Glucose homeostasis

What it normally does

• After a meal, beta cells in the pancreatic islets release insulin. It pushes glucose into muscle and fat by moving GLUT4 transporters to the cell surface, tells the liver to store glucose as glycogen, and — the part students forget — switches OFF fat breakdown in adipose tissue (it inhibits hormone-sensitive lipase). Little free fatty acid reaching the liver means little substrate for ketones.

  Explains why insulin deficiency relative to glucagon, and not the high glucose itself, is what generates diabetic ketoacidosis (pathology 1) and euglycaemic ketoacidosis (pathology 3).

• Between meals insulin falls and glucagon rises. Glucagon tells the liver to break down its glycogen store (glycogenolysis), which is the dominant source for the first several hours and is largely exhausted by about 24 hours; gluconeogenesis from lactate, amino acids and glycerol contributes from early in the fast and takes over as glycogen runs down. The brain uses roughly 120 g of glucose a day, cannot make its own, and stores almost none.

  Explains why the brain fails within minutes of a low glucose, and why a hypo is an emergency (pathology 0).

• The defence against falling glucose happens in a fixed order, at roughly fixed thresholds: insulin secretion switches off first (around 4.5 mmol/L), then glucagon and adrenaline fire (around 3.8), then you feel it — sweating, tremor, hunger, palpitations, largely adrenergic (around 3.0), and only then does the brain run out — confusion, seizure, coma (below about 2.8). Cortisol and growth hormone add a slower second line.

  Explains where hypoglycaemia symptoms come from, and why losing that adrenaline layer produces hypoglycaemia unawareness (pathology 0).

• The kidney reabsorbs essentially all filtered glucose up to a plasma level of about 10 mmol/L (the renal threshold): SGLT2 in the early proximal tubule takes about 90% of it and SGLT1 further down takes the rest. Above that threshold glucose spills into the urine and drags sodium and water with it (osmotic diuresis).

  Explains the polyuria and massive dehydration of the hyperosmolar hyperglycaemic state (pathology 2), and it is precisely the mechanism SGLT2 inhibitors exploit on purpose.

What goes wrong

• Hypoglycaemia← from “The defence against falling glucose happens in…”

  Injected insulin or a sulfonylurea keeps working while glucose is already falling — the one thing normally regulated endogenous insulin secretion does not do (an insulinoma is the classic exception, secreting insulin despite a low glucose). In type 1 diabetes the glucagon response to a low glucose is lost within about five years, so adrenaline becomes the main defence left. Repeated lows then blunt the adrenaline response too: the warning symptoms disappear (hypoglycaemia unawareness) and the first sign of a low becomes confusion or a seizure.

  Four is the floor. The warning symptoms are largely adrenergic, so non-selective beta blockers such as propranolol mask them and leave sweating (a sympathetic fibre that is cholinergic) as the surviving clue; they also blunt beta-2 mediated hepatic glucose release, so recovery is slower. Alcohol blocks gluconeogenesis, so an alcohol-related hypo is deep, late, and responds poorly to glucagon.

  You would find: Sweaty, tremulous, tachycardic, hungry and irritable, then confused or fitting. Capillary glucose below 4.0 mmol/L, and symptoms resolve within minutes of giving glucose (Whipple's triad). In an unaware patient there is no sweaty warning phase at all — they present already confused.

• Diabetic ketoacidosis (DKA)← from “After a meal, beta cells in the pancreatic isl…”

  Absent insulin means nothing restrains hormone-sensitive lipase, and the counter-regulatory hormones are unopposed. Free fatty acids flood the liver and beta-oxidation churns out acetoacetate and beta-hydroxybutyrate faster than tissues can use them. These are strong acids: bicarbonate is consumed and a high anion gap metabolic acidosis develops. Glucose climbs at the same time because the liver keeps making it and muscle cannot take it up, and the resulting osmotic diuresis strips out water and potassium.

  The number that kills is the potassium, not the glucose — total body potassium is depleted even when the serum level reads normal or high, because acidosis and insulin deficiency hold it outside cells. A low serum potassium at presentation means severe depletion. Precipitants: infection, missed insulin, first presentation, and in Australia cost or access barriers to insulin and supplies. In children, watch for cerebral oedema during treatment.

  You would find: A person with type 1 diabetes, unwell over about a day: vomiting, abdominal pain, deep sighing (Kussmaul) breathing, ketotic breath, dry mucous membranes. Glucose usually above 11 mmol/L (or known diabetes — glucose can be near-normal), blood ketones 3.0 mmol/L or more, pH below 7.30 or bicarbonate below 15 mmol/L.

• Hyperosmolar hyperglycaemic state (HHS)← from “The kidney reabsorbs essentially all filtered …”

  In type 2 diabetes there is still enough insulin to suppress lipolysis — so ketones stay low — but not enough to control glucose. Glucose climbs over days to weeks and the osmotic diuresis runs the whole time. An older person who is thirsty but cannot reach water loses litres. Plasma becomes concentrated (hyperosmolar), water is pulled out of brain cells, and consciousness falls.

  Fluid first, insulin cautiously and later — the water deficit is often 8–10 litres, and dropping glucose and osmolality too fast risks fluid shifting into the brain. Hyperviscosity brings stroke and venous thromboembolism. Aboriginal and Torres Strait Islander Australians develop type 2 diabetes roughly three to four times as often and at younger ages, so 'too young for HHS' is a dangerous assumption.

  You would find: An older patient with days to weeks of polyuria, thirst and increasing drowsiness. Profoundly dry, glucose often above 30 mmol/L, serum osmolality above 320 mOsm/kg, ketones low and no significant acidosis. Mortality is several times that of DKA.

• Euglycaemic ketoacidosis on an SGLT2 inhibitor← from “After a meal, beta cells in the pancreatic isl…”

  The drug dumps glucose into the urine, so blood glucose stays low-ish; low glucose means low insulin secretion, and glucagon is relatively (and, with these drugs, absolutely) higher. That ratio is all ketogenesis needs, and the kidney also clears ketones less well on a gliflozin. Add a trigger that raises counter-regulatory hormones and cuts carbohydrate intake — surgery, fasting, vomiting, sepsis, a low-carbohydrate diet — and the patient makes ketones while the glucose meter reads 8 or 10 mmol/L.

  Check ketones, not glucose, in any unwell patient on a gliflozin. These agents are withheld for at least 3 days before elective surgery and during acute illness for exactly this reason, and treatment still needs insulin plus glucose, because insulin is what turns ketogenesis off.

  You would find: Nausea, vomiting, breathlessness and malaise a day or two after an operation or during a fasting illness, in a patient taking empagliflozin or dapagliflozin. Glucose near normal, blood ketones high, venous gas showing a high anion gap metabolic acidosis. Missed unless someone checks ketones.

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.