Randle cycle

The Randle cycle (glucose-fatty acid cycle) is a 1963 finding by P. J. Randle. High free fatty acids in the blood block cells from fully burning glucose (blood sugar). Free fatty acids are fat molecules loose in the blood after fat stores release them (lipolysis). The block shows up in diabetes, hard exercise, failing heart muscle, IV fat emulsions, and diets heavy in seed oils.

In 1963, a researcher named P.J. Randle observed that he could block the oxidation of glucose just by feeding an increased amount of fatty acids. This is now called the Randle Cycle. When it became popular to feed hospitalized patients intravenously with a fat emulsion, they discovered it suppressed the immune system and almost immediately caused an elevation of blood glucose, exactly what Randle had noticed.

— Ray Peat

High blood sugar can be the body pushing fuel through a fat block. IV soy-oil emulsion raises blood sugar within minutes.

In hyperglycemia, what you have is the body's adjustment to the inability of cells to get enough energy because they can't oxidize glucose because the fats are blocking it. That's been known since the 1960s, called the Randle cycle, in which free fatty acids block the use of glucose. The body tries to overcome that poisonous effect of the free fatty acids by increasing glucose production.

— Ray Peat

The block is asymmetric

The competition runs stronger in one direction than the other. Fatty-acid oxidation inhibits glucose oxidation more severely, mainly by blocking pyruvate dehydrogenase, than glucose/insulin inhibits fat oxidation, which works through the slower malonyl-CoA/CPT-1 route; the reciprocal, fat-blocking side of the cycle was only worked out mechanistically decades after Randle's original description of fat blocking glucose. Practically, this means high dietary carbohydrate with fat kept low tends to raise insulin sensitivity, but that effect depends on fat staying low; it doesn't run as cleanly in reverse.

Fat and sugar trade places

More fat in the blood (from food or from breaking down body fat) slows sugar burning. Enough sugar eaten slows fat release from stores.

The antagonism between fat and sugar that Randle described can involve the suppression of sugar oxidation when the concentration of fats in the bloodstream is increased by eating fatty food, or by releasing fats from the tissues by lipolysis, but it can also involve the suppression of fat oxidation by inhibiting the release of fatty acids from the tissues, when a sufficient amount of sugar is eaten.

— Ray Peat

With free fatty acids high, cells still take in glucose and turn much of it into lactate (lactic acid), a half-burned form. Full burn to CO₂ fails. Same pattern in diabetes and in many cancer cells. Mitochondria are the cell compartments that burn fuel with oxygen for energy.

This process of substituting fat burning for sugar burning was called a cycle by P.J. Randle. It isn't really a cycle, but now it's called the Randall Cycle. This means that if you burn fatty acids, that stops you from oxidizing glucose; instead, you'll turn it into lactic acid.

— Ray Peat

Free fatty acids suppress mitochondrial respiration (Kamikawa and Yamazaki, 1981), leading to increased glycolysis (producing lactic acid) to maintain cellular energy.

— Ray Peat

Which free fats matter

Polyunsaturated free fatty acids (from seed oils and body stores of those oils) block sugar use at once and damage proteins and mitochondria over time. Fats the body makes from sugar (mostly saturated and monounsaturated) do less of that harm.

When the fatty acids involved in blocking the sugar are polyunsaturated, they produce long-range damage. … So, the free fatty acids not only block sugar use instantaneously (Randle effect), but they produce these advanced glycation end-products (AGEs) associated with diabetes and aging.

— Ray Peat

Bernardo Houssay fed sugar and coconut oil and protected animals from experimental diabetes. Heavy lard diets failed that test. Coconut oil's shorter saturated chains burn fast (closer to sugar). They displace anti-metabolic PUFA from stores. Lab "essential fatty acid deficiency" protects against diabetes.

Adrenaline, cortisol, growth hormone, estrogen, prolactin, infection, and overwork free fatty acids from fat tissue. That deepens the Randle block. Free fatty acids then demand more sugar output from the liver. Cells short on usable glucose convert less T4 to active thyroid hormone T3. Extra T3 reverses many "diabetic" breakdown signs once sugar burning returns.

Insulin resistance

The same fatty-acid block extends past acute glucose oxidation into insulin resistance itself. Elevated free fatty acids are one of the few factors that satisfy all three tests for causing a metabolic disease: they run high in the blood of people with obesity and type 2 diabetes, raising them experimentally produces insulin resistance, and lowering them reduces it. Directly measured in healthy volunteers: infusing lipids intravenously to raise free fatty acids cut insulin-stimulated glucose disposal by about 70% during a clamp test, occurring at the cellular level rather than from any change in blood flow or insulin delivery to the muscle. See Lipolysis for the hormone-sensitive-lipase mechanism that puts those fatty acids into circulation in the first place, and Insulin resistance for the disease-level picture.

Not a case for separating meals

The fat-sugar antagonism doesn't mean carbohydrate and protein should be eaten separately, the "food combining" idea some diets are built on. Ray Peat recommended the opposite: amino acids, especially from eggs, stimulate insulin secretion, which can drop blood sugar low enough to trigger a cortisol response, and eating fruit (or other carbohydrate), coconut oil, and salt at the same meal as the protein reduces that effect rather than causing one.

Diet composition versus a single meal

That point is about a single meal, not the overall diet. At the level of overall macronutrient composition, the Randle competition argues for picking one dominant fuel rather than running both high carbohydrate and high fat together day to day. Georgi Dinkov summarized the practical takeaway this way after a debate with a carnivore diet advocate:

If you're eating a high-carb diet, you better keep fat low because all those carbs and the insulin that they raise, they're going to prevent the fat from being oxidized, so you're going to store it almost completely. If you're eating a high-fat diet, then it's probably not a good idea to eat also a lot of carbs with it because the fat is going to prevent the metabolism of the glucose and it's going to float around, cause all kinds of problems: increase lactic acid, high blood pressure, etc. So maybe both pathways are okay, it's really when these two macronutrients clash. And especially if you're eating the PUFA, which also has an extra anti-metabolic effect of its own and is inflammatory, then really all hell breaks loose. It'll be better to eat predominantly one or the other, and if you're eating the fat, it would be mostly saturated.

— Georgi Dinkov

The apparent tension with the section above resolves at different scales: a little fruit, coconut oil, and salt alongside a protein-heavy meal is a small, occasional carbohydrate/fat combination that blunts a protein-driven insulin dip, not a standing high-carb-plus-high-fat diet pattern running both fuels through the Randle block all day.

Practice

Burn sugar from fruit, juice, milk sugar, honey in context. Lipolysis falls. Free fatty acids fall. Cut seed-oil PUFA. Cook with coconut oil or butter. High blood sugar marks a block on oxidation. Fix the free fatty acids and the fuel mix. IV lipid emulsions and long high-fat states lock fat burning and lactate.

See also

• Free fatty acids
• Lipolysis
• Insulin resistance
• PUFA
• Glucose
• Diabetes
• Intermittent fasting
• Stress
• CO2
• Mitochondria
• Coconut oil
• Thyroid
• Library:Glucose and sucrose for diabetes
• Library:Glycemia, starch, and sugar in context