(a) Blood glucose concentration is maintained around a set point by homeostasis.
Explain the principles of homeostasis.
(b) Glycogen phosphorylase catalyses the conversion of glycogen to glucose in liver cells. The production of glycogen phosphorylase is coded for by the gene PYGL.
A mutation in PYGL leads to a condition called glycogen storage disease type VI (GSDVI), in which glycogen is not broken down efficiently.
Suggest and explain why cell signalling by glucagon is likely to be affected in the liver cells of a person with GSDVI.
(c) Glycogen synthase catalyses the conversion of glucose to glycogen in liver cells. The production of glycogen synthase is coded for by the gene GYS2.
A mutation in GYS2 leads to a condition called glycogen storage disease type 0 (GSD0) in which glycogen is not formed efficiently.
Suggest what the consequences would be if a person with GSD0 has a meal rich in glucose.
▶️ Answer/Explanation
(a)
Homeostasis maintains stable internal conditions through several key principles:
- Detection: Specialized receptors detect changes in internal conditions (like blood glucose levels).
- Coordination: The central nervous system or endocrine system processes this information.
- Response: Effectors (muscles or glands) carry out corrective actions through impulses or hormones.
- Negative feedback: The response counteracts the initial change, bringing the system back to its set point.
- Dynamic equilibrium: The system continuously makes small adjustments to maintain stability.
For blood glucose specifically, when levels rise after eating, insulin is released to promote glucose uptake and storage. When levels fall, glucagon is released to stimulate glucose release from glycogen stores.
(b)
In GSDVI, the mutation affects glycogen phosphorylase in several ways:
- The glucagon signaling pathway remains intact initially – glucagon still binds to receptors, activates G proteins, and stimulates adenylate cyclase to produce cAMP.
- However, the final step in the pathway is compromised because the glycogen phosphorylase enzyme is either:
- Not produced in sufficient quantities
- Produced in a non-functional form due to altered tertiary structure
- As a result, even with proper signaling, glycogen cannot be effectively broken down into glucose (glycogenolysis is impaired).
- This leads to hypoglycemia (low blood sugar) because the liver cannot release glucose when needed, despite receiving proper glucagon signals.
(c)
After a glucose-rich meal, a person with GSD0 would experience:
- Impaired glycogen storage: Due to deficient or non-functional glycogen synthase, glucose cannot be effectively converted to glycogen for storage.
- Hyperglycemia: Blood glucose levels would remain elevated longer than normal because the usual storage mechanism is impaired.
- Alternative pathways activated: Excess glucose would be:
- Converted to fat through lipogenesis
- Excreted in urine if levels exceed the renal threshold (glycosuria)
- Metabolic consequences: This could lead to symptoms like:
- Increased thirst and urination
- Fatigue due to inefficient energy storage
- Potential ketoacidosis if the body starts breaking down fats excessively
The condition demonstrates the critical role of glycogen synthase in maintaining glucose homeostasis after meals.