Diabetes mellitus
Endocrine pancreas and diabetes mellitus: insulin, glucagon, crises and complications
Endocrine pancreas physiology for FCPS Part 1: insulin release, GLUT transporters, glucagon, hypoglycaemia, DKA, HHS, pregnancy and diabetic complications. It also separates diabetes mellitus from cranial and nephrogenic diabetes insipidus.
One of the most tested topics in past papers
Islet cells
| Cell | Hormone | Note |
|---|---|---|
| Beta (most numerous, central) | Insulin and C-peptide | Lost in type 1 diabetes |
| Alpha | Glucagon (the hyperglycaemic hormone of the pancreas) | Also lost after total pancreatectomy, so that diabetes is unstable |
| Delta | Somatostatin | Inhibits both insulin and glucagon |
| PP cells | Pancreatic polypeptide | Concentrated in the head |
How the beta cell releases insulin
- Glucose enters by GLUT2, is phosphorylated by glucokinase and raises ATP. ATP closes K-ATP channels, the cell depolarises, L-type Ca²⁺ channels open and Ca²⁺ triggers exocytosis. Sulfonylureas close the same channel.
- Loss of the first phase of release is an early sign of type 2 diabetes. Gut incretins (GLP-1, GIP) enhance release after oral glucose.
- Stimulate: glucose, amino acids, incretins, vagal (M3) and beta-2 input. Inhibit: somatostatin, alpha-2 adrenergic stimulation (adrenaline, noradrenaline: hyperglycaemia in stress and phaeochromocytoma), hypoglycaemia.
- Proinsulin is cleaved into insulin and C-peptide in equal amounts. The liver removes about half of insulin on first pass, but not C-peptide, so C-peptide better reflects secretion. Insulin's plasma half-life is only about 5 minutes; it is cleared mainly by liver and kidney.
Insulin signalling and glucose transporters
- Insulin binds the alpha subunits; the beta subunits autophosphorylate (tyrosine kinase), activating PI3-kinase–Akt, which moves GLUT4 to the membrane.
| Transporter | Site | Insulin-dependent? |
|---|---|---|
| GLUT1 | Red cells, blood–brain barrier, placenta | No |
| GLUT2 | Beta cell, liver, gut and renal basolateral membrane | No |
| GLUT3 | Neurons | No |
| GLUT4 | Skeletal muscle, heart and adipose tissue | Yes; exercise also moves it to the membrane |
| GLUT5 | Gut (fructose) | No |
Actions of insulin and glucagon
| Insulin (fed state: storage) | Glucagon (fasting: mobilisation) |
|---|---|
| Promotes glycogen and fat storage: glycogen synthesis, lipogenesis, activates lipoprotein lipase; inhibits lipolysis, gluconeogenesis and ketogenesis | Hepatic glycogenolysis (main action) and gluconeogenesis; decreases glycolysis and glycogen synthesis in liver |
| Stimulates protein synthesis | Ketogenesis when insulin is low |
| Moves K⁺ (Na⁺/K⁺-ATPase) and phosphate into cells | Acts on liver only: muscle lacks glucagon receptors |
- Glucagon and adrenaline share a mechanism: both act on Gs receptors, raise cAMP and activate PKA, so both raise blood glucose by glycogenolysis. Cortisol's main metabolic action is gluconeogenesis.
- Potassium shift: insulin and beta-2 agonists (salbutamol) both stimulate Na⁺/K⁺-ATPase and drive K⁺ into cells. Repeated nebulised salbutamol plus an insulin infusion causes hypokalaemia. In DKA a normal plasma potassium hides a total body deficit, so potassium is added once it is below about 5.5 mmol/L.
Defence against hypoglycaemia
- Order: first insulin secretion falls, then glucagon rises, then adrenaline; cortisol and GH act over hours.
- Repeated hypoglycaemia and autonomic neuropathy blunt the adrenaline response (hypoglycaemia unawareness); beta-blockers mask warning symptoms.
- Brain injury: neurons depend on glucose; severe prolonged hypoglycaemia causes energy failure, ATP-pump failure and cytotoxic oedema, seen as restricted diffusion in the cortex, hippocampi and basal ganglia, sparing cerebellum and brainstem. It can mimic stroke.
| Cause of hypoglycaemia | Insulin | C-peptide | Clue |
|---|---|---|---|
| Insulinoma | High | High | Sulfonylurea screen negative |
| Sulfonylurea ingestion | High | High | Drug screen positive |
| Injected insulin | High | Low | Health worker, relative with diabetes |
| Alcohol, liver failure, hypopituitarism | Low | Low | Gluconeogenesis blocked; cortisol and GH lost |
Diabetes: types, diagnosis and crises
- Type 1: autoimmune beta-cell loss (anti-GAD antibodies, low C-peptide). Type 2: insulin resistance with failing secretion; part of the metabolic syndrome.
- HbA1c (glycated haemoglobin) reflects mean glucose over the previous 2–3 months (red cell lifespan): the test for long-term control. It is falsely low with shortened red cell survival (haemolysis, recent blood loss).
- Polyuria: glucose filtered above the renal threshold (about 10 mmol/L, 180 mg/dL) exceeds proximal SGLT transport, stays in the tubule and causes osmotic diuresis.
- Ketone formation in DKA: absent insulin and high glucagon release fatty acids from fat; in liver mitochondria beta-oxidation floods acetyl-CoA beyond what the citric acid cycle can use (oxaloacetate diverted to gluconeogenesis), so acetyl-CoA is turned into acetoacetate and beta-hydroxybutyrate via HMG-CoA.
- HHS: residual insulin still suppresses lipolysis, so there is extreme glucose and osmolality without ketosis.
- Insulin treatment drives K⁺ and phosphate into cells. Dawn phenomenon: early-morning GH and cortisol raise glucose.
Diabetes insipidus: the other polyuria
| Test | Cranial DI | Nephrogenic DI | Primary polydipsia |
|---|---|---|---|
| Defect | No ADH from hypothalamus or posterior pituitary | Collecting duct does not respond to ADH (V2 receptor or aquaporin-2) | Excess drinking |
| Urine after water deprivation | Stays dilute | Stays dilute | Concentrates |
| After desmopressin | Concentrates markedly | No change | Already concentrated |
| Causes | Head injury, pituitary surgery, tumours | Lithium, hypercalcaemia, hypokalaemia, X-linked V2 mutation | Psychiatric |
Chronic complications
- Advanced glycation end products and the sorbitol (polyol) pathway damage tissues where glucose enters without insulin: lens, nerve, retina, kidney.
- Retinopathy: ischaemic retina makes VEGF, causing new vessels (proliferative retinopathy); laser photocoagulation destroys ischaemic peripheral retina to remove the stimulus.
- Neuropathy: glove-and-stocking sensory loss, autonomic neuropathy (gastroparesis, painless bladder, silent infarction, postural hypotension). Diabetics are also prone to carpal tunnel syndrome (median nerve; numb index fingertip).
- Vascular disease and foot: atherosclerosis and microangiopathy cause dry gangrene of toes and fingers; the commonest complication of the diabetic foot is a neuropathic ulcer with infection.
- Infection: high tissue glucose and impaired neutrophils. In emphysematous pyelonephritis, gas-forming bacteria (E. coli, Klebsiella) ferment tissue glucose, producing CO₂ and hydrogen in the renal parenchyma; CT shows it reliably. Malignant otitis externa (Pseudomonas, elderly diabetic, night pain, granulation in the canal floor) spreads to the skull base through the fissures of Santorini in the cartilaginous canal, then the stylomastoid foramen (facial palsy). Gram-negative septic shock is driven by endotoxin (lipid A).
- Diabetic mastopathy: long-standing type 1 diabetes with microvascular disease; hard breast lump with shadowing, histology shows dense keloid-like fibrosis with perivascular B lymphocytes. Imaging cannot separate it from cancer, so biopsy is needed.
- Kidneys stay large in diabetic nephropathy; dialysis patients develop renal osteodystrophy from secondary hyperparathyroidism.
Pregnancy
- Late pregnancy: human placental lactogen, placental GH, progesterone and cortisol cause insulin resistance. Requirements fall sharply once the placenta is delivered.
- Glucose crosses by GLUT1; insulin does not. Fetal hyperglycaemia causes fetal hyperinsulinism: macrosomia, polyhydramnios and neonatal hypoglycaemia. Screening by 75 g OGTT at 24–28 weeks.
Imaging links
- FDG is phosphorylated by hexokinase and trapped in glucose-avid cells. Insulin before FDG diverts it into muscle and fat (GLUT4); metformin increases bowel uptake.
Remember Insulin high with C-peptide low means someone injected insulin.
Exam trap The first defence against falling glucose is reduced insulin secretion, not glucagon.
Exam trap In DKA a normal potassium hides a total body deficit; insulin will expose it.
How FCPS asks about this
- Insulin-dependent glucose transporter: GLUT4 in skeletal muscle and fat.
- Main metabolic effect of insulin: promotes glycogen and fat storage.
- Hyperglycaemic factor from the pancreas: glucagon; it shares cAMP signalling with adrenaline.
- Salbutamol plus insulin infusion: hypokalaemia from a shift into cells.
- Urine concentrates only after desmopressin: cranial DI; no response on lithium is nephrogenic DI.
- Test for long-term control: HbA1c.
- Gas in renal parenchyma in a diabetic: bacteria fermenting tissue glucose.
Test yourself on this topic
5 of the 74 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 58-year-old woman with poorly controlled diabetes has fever, flank pain and shock, and is found to have gas within the left renal parenchyma (emphysematous pyelonephritis). How does the gas form?
Answer: Bacteria fermenting tissue glucose
Emphysematous pyelonephritis occurs almost always in diabetics. High tissue glucose, poor perfusion from diabetic vascular disease and impaired host defence allow facultative anaerobes, usually E. coli or Klebsiella, to ferment glucose, producing carbon dioxide and hydrogen. Gas collects in necrotic renal tissue and can spread outside the kidney. It carries a high mortality without urgent drainage or nephrectomy.
Emphysematous pyelonephritis
- Mostly in diabetics
- E. coli, Klebsiella ferment glucose
- Gas: CO₂ and hydrogen
- High mortality
Remember Gas in the kidney of a diabetic: emphysematous pyelonephritis.
Exam trap Gas-forming infection in a diabetic is usually E. coli or Klebsiella, not Clostridium.
Why the other options are wrong
- Air entering through a bowel fistula No fistula is described; gas is in the parenchyma.
- Air introduced by urinary catheter Catheter air stays in the bladder.
- Clostridial toxin dissolving fat Clostridia are not the usual cause.
- Nitrogen released from dead tissue Not the source of the gas.
A 72-year-old diabetic man has severe left ear pain worse at night, granulation tissue in the floor of the ear canal, a new left facial palsy and Pseudomonas grown from the canal. Through which route does the infection most often spread from the canal to the skull base?
Answer: Fissures of Santorini in the canal cartilage
Necrotising (malignant) otitis externa occurs mainly in elderly diabetics, whose microangiopathy and impaired neutrophil function allow infection to spread from the canal into bone. Pseudomonas aeruginosa causes most cases. It spreads through the fissures of Santorini in the floor of the cartilaginous canal into the skull base, and the facial nerve is often affected at the stylomastoid foramen. Skull base osteomyelitis follows.
Necrotising otitis externa
- Elderly diabetic
- Granulation on canal floor
- Pseudomonas
- Skull base erosion, facial palsy
Remember Diabetic with ear pain and facial palsy: think Pseudomonas skull base osteomyelitis.
Exam trap Treating it as simple otitis externa delays care of a skull base osteomyelitis.
Why the other options are wrong
- Through the tympanic membrane into the middle ear The drum is usually intact.
- Along the Eustachian tube A route for middle ear infection, not this.
- Through the internal acoustic meatus Would bring early hearing and facial nerve loss inside the skull.
- Along the sigmoid venous sinus A route for intracranial venous spread, not bone.
During an intravenous glucose tolerance test, a 50-year-old man with impaired glucose tolerance shows no insulin peak in the first 10 minutes, although his later insulin response is present. Which change in β-cell function is this?
Answer: Loss of first-phase insulin release
Glucose causes biphasic insulin secretion: a rapid first phase within about 10 minutes, from release of granules already docked at the membrane, then a slower, sustained second phase from mobilised and newly made insulin. Loss of the first phase is one of the earliest β-cell defects in type 2 diabetes and impaired glucose tolerance, leading to higher post-meal glucose. The second phase persists for longer. Incretins act on oral, not intravenous, glucose.
Biphasic insulin release
- First phase: docked granules, 10 min
- Second phase: sustained
- First phase lost early in T2DM
- Gives post-meal hyperglycaemia
Remember Type 2 diabetes loses the quick insulin spike first.
Exam trap Normal fasting glucose can hide an early loss of first-phase secretion.
Why the other options are wrong
- Loss of second-phase insulin release His later response is preserved.
- Absent incretin effect IV glucose bypasses the gut incretin effect.
- Complete β-cell destruction Some insulin is still secreted.
- Excess proinsulin cleavage Not the defect described.
An 18-year-old with cystic fibrosis who has needed pancreatic enzyme supplements since infancy develops diabetes. What is the main mechanism of her diabetes?
Answer: Islet loss from exocrine fibrosis and fat
In cystic fibrosis, thick secretions block the pancreatic ducts from early life, causing exocrine destruction, fibrosis and fatty replacement of the gland. Islets are gradually caught up and lost, so insulin secretion falls; glucagon is reduced too. Insulin resistance from infection and steroids adds to it. It is not autoimmune, and ketoacidosis is uncommon.
CF-related diabetes
- Duct plugging from birth
- Exocrine fibrosis and fat
- Islets lost secondarily
- Insulin and glucagon fall
Remember CF pancreas: islets lost with the acini.
Exam trap CF-related diabetes is not type 1 diabetes, though it needs insulin.
Why the other options are wrong
- Autoimmune destruction of β cells Autoantibodies are not the cause.
- Peripheral insulin resistance only Resistance contributes but is not the main defect.
- Mutation in the glucokinase gene That is MODY 2.
- Excess glucagon from α-cell hyperplasia Glucagon is also reduced.
In a study of β-cell function, peripheral C-peptide is used instead of peripheral insulin to estimate how much insulin the pancreas secretes. Insulin and C-peptide are released in equal molar amounts. Why does C-peptide give the better estimate?
Answer: C-peptide is not extracted by the liver
Proinsulin is cleaved in β-cell granules into insulin and C-peptide, which are secreted together in equal molar amounts into the portal vein. The liver removes about half of the insulin on first pass, but takes up almost no C-peptide. C-peptide also has a longer half-life (about 30 minutes vs 4–6 minutes for insulin). Peripheral C-peptide therefore reflects secretion more faithfully, and it is absent from injected insulin.
C-peptide
- Equal molar release with insulin
- Liver removes half the insulin
- But not C-peptide
- Longer half-life, renal clearance
Remember C-peptide tells you what the pancreas really made.
Exam trap C-peptide rises in renal failure because the kidney clears it.
Why the other options are wrong
- C-peptide is released before insulin They are released together.
- C-peptide has a shorter half-life Its half-life is longer, not shorter.
- C-peptide binds the insulin receptor It does not act on the insulin receptor.
- C-peptide is stored in the liver It is cleared mainly by the kidney.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: Endocrine and reproductive physiology, Endocrine pancreas and diabetes mellitus
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