Pancreatic islets
One to two per cent of the pancreas runs the whole of glucose control: beta cells push glucose into storage, alpha cells pull it back out, and nearly every diabetes drug either flips one of those two switches or bypasses them entirely.
What it normally does
Beta cells (roughly half to two-thirds of each islet) are a glucose meter wired to a secretory machine. Glucose enters on a glucose transporter (GLUT2 in the classic rodent account; human beta cells rely mainly on GLUT1/GLUT3 — the principle is the same, uptake is not rate-limiting), is burnt to ATP, and ATP shuts a potassium channel in the membrane (the ATP-sensitive potassium channel, K_ATP). With that exit for positive charge closed, the cell depolarises, voltage-gated calcium channels open, and calcium makes insulin granules fuse with the membrane. More glucose in, more insulin out. Insulin and C-peptide are released in equal amounts, one for one.
Explains why destroying beta cells (type 1 diabetes) leaves no insulin at all, why an insulinoma secretes regardless of glucose, and why any drug that touches the K_ATP channel controls insulin release.
Insulin is the storage signal. It opens the door for glucose into muscle and fat (moves GLUT4 transporters to the cell surface), tells the liver to stop making new glucose (gluconeogenesis) and stop breaking down glycogen, and switches off fat breakdown (lipolysis) — the supply of free fatty acids that is the main substrate for ketone production. It also drives potassium into cells by stimulating the Na+/K+-ATPase.
Explains the hyperglycaemia when insulin disappears, why ketoacidosis happens when insulin is absent or grossly deficient (it is not confined to total insulin lack — it occurs in type 2 diabetes under severe stress and with SGLT2 inhibitors), and why potassium collapses the moment you treat DKA.
Alpha cells do the opposite job. (In rodent islets they form a neat rim around the beta cell core; in human islets they are scattered through it, which is why human islets are drawn both ways.) When glucose falls they release glucagon, which tells the liver to break down glycogen and make new glucose. Insulin normally holds glucagon back, so the two hormones move in opposite directions. Behind glucagon sits the sympathoadrenal response — adrenaline and sympathetic nerve traffic — which is also what produces the warning symptoms of a low: sweating, shaking, pounding heart.
Explains hypoglycaemia and why its warning symptoms fade after repeated episodes, and explains why glucagon is the rescue drug.
Beta cells have reserve. When tissues stop responding properly to insulin (insulin resistance), beta cells simply make more, and blood glucose stays normal for years at the cost of a chronically high insulin level. Glucose only rises when the beta cell can no longer keep up (beta cell failure), and by then function has been falling for a long time.
Explains why type 2 diabetes is silent for a decade and is frequently diagnosed only after the complications have already started.
What goes wrong
- Type 1 diabetes← from “Beta cells (roughly half to two-thirds of each…”
T cells destroy beta cells (autoimmune insulitis) over months to years. Alpha cells survive, so glucagon secretion continues with little insulin to oppose it. Once roughly 80-90% of beta cells are gone, insulin output can no longer cover a meal, and soon after that there is essentially none. Without insulin, glucose cannot enter muscle and fat while the liver keeps pouring more out. Blood glucose passes the renal threshold (about 10 mmol/L), spills into the urine and drags water with it (osmotic diuresis).
Absolute insulin deficiency: low C-peptide, positive autoantibodies, ketosis-prone, insulin required from day one. No oral agent can replace a hormone that is not being made.
You would find: A thin young person with a few weeks of drinking constantly, passing large volumes, losing weight while eating well, and thrush. Glucose high, ketones on the meter or dipstick, C-peptide low, and islet autoantibodies positive (GAD, IA-2, ZnT8, insulin autoantibodies). Around 130,000 Australians live with it, and Australia sits among the higher-incidence countries internationally (behind Finland and Scandinavia). It is not only a childhood disease — a substantial share starts after age 30 and gets mislabelled as type 2.
- Diabetic ketoacidosis← from “Insulin is the storage signal. It opens the do…”
Insulin is absent or overwhelmed by illness, and glucagon is high. Nothing restrains lipolysis, so free fatty acids flood the liver and are converted into ketoacids (beta-hydroxybutyrate and acetoacetate). Those acids consume bicarbonate and produce a high anion gap metabolic acidosis. Meanwhile the osmotic diuresis strips out water, sodium and potassium. Total body potassium is badly depleted even when the measured serum potassium looks normal or high, because acidosis and the absence of insulin hold potassium outside the cells.
Ketoacidosis is a lack-of-insulin problem, not a high-glucose problem. Fluid first, then an insulin infusion, and watch the potassium — it drops as soon as insulin goes in, and insulin is held until a low potassium has been replaced.
You would find: Deep sighing breathing (Kussmaul), acetone on the breath, vomiting and abdominal pain, dry and drowsy. Venous gas shows low pH, low bicarbonate, wide anion gap, high ketones. Glucose is usually above 11 mmol/L but can be near normal in euglycaemic DKA — pregnancy, starvation, and patients on SGLT2 inhibitors.
- Type 2 diabetes← from “Beta cells have reserve. When tissues stop res…”
Fat deposited in liver and muscle blunts insulin signalling (insulin resistance). Beta cells compensate by secreting more, and glucose stays normal for years. Then beta cell function falls away: the sharp first-phase insulin response goes first, so post-meal glucose rises; alpha cells are no longer suppressed so glucagon runs high and the liver over-produces glucose overnight; fasting glucose climbs. Because insulin is still present, lipolysis stays braked and ketoacidosis is uncommon.
Resistance plus beta cell failure. Not ketosis-prone. Metformin plus lifestyle first; GLP-1 receptor agonists and SGLT2 inhibitors added for weight, heart and kidney protection. Screen Aboriginal and Torres Strait Islander patients from age 18, not 40.
You would find: Usually no symptoms at all — found on HbA1c of 6.5% (48 mmol/mol) or more, or fasting glucose of 7.0 mmol/L or more. Look for what has already happened: retinopathy on fundoscopy, lost ankle reflexes and reduced monofilament sensation, albumin in the urine. Over a million Australians are registered with the NDSS for type 2 diabetes, and registrations understate true prevalence because many cases are undiagnosed. Aboriginal and Torres Strait Islander people are diagnosed roughly three to four times more often, at younger ages, with far higher rates of kidney failure and amputation; diabetes is a leading contributor to the life expectancy gap.
A tumour of beta cells that keeps the secretory machinery but loses the glucose thermostat, so it releases insulin no matter what the blood glucose is. That insulin keeps glucose locked in muscle and fat and stops the liver releasing any, so glucose falls — and it falls furthest when the patient has not eaten or has exercised.
Endogenous hyperinsulinaemic hypoglycaemia — insulin high AND C-peptide high. Usually small, single and benign, cured by surgical enucleation; diazoxide holds the K_ATP channel open to suppress insulin release in the meantime. Its salt and water retention follows from opening K_ATP channels in vascular smooth muscle — vasodilatation triggers reflex renal sodium retention — while the hypertrichosis it also causes is well recognised but not mechanistically explained. Always exclude a sulfonylurea first — identical biochemistry.
You would find: Whipple triad: symptoms of hypoglycaemia, a genuinely low glucose measured at the time, and relief with glucose. Classically fasting or exertional confusion, odd behaviour or seizures, often written off as psychiatric or epileptic for years, plus weight gain from constant eating to stave it off. Confirm with a supervised 72-hour fast: low glucose with inappropriately high insulin and C-peptide, and suppressed ketones.
- Treatment-related hypoglycaemia and hypoglycaemia unawareness← from “Alpha cells do the opposite job. (In rodent is…”
Injected insulin and sulfonylureas keep working whether or not the patient ate. In established type 1 diabetes the alpha cell also loses its glucagon response to a falling glucose within a few years, so the first line of defence is gone and the patient depends entirely on the adrenaline response. Each hypoglycaemic episode lowers the glucose level at which adrenaline fires, so after repeated episodes the confusion arrives before the warning symptoms.
The commonest harm of diabetes treatment. Conscious: 15 g fast carbohydrate, recheck at 15 minutes, then a longer-acting snack. Unconscious: IV glucose, or IM glucagon if there is no line. Sulfonylurea hypos relapse for hours — those patients get admitted.
You would find: Sweating, tremor, pallor, hunger and palpitations first; then confusion, slurred speech, aggression, seizure, coma. Any drowsy or oddly behaving diabetic patient gets a finger-prick glucose before anything else. Ask how low they get before they feel it — that single question tells you whether the warning system still works.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- The insulin receptor, a tyrosine kinase sitting on muscle, fat and liver cell membranes.
- Which does
- Binding makes the two halves of the receptor phosphorylate each other, switching on IRS-1/PI3K/Akt. GLUT4 transporters are moved to the cell surface, glycogen synthase is switched on, gluconeogenic enzymes are switched off, and hormone-sensitive lipase in fat is switched off.
- So you see
- Blood glucose falls, ketone production stops within hours, and potassium is driven into cells — insulin stimulates the Na+/K+-ATPase, so this happens independently of the glucose entering with it.
- And the same mechanism causes
- Hypoglycaemia. The receptor has no idea how much the patient ate. The same glucose-lowering action keeps going past normal if the dose outruns the carbohydrate, so a mealtime dose given before a meal that is then skipped drives glucose down until someone treats it.
- Handling
- Because insulin also pushes potassium into cells, serum potassium falls as soon as an infusion starts in DKA — check it before the first unit, hold insulin until potassium has been replaced if it is low, and keep replacing as you go. Weight gain is not a mystery side effect; it is the same storage action working in adipose tissue.
Catches people out: Never stop insulin in type 1 diabetes because the patient is not eating. Stopping it is how DKA begins.
- Binds
- Complex I of the mitochondrial respiratory chain in hepatocytes, where the OCT1 transporter concentrates the drug.
- Which does
- Partial block of complex I lowers ATP and raises AMP, activating AMPK (some of the effect on gluconeogenesis is AMPK-independent and follows from the energy charge itself). Making new glucose is expensive, so with less ATP the liver makes less of it; the liver leans harder on anaerobic glycolysis and produces more lactate.
- So you see
- Fasting glucose and HbA1c fall, weight stays flat or drifts down, and there is no hypoglycaemia when it is used alone.
- And the same mechanism causes
- Lactic acidosis — rare, but the one that kills. The same shift towards anaerobic metabolism that shuts down gluconeogenesis generates lactate, and metformin is cleared unchanged by the kidney. If renal function drops, or the patient becomes dehydrated, septic or hypoxic, the drug accumulates and the lactate has nowhere to go.
- Handling
- Withhold during acute illness, vomiting, sepsis and dehydration, and before surgery — the sick-day rule — and dose according to eGFR (avoid below 30). Iodinated contrast no longer means automatic withholding: with eGFR 30 or above and intravenous contrast, metformin is continued; it is withheld when eGFR is under 30, when contrast is given intra-arterially with likely renal exposure, or when the patient is already unwell. Nausea, metallic taste and diarrhoea are dose-related and gut-mediated (local drug concentration, bile acid and incretin effects); start low, take with food, or move to the extended-release form. Long-term use lowers vitamin B12 — check it if there is anaemia or new neuropathy.
Catches people out: The drug is renally cleared, so the danger is the patient whose kidneys quietly get worse, not the patient who takes an extra tablet.
- Binds
- SUR1, the sulfonylurea receptor subunit of the beta cell ATP-sensitive potassium channel.
- Which does
- Binding closes the channel without waiting for ATP. The cell depolarises, voltage-gated calcium channels open, calcium floods in and insulin granules fuse with the membrane — the same final pathway as glucose, but uncoupled from it.
- So you see
- Insulin rises and blood glucose falls, within hours of the first dose.
- And the same mechanism causes
- Hypoglycaemia. Insulin is released whether the glucose is 15 or 3, because the drug replaced the glucose sensor. A missed meal, unplanned exercise, or renal impairment that prolongs the drug lets it push glucose down and keep pushing. Weight gain follows from the same fact — more insulin means more storage.
- Handling
- Sulfonylurea hypoglycaemia relapses for many hours after the first glucose is given. These patients are admitted and observed, not fed and sent home. Older people and those with poor renal function are the ones who get hurt, which is why gliclazide is chosen over glibenclamide.
Catches people out: It is the mirror image of diazoxide: one shuts the K_ATP channel to force insulin out, the other holds it open to stop insulin coming out.
- Binds
- The glucagon receptor, a Gs-coupled receptor on hepatocytes.
- Which does
- Gs raises cAMP, PKA activates glycogen phosphorylase and inhibits glycogen synthase. Stored glycogen is broken down and glucose is exported from the liver; glucagon also drives hepatic gluconeogenesis.
- So you see
- Blood glucose rises over roughly ten to fifteen minutes — enough to wake the patient so they can eat and fix the problem properly.
- And the same mechanism causes
- Nausea and vomiting. Glucagon receptors on gut smooth muscle relax it and slow transit (the same effect radiology exploits to freeze the bowel), and there is a central emetic component as well, so the patient wakes up queasy. Roll them onto their side while they come round, and give oral carbohydrate as soon as their swallow is safe.
- Handling
- It fails wherever there is no glycogen: prolonged fasting, malnutrition, advanced liver disease, and alcohol-related hypoglycaemia. Those patients need IV glucose. Intranasal glucagon is registered overseas but is not the standard Australian rescue product — assume the IM/SC kit.
Catches people out: Glucagon buys minutes, not hours. When the glycogen runs out the hypoglycaemia returns — expect that with a long-acting insulin or a sulfonylurea.
Low glucose with high insulin — always ask for the C-peptide. Insulin and C-peptide leave the beta cell together, one for one. High C-peptide means the patient's own beta cells made it: insulinoma, or a sulfonylurea, so send a sulfonylurea screen because the biochemistry is identical. Suppressed C-peptide means the insulin was injected.
Now test whether it stuck
Reading this through is not the same as being able to reconstruct it. Every question in the bank is free, with a full debrief on each option.