Regulating Blood Glucose During a Prolonged Fast
A healthy 20-year-old fasts for 24 hours, drinking only water. Blood glucose is measured at 5.0 mmol/L at the start and 4.2 mmol/L at 24 hours, remaining within the normal fasting range. Plasma insulin falls markedly, while glucagon rises. The person feels hungry but alert, with no confusion or fainting. A classmate claims that after 24 hours the brain must be running on ketone bodies because liver glycogen is exhausted by then. Liver glycogen stores in an adult are roughly 100 g, and the brain consumes about 120 g of glucose per day.
1. Evaluate the classmate's claim about liver glycogen and brain fuel, using the numbers given.
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Liver glycogen is about 100 g. The brain uses about 120 g glucose per day, and other tissues also consume glucose, so liver glycogen alone cannot supply the brain for a full 24 hours.
However, blood glucose is maintained at 4.2 mmol/L, so glucose supply is not failing. The reason is that hepatic glycogenolysis is supplemented by gluconeogenesis, which by 24 hours contributes a substantial fraction of hepatic glucose output, using lactate, glycerol, and amino acids.
Ketone bodies do rise during fasting, but their concentration becomes a major brain fuel only after several days of starvation, not by 24 hours. At 24 hours the brain still relies mainly on glucose.
Judgement: the classmate confuses the timing of glycogen depletion with the timing of ketone adaptation; the maintained glucose and the absence of symptoms indicate adequate gluconeogenesis.
2. Explain the hormonal logic that keeps this person's glucose within range and prevents hypoglycaemia.
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Falling insulin removes the signal for glucose uptake and storage, while rising glucagon drives hepatic glucose output.
Glucagon acts on liver to stimulate glycogenolysis and gluconeogenesis, and it promotes fatty acid oxidation and ketogenesis. Cortisol and growth hormone rise more slowly and support gluconeogenesis and lipolysis; adrenaline contributes if glucose falls sharply.
Insulin falling also reduces glucose uptake by muscle and adipose tissue, sparing glucose for the brain, which uses insulin-independent GLUT transporters.
Judgement: the key is the insulin-to-glucagon ratio, not the absolute level of either hormone. A person with type 1 diabetes lacks this glucagon-driven response and would develop ketoacidosis instead, so the same fasting state produces a very different outcome depending on islet function.
3. Predict what would change if this person had a defect in hepatic glucose-6-phosphatase, and explain the mechanism.
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Glucose-6-phosphatase catalyses the final step of both glycogenolysis and gluconeogenesis: glucose-6-phosphate → glucose + phosphate, in the endoplasmic reticulum of liver and kidney cells.
Without it, glucose-6-phosphate cannot be released as free glucose into the blood. Glycogen can still be broken down to glucose-6-phosphate, and gluconeogenesis can still make glucose-6-phosphate, but neither can raise blood glucose.
The result is fasting hypoglycaemia, with accumulation of glycogen in the liver (hepatomegaly) and lactic acidosis, because lactate-derived gluconeogenesis stalls at glucose-6-phosphate. This is the pattern of glycogen storage disease type I (von Gierke disease).
Judgement: the enzyme is the shared exit step for both pathways, so a defect blocks both sources of blood glucose; the clinical prediction follows from the pathway position, not from memorised disease names.