Homeostasis in Mammals – Cambridge International AS & A Level (Topic 14)

Learning Outcomes (mapped to syllabus Assessment Objectives)

• AO1 – Knowledge & Understanding: Explain the physiological basis of the major homeostatic mechanisms in mammals (blood glucose, calcium, water, temperature and nitrogen waste).
• AO2 – Application: Predict the effect of a disturbance (e.g., hormone deficiency, renal failure) on each system and describe how the body restores balance.
• AO3 – Analysis & Evaluation: Analyse experimental data, evaluate methods, and discuss clinical implications of homeostatic failure.

1. General Features of Homeostatic Control

All homeostatic systems operate as negative‑feedback loops:

1. Sensor (receptor): Detects a change in a physiological variable.
2. Integrator (control centre): Usually the hypothalamus or an endocrine gland; compares the input with a set‑point.
3. Effector: Organ or tissue that produces a response that opposes the original change.

When the variable returns to the set‑point, the loop is switched off.

2. Blood‑Glucose Regulation

Key Hormones & Primary Organs

Hormone	Source	Target Organ(s)	Principal Action
Insulin	β‑cells of pancreatic islets	Liver, skeletal muscle, adipose tissue	Stimulates GLUT‑4 translocation, glycogen synthesis, lipogenesis; lowers plasma glucose.
Glucagon	α‑cells of pancreatic islets	Liver	Activates glycogenolysis and gluconeogenesis; raises plasma glucose.
Epinephrine (adrenal medulla)	Adrenal medulla (sympathetic stimulation)	Liver, skeletal muscle	Promotes glycogenolysis and inhibits insulin release; important in acute stress.

Feedback Loop (≈150 words)

After a carbohydrate‑rich meal, plasma glucose rises → β‑cells secrete insulin. Insulin stimulates GLUT‑4 insertion in muscle and adipose cells, increasing glucose uptake, and activates hepatic glycogen synthase, storing glucose as glycogen. As glucose falls, insulin secretion declines. During fasting or stress, low glucose (or catecholamine release) stimulates α‑cells to release glucagon and the adrenal medulla to release epinephrine. Both hormones activate hepatic glycogen phosphorylase (glycogenolysis) and phosphoenolpyruvate carboxykinase (gluconeogenesis), restoring glucose to the 4–6 mmol L⁻¹ range. The loop is terminated when glucose reaches the set‑point, reducing glucagon and epinephrine output.

Practical Investigation (AO3 focus)

• Measure capillary blood glucose before, 30 min, 60 min and 120 min after a standardized 75 g oral glucose load using a calibrated glucometer.
• Plot glucose concentration versus time for a control group and a group with known insulin resistance (e.g., obese adolescents).
• Calculate the area under the curve (AUC) and discuss sources of error (sampling time, haemolysis, device calibration) and how they affect the reliability of conclusions.

3. Calcium Homeostasis

Hormonal Control

Hormone	Source	Target	Action
Parathyroid Hormone (PTH)	Parathyroid glands	Bone, kidney, intestine	↑ serum Ca²⁺ by stimulating osteoclast‑mediated bone resorption, renal Ca²⁺ re‑absorption, and activation of 1α‑hydroxylase → ↑ 1,25‑(OH)₂ D.
Calcitonin	Thyroid C‑cells	Bone	↓ serum Ca²⁺ by inhibiting osteoclast activity.
1,25‑(OH)₂ Vitamin D (calcitriol)	Kidney (1α‑hydroxylase)	Intestine (and kidney)	↑ intestinal Ca²⁺ absorption; also enhances renal Ca²⁺ re‑absorption.

Feedback Mechanism (short paragraph)

A fall in plasma Ca²⁺ is detected by calcium‑sensing receptors on parathyroid cells → PTH release. PTH raises Ca²⁺ by (i) stimulating osteoclasts, (ii) increasing distal tubular Ca²⁺ re‑absorption, and (iii) converting 25‑hydroxy‑vitamin D to calcitriol, which up‑regulates intestinal Ca²⁺ transporters. When Ca²⁺ rises, calcitonin secretion from thyroid C‑cells increases, inhibiting osteoclasts and allowing bone to act as a Ca²⁺ sink, restoring the set‑point. Chronic PTH excess → hypercalcaemia, renal calculi; PTH deficiency → hypocalcaemia, tetany.

Clinical Note – Vitamin D Deficiency

Insufficient sunlight or dietary vitamin D reduces hepatic 25‑hydroxylation and renal 1α‑hydroxylation, lowering calcitriol levels. Resulting ↓ intestinal Ca²⁺ absorption leads to secondary hyperparathyroidism, bone demineralisation (osteomalacia in adults, rickets in children) and increased fracture risk.

Practical Idea (AO3)

• Randomised, double‑blind trial of vitamin D₃ supplementation (2000 IU day⁻¹) vs. placebo for 8 weeks in adults with low baseline 25‑OH‑vitamin D.
• Measure serum Ca²⁺, PTH and 25‑OH‑vitamin D at baseline and after 8 weeks using ion‑selective electrodes and immunoassay.
• Analyse data with paired t‑tests; discuss confounders (dietary calcium, seasonal sunlight, adherence).

4. Water Balance & Osmoregulation

Key Hormone – Antidiuretic Hormone (ADH)

• Source: Supraoptic & paraventricular nuclei of the hypothalamus; stored and released from the posterior pituitary.
• Target: Principal cells of the collecting ducts (medullary region).
• Action: Binds V₂ receptors → cAMP‑mediated insertion of aquaporin‑2 channels → ↑ water permeability → water re‑absorption → concentrated urine.

Nephron Flow (simplified)

1. Glomerular filtration: Isotonic filtrate formed.
2. Proximal tubule: Re‑absorbs ~65 % of filtered water, Na⁺, glucose, amino acids.
3. Loop of Henle: Counter‑current multiplication creates a medullary osmotic gradient.
4. Distal tubule: Fine‑tunes Na⁺/Cl⁻ re‑absorption (aldosterone‑dependent).
5. Collecting duct: ADH‑dependent water re‑absorption; urine osmolality varies from ~50 mOsm kg⁻¹ (no ADH) to >1200 mOsm kg⁻¹ (max ADH).

Practical Investigation (AO3)

• Collect urine samples from volunteers before and after 24 h water restriction.
• Measure specific gravity (refractometer) and plasma osmolality (free‑zing point osmometer).
• Correlate the two variables and discuss the role of ADH, potential sources of error (incomplete urine collection, dietary solutes) and how they affect interpretation.

5. Temperature Regulation

Thermoregulatory Loop

• Receptors: Cutaneous and hypothalamic thermoreceptors detect skin and core temperature.
• Integrating centre: Pre‑optic area of the hypothalamus compares input with the set‑point (~37 °C).
• Effectors:
  • Heat‑loss mechanisms: Cutaneous vasodilation, sweating (evaporation), increased respiratory heat loss.
  • Heat‑gain mechanisms: Cutaneous vasoconstriction, shivering (skeletal muscle activity), non‑shivering thermogenesis (brown adipose tissue, mediated by thyroid hormones).

Clinical Note

Failure of thermoregulation leads to hyperthermia (heat stroke) or hypothermia. Antipyretics (e.g., paracetamol) lower the hypothalamic set‑point by inhibiting prostaglandin E₂ synthesis.

Practical Example (AO2)

• Measure skin temperature (infrared thermometer), core temperature (tympanic probe) and heart rate at rest, then after a 15‑minute treadmill run in a climate‑controlled chamber (22 °C, 50 % RH).
• Determine sweat loss by weighing participants pre‑ and post‑exercise; calculate evaporative heat loss and discuss efficiency of the cooling response.

6. Nitrogenous Waste – Urea Production (Deamination of Excess Amino Acids)

Why Convert Ammonia to Urea?

Protein turnover continuously releases free ammonia (NH₃) via deamination of amino acids. NH₃ is highly neurotoxic and readily crosses the blood‑brain barrier. Mammals therefore convert it to the far less toxic, water‑soluble urea, which can be safely transported in plasma and excreted by the kidneys.

Deamination of Excess Amino Acids

• Aminotransferases (e.g., ALT, AST) transfer the α‑amino group from a non‑essential amino acid to α‑ketoglutarate, forming glutamate.
• Glutamate dehydrogenase then oxidative deaminates glutamate, releasing NH₃ and regenerating α‑ketoglutarate.

The Urea (Ornithine) Cycle – Step‑by‑Step

1. Carbamoyl‑phosphate synthesis (mitochondrial): NH₃ + CO₂ + 2 ATP → carbamoyl‑phosphate (enzyme: carbamoyl‑phosphate synthetase I, CPS‑I).
2. Formation of citrulline: Carbamoyl‑phosphate + ornithine → citrulline (ornithine transcarbamylase, OTCase).
3. Citrulline transport: Citrulline moves to the cytosol via the citrin carrier.
4. Argininosuccinate synthesis: Citrulline + aspartate + ATP → argininosuccinate (argininosuccinate synthetase, ASS).
5. Argininosuccinate cleavage: Argininosuccinate → arginine + fumarate (argininosuccinate lyase, ASL).
6. Urea formation: Arginine + H₂O → urea + ornithine (arginase). Ornithine re‑enters the mitochondrion, completing the cycle.

Overall Stoichiometry

\[ 2\;\text{NH}_3 + \text{CO}_2 + 3\;\text{ATP} + \text{H}_2\text{O} \;\longrightarrow\; \text{(NH}_2)_2\text{CO} + 2\;\text{ADP} + 4\;\text{P}_i + \text{AMP} \]

Regulation of the Cycle

• Allosteric activation: CPS‑I is activated by N‑acetyl‑glutamate (NAG), whose synthesis is stimulated by high concentrations of amino acids.
• Hormonal influence: Glucagon and epinephrine increase urea‑cycle enzyme transcription during fasting or high‑protein intake.
• Nutritional control: After a protein‑rich meal, urea synthesis rises sharply; during prolonged fasting the cycle slows.

Clinical Relevance

• Hyperammonemia: Genetic defects (e.g., OTC deficiency) or severe liver disease impair the cycle → NH₃ accumulation → cerebral oedema, lethargy, coma.
• Liver failure: Reduced CPS‑I activity raises blood ammonia; treatment may include lactulose (acidifies colon, trapping NH₃ as NH₄⁺) and low‑protein diets.
• Urea Cycle Disorders (UCDs): Early‑infancy presentation with vomiting, seizures; management includes nitrogen‑scavenging drugs (sodium phenylbutyrate) and dietary protein restriction.

Practical/Assessment Idea (AO2/AO3)

• Recruit healthy volunteers; obtain baseline blood urea nitrogen (BUN) and plasma ammonia.
• Place participants on a high‑protein diet (≈1.5 g kg⁻¹ day⁻¹) for 5 days.
• Re‑measure BUN and ammonia; analyse changes with paired t‑tests.
• Discuss confounding factors (hydration status, renal function, timing of blood draw) and how they affect the validity of conclusions.

7. Comparison of Nitrogenous Waste Across Animal Groups

Animal Group	Primary Nitrogenous Waste	Site of Synthesis	Excretion Route
Mammals	Urea	Liver (urea cycle)	Kidneys → urine
Birds & Reptiles	Uric Acid	Liver	Kidneys → semi‑solid uric‑acid paste
Aquatic Fish	Ammonia	Various tissues (muscle, liver)	Gills → diffusion into water

8. Integrated View of Homeostasis

In a living organism the five systems interact:

• Water balance & urea: ADH‑mediated water re‑absorption in the collecting duct also enhances urea re‑absorption, concentrating nitrogenous waste while conserving water.
• Calcium & temperature: Severe hypocalcaemia increases neuronal excitability, which can raise basal metabolic rate and alter thermoregulatory responses.
• Glucose & nitrogen: During prolonged fasting, glucagon‑driven gluconeogenesis uses amino acids as substrates, increasing deamination and urea production.

9. Suggested Diagrams (placeholders for classroom use)

• Negative‑feedback loop for blood glucose (insulin ↔ glucagon ↔ epinephrine).
• Calcium‑homeostasis cycle (PTH ↔ calcitonin ↔ calcitriol, showing renal re‑absorption).
• Nephron schematic highlighting ADH‑induced aquaporin‑2 insertion and urea recycling.
• Thermoregulatory centre with effectors (vasodilation, sweating, shivering, brown‑fat thermogenesis).
• Urea (ornithine) cycle flowchart from deamination to excretion, with N‑acetyl‑glutamate activation highlighted.