A crucial mechanism in bioenergetics is a well documented fuel switch in mitochondria known as the Randle Cycle. It is a big reason why many people have trouble metabolizing sugar. You may have heard the term Metabolic Flexibility, which loosely refers to the Randle Cycle. Unfortunately, dietitians and health gurus often say we should focus on burning fat when nothing is further from the truth.

What are the factors that determine whether fats or sugars get converted to energy? Is upregulating fat burning actually healthy? What is the best fuel for overall energy and fat loss? How do calories fit into this calculus?

TLDR:

Gluconeogenesis requires cortisol to convert protein into sugar
Lipolysis requires adrenaline to liberate fatty acids from adipose tissue
The Randle Cycle tells us that if fat intake is too high sugar burning will be impaired
Excessive fat burning often leads to metabolic syndrome
High carb, moderate protein, low fat diets keep gluconeogenesis and lipolysis relatively low, improve sugar burning and metabolic syndrome

All the macros - protein, fats, and carbs - can be converted into fuel that’s used in the mitochondria. Of the three macros, protein is the most inefficient and requires gluconeogenesis by the stress hormones to become glucose. This means either breaking down your own muscle or dietary protein to make sugar. Because of the cost involved, protein should be used to build structure not provide energy. Additionally, a high protein diet will induce gluceneogenesis. High protein diets can also lead to excess nitrogen, ammonia (a poison) and urea. We’ve already established there is no growth benefit for most humans above .82 g/lb. That leaves us with fats and carbs as energy sources.

The Randle cycle, also known as the glucose-fatty acid cycle, is a metabolic process that describes the competition between glucose and fatty acids as fuel sources in cells, particularly in muscle and adipose tissue. This cycle was first proposed by Philip Randle and his colleagues in 1963. Essentially the mechanism is that when fatty acid substrate increases, glucose oxidation is inhibited.

When there's a high intake of dietary fat with a meal or during a carbohydrate-fasted state (low carb diet), the level of free fatty acids (FFAs) in the blood increases, leading to preferential oxidation of FFAs by the mitochondria over glucose.

When the relationship between carbs and fats favors carbs in your diet the Randle Cycle switches mitochondrial preference to carbohydrates (glucose).

This metabolic switch is known as metabolic flexibility. The ease at which your mitochondria switch between these two fuel substrates is a good benchmark for metabolic health. These days due to reasons we’re about to explore, people are having a far more difficult time burning sugar than fat.

During carbohydrate-fasted states, several hormones work together to elevate free fatty acids (FFAs) in the blood including adrenaline, noradrenaline, glucagon, cortisol and growth hormone. Its important to know that while this process is occurring, gluconeogenesis is also active to prevent blood sugar dropping too low. This liberation of FFAs is called lipolysis and serves to provide emergency fuel as well as dampen the catabolic effects of gluconeogenesis. Both of these happen together.

Chronically elevated FFAs, caused by the effects of the Randle Cycle, are a significant contributor of obesity, diabetes, insulin resistance and generalized metabolic syndrome. High FFAs lower the NAD+/NADH ratio, something called reductive stress. This precedes oxidative stress in the cell. For more on reductive stress see here. This study even suggested inhibiting fat burning to correct insulin resistance.

Intentionally increasing lipolysis and gluconeogensis beyond the basal amount are detrimental because they both necessitate stress hormone increases and cause metabolic problems in the mid and long term.

Gluconeogenesis requires sustained activation of cortisol and glucagon. It involves proteolysis (breaking down muscle protein), which is metabolically expensive and stressful for the body. Chronic reliance on gluconeogenesis (e.g., during prolonged low-carb or high-protein diets) is highly likely to elevate stress hormones over time.

Lipolysis is primarily driven by catecholamines ( adrenaline and noradrenaline) with some contribution from glucagon and cortisol. It acts more acutely during short-term energy needs and does not require sustained cortisol unless paired with extreme caloric deficits or fasting.

The central nervous system, skeletal muscle and smooth muscle (except heart) prefer to burn sugar when active and fatty acids while at rest. The liver, heart and kidneys prefer to oxidize fatty acids in both circumstances. The body's ability to switch between fuel sources (metabolic flexibility) is more efficient than constantly being in a "fat-burning" state. Optimal health involves periods of both glucose and fatty acid utilization, depending on activity level and nutritional status.

Stress hormones and the Randle Cycle need to be considered when deciding what to eat. If your diet is high in fat and sugar, your mitochondria will primary burn fat and not sugar. Sugar will rise in your blood causing insulin to rise. But the cells are “resistant” to insulin because the mitochondria can’t use the sugar insulin is trying to shuttle into the cell. If this happens long enough type 2 diabetes develops, a person gets fat, triglycerides increase and other metabolic issues develop. Additionally, most humans eating a modern diet are consuming the majority of their fat calories from metabolically-destructive polyunsaturated fats (PUFA) instead of saturated fats (SFAs).

A donut is the perfect example. What’s the problem with a donut? If you’re thinking sugar, your wrong. A donut is more fat 60% (coming from the fry oil) than sugar 40%. The fry oil is seed oil (PUFA) which are highly oxidized and inflammatory. The high intake of PUFA as a macronutrient and its fragile nature are massively detrimental. And most processed foods are designed to be hyper-palatable using PUFA and sugar.

Here are the macro breakdowns for other common convenience foods.

Pizza: Fat: 32-33%, Carbs: 49-50%, Protein: 18-20%

French Fries: Fat: 46-53%, Carbs: 46-49%, Protein: 4-5%

Potato Chips: Fat: 53%, Carbs: 43%, Protein: 4%

Assuming these foods are clear of ultra-processed foods (lab chemicals) and PUFA , I’m not saying they’re inherently bad. But look at their macro splits and fat content. If your diet was primary composed of these things, you’d see the Randle Cycle cause fat burning. Sugar would build up in the blood, insulin would increase in a futile attempt to drive the sugar into the cell, and you’d see the metabolic chaos listed before. Considering these convenience foods are also typically high in PUFA and lab chems, you could expect accelerated metabolic problems.

The upper end of the fat percentage of total calories if eating carbs is around 35% and would only be suitable for a metabolically healthy individuals.

Sugar was never the problem, it was the patsy.

Reducing your overall fat intake, consuming predominately saturated fats and increasing carbohydrate intake dramatically improve glucose oxidation. Here’s an example of someone who’s eating 370 grams of carbs/172g protein/18g fat and their fasting glucose is 71. How is this possible if sugar is the bad actor?

There is a low-key popular diet emerging called the Honey Diet by @anabology, a chemistry PhD candidate. Essentially its ad libitum sugar consumption (restricting fat and protein) until dinner. Then a high protein, moderate saturated fat dinner plus veggies. I’ve seen tens of testimonials like the one above.

This diet philosophy is based on the Randle Cycle and bioenergetic principles. When he first ran the diet, Anabology was eating over 500 g of honey from the time he woke up until 3pm and his blood glucose returned to baseline (90 ng/dl) 2 hrs after eating. If he increased the amount of honey consumed per meal he got the same post-prandial glucose. This is the Randle Cycle in effect. Because there wasn’t any fat to impair glucose oxidation, the sugar was rapidly taken up by the cell, turned into energy and blood levels decreased accordingly. This high energy state is what contributes to every honey-diet participant report of crystal clear cognition.

Walter Kempner founded the Rice Diet Program at Duke University in 1939. He developed the diet to treat patients with malignant hypertension, kidney failure and obesity. The original diet consisted almost entirely of white rice, fruit, fruit juices, and sugar. It provided about 2000 calories, was 97% carbohydrate and included exercise and motivational training. Kempner documented remarkable improvements in patients, including decreases in heart size, improved kidney function, reversal of high blood pressure, and reductions in cholesterol levels.

In one study, obese participants lost an average 141 lbs over 11 months. Healthy weight was achieved by 43 of the patients during this term.

An ideal macro balance for restoring glucose oxidation and resolving metabolic syndrome would be high carb/moderate protein/low fat. The ranges can vary depending on the severity of metabolic issues. This means the worse the metabolic issues, the lower the fat and higher the carb. A metabolically healthy person would probably perform best at 45-50% carb/25% protein/25-30% fat (no PUFA). A metabolically deranged person 55-60% carb/25% protein/15-20% fat (no PUFA) macro split.

Additionally, if you were interested in decreasing body fat you’d maintain this macro balance while running a 20% calorie deficit. This is exactly what I did in December 2024 and here’s what happened.

Before starting the protocol I was 200 lbs, 20% body fat eating maintenance calories of 3278 calories/day with a macro split of 50% carb/25% protein/25% fat. At the end of 30 days I was 190, 15% body fat, eating 2600 calories with a macro split of 58% carb/25% protein/18% fat.

This translated into 10 lbs of fat loss with zero loss in muscle mass over 30 days.

In stage two, once you achieve your desired outcome, slowly being to titrate your fat up and carbs down (maintaining calorie deficit) until reaching the macro split of a metabolically healthy person 45-50% carb/25% protein/25-30% fat. Stage three is titrating your calories back to maintenance level (removing the deficit).

There is a lower limit to fat percentage determined by sex hormone deterioration. Generally speaking 20% is the lowest one can go in their macro composition before cortisol increases and depletion of youth steroid hormones occurs. Sometimes people can get away with going as low as 15% for more aggressive outcomes like rapid fat loss or rapid restoration of glucose oxidation but it would only be for a short term.

How do you know if you’ve gone to low in fat? You start feeling adrenaline and cortisol through daytime anxiety, jitteriness (like over caffeinated), loosing muscle mass and sleep disruptions. My personal barometer is based off sleep. If I’m sleeping through the night I’m within tolerable limits. If I’m waking up around 3 and taking awhile to get back to sleep, I’ve overdone it.

To your health,

Jonathan

This is for informational purposes only and should not replace professional medical advice. Consult with your physician or other health care professional if you have any concerns or questions about your health.

Sugar was Never the Problem, it was the Patsy