Insulin and glucose metabolism

Clinical relevance to anaesthesia & critical care

• Perioperative stress causes hyperglycaemia via increased counter-regulatory hormones and insulin resistance; associated with infection, poor wound healing, and worse outcomes in critical illness.
  • Drivers: catecholamines, cortisol, glucagon, growth hormone, inflammatory cytokines → ↑ hepatic glucose output + ↓ peripheral uptake.
  • Anaesthetic/analgesic depth and regional techniques can attenuate stress response and reduce hyperglycaemia.
• Hypoglycaemia under anaesthesia may be masked (no symptoms); risk increased by insulin, fasting, sepsis, liver failure, renal failure, and reduced intake.
  • Neuroglycopenia → seizures, coma; autonomic signs (tachycardia, sweating) may be blunted by anaesthesia/beta-blockers.
• Diabetes and insulin therapy influence fluid/electrolytes: insulin shifts potassium intracellularly; DKA/HHS cause major total body deficits.
  • Insulin activates Na+/K+-ATPase → ↓ serum K+; risk of hypokalaemia during treatment of DKA/HHS.
  • Hyperglycaemia causes osmotic diuresis → dehydration, electrolyte loss; corrected sodium and osmolality guide management.
• Common perioperative glucose targets: avoid both severe hyperglycaemia and hypoglycaemia; many ICUs aim ~6–10 mmol/L (institution-dependent).
  • Tight control increases hypoglycaemia risk; moderate control generally preferred.

High-yield definitions & normal values

• Fasting plasma glucose: typically ~4–6 mmol/L; post-prandial rises limited by insulin response.
• Hypoglycaemia (pragmatic): <4.0 mmol/L; clinically significant often <3.0 mmol/L (context dependent).
• Hyperosmolar state risk increases with marked hyperglycaemia; effective osmolality (approx): 2×[Na+] + glucose (mmol/L).

Overview: glucose homeostasis

• Goal: maintain plasma glucose within narrow range to supply obligate glucose users (brain, RBCs, renal medulla) while storing excess energy.
  • Fed state: insulin predominates → storage and utilisation.
  • Fasting/stress: counter-regulatory hormones predominate → mobilisation and production.
• Key processes: glycogenesis, glycogenolysis, gluconeogenesis, glycolysis, lipolysis, ketogenesis.

Insulin: synthesis, storage, secretion

• Source: pancreatic β-cells (islets of Langerhans).
• Synthesis: preproinsulin → proinsulin (ER) → insulin + C-peptide (Golgi) stored in secretory granules.
  • C-peptide helps distinguish endogenous insulin secretion from exogenous insulin administration.
• Glucose-stimulated insulin secretion mechanism: glucose uptake (GLUT2) → phosphorylation (glucokinase) → ↑ ATP/ADP → closure of ATP-sensitive K+ channels → membrane depolarisation → opening of voltage-gated Ca2+ channels → Ca2+-triggered exocytosis.
  • Sulfonylureas close KATP channels → ↑ insulin release; diazoxide opens KATP channels → ↓ insulin release.
• Secretion pattern: biphasic (rapid first phase from readily releasable granules; slower second phase from mobilisation/synthesis).
• Stimulators: glucose, amino acids (esp leucine/arginine), incretins (GLP-1, GIP), vagal ACh (M3), β2-adrenergic stimulation.
• Inhibitors: hypoglycaemia, somatostatin, α2-adrenergic stimulation (catecholamines), leptin (context dependent).
• Clearance: mainly hepatic first-pass (portal delivery) and renal; short plasma half-life (~5–10 min).

Insulin receptor and signalling

• Receptor: transmembrane tyrosine kinase (α2β2); insulin binding → autophosphorylation → IRS proteins → downstream pathways.
• Major signalling arms: PI3K-Akt (metabolic effects) and MAPK (growth/mitogenic effects).
• GLUT4 translocation (skeletal muscle and adipose) is insulin-dependent; increases glucose uptake.
  • GLUT1: basal uptake (many tissues, incl brain endothelium).
  • GLUT2: liver, β-cells, kidney, intestine; high capacity, bidirectional; glucose sensor.
  • GLUT3: neurons; high affinity.

Metabolic actions of insulin (organ-based)

• Liver: ↑ glycogenesis, ↑ glycolysis, ↓ glycogenolysis, ↓ gluconeogenesis; ↑ lipogenesis and VLDL synthesis; ↓ ketogenesis.
  • Mechanisms include dephosphorylation/activation of glycogen synthase and inhibition of gluconeogenic gene expression.
• Skeletal muscle: ↑ GLUT4-mediated glucose uptake; ↑ glycogen synthesis; ↑ amino acid uptake and protein synthesis; ↓ proteolysis.
• Adipose: ↑ GLUT4-mediated glucose uptake; ↑ triglyceride synthesis; ↑ lipoprotein lipase activity; ↓ hormone-sensitive lipase → ↓ lipolysis.
• Electrolytes: drives K+ (and phosphate, Mg2+) into cells; stimulates Na+/K+-ATPase.

Counter-regulatory hormones and their effects

• Glucagon (α-cells): ↑ hepatic glycogenolysis and gluconeogenesis; promotes ketogenesis; key in fasting.
• Catecholamines: ↑ glycogenolysis (liver and muscle), ↑ lipolysis; inhibit insulin secretion via α2; stimulate glucagon.
• Cortisol: permissive and longer-term; ↑ gluconeogenesis, ↑ proteolysis, ↑ lipolysis; causes insulin resistance.
• Growth hormone: ↓ glucose uptake in muscle/adipose, ↑ lipolysis; contributes to insulin resistance.

Fed vs fasting physiology

• Fed state (0–4 h): insulin high → hepatic glycogenesis; muscle glycogen synthesis; lipogenesis in adipose.
• Early fasting (4–24 h): ↓ insulin, ↑ glucagon → hepatic glycogenolysis dominates; gluconeogenesis begins to rise.
• Prolonged fasting (>24 h): gluconeogenesis predominates (lactate, alanine, glycerol); ketogenesis increases; brain gradually uses ketones reducing glucose requirement.
  • RBCs always require glucose (no mitochondria) → produce lactate (Cori cycle).

Gluconeogenesis: substrates and sites

• Main sites: liver (major), kidney cortex (increases in prolonged fasting).
• Substrates: lactate (Cori cycle), alanine and other glucogenic amino acids (glucose-alanine cycle), glycerol (from lipolysis).
• Key irreversible bypass enzymes: pyruvate carboxylase, PEP carboxykinase, fructose-1,6-bisphosphatase, glucose-6-phosphatase.

Glucose utilisation by organs

• Brain: high glucose demand; can use ketone bodies during prolonged fasting; limited fatty acid use (BBB transport and metabolic constraints).
• Red blood cells: anaerobic glycolysis only → lactate; no glycogen stores; no ketone use.
• Skeletal muscle: uses glucose, fatty acids, ketones; insulin increases uptake via GLUT4; exercise increases GLUT4 translocation via insulin-independent pathways (AMPK).
• Heart: prefers fatty acids but can use glucose and lactate; insulin increases glucose uptake.

Stress response, surgery, and critical illness

• Surgery/trauma/sepsis: ↑ hepatic glucose production (glycogenolysis + gluconeogenesis) and peripheral insulin resistance; lipolysis and proteolysis increase.
• Inflammation-mediated insulin resistance: cytokines (e.g., TNF-α, IL-6) impair insulin signalling; contributes to hyperglycaemia despite high insulin levels.
• Anaesthetic considerations: dextrose-containing fluids can worsen hyperglycaemia; insulin infusions require frequent glucose and potassium monitoring.

Hypoglycaemia: physiology and perioperative features

• Defences against falling glucose: ↓ insulin secretion (first), ↑ glucagon and adrenaline, then ↑ cortisol and GH.
• Symptoms: autonomic (sweating, tremor, palpitations, anxiety) and neuroglycopenic (confusion, seizures, coma).
• Under anaesthesia: autonomic warning signs may be absent; unexplained tachycardia/hypertension or delayed emergence may be clues.

Diabetes-related metabolic emergencies (conceptual physiology)

• DKA: absolute insulin deficiency + high counter-regulatory hormones → hyperglycaemia, ketogenesis, metabolic acidosis; total body K+ depleted despite normal/high serum K+ initially.
• HHS: relative insulin deficiency sufficient to suppress ketogenesis but not hyperglycaemia → very high glucose and osmolality with profound dehydration.