Control & Coordination – Homeostasis of Blood Glucose (Cambridge 9700/9702)
1. What is Homeostasis?
- Definition: Maintenance of a stable internal environment despite external changes.
- Key components of a homeostatic loop (Cambridge terminology)
- Set‑point (normal range) – e.g. fasting blood glucose ≈ 5 mmol L⁻¹ (90 mg dL⁻¹).
- Sensor (receptor) – cells that detect a deviation from the set‑point.
- Integrating (control) centre – receives the sensor signal and decides which hormone to release.
- Effector – organ/tissue that carries out the corrective action.
- Negative feedback – the response opposes the original change and returns the variable toward the set‑point.
2. Syllabus Checklist (Topic 14 – Control & Coordination)
| Syllabus requirement (14.1‑14.5) | How the notes satisfy it | What has been added |
|---|
| Sensor, integrating centre, effectors, negative‑feedback loop | Described in sections 2 and 8 | Explicit label of the integrating centre (islets of Langerhans) and its link to the hypothalamic‑pituitary‑adrenal axis. |
| Hormones: insulin, glucagon, epinephrine, cortisol, growth hormone | Insulin, glucagon, epinephrine covered | New subsections on cortisol and growth hormone (long‑term glucose‑raising hormones). |
| Signal‑transduction pathways (AO2) | Basic pathways listed | Detailed cascade for insulin (tyrosine‑kinase → IRS‑1 → PI3K → Akt) and glucagon (G‑protein → cAMP → PKA) plus downstream phosphorylation of key enzymes. |
| Target‑organ responses (muscle, liver, adipose) | Actions on muscle and liver given | Added adipose‑tissue actions and cross‑reference to lipid metabolism. |
| Clinical relevance (diabetes, hormonal imbalance) | Brief mention in key points | Expanded clinical note, practice question and link to metabolic pathways. |
3. Sensors, Integrating Centre and Effectors for Blood Glucose
| Component | Structure | Role in glucose regulation |
|---|
| Sensor | Pancreatic β‑cells (detect high glucose) and α‑cells (detect low glucose) | Measure plasma glucose and trigger hormone release when the set‑point is crossed. |
| Integrating centre | Islets of Langerhans (β‑cells → insulin; α‑cells → glucagon) together with the hypothalamic‑pituitary‑adrenal (HPA) axis for epinephrine, cortisol and GH. | Processes sensor information and coordinates the appropriate hormonal response. |
| Effectors | Muscle, adipose tissue, liver (and, in stress, heart & brain) | Carry out insulin‑ or glucagon‑mediated actions that change blood glucose. |
4. Hormonal Control of Blood Glucose
- Insulin – secreted by β‑cells when blood glucose is high (post‑prandial).
- Glucagon – secreted by α‑cells when blood glucose is low (fasting).
- Epinephrine – released from the adrenal medulla during stress or vigorous exercise; raises glucose.
- Cortisol – secreted by the adrenal cortex (ACTH‑stimulated); promotes gluconeogenesis and reduces peripheral glucose utilisation (long‑term).
- Growth Hormone (GH) – released from anterior pituitary (GHRH‑stimulated); reduces insulin‑stimulated glucose uptake and enhances lipolysis, indirectly raising blood glucose.
5. Signal‑Transduction Pathways
5.1 Insulin (Tyrosine‑Kinase Pathway)
- Insulin binds the extracellular α‑subunits of the insulin receptor (a receptor tyrosine kinase).
- Receptor autophosphorylates on intracellular β‑subunits → creates docking sites for Insulin Receptor Substrate‑1 (IRS‑1).
- IRS‑1 is phosphorylated and recruits Phosphoinositide‑3‑Kinase (PI3K).
- PI3K converts PIP₂ → PIP₃, activating Akt (Protein Kinase B).
- Akt phosphorylates several downstream targets:
- GLUT4 vesicles – translocate to the plasma membrane (muscle & adipose) → ↑glucose uptake.
- Glycogen synthase – de‑phosphorylated (activated) → glycogenesis.
- Glycogen phosphorylase – de‑phosphorylated (inactivated) → ↓glycogenolysis.
- PDK‑1 & mTOR – stimulate protein synthesis (muscle growth, A‑Level detail).
- Insulin also activates the transcriptional repression of gluconeogenic enzymes (PEPCK, G6Pase) via the fork‑head box O (FOXO) pathway.
5.2 Glucagon (G‑Protein‑Coupled cAMP Pathway)
- Glucagon binds a Gs‑protein‑coupled receptor on hepatocyte membranes.
- Gs activates adenylate cyclase → ↑cAMP.
- cAMP activates Protein Kinase A (PKA).
- PKA phosphorylates key enzymes:
- Glycogen phosphorylase kinase → activates glycogen phosphorylase → glycogenolysis.
- Glycogen synthase → phosphorylated (inactive) → ↓glycogen synthesis.
- Fructose‑2,6‑bisphosphatase → de‑phosphorylated (active) → ↓ fructose‑2,6‑bisphosphate → favours gluconeogenesis.
- PKA‑mediated phosphorylation of transcription factors (CREB) up‑regulates genes for PEPCK and glucose‑6‑phosphatase, enhancing gluconeogenesis.
5.3 Epinephrine (cAMP/PKA – similar to glucagon) – acts mainly on muscle and liver during acute stress.
5.4 Cortisol (Genomic pathway)
- Glucocorticoid binds intracellular receptor → receptor‑hormone complex translocates to nucleus.
- Binds glucocorticoid response elements → ↑ transcription of PEPCK, G6Pase, and enzymes of amino‑acid catabolism.
- Promotes proteolysis in muscle → substrates for gluconeogenesis.
5.5 Growth Hormone (JAK‑STAT pathway)
- GH binds a cytokine‑type receptor → activates JAK2 → phosphorylates STAT5.
- STAT5 dimerises, enters nucleus and induces expression of IGF‑1 and enzymes that reduce insulin‑mediated glucose uptake.
6. Hormonal Actions on Specific Target Cells
6.1 Insulin – Muscle Cells
- GLUT4 translocation – ↑ glucose entry.
- Glycogen synthesis – Akt‑mediated activation of glycogen synthase.
- Inhibition of glycogenolysis – de‑phosphorylation (inactivation) of glycogen phosphorylase.
- Protein synthesis – Akt‑mTOR signalling → muscle growth (A‑Level).
- Fatty‑acid synthesis (adipose link) – insulin promotes acetyl‑CoA carboxylase activity, providing a metabolic context for the “storage hormone” concept.
6.2 Insulin – Liver Cells
- Glucose entry – GLUT2 provides bidirectional transport; insulin stimulates glucokinase (high‑Km hexokinase) to phosphorylate glucose.
- Glycogenesis – activation of glucokinase and glycogen synthase.
- Inhibition of glycogenolysis – de‑phosphorylation (inactivation) of glycogen phosphorylase.
- Suppression of gluconeogenesis – down‑regulation of PEPCK, fructose‑1,6‑bisphosphatase and glucose‑6‑phosphatase transcription.
- Lipogenesis – insulin activates acetyl‑CoA carboxylase and fatty‑acid synthase (connects to Energy & Respiration syllabus).
6.3 Glucagon – Liver Cells
- Glycogenolysis – PKA activates glycogen phosphorylase kinase → glycogen phosphorylase.
- Gluconeogenesis – PKA‑mediated CREB activation ↑ PEPCK and G6Pase transcription.
- Inhibition of glycogen synthesis – PKA phosphorylates (inactivates) glycogen synthase.
- Fatty‑acid oxidation – glucagon promotes CPT‑I activity, providing acetyl‑CoA for the TCA cycle (link to cellular respiration).
6.4 Epinephrine – Muscle & Liver (acute stress)
- Acts via the same cAMP/PKA cascade as glucagon.
- In muscle: ↑ glycogenolysis and glycolysis → rapid ATP supply.
- In liver: ↑ glycogenolysis and gluconeogenesis.
6.5 Cortisol & Growth Hormone – Long‑Term Regulation
- Cortisol: ↑ gluconeogenic enzyme synthesis, ↓ peripheral glucose utilisation, promotes protein breakdown.
- GH: ↓ insulin‑stimulated glucose uptake, ↑ lipolysis, provides amino‑acid substrates for gluconeogenesis.
7. Comparison of Insulin and Glucagon (Exam‑style Table)
| Feature | Insulin (high glucose) | Glucagon (low glucose) |
|---|
| Source cell | Pancreatic β‑cells | Pancreatic α‑cells |
| Main target organs | Muscle, adipose, liver | Liver (and kidney) |
| Second messenger | Receptor tyrosine kinase → IRS‑1 → PI3K → Akt | Gs‑protein → ↑cAMP → PKA |
| Effect on glucose transporters | ↑ GLUT4 insertion (muscle, adipose); ↑ GLUT2 activity via glucokinase (liver) | No direct effect on GLUT transporters |
| Glycogen metabolism | ↑ glycogen synthase (active); ↓ glycogen phosphorylase (inactive) | ↑ glycogen phosphorylase (active); ↓ glycogen synthase (inactive) |
| Gluconeogenesis | Inhibited – ↓ PEPCK, G6Pase transcription | Stimulated – ↑ PEPCK, G6Pase transcription |
| Net effect on blood glucose | ↓ | ↑ |
8. Full Negative‑Feedback Loop (Step‑by‑Step)
- Meal ingestion → blood glucose rises.
- Sensors (β‑cells) detect ↑ glucose. Threshold ≈ 7 mmol L⁻¹.
- Integrating centre (islets) releases insulin** into the bloodstream.
- Effectors respond
- Muscle: GLUT4 translocation → ↑ glucose uptake → glycogen synthesis.
- Liver: GLUT2 uptake + glucokinase activation → glycogenesis; gluconeogenic enzymes are switched off.
- Adipose: ↑ lipogenesis & ↓ lipolysis.
- Blood glucose falls toward the set‑point. Sensor activity diminishes → insulin secretion tapers.
- During fasting → blood glucose falls below set‑point.
- Sensors (α‑cells) detect ↓ glucose. Threshold ≈ 4 mmol L⁻¹.
- Integrating centre releases glucagon** (and, if stress is present, epinephrine).
- Effectors respond (liver)
- cAMP/PKA → glycogen phosphorylase activation → glycogenolysis.
- PKA → CREB‑mediated transcription ↑PEPCK & G6Pase → gluconeogenesis.
- PKA phosphorylates glycogen synthase → inactivation.
- Blood glucose rises back to the set‑point. α‑cell activity falls → glucagon secretion declines.
9. Diagram Suggestion (for revision)
Draw a flow diagram with the following elements (label each arrow):
- Pancreas – β‑cell → insulin (arrow to muscle, adipose, liver).
- Pancreas – α‑cell → glucagon (arrow to liver).
- Adrenal medulla → epinephrine (arrow to muscle & liver, optional).
- Feedback arrows from “blood glucose ↑” to β‑cell and from “blood glucose ↓” to α‑cell.
- Include notes on signalling pathways (PI3K‑Akt for insulin; cAMP‑PKA for glucagon/epinephrine).
10. Clinical Relevance – Diabetes Mellitus
- Type 1 diabetes – autoimmune destruction of β‑cells → no insulin → chronic hyperglycaemia, polyuria, polydipsia, ketoacidosis.
- Type 2 diabetes – insulin resistance in muscle and liver; β‑cells may initially over‑produce insulin, later fail.
- Both conditions illustrate the importance of the negative‑feedback loop; disruption leads to loss of glucose homeostasis.
11. Practice Question (AO2 – Application)
Question: A person with a pancreatic tumour destroys β‑cells but retains functional α‑cells. Explain how this condition would affect blood‑glucose regulation after a meal, and describe two possible clinical symptoms.
Answer outline (8 marks)
- No insulin released → glucose cannot be taken up efficiently by muscle or stored as glycogen in liver (1 mark).
- Blood glucose therefore remains high (post‑prandial hyperglycaemia) (1 mark).
- α‑cells continue to secrete glucagon → liver continues glycogenolysis and gluconeogenesis, further raising glucose (1 mark).
- Resulting osmotic diuresis causes polyuria and compensatory polydipsia (2 marks).
- Long‑term lack of insulin leads to increased lipolysis, free‑fatty‑acid overload in the liver and production of ketone bodies → risk of ketoacidosis (1 mark).
- Possible secondary symptom: weight loss due to catabolism of fat and protein (1 mark).
12. Quick Revision Summary (Bullet Box)
- Set‑point: ≈5 mmol L⁻¹ (fasting).
- Sensor: β‑cells (high glucose) & α‑cells (low glucose).
- Integrating centre: Islets of Langerhans + HPA axis.
- Effectors: Muscle (GLUT4), Liver (GLUT2, glycogen), Adipose (lipogenesis).
- Insulin pathway: Receptor tyrosine kinase → IRS‑1 → PI3K → Akt → ↑GLUT4, ↑glycogen synthase, ↓glycogen phosphorylase, ↓PEPCK/G6Pase.
- Glucagon pathway: Gs‑protein → ↑cAMP → PKA → ↑glycogen phosphorylase, ↓glycogen synthase, ↑PEPCK/G6Pase.
- Epinephrine: Same cAMP/PKA cascade – acute stress response.
- Cortisol & GH: Genomic actions → ↑ gluconeogenesis, ↓ peripheral glucose use (long‑term).
- Result: Negative feedback returns blood glucose to the set‑point.