FRCA Notes

Insulin Physiology

Resources

Diabetes medication pharmacology (BJA Education, 2017)
Non-insulin diabetes medicines: a narrative review for anaesthetists and intensivists (BJA, 2025)
Glucagon-like peptide-1 receptor agonists: a narrative review of clinical pharmacology and implications for peri-operative practice (Anaesthesia, 2024)

Insulin is a peptide hormone produced by the β-cells of the islets of Langerhans in the pancreas
It is the body's only major anabolic hormone, and the only hormone that lowers blood glucose
Its actions are opposed by a number of counter-regulatory (catabolic) hormones, most importantly glucagon
The pharmacology of therapeutic insulin is covered on the insulin page

The islets of Langerhans make up only 1-2% of pancreatic mass and contain several cell types:

α-cells: glucagon
β-cells (~70%): insulin and amylin
δ-cells: somatostatin
PP cells: pancreatic polypeptide

Insulin is synthesised as preproinsulin, cleaved to proinsulin in the endoplasmic reticulum
Proinsulin is packaged into secretory granules in the Golgi apparatus, where C-peptide is cleaved off

Insulin and C-peptide are released in equimolar amounts
C-peptide is therefore a marker of endogenous insulin secretion, useful in distinguishing exogenous insulin administration

Mature human insulin is a 51 amino acid polypeptide:

An A-chain (21 amino acids) and a B-chain (30 amino acids)
Linked by two disulphide bridges, with a third within the A-chain

Glucose-stimulated insulin release

Glucose is the most potent stimulus for insulin release
It enters the β-cell via GLUT2 transporters, independent of insulin
Glucokinase phosphorylates glucose and acts as the β-cell's 'glucose sensor'
Glycolysis increases the intracellular ATP:ADP ratio, which closes ATP-sensitive K⁺ (K_ATP) channels
The β-cell depolarises, opening voltage-gated Ca²⁺ channels
Ca²⁺ influx triggers exocytosis of insulin-containing granules

This is the pathway targeted by sulphonylureas and meglitinides, which close K_ATP channels directly

Pattern of secretion

There is continuous basal secretion, supplemented by bursts when plasma glucose rises
The response to a glucose load is biphasic:

First phase: rapid release of pre-formed granules over 5-10mins
Second phase: sustained release of newly synthesised insulin, lasting as long as the stimulus

Loss of the first phase response is an early feature of type 2 diabetes
Oral glucose provokes a greater insulin response than the same dose of intravenous glucose; this is the incretin effect

Factors affecting secretion

Stimulate insulin release	Inhibit insulin release
Glucose	Somatostatin
Amino acids e.g. leucine, arginine	α₂-adrenoceptor agonism (adrenaline, noradrenaline)
Incretins (GLP-1, GIP)	Hypoglycaemia
Vagal (parasympathetic) stimulation	Fasting
β₂-adrenoceptor agonism	Diazoxide (opens K_ATP channels)
Glucagon (paracrine effect)
Theophylline (↑ cAMP)

The net effect of catecholamines is inhibition of insulin release, as α₂ effects predominate

A transmembrane tyrosine kinase receptor made of two extracellular α-subunits and two transmembrane β-subunits
Insulin binds the α-subunits, causing autophosphorylation of the β-subunits
The activated receptor phosphorylates insulin receptor substrates (IRS), triggering two main pathways:

PI3-kinase pathway: metabolic effects, including translocation of GLUT4 transporters to the cell membrane in muscle and adipose tissue
MAP-kinase pathway: growth and mitogenic effects

Insulin also lowers intracellular cAMP by activating phosphodiesterase, opposing the actions of glucagon and catecholamines
The insulin-receptor complex is then internalised and degraded, which contributes to insulin clearance

Metabolism	Effects of insulin
Carbohydrate	↑ glucose uptake into muscle and adipose tissue (GLUT4) ↑ glycogen synthesis ↓ glycogenolysis ↓ gluconeogenesis
Fat	↑ lipogenesis and triglyceride storage ↓ lipolysis (inhibits hormone-sensitive lipase) ↓ ketogenesis
Protein	↑ amino acid uptake and protein synthesis ↓ proteolysis
Electrolytes	↑ intracellular K⁺ shift via Na⁺/K⁺-ATPase ↑ cellular uptake of phosphate and magnesium

The liver is the main target organ; hepatic glucose uptake is via GLUT2 and is not itself insulin-dependent, but insulin drives its storage as glycogen
Some tissues take up glucose independently of insulin: brain, red blood cells, renal medulla, β-cells and the gut
The K⁺ shift underlies the use of insulin and glucose to treat hyperkalaemia, and the hypokalaemia seen when treating DKA

These raise blood glucose and are catabolic; they are released in fasting, hypoglycaemia, exercise and the stress response

Hormone	Main actions on glucose
Glucagon	↑ hepatic glycogenolysis and gluconeogenesis; ↑ ketogenesis. The main acute defence against hypoglycaemia
Adrenaline	↑ glycogenolysis and gluconeogenesis; ↓ insulin release; ↑ lipolysis
Cortisol	↑ gluconeogenesis; ↓ peripheral glucose uptake (insulin resistance); acts over hours
Growth hormone	↓ peripheral glucose uptake; ↑ lipolysis; acts over hours

It is the insulin:glucagon ratio, rather than either hormone alone, that determines whether the liver stores or releases glucose
Glucagon is released from α-cells in response to low glucose and amino acids, and inhibited by glucose, insulin, somatostatin and GLP-1

Incretins are gut hormones released in response to food that enhance insulin secretion:

Glucagon-like peptide-1 (GLP-1), from L-cells of the distal small bowel and colon
Glucose-dependent insulinotropic polypeptide (GIP), from K-cells of the duodenum and jejunum

GLP-1 has several effects:

Glucose-dependent increase in insulin secretion from β-cells
Inhibition of glucagon secretion from α-cells
Slowed gastric emptying, reducing the post-prandial rise in glucose
Increased satiety and reduced appetite via the hypothalamus and brainstem

Endogenous GLP-1 has a half-life of ~2mins, as it is rapidly broken down by the circulating enzyme dipeptidyl peptidase-4 (DPP-4)
This pathway is the target of GLP-1 receptor agonists and DPP-4 inhibitors

Insulin is secreted into the portal vein, so the liver receives the highest concentrations
Approximately 50% is removed by the liver on first pass; most of the remainder is cleared by the kidney
Degraded by insulin-degrading enzyme (insulinase) following receptor-mediated internalisation
Plasma half-life is short, at approximately 5-10mins

Insulin requirements fall in renal failure owing to reduced clearance, increasing the risk of hypoglycaemia
Exogenous subcutaneous insulin bypasses the portal circulation, so patients receiving it have relatively higher peripheral and lower hepatic insulin concentrations than in health