Biochemistry chapters
Ketone bodies, fed and fasting states and fatty liver
How the body switches fuels between meals: the fed (absorptive) state under insulin, the fasting state under glucagon, prolonged starvation, ketone body formation and use, diabetic and alcoholic ketoacidosis, the metabolic differences between type 1 and type 2 diabetes, and why fat builds up in the liver.
- In the fed state (high insulin:glucagon ratio) the body stores fuel: glycogen synthesis, fat synthesis and protein synthesis; in early fasting the liver releases glucose from glycogen (lasts about a day), then gluconeogenesis from amino acids, lactate and glycerol takes over, while lipolysis releases fatty acids.
- In prolonged starvation the liver makes ketone bodies (acetoacetate, β-hydroxybutyrate (the main one), acetone) in mitochondria via HMG-CoA synthase; the brain adapts to use ketones (sparing muscle protein), but the liver cannot use ketones (it lacks thiophorase) and red cells cannot either (no mitochondria).
- Diabetic ketoacidosis (absolute insulin lack + high glucagon) causes hyperglycaemia, ketonaemia and high anion gap acidosis with Kussmaul breathing and fruity breath; the nitroprusside (Rothera) test detects acetoacetate and acetone but not β-hydroxybutyrate; fatty liver results from more fatty acids reaching the liver or less VLDL export (alcohol, obesity/insulin resistance, kwashiorkor, lack of choline).
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Insulin and glucagon
| Effect | Insulin (fed; "storage") | Glucagon (fasting; "mobilisation") |
|---|---|---|
| Glucose uptake (muscle, fat) | ↑ (GLUT4) | (none commonly tested) |
| Glycogen | Synthesis ↑ | Breakdown ↑ (liver) |
| Gluconeogenesis | ↓ | ↑ |
| Glycolysis (liver) | ↑ | ↓ |
| Fat | Synthesis ↑, lipolysis ↓ (hormone-sensitive lipase) | Lipolysis ↑ |
| Ketogenesis | ↓ | ↑ |
| Protein | Synthesis ↑ | Breakdown ↑ (with cortisol) |
| Potassium | Into cells | (none commonly tested) |
| Mechanism | Dephosphorylation of key enzymes (tyrosine kinase receptor) | Phosphorylation of key enzymes (cAMP, protein kinase A) |
The insulin:glucagon ratio decides whether the body stores or releases fuel. Adrenaline and cortisol act with glucagon in stress.
The fed (absorptive) state (0–4 hours after a meal)
- Liver: takes up glucose (glucokinase), makes glycogen, runs glycolysis, makes fatty acids and exports them as VLDL; makes cholesterol and proteins.
- Muscle: takes up glucose (GLUT4) → glycogen; takes up amino acids → protein (especially branched-chain amino acids).
- Adipose tissue: takes up glucose (glycerol 3-phosphate) and fatty acids (lipoprotein lipase) → stores triglyceride.
- Brain: uses glucose (always, if available).
The fasting (post-absorptive) state
Early fasting (about 4–24 hours)
- Insulin falls, glucagon rises.
- Liver glycogenolysis keeps blood glucose up; liver glycogen is largely used up within about 24 hours.
- Gluconeogenesis starts and increases (lactate, alanine, glycerol).
- Lipolysis in adipose tissue releases fatty acids and glycerol; muscle and heart switch to fatty acids.
Prolonged fasting and starvation (days to weeks)
- Gluconeogenesis from amino acids (muscle protein) peaks in the first days, then falls as the brain adapts.
- Ketogenesis rises sharply; ketone levels climb over days.
- The brain switches to ketone bodies for a large share of its energy (up to about two-thirds after a few weeks), sparing muscle protein.
- Red cells still need glucose (no mitochondria); the renal medulla too.
- Survival depends on fat stores; death follows when protein loss affects vital functions (respiratory muscles, immunity).
| Tissue | Fed | Early fast | Prolonged starvation |
|---|---|---|---|
| Brain | Glucose | Glucose | Ketones + glucose |
| Red cells | Glucose | Glucose | Glucose (from gluconeogenesis) |
| Muscle | Glucose | Fatty acids | Fatty acids (spares ketones for the brain) |
| Liver | Glucose, amino acids | Fatty acids | Fatty acids (makes ketones) |
Ketone bodies
Synthesis (ketogenesis)
Location: liver mitochondria.
- Fatty acids → acetyl-CoA (β-oxidation). When oxaloacetate is used for gluconeogenesis, acetyl-CoA cannot enter the TCA cycle.
- 2 acetyl-CoA → acetoacetyl-CoA (thiolase).
- → HMG-CoA (mitochondrial HMG-CoA synthase: rate-limiting step of ketogenesis; the cytosolic form is for cholesterol).
- → acetoacetate (HMG-CoA lyase).
- Acetoacetate → β-hydroxybutyrate (β-hydroxybutyrate dehydrogenase, using NADH) or → acetone (spontaneous; exhaled, fruity breath, not used as fuel).
β-hydroxybutyrate is the main ketone in the blood (usually about three times acetoacetate, more in DKA and alcohol excess because of high NADH).
Use (ketolysis)
In extrahepatic tissues (heart, muscle, kidney cortex, brain in starvation): β-hydroxybutyrate → acetoacetate → acetoacetyl-CoA (by thiophorase, succinyl-CoA:acetoacetate CoA transferase) → 2 acetyl-CoA → TCA cycle.
The liver makes but cannot use ketone bodies because it lacks thiophorase. Red cells cannot use them (no mitochondria).
Ketosis and ketoacidosis
| Cause | Mechanism |
|---|---|
| Starvation and prolonged fasting, low-carbohydrate diets | Physiological ketosis; mild acidosis at most |
| Diabetic ketoacidosis | Absolute insulin lack + high glucagon → uncontrolled lipolysis and ketogenesis |
| Alcoholic ketoacidosis | Alcohol binge with poor intake: high NADH favours β-hydroxybutyrate; glucose often normal or low |
| Severe vomiting (hyperemesis), stress, high-fat diet | Low carbohydrate availability |
Features of DKA: polyuria, polydipsia, dehydration, abdominal pain, vomiting, Kussmaul (deep, sighing) breathing (respiratory compensation), fruity (acetone) breath, confusion; labs: hyperglycaemia, ketonaemia/ketonuria, high anion gap metabolic acidosis, low bicarbonate, high or normal potassium (despite total body depletion). See antidiabetic drugs for treatment.
Tests:
- Rothera (nitroprusside) test / urine dipsticks: detect acetoacetate (and acetone) but not β-hydroxybutyrate. In alcoholic ketoacidosis, or early in DKA treatment, they may under-read; as treatment converts β-hydroxybutyrate back to acetoacetate, urine tests can seem worse while the patient improves.
- Blood β-hydroxybutyrate meters are preferred for monitoring DKA.
Anion gap = Na⁺ − (Cl⁻ + HCO₃⁻)
DKA: Na 132, Cl 96, HCO₃ 6
Gap = 132 − (96 + 6) = 132 − 102 = 30 mmol/L (normal about 8–14)
Extra unmeasured anions (ketoacids) ≈ 30 − 12 = 18 mmol/L
Ratio of β-hydroxybutyrate to acetoacetate in DKA can reach 10 : 1
If total ketones = 11 mmol/L: β-OHB ≈ 10, acetoacetate ≈ 1
→ a nitroprusside strip sees only about 1/11 of the ketones
Metabolic changes in diabetes
| Feature | Type 1 | Type 2 |
|---|---|---|
| Problem | Absolute insulin deficiency (autoimmune β-cell destruction) | Insulin resistance with relative deficiency |
| Glucagon | High | Often high |
| Ketoacidosis | Common (DKA) | Rare (some insulin stops lipolysis and ketogenesis); hyperosmolar hyperglycaemic state instead |
| Lipids | Raised triglycerides (low lipoprotein lipase) | High triglycerides, low HDL, small dense LDL |
| Body build | Usually thin | Usually overweight |
In uncontrolled diabetes, glucose cannot enter muscle and fat, gluconeogenesis and glycogenolysis continue, lipolysis is unchecked, and muscle protein breaks down: the body behaves as if starving despite high blood glucose.
Long-term damage comes from non-enzymatic glycation (HbA1c reflects the average glucose over about 2–3 months) and the polyol (sorbitol) pathway (aldose reductase: cataracts, neuropathy).
Fatty liver (steatosis)
Triglyceride builds up in hepatocytes when fatty acid delivery or synthesis exceeds oxidation and export as VLDL.
| Mechanism | Causes |
|---|---|
| More fatty acids reach the liver | Obesity, insulin resistance (type 2 diabetes), starvation, high-fat diet, steroids |
| More synthesis / less oxidation | Alcohol (high NADH: less β-oxidation, more glycerol 3-phosphate and fat synthesis) |
| Less VLDL export | Protein deficiency (kwashiorkor): too little apoprotein; choline and methionine deficiency (needed for phosphatidylcholine); toxins (carbon tetrachloride, phosphorus); abetalipoproteinaemia |
| Others | Pregnancy (acute fatty liver), Reye syndrome (aspirin in children), drugs (tetracyclines, valproate, amiodarone) |
Non-alcoholic fatty liver disease (NAFLD, now called MASLD) is the commonest liver disease worldwide, linked to obesity and type 2 diabetes; it can progress to steatohepatitis (NASH), fibrosis and cirrhosis.
Lipotropic factors prevent fat building up in the liver: choline, methionine (methyl donor), betaine, inositol, vitamin B12, folate, essential fatty acids.
Refeeding syndrome
When a starved patient is fed (especially carbohydrate), insulin drives phosphate, potassium and magnesium into cells → hypophosphataemia (the hallmark), hypokalaemia, hypomagnesaemia, thiamine deficiency (Wernicke), fluid retention → heart failure, arrhythmias, respiratory failure, confusion. Prevent with slow feeding, thiamine and electrolyte replacement and monitoring.
Expect: actions of insulin vs glucagon, fuel use in fed, fasting and starvation states (how long glycogen lasts, brain adaptation, red cells), ketone body names and the main one, site and rate-limiting enzyme of ketogenesis, why the liver cannot use ketones (thiophorase), DKA features and anion gap, what the nitroprusside test misses, type 1 vs type 2 metabolism, causes of fatty liver including kwashiorkor and choline, lipotropic factors, refeeding syndrome.
Quick revision
- Insulin stores (glycogen, fat, protein); glucagon mobilises (glycogenolysis, gluconeogenesis, lipolysis, ketogenesis).
- Liver glycogen lasts about 24 hours of fasting.
- Starvation: brain adapts to ketones; red cells still need glucose.
- Ketones: acetoacetate, β-hydroxybutyrate (main), acetone; made in liver mitochondria (HMG-CoA synthase).
- Liver lacks thiophorase → cannot use ketones.
- Nitroprusside test misses β-hydroxybutyrate.
- DKA: Kussmaul breathing, fruity breath, high anion gap.
- Fatty liver: alcohol, insulin resistance, kwashiorkor, choline deficiency. Refeeding: hypophosphataemia.
Written by The House Job from standard biochemistry references (Lippincott Illustrated Reviews: Biochemistry).
FAQ
Where are ketone bodies made and why can the liver not use them?
They are made in liver mitochondria; the liver lacks thiophorase (succinyl-CoA:acetoacetate CoA transferase), the enzyme needed to use them.
Which ketone body is not detected by the nitroprusside test?
β-hydroxybutyrate, which is the main ketone body in the blood.
What does the brain use for fuel in prolonged starvation?
Mainly ketone bodies, with some glucose from gluconeogenesis, which spares muscle protein.
Why does kwashiorkor cause fatty liver?
Protein deficiency reduces apolipoprotein synthesis, so the liver cannot export triglycerides as VLDL.