Questions: Carbohydrate Homeostasis and Glucose Regulation

Question 1

A patient has a genetic defect that eliminates hepatic glucose-6-phosphatase activity. During a 16-hour fast, what will happen to blood glucose, and why?

• A. Blood glucose will remain normal because skeletal muscle glycogen can compensate for the loss of hepatic glucose output
• B. Blood glucose will fall because the liver cannot release free glucose from glycogen breakdown or gluconeogenesis into the bloodstream
• C. Blood glucose will rise because the loss of glucose export from the liver means glucose accumulates in hepatocytes and leaks into blood
• D. Blood glucose will fall initially, then recover as cortisol stimulates peripheral tissues to produce glucose

Answer: (B)

Glucose-6-phosphatase is the enzyme that converts glucose-6-phosphate into free glucose, which can then exit the cell and enter the blood. The liver expresses this enzyme; skeletal muscle does not. Without it, hepatic glycogenolysis and gluconeogenesis still occur — but the product (glucose-6-phosphate) is trapped in the hepatocyte and cannot be exported. Skeletal muscle cannot compensate because it also lacks glucose-6-phosphatase — muscle glycogen serves the muscle's own energy needs and cannot contribute to blood glucose. This is why the liver, not muscle, is the organ responsible for maintaining blood glucose during fasting.

Question 2

During intense exercise, epinephrine is released. What is its primary effect on carbohydrate metabolism?

• A. It promotes glycogen synthesis in liver and muscle to build reserves for sustained effort
• B. It suppresses glucagon secretion to prevent blood glucose from rising excessively during exercise
• C. It stimulates glycogenolysis in both liver and muscle to rapidly mobilize glucose for immediate energy demand
• D. It activates insulin secretion to drive rapid glucose uptake into exercising muscles

Answer: (C)

Epinephrine is the 'emergency override' hormone — it acts rapidly to mobilize fuel when demand spikes. In the liver, it activates glycogen phosphorylase to break down glycogen and release glucose into the blood. In muscle, it also activates glycogen phosphorylase, releasing glucose-6-phosphate for immediate glycolytic energy production within the muscle. Activating insulin (option D) would be counterproductive: insulin promotes storage, not mobilization. Suppressing glucagon (option B) would also be counterproductive. Epinephrine's role is to ensure glucose is available within seconds, before the slower hormonal responses can act.

Question 3

Skeletal muscle glycogen cannot maintain blood glucose levels during fasting because muscle cells lack glucose-6-phosphatase and cannot release free glucose into the bloodstream.

• T. True
• F. False

Answer: True

This is the key distinction between liver and muscle glycogen. Both organs store glycogen and can perform glycogenolysis under glucagon or epinephrine stimulation. But muscle lacks glucose-6-phosphatase — the enzyme that converts glucose-6-phosphate into exportable free glucose. So muscle glycogenolysis produces glucose-6-phosphate, which is directed into glycolysis within the muscle cell for its own energy use. It never enters the blood. The liver, which expresses glucose-6-phosphatase, is the only organ that can export glucose from glycogen stores to support other tissues, particularly the glucose-dependent brain.

Question 4

Glucagon and insulin are released simultaneously after a carbohydrate-rich meal to coordinate the absorption and storage of glucose.

• T. True
• F. False

Answer: False

Insulin and glucagon have opposing actions and are released in opposing circumstances. After a carbohydrate-rich meal, rising blood glucose triggers insulin secretion from pancreatic beta cells and simultaneously *suppresses* glucagon secretion from alpha cells. Insulin drives glucose uptake, glycogen synthesis, and suppression of gluconeogenesis. Glucagon has no useful role in the fed state — its job is to mobilize glucose when blood glucose is low, which is exactly the opposite situation. Releasing both together would produce futile cycling and metabolic chaos. The coordinated suppression of glucagon by insulin is an important part of the fed-state response.

Question 5

Why can the liver maintain blood glucose during fasting but skeletal muscle cannot, even though both tissues store glycogen?

Model answer: The liver expresses glucose-6-phosphatase, which converts glucose-6-phosphate into free glucose that can be exported into the bloodstream. Skeletal muscle lacks this enzyme, so glycogenolysis in muscle produces glucose-6-phosphate that is trapped in the cell and used for the muscle's own glycolysis. Only the liver can export free glucose, which is why hepatic glycogen (and hepatic gluconeogenesis) is the primary source of blood glucose during fasting, while muscle glycogen serves only local energy needs.

This question targets the most commonly misunderstood aspect of glucose homeostasis: the assumption that more glycogen storage = more glucose available to the body. Muscle actually stores more total glycogen than the liver, but it is metabolically 'private' storage. The critical metabolic difference is the presence or absence of a single enzyme. This principle — that enzyme expression determines the metabolic fate of a pathway — recurs throughout biochemistry and is worth internalizing as a general pattern.