Integration of Metabolism

Two facts about the brain make it the tissue around which all of metabolism is organised.

Glucose is the exclusive fuel for brain tissue, except in periods of extreme starvation, and brain metabolism is entirely aerobic. It cannot use fatty acids at all — they travel bound to albumin and cannot cross the blood-brain barrier (Unit 18). It has no meaningful glycogen store of its own.

The erythrocyte is even more restricted: no mitochondria at all, so it is obligately glycolytic and its dependence on glucose is absolute in every state, including starvation.

So the body is permanently supplying a large, non-negotiable glucose demand from a store — liver glycogen — that lasts less than a day. Everything that follows in this unit is the consequence of that arithmetic.

Look at the negatives in that table. Each one is a design decision with visible consequences.

Muscle has no glucose-6-phosphatase. So muscle glycogen can never leave the muscle as glucose — it is a private store, for that muscle's own use. Skeletal muscle donates amino acids for gluconeogenesis in the liver, but it keeps its glycogen to itself. Muscle carbon reaches the blood only as lactate (Cori cycle) or alanine (glucose-alanine cycle) — and both require the liver to convert them back.

Adipose tissue has no glycerol kinase. So the glycerol released by lipolysis cannot be reused by the adipocyte and passes to the liver. It follows that fat storage requires a supply of glucose, to make glycerol-3-phosphate by glycolysis — and therefore requires insulin. This is why lipolysis runs unopposed in diabetes.

The liver lacks succinyl-CoA-acetoacetate CoA transferase. So it exports the ketone bodies it makes rather than burning them (Unit 17).

Ask what an organ cannot do, and its role in the whole becomes obvious.

This is Unit 6's K_m doing physiology, and it is one of the most satisfying examples in the subject.

Hexokinase, with a K_m of 0.1 mM, is saturated at every physiological glucose concentration. That is exactly what a peripheral tissue wants: take up glucose at a constant rate whatever the supply, because you need it to survive.

But the liver's job is the opposite. It is not feeding itself; it is buffering the blood. It must take up a great deal of glucose when there is plenty and none at all when there is little — otherwise it would compete with the brain. A high-K_m, non-inhibited enzyme does precisely that: its rate rises steeply with concentration and falls to nearly nothing at fasting levels.

The enzyme's kinetics ARE its physiological role. Recall too that in the pancreatic β cell, the same enzyme acts as the glucose sensor that triggers insulin release — the same kinetics used to measure rather than to store.

Notice the elegance of that list. Fatty acids are not glucogenic — pyruvate dehydrogenase is irreversible, so not one carbon of a fatty acid becomes glucose (Unit 17). And yet fatty acid oxidation is what makes gluconeogenesis possible.

It contributes in three ways without contributing carbon: it signals (acetyl-CoA activating pyruvate carboxylase), it funds (ATP and NADH), and it spares (every tissue burning fat is a tissue not burning glucose).

The fat is the fuel; the amino acids and glycerol are the carbon. If you can state that division of labour, you have understood the fasting liver.

Take the rows in pairs and the whole physiology of starvation falls out of them.

Brain glucose falls 100 → 40 while brain ketone bodies rise 50 → 100. The brain has switched fuels. It has not reduced its energy consumption — it has changed what it burns. This is the adaptation that makes prolonged starvation survivable.

Muscle-protein degradation falls 75 → 20. That is the payoff, and it is the whole point of the exercise. Every gram of glucose the brain does not demand is a gram the liver does not have to make from amino acids — which means muscle it does not have to dismantle. Ketone bodies exist to spare protein.

Adipose lipolysis is unchanged at 180 on both days. Fat is the one store deep enough not to need rationing; it is simply drawn on at a constant rate throughout. Survival time in starvation is set by the size of the fat depot.

Liver ketone body output is unchanged at 150, while glucose output halves. The liver has not slowed down; it has changed product. And note what has not changed: all other use of glucose stays around 40–50, because the erythrocyte has no mitochondria and no alternative. Its demand is the irreducible floor.

Both states produce ketone bodies for the same reason — oxaloacetate diverted into gluconeogenesis, acetyl-CoA overflowing into ketogenesis (Unit 17). So why is one physiological and the other lethal?

Because in starvation, insulin is low but not absent, and it still restrains lipolysis. Insulin is the principal antilipolytic hormone, and the brake is still partly applied. In type 1 diabetes there is no insulin at all: lipolysis is completely unopposed, free fatty acid delivery to the liver is enormous, and ketogenesis runs at a rate much greater than is seen in starvation.

Then add the second difference. In starvation, glucose is scarce, so the brain adapts to ketone bodies and consumes them. In diabetes, blood glucose is high, the peripheral tissues do not adapt — and the ketone bodies simply accumulate. Production is maximal and consumption is not.

Since acetoacetate and 3-hydroxybutyrate are relatively strong acids, the result is ketoacidosis rather than the harmless ketosis of the fasting state. Same pathway, no brake, no consumer.

Read the table as a sequence and it is really one principle: the faster you need ATP, the less efficient the pathway you must use.

Stored ATP and creatine phosphate are instantaneous but last seconds. Anaerobic glycolysis is fast but yields only 2 ATP per glucose and generates the lactate that goes to the liver for the Cori cycle. Oxidative phosphorylation yields 30–32 per glucose but is limited by oxygen delivery. Fat oxidation yields most of all — 106 ATP per palmitate — but is the slowest to mobilise and the most oxygen-hungry.

So the marathon is the interesting case, because it is where the whole of this unit is visible at once: adipose tissue releasing free fatty acids, muscle oxidising them and exporting alanine and lactate, and the liver running gluconeogenesis to defend blood glucose. “Hitting the wall” is hepatic glycogen depletion — and the symptoms that follow are cerebral, because the brain is the tissue that misses the glucose.

Leptin looks, at first sight, like the perfect drug target: an adipocyte hormone that reports fat mass to the brain, whose absence makes mice obese and whose administration makes them thin again.

But note the careful wording — “preliminary evidence indicates that leptin and its receptor play a role in human obesity.” The receptor is named alongside the hormone for a reason. Most obese humans have high leptin, in proportion to their fat mass, exactly as the definition predicts. Giving more of a hormone to which the system has become resistant achieves little.

This is the same lesson as type 2 diabetes, where insulin is present and the tissues do not listen. A hormone deficiency and a hormone resistance can produce the same phenotype and demand opposite treatments — which is why the distinction is worth making explicitly in an answer.

Ethanol has no receptor and no signalling pathway in this story. It causes disease by chemistry: it dumps reducing equivalents into the liver and drives the NADH/NAD⁺ ratio up. Now walk through what needs NAD⁺.

1 · Gluconeogenesis fails. Lactate dehydrogenase and malate dehydrogenase both need NAD⁺; with NADH high, the equilibria are pushed towards lactate and malate and away from pyruvate and oxaloacetate. Substrates for gluconeogenesis disappear — hence alcoholic hypoglycemia, and it is worst in someone who has not eaten, whose glycogen is already gone.

2 · Lactic acidosis, from the same shifted equilibrium. And since lactate competes with urate for renal excretion, this raises the renal threshold for urate — which is why heavy drinking precipitates gout.

3 · Fatty liver. β-oxidation and the citric acid cycle both need NAD⁺, so fatty acid oxidation is inhibited and esterification is favoured (Unit 18). Prolonged, this progresses to fibrosis and cirrhosis — and cirrhosis brings portal-systemic shunting and ammonia intoxication (Unit 20).

4 · Ketosis, since the acetyl-CoA that cannot enter the cycle overflows into ketogenesis.

Four presentations, one number. If you can derive them from the NADH/NAD⁺ ratio rather than listing them, you will not forget them.