explain how negative feedback control mechanisms regulate blood glucose concentration, with reference to the effects of insulin on muscle cells and liver cells and the effect of glucagon on liver cells

Homeostasis in Mammals

Homeostasis is the maintenance of a stable internal environment despite external fluctuations. In mammals, the concentration of blood glucose is tightly regulated because glucose is the primary fuel for the brain and a key substrate for many tissues.

Negative Feedback Control of Blood Glucose

Negative feedback is a control mechanism in which a change in a physiological variable triggers responses that oppose the initial change, returning the variable toward its set‑point.

1. Set‑point: Normal fasting blood glucose ≈ 5 mmol L⁻¹ (90 mg dL⁻¹).
2. Sensor: Pancreatic β‑cells (detect high glucose) and α‑cells (detect low glucose).
3. Control centre: Islets of Langerhans release the hormones insulin and glucagon.
4. Effector organs: Muscle, adipose tissue, and liver respond to these hormones.

The loop can be summarised as:

\$\text{High blood glucose} \xrightarrow{\text{β‑cells}} \text{Insulin release} \xrightarrow{\text{target cells}} \text{Glucose uptake / storage} \xrightarrow{\text{lowered glucose}} \text{Reduced insulin secretion}\$

\$\text{Low blood glucose} \xrightarrow{\text{α‑cells}} \text{Glucagon release} \xrightarrow{\text{liver}} \text{Glycogenolysis / gluconeogenesis} \xrightarrow{\text{raised glucose}} \text{Reduced glucagon secretion}\$

Insulin – Effects on Muscle Cells

Insulin is released when blood glucose rises after a meal. In skeletal muscle it promotes glucose utilisation and storage.

• Glucose transporter translocation: Insulin triggers the movement of GLUT4 vesicles to the plasma membrane, increasing glucose entry.
• Glycogen synthesis: Activated glycogen synthase converts glucose‑6‑phosphate to glycogen.
• Inhibition of glycogenolysis: Insulin de‑phosphorylates and inactivates glycogen phosphorylase.
• Stimulation of protein synthesis: Via the PI3K‑Akt‑mTOR pathway, supporting muscle growth.

Insulin – Effects on Liver Cells

The liver is the principal organ for glucose storage and release.

• GLUT2 uptake: Liver cells continuously take up glucose via GLUT2; insulin enhances intracellular phosphorylation.
• Glycogenesis: Insulin activates glucokinase and glycogen synthase, promoting conversion of glucose to glycogen.
• Inhibition of gluconeogenesis: Down‑regulates key enzymes (PEPCK, glucose‑6‑phosphatase) through transcriptional mechanisms.
• Suppression of glycogenolysis: Reduces activity of glycogen phosphorylase.

Glucagon – Effects on Liver Cells

Glucagon is secreted when blood glucose falls, such as during fasting.

• Activation of glycogenolysis: Glucagon binds G‑protein‑coupled receptors, raising cAMP and activating protein kinase A (PKA), which phosphorylates and activates glycogen phosphorylase.
• Stimulation of gluconeogenesis: PKA‑mediated phosphorylation increases transcription of PEPCK and glucose‑6‑phosphatase, generating glucose from non‑carbohydrate precursors.
• Inhibition of glycogen synthesis: Phosphorylation inactivates glycogen synthase.

Comparison of Insulin and Glucagon Actions

Overall Flow of the Negative Feedback Loop

When a meal raises blood glucose, β‑cells release insulin, which drives glucose into muscle and liver, storing it as glycogen and suppressing further glucose production. As glucose levels fall toward the set‑point, insulin secretion diminishes. During fasting, falling glucose triggers α‑cells to secrete glucagon, which signals the liver to release glucose via glycogenolysis and gluconeogenesis, restoring the set‑point.

Key Points to Remember

• Negative feedback restores blood glucose to a narrow physiological range.
• Insulin lowers blood glucose by enhancing uptake and storage, especially in muscle and liver.
• Glucagon raises blood glucose by stimulating hepatic glycogen breakdown and new glucose synthesis.
• The balance between insulin and glucagon actions is essential; disruption leads to metabolic disorders such as diabetes mellitus.