Metabolism

Carbohydrate Metabolism

Carbohydrate metabolism centres on maintaining plasma glucose for obligate or preferentially glucose-dependent tissues, notably brain, renal medulla, erythrocytes and exercising skeletal muscle. Normal fasting plasma glucose is approximately 3.9–5.5 mmol/L; diagnostic thresholds for diabetes are fasting plasma glucose ≥7.0 mmol/L, 2-hour OGTT glucose ≥11.1 mmol/L, random glucose ≥11.1 mmol/L with symptoms, or HbA1c ≥48 mmol/mol according to WHO/NICE criteria. Hypoglycaemia is clinically defined by Whipple’s triad; in diabetes practice, clinically important hypoglycaemia is often <3.0 mmol/L, while alert-level hypoglycaemia is <3.9 mmol/L.

Core pathways and subcellular localisation

Pathway	Principal site	Key function	Rate-limiting / key enzymes
Glycolysis	Cytosol; all tissues	Glucose to pyruvate/lactate; ATP generation	Hexokinase/glucokinase, phosphofructokinase-1, pyruvate kinase
Gluconeogenesis	Liver, renal cortex; cytosol/mitochondria/ER	Glucose synthesis from lactate, alanine, glycerol	Pyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase, glucose-6-phosphatase
Glycogenesis/glycogenolysis	Liver and skeletal muscle	Glucose storage and mobilisation	Glycogen synthase; glycogen phosphorylase, debranching enzyme
Pentose phosphate pathway	Cytosol; erythrocytes, liver, adrenal cortex	NADPH and ribose-5-phosphate generation	Glucose-6-phosphate dehydrogenase

Glycolysis yields a net 2 ATP and 2 NADH per glucose under aerobic conditions before pyruvate enters mitochondria. Pyruvate dehydrogenase, requiring thiamine pyrophosphate, lipoate, FAD, NAD⁺ and CoA, links glycolysis to the tricarboxylic acid cycle by producing acetyl-CoA; inhibition occurs via ATP, NADH and acetyl-CoA, while activation occurs by ADP and pyruvate. In anaerobic tissues such as erythrocytes, lactate dehydrogenase regenerates NAD⁺; excess lactate contributes to lactic acidosis, typically defined as lactate >5 mmol/L with pH <7.35, although clinically concerning hyperlactataemia begins above 2 mmol/L.

Hormonal and allosteric regulation

Insulin promotes glucose uptake in adipose tissue and skeletal muscle via GLUT4 translocation, stimulates glycogen synthase and glycolysis, and suppresses hepatic gluconeogenesis. Glucagon, catecholamines and cortisol oppose insulin: hepatic glucagon raises cAMP, activates protein kinase A, stimulates glycogen phosphorylase and inhibits glycogen synthase. A central reciprocal regulator is fructose-2,6-bisphosphate, which activates phosphofructokinase-1 and inhibits fructose-1,6-bisphosphatase; hepatic glucagon lowers fructose-2,6-bisphosphate, favouring gluconeogenesis. Muscle lacks glucose-6-phosphatase, so muscle glycogen supplies local ATP rather than circulating glucose.

Transporters and tissue specificity

• GLUT1: basal uptake; erythrocytes and blood–brain barrier. Deficiency causes infantile seizures, developmental delay and low CSF glucose.
• GLUT2: liver, pancreatic beta-cells, renal tubule, intestine; high-capacity, low-affinity glucose sensing. Mutations cause Fanconi–Bickel syndrome.
• GLUT4: insulin-responsive transporter in skeletal muscle and adipose tissue.
• SGLT2: proximal renal tubular glucose reabsorption; pharmacological inhibition causes glycosuria and is used therapeutically in diabetes, heart failure and CKD, but may precipitate euglycaemic ketoacidosis.

Clinically important disorders of carbohydrate metabolism

Disorder	Defect	Key clinical/exam features
G6PD deficiency	Reduced NADPH generation in pentose phosphate pathway	Oxidative haemolysis after infection, fava beans, dapsone, primaquine or sulfonamides; bite cells and Heinz bodies
Von Gierke disease, GSD I	Glucose-6-phosphatase deficiency	Severe fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hypertriglyceridaemia, hepatomegaly
Pompe disease, GSD II	Lysosomal acid alpha-glucosidase deficiency	Cardiomyopathy, hypotonia; normal fasting glucose; treatable with enzyme replacement
McArdle disease, GSD V	Muscle glycogen phosphorylase deficiency	Exercise intolerance, cramps, myoglobinuria, “second-wind” phenomenon; flat lactate response to ischaemic exercise
Classic galactosaemia	Galactose-1-phosphate uridyltransferase deficiency	Neonatal jaundice, hepatomegaly, cataracts, E. coli sepsis; treat with lactose/galactose exclusion
Hereditary fructose intolerance	Aldolase B deficiency	Vomiting, hypoglycaemia and liver dysfunction after fructose/sucrose; avoid fructose, sucrose and sorbitol

Diabetes-related carbohydrate handling: exam-relevant principles

In type 1 diabetes, absolute insulin deficiency causes uninhibited lipolysis, ketogenesis and hepatic glucose output; diabetic ketoacidosis is characterised by hyperglycaemia usually >11 mmol/L, ketonaemia ≥3.0 mmol/L or significant ketonuria, and acidosis with venous pH <7.3 or bicarbonate <15 mmol/L. In type 2 diabetes, insulin resistance and progressive beta-cell failure produce post-prandial then fasting hyperglycaemia, with hepatic gluconeogenesis a major contributor. The UKPDS established that intensive glycaemic control reduced microvascular endpoints in newly diagnosed type 2 diabetes; modern guidelines individualise HbA1c targets, commonly around 48–58 mmol/mol depending on frailty, hypoglycaemia risk and comorbidity.

Carbohydrate metabolism is therefore best understood as a regulated network rather than isolated pathways: fed-state insulin stores glucose as glycogen and fat, fasting glucagon preserves plasma glucose through hepatic glycogenolysis and gluconeogenesis, and prolonged starvation shifts cerebral substrate use towards ketone bodies while erythrocytes remain entirely dependent on anaerobic glycolysis.

Protein Metabolism

Protein metabolism comprises dietary protein digestion, amino acid absorption and transport, intracellular protein turnover, amino acid catabolism, nitrogen disposal via the urea cycle, and synthesis of specialised nitrogenous compounds. In adults, total body protein is approximately 10–12 kg, with a dynamic amino acid pool of only about 100 g; therefore flux through protein turnover is substantial, around 250–300 g/day, greatly exceeding dietary intake. Normal adult protein requirement is approximately 0.8 g/kg/day, rising to 1.2–2.0 g/kg/day in catabolic illness, burns, sepsis, trauma, and postoperative states; chronic kidney disease without dialysis usually requires restriction to about 0.6–0.8 g/kg/day, whereas haemodialysis patients typically require 1.0–1.2 g/kg/day.

Digestion, absorption and amino acid handling

Gastric acid denatures protein and activates pepsinogen to pepsin. Pancreatic proteases are secreted as zymogens: trypsinogen, chymotrypsinogen, proelastase and procarboxypeptidases. Enterokinase activates trypsinogen to trypsin, which then activates other proteases. Brush-border peptidases generate free amino acids and di-/tripeptides. Amino acids are absorbed by sodium-dependent transporters; di-/tripeptides by the proton-coupled transporter PEPT1 and hydrolysed intracellularly. Congenital transporter defects are exam-relevant: cystinuria affects renal and intestinal transport of COLA amino acids—cystine, ornithine, lysine and arginine—causing recurrent hexagonal cystine stones; Hartnup disease affects neutral amino acid transport, particularly tryptophan, producing pellagra-like photosensitive rash, ataxia and psychiatric symptoms.

Amino acid classification and clinical relevance

Category	Examples	Clinical/exam significance
Essential	Histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine	Must be supplied nutritionally; deficiency contributes to negative nitrogen balance and impaired wound healing.
Conditionally essential	Arginine, glutamine, cysteine, tyrosine	Required in growth, critical illness, prematurity or precursor deficiency; tyrosine becomes essential in phenylketonuria treatment.
Branched-chain amino acids	Leucine, isoleucine, valine	Catabolised predominantly in muscle; impaired degradation causes maple syrup urine disease.
Glucogenic/ketogenic	Leucine and lysine are purely ketogenic; many are glucogenic	Determines entry into citric acid cycle intermediates or ketone-body pathways during fasting/catabolism.

Transamination transfers amino groups to α-ketoglutarate, forming glutamate; aminotransferases require pyridoxal phosphate derived from vitamin B6. Alanine aminotransferase and aspartate aminotransferase are clinically important markers of hepatocellular injury but also reflect amino acid flux. Oxidative deamination of glutamate by glutamate dehydrogenase generates free ammonia. Peripheral tissues safely transport nitrogen mainly as alanine and glutamine: alanine participates in the glucose-alanine cycle, while glutamine synthetase incorporates ammonia into glutamate, especially in muscle and brain.

Urea cycle and hyperammonaemia

The urea cycle occurs largely in hepatocytes, with mitochondrial and cytosolic steps. Carbamoyl phosphate synthetase I, activated by N-acetylglutamate, combines ammonia and bicarbonate in mitochondria; ornithine transcarbamylase forms citrulline; cytosolic argininosuccinate synthetase and lyase generate arginine and fumarate; arginase produces urea and regenerates ornithine. Normal adult plasma ammonia is approximately 10–50 µmol/L, although ranges vary by laboratory and pre-analytical error is common. Hyperammonaemia causes astrocyte glutamine accumulation, cerebral oedema and encephalopathy.

Disorder	Biochemical clue	Clinical point
Ornithine transcarbamylase deficiency	High ammonia, high orotic acid, low citrulline	X-linked; may present in adults with episodic encephalopathy after infection, postpartum state, high-protein intake or valproate.
CPS I deficiency	High ammonia, low orotic acid	Severe neonatal or episodic adult presentations; no carbamoyl phosphate for pyrimidine overflow.
Argininosuccinate lyase deficiency	High argininosuccinate	May cause brittle hair, hepatomegaly and neurocognitive impairment.
Hepatic failure/portosystemic shunting	High ammonia with abnormal synthetic function or shunt	Common acquired cause; precipitated by GI bleed, constipation, infection, renal failure or excess diuretics.

Acute severe hyperammonaemia is a medical emergency. Management includes stopping protein temporarily, high-calorie intravenous glucose often with lipid to suppress catabolism, treating precipitants, and nitrogen-scavenging therapy. Sodium benzoate conjugates glycine to hippurate; sodium phenylbutyrate or phenylacetate conjugates glutamine to phenylacetylglutamine. Intravenous arginine is used in several urea-cycle defects except arginase deficiency. Haemodialysis is considered when ammonia is very high, commonly >150–200 µmol/L with encephalopathy or rapidly rising levels; many metabolic protocols use lower thresholds in neonates, but adult practice depends on clinical trajectory.

Inherited amino acid disorders

Phenylketonuria results from phenylalanine hydroxylase deficiency or tetrahydrobiopterin defects. Untreated, phenylalanine accumulation causes severe intellectual disability, seizures, eczema and hypopigmentation. Adult target phenylalanine concentrations vary by guideline, but UK practice commonly aims for approximately 120–360 µmol/L in children and pregnancy, with relaxation in some adults; strict control is essential preconception and throughout pregnancy because maternal phenylalanine is teratogenic. Treatment is phenylalanine restriction with tyrosine supplementation; sapropterin, a tetrahydrobiopterin analogue, benefits selected responsive patients.

Maple syrup urine disease is due to branched-chain α-ketoacid dehydrogenase deficiency, causing leucine, isoleucine and valine accumulation. Leucine is particularly neurotoxic; crises produce vomiting, encephalopathy, dystonia and a sweet odour. Homocystinuria classically reflects cystathionine β-synthase deficiency, associated with ectopia lentis, marfanoid habitus, osteoporosis, developmental issues and arterial/venous thrombosis; treatment may include pyridoxine responsiveness testing, methionine restriction, cysteine supplementation, betaine, folate and B12. Alkaptonuria arises from homogentisate oxidase deficiency, causing ochronosis, dark urine and early degenerative arthropathy.

Protein turnover, nitrogen balance and systemic disease

Protein synthesis is regulated by insulin, amino acid availability, mTOR signalling and anabolic hormones; degradation occurs via lysosomal autophagy and the ubiquitin-proteasome system. In sepsis, burns, malignancy and glucocorticoid excess, cytokine-driven proteolysis and insulin resistance produce negative nitrogen balance, sarcopenia and hypoalbuminaemia. Albumin has a half-life of approximately 20 days and is a poor acute nutritional marker; prealbumin has a shorter half-life of about 2 days but is strongly affected by inflammation. Urea reflects hepatic nitrogen disposal and renal excretion; low urea may indicate severe liver disease or low protein intake, whereas high urea may reflect renal failure, catabolism, corticosteroids or gastrointestinal bleeding.

Lipid Metabolism

Core pathways: absorption, transport, storage and oxidation

Lipid metabolism integrates dietary fat handling, endogenous lipoprotein synthesis, fatty acid oxidation, ketogenesis and cholesterol homeostasis. Dietary triglycerides are emulsified by bile salts and hydrolysed by pancreatic lipase/colipase to free fatty acids and 2-monoacylglycerol; micellar absorption occurs in the jejunum. Enterocytes re-esterify triglyceride and package it with cholesterol, phospholipid and apolipoprotein B-48 into chylomicrons. Chylomicrons enter lymphatics, acquire apoC-II and apoE from HDL, and deliver triglyceride to adipose and muscle via lipoprotein lipase (LPL), which is activated by apoC-II and insulin. Chylomicron remnants, enriched in cholesterol ester, are cleared by hepatic apoE-mediated receptors.

The liver secretes VLDL containing apoB-100 to export endogenous triglyceride. VLDL is hydrolysed by LPL to IDL, then to LDL, the principal cholesterol-delivery particle. LDL is cleared through hepatic LDL receptors recognising apoB-100; receptor expression is upregulated by intracellular cholesterol depletion and inhibited by PCSK9-mediated lysosomal degradation. HDL mediates reverse cholesterol transport: apoA-I activates lecithin-cholesterol acyltransferase (LCAT), forming cholesterol esters for hepatic return directly via scavenger receptor B1 or indirectly via cholesteryl ester transfer protein (CETP).

Lipoprotein	Main apolipoprotein	Major lipid	Principal function
Chylomicron	B-48, C-II, E	Triglyceride	Transport dietary triglyceride; remnant uptake by liver
VLDL	B-100, C-II, E	Triglyceride	Export hepatic triglyceride
LDL	B-100	Cholesterol ester	Cholesterol delivery to peripheral tissues; atherogenic
HDL	A-I, A-II	Cholesterol ester	Reverse cholesterol transport

Fatty acid oxidation and ketone body metabolism

Free fatty acids are released from adipose tissue by hormone-sensitive lipase, stimulated by catecholamines, glucagon and cortisol, and inhibited by insulin. Long-chain fatty acids enter mitochondria via the carnitine shuttle: carnitine palmitoyltransferase I (CPT-I), translocase and CPT-II. CPT-I is inhibited by malonyl-CoA, preventing simultaneous fatty acid synthesis and oxidation. β-oxidation sequentially generates acetyl-CoA, FADH₂ and NADH; acetyl-CoA enters the tricarboxylic acid cycle or, in fasting, uncontrolled diabetes, prolonged exercise or alcohol excess, hepatic mitochondria generate ketone bodies: acetoacetate, β-hydroxybutyrate and acetone. β-hydroxybutyrate predominates in diabetic ketoacidosis; modern blood ketone meters detect β-hydroxybutyrate, with >3.0 mmol/L supporting clinically significant ketoacidosis in the appropriate context.

Cholesterol synthesis and regulation

Cholesterol synthesis occurs mainly in liver and intestine. The rate-limiting step is conversion of HMG-CoA to mevalonate by HMG-CoA reductase, targeted by statins. Cholesterol is required for cell membranes, steroid hormones, bile acids and vitamin D. Intracellular cholesterol regulates sterol regulatory element-binding proteins (SREBPs), altering LDL receptor and HMG-CoA reductase transcription. Bile acid synthesis via cholesterol 7α-hydroxylase represents the major route of cholesterol elimination; enterohepatic recirculation is interrupted by bile acid sequestrants.

Clinical classification and examination-relevant dyslipidaemias

For MRCP, recognise patterns rather than memorising rare eponyms alone. Familial hypercholesterolaemia is typically autosomal dominant due to LDLR, APOB or PCSK9 variants; heterozygous prevalence is approximately 1:250. Suspect in adults with LDL-C >4.9 mmol/L, premature coronary disease, tendon xanthomata or relevant family history. Homozygous disease may present in childhood with LDL-C often >13 mmol/L. Familial chylomicronaemia, commonly LPL or apoC-II deficiency, causes fasting triglycerides often >10–20 mmol/L, eruptive xanthomata, lipaemia retinalis and pancreatitis.

Pattern	Typical biochemical abnormality	Key associations
Isolated hypercholesterolaemia	Raised LDL-C	Familial hypercholesterolaemia, hypothyroidism, nephrotic syndrome, cholestasis
Hypertriglyceridaemia	Raised VLDL/chylomicrons	Diabetes, alcohol, obesity, pregnancy, corticosteroids, retinoids, protease inhibitors
Mixed dyslipidaemia	Raised LDL-C and triglycerides, low HDL-C	Metabolic syndrome, type 2 diabetes, chronic kidney disease

Therapeutic targets and pharmacology

NICE guidance uses QRISK3 for primary prevention in adults up to 84 years and recommends atorvastatin 20 mg once daily when 10-year CVD risk is ≥10%, after addressing secondary causes and lifestyle. For established atherosclerotic cardiovascular disease, high-intensity statin therapy is standard, usually atorvastatin 80 mg once daily unless contraindicated or interacting drugs are present. Treatment response is assessed using non-HDL-C: target reduction is >40% from baseline in NICE guidance. ESC/EAS guidance is more LDL-target based, aiming for LDL-C <1.4 mmol/L and ≥50% reduction in very-high-risk patients, and <1.0 mmol/L after recurrent events within 2 years.

Drug class	Mechanism	Typical dose	Key examination points
Statins	HMG-CoA reductase inhibition; ↑ LDL receptors	Atorvastatin 20–80 mg nocte/OD; rosuvastatin 5–40 mg OD	LDL-C reduction ~30–55%; myalgia, transaminitis; avoid statins in pregnancy
Ezetimibe	NPC1L1 intestinal cholesterol absorption blockade	10 mg OD	IMPROVE-IT: addition to simvastatin after ACS modestly reduced events; useful if statin-intolerant or inadequate response
PCSK9 inhibitors	Prevent LDL receptor degradation	Alirocumab 75–150 mg SC every 2 weeks; evolocumab 140 mg SC every 2 weeks or 420 mg monthly	LDL-C reduction ~50–60%; FOURIER and ODYSSEY OUTCOMES reduced major CV events
Fibrates	PPAR-α activation; ↑ LPL, ↓ VLDL	Fenofibrate 145–160 mg OD	Lower triglycerides 30–50%; consider when TG >10 mmol/L to reduce pancreatitis risk; caution with statins
Omega-3 ethyl esters/icosapent ethyl	Reduced hepatic VLDL production	Icosapent ethyl 2 g BD	REDUCE-IT showed event reduction in selected high-risk patients with raised TG on statins

Landmark statin trials underpin risk reduction: 4S demonstrated simvastatin reduced mortality in secondary prevention, while HPS showed broad benefit of simvastatin 40 mg across high-risk groups irrespective of baseline cholesterol. A practical exam principle is that absolute benefit depends on baseline cardiovascular risk, whereas relative LDL-C lowering is pharmacologically predictable. Severe hypertriglyceridaemia is managed urgently by removing precipitants, strict glycaemic control, alcohol cessation, fibrates and sometimes insulin infusion or plasma exchange if pancreatitis is severe, although trial evidence for plasma exchange is limited.