After a meal, glucose floods into the blood; during a long run it is used up fast. Two hormones from the pancreas, insulin and glucagon, pull it back towards about 5 mmol per cubic decimetre. Glucagon also shows how a cell turns a single signal molecule into a huge response.
Blood glucose is kept near 5 mmol dm−3 by negative feedback. The α and β cells of the islets of Langerhans in the pancreas are both receptors and the source of the hormones. When glucose is high, β cells secrete insulin: in muscle cells vesicles with GLUT4 transporters fuse with the cell surface membrane, so more glucose enters by facilitated diffusion; in liver cells (and muscle) enzymes for glycogenesis are activated, and glucose is respired faster. When glucose is low, α cells secrete glucagon, which acts on liver cells: it binds to a cell surface receptor, causing a conformational change that activates a G protein, which stimulates adenylyl cyclase to make cyclic AMP (the second messenger). cAMP activates protein kinase A, starting an enzyme cascade of phosphorylations that amplifies the signal until glycogen phosphorylase breaks down glycogen to glucose. Test strips and biosensors measure glucose using glucose oxidase (glucose to gluconic acid and hydrogen peroxide) and, on strips, peroxidase with a colourless chromogen that becomes coloured.
Fig. 1: the glucagon signalling pathway in a liver cell; each active enzyme activates many molecules of the next, so the signal is amplified
Section 01
Glucagon and the cAMP cascade.
Press Next step to move through all seven stages. Watch the ACTIVE MOLECULES reading go from 1 (glucagon, receptor, G protein) to many cAMP, then more, even more, and finally thousands of glucose molecules leaving the cell.
1. Binding: glucagon is a peptide hormone and cannot cross the membrane, so it binds to a specific receptor on the cell surface membrane of a liver cell.
2. Conformational change: binding changes the shape of the receptor on the inside of the membrane.
3. G protein: the receptor activates a G protein, which then activates the membrane enzyme adenylyl cyclase.
4. Second messenger: adenylyl cyclase converts ATP into cyclic AMP (cAMP). One enzyme molecule makes many cAMP molecules, which diffuse through the cytoplasm.
5. Protein kinase A: cAMP activates protein kinase A, the first enzyme of the cascade.
6. Cascade and amplification: each active kinase activates many molecules of the next enzyme by phosphorylation (adding a phosphate group from ATP), so at every step more and more enzyme molecules are active.
7. Cellular response: the final enzyme, glycogen phosphorylase, is activated and catalyses the breakdown of glycogen to glucose (glycogenolysis). Glucose diffuses out of the liver cell into the blood.
Examiner trap
The hormone is the first messenger; it never enters the cell. cAMP is the second messenger that carries the signal through the cytoplasm.
Section 02
Insulin and glucagon: negative feedback.
Press After a meal (blood glucose jumps to 9 mmol dm−3) and watch insulin act on the muscle cell and liver cell; the green GLUT4 vesicles move to the membrane. Then press Fasting or exercise (3.2 mmol dm−3) and watch glucagon act on the liver cell only. Both curves return to about 5.
Blood glucose rises
Blood glucose falls
detected by
β cells in the islets of Langerhans
α cells in the islets of Langerhans
hormone secreted
insulin (and less glucagon)
glucagon (and less insulin)
target cells
muscle cells, liver cells and many others
liver cells (muscle cells have no glucagon receptors)
effects
muscle: GLUT4 vesicles fuse with the membrane, so more glucose enters by facilitated diffusion; liver and muscle: glycogenesis (glucose → glycogen) and faster respiration of glucose
liver: glycogenolysis (glycogen → glucose) via the cAMP cascade, and gluconeogenesis (glucose made from amino acids and glycerol)
result
blood glucose falls back towards the set point
glucose leaves liver cells and blood glucose rises
Negative feedback: as glucose returns to normal, the β or α cells are stimulated less and secretion falls, so the response switches itself off.
Liver cells take up glucose through transporters that are always in the membrane; insulin speeds their uptake mainly by activating glycogen synthesis, which keeps the glucose concentration inside low.
Examiner trap
Glycogen, glucagon and glycogenesis are easy to confuse. Glucagon is the hormone; glycogen is the storage polysaccharide; glycogenesis makes glycogen; glycogenolysis breaks it down.
Stage 1 · Learn
Check what the sim just showed you
Four quick checks. Each correct answer earns XP and records this skill on your profile.
Quick check+10 XP
In the signalling simulator, at which step does the ACTIVE MOLECULES reading first change from 1 to many?
Quick check+10 XP
In the simulator, which enzyme catalyses the final step, the breakdown of glycogen?
Quick check+10 XP
You press After a meal. What does insulin do to the muscle cell in the simulator?
Quick check+10 XP
Why does the test strip only give a reading such as about 10 mmol dm−3 while the biosensor gives 9.9?
Section 03
Measuring glucose: strips and biosensors.
Choose test strip, set the glucose slider (0 to 20 mmol dm−3) and press Test: the pad darkens and you match it against the colour chart, which only reads to the nearest 5. Then choose biosensor and test the same value: it gives a digital reading to 0.1 mmol dm−3.
Glucose oxidase: catalyses glucose + oxygen → gluconic acid (gluconolactone) + hydrogen peroxide. It is specific to glucose, so other sugars do not interfere.
Test strip (dipstick): the pad holds immobilised glucose oxidase, peroxidase and a colourless chromogen. Peroxidase catalyses the reaction of hydrogen peroxide with the chromogen, forming a coloured compound. More glucose gives a darker colour, which is compared with a colour chart after a set time. Used for urine (and blood); the result is only semi-quantitative.
Biosensor: glucose oxidase is immobilised on an electrode. The reaction with glucose in a drop of blood produces a small electric current proportional to the glucose concentration; the meter converts this into a precise digital reading.
Why urine tests are limited: glucose appears in urine only when the blood concentration is so high that the PCT cotransporters cannot reabsorb it all, and the urine reflects the average over the hours it collected. A blood biosensor shows the concentration now, so a person with diabetes can decide on an insulin dose.
Stage 2 · Exam
Exam-style questions
Unlocks once the four checks above are done. Worth more XP, written to A Level Paper 4 standard.
Finish the four checks above to unlock the exam questions
Exam style+20 XP
Which correctly describes the role of cyclic AMP in a liver cell stimulated by glucagon?
Exam style+20 XP
Why does a single glucagon molecule lead to the release of thousands of glucose molecules?
Exam style+20 XP
Which is an effect of insulin but not of glucagon?
Exam style+20 XP
In a glucose test strip, which reaction directly produces the colour?
Skill unlocked
Cell signalling and blood glucose, mastered.
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