What cells make up the endocrine pancreas?
The pancreas is a composite organ with exocrine (acinar) and endocrine functions. The endocrine tissue is arranged as discrete islets of Langerhans, which contain five endocrine cell types that secrete at least five hormones. They work together to regulate glucose homeostasis, energy storage and metabolism, acting on the liver, muscle and adipose tissue.
| Cell | Hormone | Main action |
|---|---|---|
| Beta cell | Insulin, C-peptide, amylin | Lower blood glucose; amylin suppresses glucagon and slows gastric emptying |
| Alpha cell | Glucagon | Raises blood glucose via the liver |
| Delta cell | Somatostatin | Inhibits secretion of many hormones, including insulin and glucagon |
| Epsilon cell | Ghrelin | Inhibits insulin secretion; stimulates appetite and growth hormone |
| PP cell | Pancreatic polypeptide | Minor regulatory role (listed as 'upsilon' cells in StatPearls) |
How is insulin synthesised and what is C-peptide?
Insulin is a peptide hormone made in beta cells. The mRNA is translated into the single-chain precursor preproinsulin; removal of its signal peptide in the endoplasmic reticulum gives proinsulin. Endopeptidases then excise the C-peptide, generating mature insulin. Insulin leaves the cell by exocytosis and diffuses into islet capillary blood.
- C-peptide is secreted in a 1:1 molar ratio with insulin. It has no established biological activity but is used as a marker of insulin secretion.
- Insulin circulates entirely unbound with a half-life of about 6 minutes.
- Amylin is co-secreted with insulin in the fed state; it suppresses glucagon from alpha cells, slows gastric emptying and acts on the brain's satiety centre.
What stimulates insulin secretion?
Plasma glucose is the primary regulator; the change in glucose with feeding or fasting is the main determinant of insulin secretion, and modest increases provoke a marked rise in plasma insulin. The sequence inside the beta cell is a classic exam flowchart.
- Glucose enters the beta cell through glucose transporters.
- Glucose metabolism raises intracellular ATP.
- ATP closes ATP-dependent potassium channels in the membrane.
- The membrane depolarises, and calcium enters.
- Rising intracellular calcium triggers insulin exocytosis.
Raised plasma amino acids and free fatty acids also induce insulin secretion. Somatostatin and ghrelin inhibit it. For the drugs that act on glucose homeostasis, see anti-diabetic drugs.
How does insulin act on its target cells?
Insulin binds a receptor tyrosine kinase on the plasma membrane. Binding to the receptor's alpha subunit activates the beta-subunit tyrosine kinase, causing autophosphorylation and phosphorylation of insulin receptor substrates, which activates the PI3K–Akt and MAPK pathways. These cascades control glucose uptake, glycogen synthesis, lipid synthesis and protein metabolism. The main target cells are hepatic, muscle and adipose cells — the tissues specialised for energy storage.
| Tissue / pathway | Effect of insulin |
|---|---|
| Muscle and adipose — glucose uptake | Increases GLUT4 translocation to the membrane. Exercise also stimulates GLUT4 uptake, independently of insulin |
| Liver — glycogen | Promotes glycogenesis (via dephosphorylation that activates glycogen synthase) and inhibits glycogenolysis |
| Liver — glucose output | Inhibits gluconeogenesis by down-regulating PEPCK, fructose-1,6-bisphosphatase and glucose-6-phosphatase; raises glucokinase and pyruvate kinase |
| Adipose — fat | Increases lipogenesis and glucose uptake (supplying glycerol-3-phosphate); inhibits hormone-sensitive lipase (reduced lipolysis) |
| Protein | Increases amino acid uptake and protein synthesis; decreases proteolysis (inhibits the ubiquitin–proteasome pathway) |
What does glucagon do and how is it released?
Glucagon is a 29-amino-acid peptide made by alpha cells. It derives from proglucagon, which prohormone convertase 2 cleaves in the pancreas. Its main function is to increase hepatic glucose production and restore normal glucose; it opposes insulin and is released in fasting, exercise or stress. It has a short half-life of 3 to 6 minutes.
| Stimulates glucagon | Inhibits glucagon |
|---|---|
| Low plasma glucose (hypoglycaemia) | High plasma glucose |
| Amino acids from a protein meal (the main determinant) | Insulin (inhibits proglucagon-expressing alpha cells) |
| Gluconeogenic amino acids such as alanine | GLP-1, amylin, somatostatin |
- Receptor: a 7-transmembrane G-protein–coupled receptor linked to the stimulatory G protein (Gs). It stimulates adenylyl cyclase, raising cAMP, which activates protein kinase A.
- Site of action: glucagon acts exclusively on the liver to antagonise insulin's effects on hepatocytes (the receptor gene is also expressed in kidney).
- Actions: enhances glycogenolysis and gluconeogenesis, inhibits glycogen synthesis (PKA phosphorylates glycogen synthase), and promotes fat oxidation that can lead to ketone body formation.
How do insulin and glucagon compare?
| Feature | Insulin | Glucagon |
|---|---|---|
| Source | Beta cells | Alpha cells |
| State | Fed (anabolic) | Fasting, exercise, stress (catabolic) |
| Receptor | Receptor tyrosine kinase | G-protein–coupled receptor (Gs, cAMP, PKA) |
| Glycogen | Synthesis up, breakdown down | Breakdown up, synthesis down |
| Gluconeogenesis | Inhibited | Stimulated |
| Fat | Lipogenesis up, lipolysis down | Fat oxidation and ketogenesis up |
| Half-life | About 6 minutes | 3 to 6 minutes |
What do somatostatin, amylin and ghrelin do?
- Somatostatin (delta cells, also hypothalamus and gastric D cells): binds a receptor linked to the inhibitory G protein, which lowers cAMP. It inhibits growth hormone, insulin, glucagon, gastrin, VIP and TSH. Glucagon stimulates its secretion.
- Amylin (beta cells, co-secreted with insulin): suppresses alpha-cell glucagon secretion, slows gastric emptying and stimulates the satiety centre.
- Ghrelin (epsilon cells, stomach and hypothalamus): inhibits insulin secretion from beta cells and stimulates appetite and growth hormone secretion.
The gut also signals to the pancreas: GLP-1 inhibits glucagon, which is the basis of incretin-based diabetes drugs (see gastrointestinal hormones).
How do different tissues handle glucose in the fed and fasting states?
In the fed state, rising glucose stimulates beta cells to secrete insulin, which facilitates uptake in insulin-sensitive tissues and promotes utilisation and storage, restoring euglycaemia. Each tissue does something different with the glucose.
| Tissue | Fate of glucose |
|---|---|
| Liver (after a meal) | Extracts glucose from the portal circulation; oxidises it for ATP or stores it as glycogen. When glycogen stores near capacity, excess glucose is converted to fatty acids, esterified to triglycerides and exported as VLDL to adipose tissue |
| Skeletal muscle | Glycolysis during exercise or stress; at rest it stores glucose as glycogen |
| Adipose tissue | ATP production and glycerol-3-phosphate for triglyceride synthesis; insulin stimulates lipogenesis and inhibits lipolysis |
| Brain | Primary energy substrate; uptake is largely insulin-independent through GLUT1 and GLUT3. Hypoglycaemia causes confusion, dizziness and light-headedness |
| Red blood cells | Sole fuel is glucose, used by anaerobic glycolysis because they lack mitochondria |
At the molecular level, preproinsulin consists of a signal peptide, B chain, C-peptide and A chain. After cleavage of the signal peptide, proinsulin folds in the endoplasmic reticulum, passes through the Golgi into secretory granules and is cleaved by the prohormone convertases PC1/3 and PC2 and carboxypeptidase E into insulin (A and B chains) and C-peptide. Insulin is stored in granules as zinc-coordinated hexamers. Insulin also has vasodilatory and anti-inflammatory effects: it raises endothelial nitric oxide synthase activity and decreases NF-κB activation.
How do abnormal insulin states produce diabetes, DKA and HHS?
Diabetes mellitus is a chronic disorder from either insufficient insulin production (type 1) or ineffective use of insulin by target tissues (type 2). Chronic hyperglycaemia arises when glucose entry (diet and hepatic production) outstrips uptake by insulin-dependent tissues: decreased uptake in muscle and fat plus increased hepatic gluconeogenesis and glycogenolysis.
| Feature | Type 1 | Type 2 |
|---|---|---|
| Defect | Autoimmune destruction of beta cells, absolute insulin deficiency | Insulin resistance with relative insulin deficiency |
| Mechanism | T-cell mediated, type IV hypersensitivity; insulitis (lymphocytic infiltration) | Resistance in muscle and fat, then compensatory hyperinsulinaemia and eventual beta-cell exhaustion |
| Serology / histology | Anti-GAD, anti-insulin and anti-islet cell antibodies | Islet amyloid deposition composed of amylin |
| Acute emergency | DKA | HHS |
DKA occurs mainly in type 1 diabetes and results from absolute insulin deficiency: lipolysis and ketone body production increase, causing a high anion gap metabolic acidosis with Kussmaul respirations, fruity breath from acetone, and dehydration. HHS is mainly a type 2 emergency, with severe hyperglycaemia without significant ketosis. See anion gap and Kussmaul breathing.
Which diseases arise from abnormal insulin and glucagon?
- Type 1 diabetes: chronic autoimmune destruction of beta cells causing insulin deficiency, from genetic susceptibility, autoimmunity and environmental insults.
- Type 2 diabetes and insulin resistance: decreased peripheral glucose uptake in muscle and adipose tissue and increased hepatic glucose output. See diabetes mellitus diagnosis and complications.
- Glucagonoma: a tumour of the pancreatic body or tail with excess glucagon causing the glucagonoma syndrome: weight loss, necrolytic migratory erythema, diabetes, and stomatitis, cheilitis and glossitis. See pancreatic tumours.
- Hypoglycaemia: low glucose stimulates glucagon, epinephrine and cortisol to restore glucose levels.
- Kidney failure: glucagon assays can overestimate secretion because of an elongated proglucagon fragment, so plasma glucagon is not recommended for diagnosing or treating diabetes.