mode and restore resilience.