Homeostasis

Homeostasis

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Board Coverage AQA Paper 2 | Edexcel A Paper 2 | OCR (A) Paper 2 | CIE Paper 4

1. Principles of Homeostasis

1.1 Definition

Homeostasis is the maintenance of a constant internal environment within narrow limits, despite changes in the external environment. It is essential for the optimal functioning of enzymes and metabolic processes, which are sensitive to changes in temperature, pH, water potential, and the concentration of dissolved substances.

Claude Bernard (19th century) first proposed the concept of the "milieu interieur" (internal environment), and Walter Cannon (1926) coined the term "homeostasis."

1.2 Key Components of Homeostatic Control

All homeostatic mechanisms share the same general structure:

1. Receptor (detector): detects changes in the internal environment (the stimulus). Receptors are typically specialised cells or proteins that convert the stimulus into an electrical signal (transduction).

2. Coordination centre (controller): receives information from the receptor, processes it, and sends signals to effectors. In mammals, the coordination centre is typically the brain (hypothalamus, medulla oblongata) or endocrine glands (pancreas).

3. Effector: carries out the response that restores the internal environment to its optimum value. Effectors may be muscles (which contract or relax) or glands (which secrete hormones or other substances).

1.3 Negative Feedback

Negative feedback is the primary mechanism of homeostatic control. When a parameter deviates from its set point, the system generates a response that opposes the change, restoring the parameter to its optimum.

General pattern:

1. Parameter deviates from set point.
2. Receptor detects the deviation.
3. Coordination centre processes the information.
4. Effector produces a response that counteracts the deviation.
5. Parameter returns towards set point.
6. Receptor detects the correction; the response is reduced or stopped.

Negative feedback prevents overcorrection and maintains stability. Examples: blood glucose regulation, thermoregulation, osmoregulation, heart rate regulation.

1.4 Positive Feedback

Positive feedback amplifies a deviation from the set point, pushing the parameter further from its optimum. This is less common and typically occurs in situations where a rapid, self-amplifying response is beneficial.

Examples:

• Oxytocin and childbirth: pressure of the baby's head on the cervix stimulates the posterior pituitary to release oxytocin, which causes uterine contractions. Stronger contractions push the baby further against the cervix, stimulating more oxytocin release, further increasing contractions. This positive feedback loop continues until the baby is born.
• Blood clotting: damaged tissue releases clotting factors that activate more clotting factors, amplifying the clotting cascade until the clot is formed.

Positive feedback loops require an external event or separate mechanism to terminate them (e.g., the birth of the baby terminates the oxytocin loop).

warning

Common Pitfall Students often confuse negative and positive feedback. Negative feedback opposes changes and maintains stability (the most common mechanism in homeostasis). Positive feedback amplifies changes and destabilises the system. In examination answers, always specify which type of feedback is operating and explain why.

2. Blood Glucose Regulation

2.1 Normal Blood Glucose Concentration

Blood glucose concentration is maintained at approximately $4$--$6\ \mathrm{mmol\ dm^{-3}}$ (approximately $0.7$--$1.1\ \mathrm{g\ dm^{-3}}$). After a meal, blood glucose may rise to approximately $8\ \mathrm{mmol\ dm^{-3}}$; during fasting or exercise, it may fall to approximately $3.5\ \mathrm{mmol\ dm^{-3}}$.

Glucose regulation involves the pancreas, which functions as both an exocrine gland (producing digestive enzymes) and an endocrine gland (producing hormones).

2.2 The Pancreas as an Endocrine Gland

The endocrine tissue of the pancreas consists of clusters of cells called the islets of Langerhans, which contain two types of cell:

Cell Type	Hormone Secreted	Effect on Blood Glucose	Stimulus for Secretion
$\alpha$ cells	Glucagon	Increases	Low blood glucose
$\beta$ cells	Insulin	Decreases	High blood glucose

2.3 Mechanism: Blood Glucose Too High (After a Meal)

1. Blood glucose concentration rises above the set point.
2. $\beta$ cells in the islets of Langerhans detect the increased glucose concentration.
3. $\beta$ cells secrete insulin into the blood.
4. Insulin binds to receptors on the cell surface of target cells (especially liver cells, muscle cells, and adipose tissue).
5. Insulin activates the translocation of GLUT4 glucose transporters to the cell membrane, increasing the uptake of glucose from the blood into cells.
6. In the liver, insulin stimulates:
   • Glycogenesis: conversion of glucose to glycogen (storage).
   • Increased glycolysis: increased respiration of glucose.
   • Decreased gluconeogenesis: reduced synthesis of glucose from amino acids and glycerol.
7. Blood glucose concentration decreases towards the set point.
8. As glucose returns to normal, $\beta$ cells reduce insulin secretion (negative feedback).

2.4 Mechanism: Blood Glucose Too Low (After Fasting or Exercise)

1. Blood glucose concentration falls below the set point.
2. $\alpha$ cells in the islets of Langerhans detect the decreased glucose concentration.
3. $\alpha$ cells secrete glucagon into the blood.
4. Glucagon binds to receptors on the cell surface of liver cells (the primary target).
5. Glucagon stimulates:
   • Glycogenolysis: conversion of glycogen to glucose (release from storage).
   • Gluconeogenesis: synthesis of glucose from non-carbohydrate precursors (amino acids, lactate, glycerol).
   • The release of glucose from liver cells into the blood.
6. Blood glucose concentration increases towards the set point.
7. As glucose returns to normal, $\alpha$ cells reduce glucagon secretion (negative feedback).

Adrenaline (from the adrenal medulla) also raises blood glucose during the fight-or-flight response by stimulating glycogenolysis in the liver and muscles.

2.5 Second Messenger Model

Both insulin and glucagon act through second messenger systems:

Insulin signalling: insulin binds to a receptor tyrosine kinase on the cell membrane. This activates an intracellular phosphorylation cascade (involving IRS proteins, PI3K, and Akt), which ultimately triggers the translocation of GLUT4 vesicles to the cell membrane.

Glucagon signalling: glucagon binds to a G-protein coupled receptor on liver cells. This activates adenylate cyclase, which converts ATP to cyclic AMP (cAMP), the second messenger. cAMP activates protein kinase A (PKA), which phosphorylates enzymes involved in glycogenolysis and gluconeogenesis.

2.6 Diabetes Mellitus

Type 1 diabetes (insulin-dependent):

• Cause: autoimmune destruction of $\beta$ cells in the islets of Langerhans, resulting in little or no insulin production.
• Onset: typically in childhood or adolescence (juvenile-onset).
• Mechanism: without insulin, glucose cannot be taken up by cells. Blood glucose rises to very high levels (hyperglycaemia). The kidneys cannot reabsorb all the glucose, so glucose appears in the urine (glycosuria), causing water to follow by osmosis (polyuria, excessive urine production). Cells are starved of glucose despite high blood levels, causing fatigue and weight loss. The body resorts to breaking down fat and protein for energy, producing ketones (ketosis), which can lower blood pH (ketoacidosis), a medical emergency.
• Treatment: insulin injections (subcutaneous), blood glucose monitoring, careful diet.

Type 2 diabetes (non-insulin-dependent):

• Cause: target cells become less responsive to insulin (insulin resistance); $\beta$ cells may initially produce more insulin to compensate but eventually become exhausted.
• Onset: typically in adulthood, strongly associated with obesity, sedentary lifestyle, and genetic predisposition.
• Mechanism: insulin receptors or downstream signalling pathways become less responsive. Blood glucose rises but $\beta$ cells continue to produce insulin (initially). Risk factors include obesity (adipose tissue releases inflammatory cytokines that impair insulin signalling), age, family history, and ethnicity.
• Treatment: lifestyle changes (diet, exercise), oral medication (metformin increases insulin sensitivity), and in some cases insulin therapy.

Feature	Type 1 Diabetes	Type 2 Diabetes
Age of onset	Childhood/adolescence	Usually adulthood
Insulin production	None or very low	Initially normal; may decline over time
Insulin resistance	No	Yes
Body weight	Often normal or underweight	Usually overweight or obese
Treatment	Insulin injections essential	Diet, exercise, oral drugs, sometimes insulin
Ketoacidosis risk	High	Low

For more on the immune system and autoimmunity, see Immunology.

warning

Common Pitfall Students often write that "insulin converts glucose to glycogen." Insulin does not perform this conversion itself -- it is a signalling molecule that stimulates liver and muscle cells to perform glycogenesis via enzyme activation. The insulin binds to receptors on the cell surface and triggers a signalling cascade that activates the relevant enzymes.

3. Temperature Regulation (Thermoregulation)

3.1 The Hypothalamus

The hypothalamus is the body's thermostat. It contains a thermoregulatory centre that receives input from thermoreceptors and sends output to effectors.

Thermoreceptors:

• Central thermoreceptors: in the hypothalamus itself, monitoring the temperature of the blood.
• Peripheral thermoreceptors: in the skin (dermis), monitoring the external temperature.

The hypothalamus compares the information from both sets of receptors with the set point (approximately $37\ ^\circ\mathrm{C}$ in humans).

3.2 Response to Cold (Below Set Point)

When the hypothalamus detects a fall in core body temperature:

Behavioural responses (conscious): putting on warm clothing, moving to a warmer environment, curling up to reduce surface area.

Physiological responses (involuntary, negative feedback):

Response	Mechanism
Vasoconstriction	Arterioles supplying the skin surface constrict (smooth muscle contraction, controlled by the sympathetic nervous system). This reduces blood flow near the skin surface, reducing heat loss by radiation and convection.
Piloerection (goose bumps)	Hair erector muscles contract, raising hairs and trapping a layer of insulating air next to the skin.
Shivering	Rapid, involuntary contraction and relaxation of skeletal muscles. Muscle contraction generates heat as a by-product of respiration.
Increased metabolic rate	The thyroid gland releases more thyroxine, which increases the basal metabolic rate, generating more heat from cellular respiration.
Behavioural changes	Seeking warmth, curling up, reduced activity to conserve energy

3.3 Response to Heat (Above Set Point)

When the hypothalamus detects a rise in core body temperature:

Behavioural responses: removing clothing, moving to a cooler environment, drinking cold water.

Physiological responses (involuntary, negative feedback):

Response	Mechanism
Vasodilation	Arterioles supplying the skin surface dilate (smooth muscle relaxation). This increases blood flow near the skin surface, increasing heat loss by radiation.
Sweating	Sweat glands (eccrine glands) secrete sweat onto the skin surface. Water in sweat evaporates, absorbing latent heat of vaporisation ($2.26\ \mathrm{kJ\ g^{-1}}$), cooling the skin.
Decreased metabolic rate	Reduced thyroxine secretion, lowering the basal metabolic rate.
Behavioural changes	Reducing activity, seeking shade

Sweat as a negative feedback mechanism: as sweat evaporates and cools the skin, skin thermoreceptors detect the reduced temperature and send signals to the hypothalamus, which reduces the stimulation of sweat glands. This is a classic negative feedback loop.

3.4 Temperature Regulation in Extremophiles

Some organisms have adaptations to extreme temperatures:

• Hyperthermophiles (e.g., Thermus aquaticus, source of Taq polymerase): enzymes with high optimum temperatures and enhanced thermal stability (more disulfide bonds, more hydrophobic interactions, more salt bridges).
• Psychrophiles (cold-adapted organisms): enzymes with more flexible active sites and lower optimum temperatures; more unsaturated fatty acids in membranes to maintain fluidity at low temperatures.
• Camels: large body mass with low surface-area-to-volume ratio reduces heat absorption; fat stored in a single hump (reducing insulation over most of the body surface); concentrated urine reduces water loss; body temperature can fluctuate more widely than in humans (reducing the need for sweating).

4. Osmoregulation

4.1 Principles

Osmoregulation is the control of the water potential of body fluids. In mammals, the kidneys regulate the water content and solute concentration of the blood.

The hypothalamus contains osmoreceptors that detect changes in the water potential of the blood (specifically, changes in solute concentration). When blood water potential decreases (becomes more negative, indicating dehydration), the osmoreceptors are stimulated.

4.2 ADH and the Kidneys

Antidiuretic hormone (ADH, vasopressin) is produced by neurosecretory cells in the hypothalamus and stored in and released from the posterior pituitary gland.

Mechanism:

1. Blood water potential decreases (blood becomes more concentrated).
2. Osmoreceptors in the hypothalamus detect the change.
3. Neurosecretory cells in the hypothalamus produce ADH, which travels down their axons to the posterior pituitary.
4. The posterior pituitary releases ADH into the blood.
5. ADH binds to receptors on the cells of the distal convoluted tubule (DCT) and collecting duct in the kidney nephrons.
6. ADH increases the permeability of the DCT and collecting duct to water by stimulating the insertion of aquaporin (water channel) proteins into the luminal membrane.
7. More water is reabsorbed from the filtrate back into the blood (by osmosis).
8. A smaller volume of more concentrated urine is produced.
9. Blood water potential increases (blood becomes more dilute), reducing the stimulation of osmoreceptors (negative feedback).

When blood water potential is high (overhydration):

1. Osmoreceptors are less stimulated.
2. Less ADH is released.
3. The DCT and collecting duct become less permeable to water.
4. Less water is reabsorbed; a larger volume of dilute urine is produced.
5. Blood water potential decreases towards normal (negative feedback).

4.3 Kidney Structure and the Nephron

The kidney contains approximately one million nephrons, the functional units of filtration and reabsorption.

Structure of the nephron:

Region	Function
Bowman's capsule + glomerulus	Ultrafiltration: high-pressure filtration of blood plasma
Proximal convoluted tubule (PCT)	Selective reabsorption: all glucose, all amino acids, most $\mathrm{Na^+}$ and water, by active transport and co-transport
Loop of Henle (descending limb)	Water permeable; water passes out by osmosis into the hypertonic medulla
Loop of Henle (ascending limb)	Impermeable to water; actively transports $\mathrm{Na^+}$ and $\mathrm{Cl^-}$ out, creating a salt gradient in the medulla
Distal convoluted tubule (DCT)	Fine-tuning of $\mathrm{Na^+}$ and water reabsorption; regulated by ADH and aldosterone
Collecting duct	Final water reabsorption regulated by ADH

Ultrafiltration at the glomerulus is driven by hydrostatic pressure of the blood in the glomerular capillaries. The filtrate passes through the basement membrane and the pores in the podocytes (cells of the Bowman's capsule). Large molecules (proteins, blood cells) are too large to pass through and remain in the blood.

4.4 Countercurrent Multiplier

The loop of Henle acts as a countercurrent multiplier that creates and maintains a concentration gradient in the medulla of the kidney:

1. The descending limb is permeable to water but not to solutes. Water passes out by osmosis into the increasingly concentrated medulla.
2. The ascending limb actively transports $\mathrm{Na^+}$ and $\mathrm{Cl^-}$ out into the medulla, making the medulla progressively more concentrated towards the papilla (inner tip).
3. The arrangement of the two limbs (fluid flowing in opposite directions) multiplies the concentration gradient.
4. This hypertonic medulla (up to $1200\ \mathrm{mOsmol\ kg^{-1}}$ at the papilla) provides the osmotic gradient that drives water reabsorption from the collecting duct.

5. Control of Heart Rate

5.1 The Sinoatrial Node (SAN)

The sinoatrial node (SAN), located in the wall of the right atrium, is the heart's natural pacemaker. It generates rhythmic waves of electrical depolarisation that spread across the atria, causing atrial systole. The wave then passes to the atrioventricular node (AVN), which delays the impulse before passing it to the Bundle of His, the Purkyne tissue, and the ventricular muscle, causing ventricular systole.

For detailed cardiac cycle mechanics, see Exchange and Transport.

5.2 Autonomic Nervous System Control

Heart rate is controlled by the autonomic nervous system:

• Sympathetic nervous system: releases noradrenaline at the SAN, increasing the rate of depolarisation and therefore the heart rate. This is the "fight-or-flight" response.
• Parasympathetic nervous system (vagus nerve): releases acetylcholine at the SAN, decreasing the rate of depolarisation and therefore the heart rate. This is the "rest-and-digest" response.

At rest, parasympathetic stimulation predominates, keeping the heart rate at approximately 72 beats per minute.

5.3 Chemical and Pressure Control

Chemoreceptors in the aortic and carotid bodies detect changes in blood $\mathrm{CO_2}$ concentration and pH:

• High $p\mathrm{CO_2}$ (hypercapnia) or low pH: detected by chemoreceptors, which send impulses to the medulla oblongata. The cardiovascular centre increases sympathetic stimulation and decreases parasympathetic stimulation, increasing heart rate and ventilation rate.

Baroreceptors in the aortic arch and carotid sinus detect changes in blood pressure:

• High blood pressure: baroreceptors are stretched more, sending more impulses to the medulla. The medulla increases parasympathetic stimulation and decreases sympathetic stimulation, slowing the heart rate and causing vasodilation.

6. Control of Blood $p\mathrm{CO_2}$ and pH

6.1 The Carbonic Acid-Bicarbonate Buffer System

Blood pH is maintained between 7.35 and 7.45 by the carbonic acid-bicarbonate buffer system:

$\mathrm{CO_2 + H_2O \rightleftharpoons H_2CO_3 \rightleftharpoons H^+ + HCO_3^-}$

This reaction is catalysed by carbonic anhydrase in red blood cells. When $p\mathrm{CO_2}$ rises, the equilibrium shifts to the right, producing more $\mathrm{H^+}$ and lowering pH. The $\mathrm{H^+}$ is buffered by haemoglobin (the Bohr effect).

6.2 Respiratory Compensation

Changes in ventilation rate can compensate for pH disturbances:

• Respiratory acidosis (high $p\mathrm{CO_2}$, low pH): increased ventilation rate removes $\mathrm{CO_2}$ from the blood, shifting the equilibrium to the left and raising pH.
• Respiratory alkalosis (low $p\mathrm{CO_2}$, high pH, e.g., due to hyperventilation): decreased ventilation rate allows $\mathrm{CO_2}$ to accumulate, shifting the equilibrium to the right and lowering pH.

6.3 Renal Compensation

The kidneys provide long-term pH regulation by:

• Excreting excess $\mathrm{H^+}$ in the urine.
• Reabsorbing or secreting $\mathrm{HCO_3^-}$ to adjust the bicarbonate buffer capacity.

Practice Problems

Details

Problem 1

Describe how insulin and glucagon work together to regulate blood glucose concentration. In your answer, explain the role of negative feedback. (6 marks)

Answer. After a meal, blood glucose rises above the set point ($\approx 5\ \mathrm{mmol\ dm^{-3}}$). This is detected by $\beta$ cells in the islets of Langerhans, which secrete insulin. Insulin binds to receptors on liver cells, muscle cells, and adipose tissue, stimulating glucose uptake (via GLUT4 transporter translocation), glycogenesis (conversion of glucose to glycogen), glycolysis, and inhibiting gluconeogenesis. Blood glucose decreases towards the set point. When blood glucose falls below the set point (e.g., during fasting), $\alpha$ cells detect the decrease and secrete glucagon. Glucagon binds to receptors on liver cells, stimulating glycogenolysis (breakdown of glycogen to glucose) and gluconeogenesis (synthesis of glucose from amino acids and glycerol). Blood glucose increases towards the set point. Both mechanisms involve negative feedback: as blood glucose returns to the set point, the stimulus for hormone secretion diminishes, reducing hormone release. This prevents overcorrection and maintains blood glucose within a narrow range.

If you get this wrong, revise: Blood Glucose Regulation

Details

Problem 2

Explain how the body responds to a decrease in core body temperature. Describe the role of the hypothalamus, thermoreceptors, and effectors. (5 marks)

Answer. A decrease in core body temperature is detected by central thermoreceptors (in the hypothalamus) and peripheral thermoreceptors (in the skin). Impulses are sent to the thermoregulatory centre in the hypothalamus, which coordinates the response. The hypothalamus sends impulses via the sympathetic nervous system to effectors: (1) vasoconstriction of arterioles supplying the skin surface, reducing blood flow near the skin and minimising heat loss by radiation; (2) piloerection, where hair erector muscles contract, raising body hairs and trapping an insulating layer of air; (3) shivering, where skeletal muscles contract and relax rapidly, generating heat from increased metabolic activity; (4) increased secretion of thyroxine from the thyroid gland, raising the basal metabolic rate and increasing heat production from cellular respiration. As body temperature returns towards $37\ ^\circ\mathrm{C}$, the thermoreceptors send fewer impulses, reducing the hypothalamic response (negative feedback).

If you get this wrong, revise: Response to Cold

Details

Problem 3

Explain the role of ADH in osmoregulation. Describe how ADH secretion is controlled by negative feedback. (5 marks)

Answer. When the water potential of the blood decreases (blood becomes more concentrated), osmoreceptors in the hypothalamus detect the change and stimulate neurosecretory cells. These cells produce ADH, which is transported down their axons to the posterior pituitary and released into the blood. ADH binds to receptors on the cells of the distal convoluted tubule and collecting duct in the kidney nephrons, stimulating the insertion of aquaporin water channel proteins into the luminal membrane. This increases the permeability of the tubule to water, so more water is reabsorbed from the filtrate into the blood by osmosis. The kidneys produce a smaller volume of more concentrated urine. As blood water potential increases (blood becomes more dilute), the osmoreceptors are less stimulated, reducing ADH secretion. The collecting duct becomes less permeable to water, more water is lost in the urine, and blood water potential decreases towards normal. This is negative feedback.

If you get this wrong, revise: ADH and the Kidneys

Details

Problem 4

Compare the causes and treatments of Type 1 and Type 2 diabetes. Explain why a person with Type 1 diabetes may experience weight loss despite eating normally. (5 marks)

Answer. Type 1 diabetes is caused by the autoimmune destruction of $\beta$ cells in the islets of Langerhans, resulting in no insulin production. It is treated with lifelong insulin injections and blood glucose monitoring. Type 2 diabetes is caused by insulin resistance (target cells become less responsive to insulin) combined with eventual $\beta$ cell exhaustion. It is associated with obesity, age, and genetic factors, and is initially treated with lifestyle changes and oral medication (e.g., metformin), progressing to insulin therapy if needed. In Type 1 diabetes, the lack of insulin means glucose cannot be taken up by cells. Despite normal or increased food intake, cells are starved of glucose and cannot carry out respiration efficiently. The body therefore metabolises fat stores (lipolysis) and protein (proteolysis) for energy, leading to weight loss. The breakdown of fat produces ketones, which can accumulate and cause ketoacidosis if untreated.

If you get this wrong, revise: Diabetes Mellitus

Details

Problem 5

A student exercises vigorously. Explain how the body detects and responds to the resulting changes in blood $\mathrm{CO_2}$ concentration and pH. (5 marks)

Answer. During vigorous exercise, muscle cells respire more rapidly (aerobic and anaerobic respiration), producing more $\mathrm{CO_2}$ and lactic acid. This increases $p\mathrm{CO_2}$ and decreases blood pH. The increase in $p\mathrm{CO_2}$ is detected by chemoreceptors in the aortic body and carotid body, which send impulses to the respiratory centre in the medulla oblongata. The respiratory centre increases the rate and depth of breathing (ventilation), which increases the rate of $\mathrm{CO_2}$ removal from the lungs, restoring normal $p\mathrm{CO_2}$ and pH. Simultaneously, the decrease in pH is detected by chemoreceptors and by the cardiovascular centre. The cardiovascular centre increases sympathetic stimulation to the SAN, increasing heart rate and cardiac output. This increases blood flow to the lungs for gas exchange and to the muscles for $\mathrm{O_2}$ delivery. Both responses are negative feedback mechanisms.

If you get this wrong, revise: Control of Blood PCO2 and pH

7. The Kidney Nephron in Detail

7.1 Ultrafiltration

Ultrafiltration occurs in the Bowman's capsule. Blood enters the glomerulus via the afferent arteriole (wider) and leaves via the efferent arteriole (narrower), creating high hydrostatic pressure ($\approx 7\ \mathrm{kPa}$). This pressure forces small molecules (water, glucose, amino acids, urea, ions) out of the blood through the endothelial pores of the glomerular capillaries, across the basement membrane, and through the filtration slits of the podocytes, into the capsular space.

Three barriers to filtration:

1. Fenestrated endothelium: pores ($\approx 100\ \mathrm{nm}$) in capillary walls allow passage of small molecules but not cells.
2. Basement membrane: a negatively charged mesh of collagen and glycoproteins. It acts as a molecular sieve and repels negatively charged proteins (e.g., albumin).
3. Podocyte foot processes: epithelial cells with filtration slits ($\approx 25\ \mathrm{nm}$) that prevent passage of medium-sized proteins.

The filtrate has the same composition as blood plasma minus proteins and blood cells.

7.2 Selective Reabsorption

Approximately 99% of the filtrate is reabsorbed as it passes through the nephron tubule:

Substance	% of filtrate reabsorbed	Location	Mechanism
Water	99%	Proximal convoluted tubule, loop of Henle, collecting duct	Osmosis
$\mathrm{Na^+}$	99%	PCT (active transport), ascending limb (active), DCT (active)	$\mathrm{Na^+/K^+}$ ATPase
Glucose	100%	PCT	Co-transport with $\mathrm{Na^+}$
Amino acids	100%	PCT	Co-transport with $\mathrm{Na^+}$
Urea	50%	PCT, collecting duct	Diffusion and water reabsorption concentrating it
$\mathrm{K^+}$	90%	PCT, loop of Henle	Active transport

7.3 The Loop of Henle and the Countercurrent Multiplier

The loop of Henle creates a gradient of increasing osmolarity in the medulla, from approximately $300\ \mathrm{mOsmol\ kg^{-1}}$ in the cortex to approximately $1200\ \mathrm{mOsmol\ kg^{-1}}$ at the tip of the medulla. This gradient is essential for water reabsorption from the collecting duct.

Descending limb: permeable to water (aquaporins), impermeable to ions. As the filtrate descends deeper into the medulla, the increasing osmolarity of the interstitial fluid draws water out by osmosis. The filtrate becomes progressively more concentrated.

Ascending limb: impermeable to water, actively transports $\mathrm{Na^+}$, $\mathrm{K^+}$, and $\mathrm{Cl^-}$ out of the filtrate (via the $\mathrm{Na^+/K^+/2Cl^-}$ co-transporter in the thick segment). This dilutes the filtrate and adds ions to the medullary interstitial fluid, maintaining the osmotic gradient.

This arrangement is called a countercurrent multiplier because the two limbs run in opposite directions (countercurrent), and the active transport in the ascending limb multiplies (amplifies) the osmotic gradient established by the descending limb.

The vasa recta (hairpin-shaped blood capillaries surrounding the loop of Henle) maintain this gradient by acting as a countercurrent exchanger: blood flowing down the descending limb of the vasa recta loses water and gains ions, while blood flowing up the ascending limb gains water and loses ions. This prevents the vasa recta from washing away the medullary gradient.

7.4 ADH: Second Messenger Mechanism

ADH (antidiuretic hormone, vasopressin) acts through a second messenger system:

1. ADH binds to V2 receptors on the basolateral membrane of collecting duct cells (a G-protein-coupled receptor).
2. The receptor activates a G-protein ($\mathrm{G_s}$), which activates adenylate cyclase.
3. Adenylate cyclase converts ATP to cyclic AMP (cAMP), the second messenger.
4. cAMP activates protein kinase A (PKA).
5. PKA phosphorylates vesicles containing aquaporin-2 water channel proteins, triggering their fusion with the apical (luminal) membrane.
6. Aquaporin channels are inserted into the luminal membrane, increasing water permeability.
7. Water is reabsorbed from the filtrate into the medullary interstitium and then into the vasa recta.

When ADH levels decrease, aquaporin channels are removed from the membrane by endocytosis, reducing water permeability.

7.5 Calculating Water Potential of Urine

Worked Example. A person produces $1.5\ \mathrm{dm^3}$ of urine per day with an osmolarity of $600\ \mathrm{mOsmol\ kg^{-1}}$. A second person (dehydrated) produces $0.5\ \mathrm{dm^3}$ of urine with an osmolarity of $1200\ \mathrm{mOsmol\ kg^{-1}}$.

Person 1: total solute excreted $= 1.5 \times 600 = 900\ \mathrm{mOsmol\ day^{-1}}$.

Person 2: total solute excreted $= 0.5 \times 1200 = 600\ \mathrm{mOsmol\ day^{-1}}$.

Both people excrete approximately the same amount of solute (within normal variation), but the dehydrated person excretes it in a smaller volume of more concentrated urine. This demonstrates the kidney's ability to independently regulate water reabsorption (via ADH) and solute excretion.

8. Temperature Regulation in Detail

8.1 Endotherms vs Ectotherms

Feature	Endotherms	Ectotherms
Heat source	Internal (metabolism)	External (sun, conduction)
Body temperature	Relatively constant	Varies with environment
Basal metabolic rate	High (to maintain body temperature)	Low
Insulation	Fur, feathers, blubber	None (behavioural adaptations)
Activity at low temperatures	Can remain active	Sluggish or inactive
Examples	Mammals, birds	Reptiles, amphibians, fish, invertebrates

8.2 Endothermic Responses to Heat and Cold

When body temperature rises above 37 degrees C:

Response	Mechanism	Effect
Vasodilation	Relaxation of smooth muscle in arterioles supplying skin capillaries	More blood flows near the surface, increasing heat loss by radiation and convection
Sweating	Sweat glands secrete sweat onto the skin surface	Evaporation of water absorbs latent heat, cooling the skin ($2.26\ \mathrm{MJ\ kg^{-1}}$ of water evaporated)
Flattening of body hair (piloerection reversal)	Erector pili muscles relax	Reduces the insulating layer of trapped air, allowing more heat loss
Behavioural responses	Seeking shade, removing clothing, reducing activity	Reduces heat gain from environment and metabolism

When body temperature falls below 37 degrees C:

Response	Mechanism	Effect
Vasoconstriction	Contraction of smooth muscle in skin arterioles	Less blood near surface, reducing heat loss
Shivering	Rapid involuntary contraction and relaxation of skeletal muscles	Muscle contraction generates heat as a by-product of respiration
Piloerection	Erector pili muscles contract, raising body hairs	Traps a layer of insulating air next to the skin
Increased metabolic rate	Thyroid hormones ($\mathrm{T_3}$, $\mathrm{T_4}$) stimulate basal metabolic rate	More heat generated by cellular respiration
Non-shivering thermogenesis	Brown adipose tissue (brown fat) is stimulated by noradrenaline to oxidise fatty acids	Uncoupling protein 1 (UCP1) in brown fat mitochondria uncouples electron transport from ATP synthesis, releasing energy as heat
Behavioural responses	Curling up, huddling, seeking warmth, putting on clothes	Reduces surface area exposed, gains heat from environment

8.3 The Role of the Hypothalamus

The hypothalamus contains two thermoregulatory centres:

• Heat loss centre (anterior hypothalamus): when activated, it triggers vasodilation, sweating, and behavioural responses to cool the body.
• Heat gain centre (posterior hypothalamus): when activated, it triggers vasoconstriction, shivering, and increased metabolic rate.

Temperature receptors:

• Peripheral thermoreceptors: in the skin (cold and warm receptors). These provide early warning of environmental temperature changes.
• Central thermoreceptors: in the hypothalamus and other internal organs. These monitor core body temperature and are the primary drivers of the thermoregulatory response.

The hypothalamus integrates signals from both peripheral and central thermoreceptors to determine the appropriate response.

8.4 Negative Feedback with a Threshold

Thermoregulation demonstrates an important feature of negative feedback: the set point is not a single value but a range. The body does not respond to tiny deviations from 37 degrees C; there is a threshold (typically $\pm 0.5$ degrees C) below which no response is triggered. This prevents unnecessary oscillations (the system would constantly overcorrect if it responded to every tiny fluctuation).

9. Hormonal Control of the Menstrual Cycle

9.1 Overview

The menstrual cycle is controlled by four hormones: FSH, LH, oestrogen, and progesterone.

Hormone	Source	Function
FSH (follicle-stimulating hormone)	Anterior pituitary	Stimulates development of follicles in the ovary; stimulates oestrogen production
LH (luteinising hormone)	Anterior pituitary	Triggers ovulation; stimulates formation of the corpus luteum
Oestrogen	Developing follicle (ovary)	Stimulates proliferation of the endometrium (uterine lining); inhibits FSH at high concentration (negative feedback); stimulates LH surge at peak (positive feedback)
Progesterone	Corpus luteum (ovary)	Maintains the thick endometrium; inhibits FSH and LH (negative feedback)

9.2 Phases of the Cycle

Days 1--5: Menstruation. The endometrium breaks down and is shed. Low levels of oestrogen and progesterone.

Days 1--13: Follicular phase. FSH stimulates follicle development. The developing follicle secretes increasing amounts of oestrogen. Oestrogen initially inhibits FSH (negative feedback), ensuring only one follicle develops (the dominant follicle). Oestrogen stimulates repair and thickening of the endometrium.

Day 14: Ovulation. Oestrogen concentration reaches a peak, which triggers a positive feedback loop: high oestrogen stimulates the anterior pituitary to release a surge of LH. The LH surge triggers the release of the mature oocyte from the ovary.

Days 15--28: Luteal phase. LH stimulates the ruptured follicle to develop into the corpus luteum, which secretes progesterone (and some oestrogen). Progesterone maintains the thick, blood-rich endometrium in preparation for implantation. Progesterone also inhibits FSH and LH (negative feedback), preventing new follicle development and ovulation.

If the oocyte is not fertilised: the corpus luteum degenerates after approximately 10 days (day 24). Progesterone and oestrogen levels drop. The endometrium can no longer be maintained and breaks down (menstruation). FSH levels begin to rise again.

9.3 Hormone Interactions: Feedback Loops

The menstrual cycle involves both negative feedback and positive feedback:

• Negative feedback: oestrogen (at low-to-moderate levels) inhibits FSH secretion. Progesterone inhibits both FSH and LH secretion. This prevents multiple ovulations and excessive follicular development.
• Positive feedback: when oestrogen reaches a critical threshold (high concentration), it switches from inhibiting to stimulating LH secretion. This positive feedback loop amplifies the LH signal, producing the LH surge that triggers ovulation. This is one of the few examples of positive feedback in human physiology.

10. Plant Hormones and Growth Responses

10.1 Auxin (IAA)

Indole-3-acetic acid (IAA) is the primary auxin in plants. It is produced in the shoot tip (apical meristem) and transported down the shoot by polar auxin transport (via auxin efflux carriers, PIN proteins, on the basolateral membranes of cells).

Effects of auxin:

• Cell elongation: auxin increases the plasticity (stretchability) of the cell wall by activating proton pumps ($\mathrm{H^+}$-ATPases) that pump $\mathrm{H^+}$ into the cell wall. The low pH activates enzymes (expansins) that break cross-links between cellulose microfibrils, allowing the wall to expand as the cell takes up water by osmosis.
• Apical dominance: auxin produced by the apical bud inhibits the growth of lateral buds. Removing the apical bud (decapitation) allows lateral buds to grow. This ensures the plant grows taller (competing for light) rather than bushier.
• Root initiation: auxin stimulates the formation of lateral roots from pericycle cells.
• Fruit development: auxin promotes fruit set and development after fertilisation. In parthenocarpic fruits, auxin is applied artificially to produce seedless fruit.

10.2 Phototropism

Phototropism is the directional growth of a plant shoot towards light. The mechanism:

1. Light is detected by phototropins (blue-light receptors) in the shoot tip.
2. Auxin is redistributed to the shaded side of the shoot (by lateral transport via PIN proteins).
3. Higher auxin concentration on the shaded side stimulates greater cell elongation.
4. The shoot bends towards the light.

10.3 Gibberellin

Gibberellins are a group of hormones produced in young leaves, roots, and developing seeds.

Effects of gibberellin:

• Stem elongation: gibberellins stimulate cell division and cell elongation in the internodes of stems. Dwarf varieties of plants (e.g., dwarf peas) often have a mutation that reduces gibberellin production.
• Seed germination: when a seed absorbs water, the embryo produces gibberellin, which diffuses to the aleurone layer of the endosperm. Gibberellin stimulates the aleurone cells to synthesise and secrete amylase, which breaks down starch into maltose for the growing embryo. This is a classic example of hormonal control of gene expression.

10.4 Ethylene

Ethylene ($\mathrm{C_2H_4}$) is a gaseous hormone produced by ripening fruits. It stimulates:

• Fruit ripening (conversion of starch to sugars, breakdown of chlorophyll, softening of cell walls).
• Leaf abscission (formation of the abscission zone at the base of the petiole).
• Flowering in some species.

Because ethylene is a gas, it can diffuse between fruits, causing them to ripen simultaneously. This is why placing unripe fruit in a bag with a ripe banana accelerates ripening.

11. Nervous and Hormonal Coordination Compared

11.1 Similarities and Differences

Feature	Nervous System	Endocrine System
Signal type	Electrical impulses (action potentials)	Chemical (hormones in blood)
Transmission speed	Fast (up to $120\ \mathrm{m\ s^{-1}}$)	Slow (seconds to hours)
Duration of response	Short (seconds to minutes)	Long (hours to days)
Target	Specific (localised effectors)	Widespread (any cell with receptors)
Adaptability	Highly adaptable (learned responses)	Less adaptable (genetically programmed)

11.2 Examples of Dual Control

Many physiological processes are controlled by both nervous and hormonal mechanisms:

Heart rate: the autonomic nervous system provides rapid, short-term control (sympathetic accelerates; parasympathetic decelerates). Adrenaline (hormone) provides slower, sustained increase during stress.

Blood glucose: the nervous system can stimulate the adrenal medulla to release adrenaline, which rapidly increases blood glucose by stimulating glycogenolysis. Insulin and glucagon (hormones) provide slower, sustained regulation.

Osmoregulation: osmoreceptors (nervous) detect changes in blood water potential and trigger ADH release (hormonal) from the posterior pituitary.

12. Diabetes in Detail

12.1 Type 1 Diabetes Mellitus (T1DM)

• Cause: autoimmune destruction of $\beta$ cells in the islets of Langerhans. T lymphocytes (T killer cells) recognise $\beta$ cell antigens as foreign and destroy them.
• Onset: typically in childhood or adolescence (juvenile-onset).
• Genetics: associated with HLA-DR3 and HLA-DR4 genes (major histocompatibility complex on chromosome 6).
• Treatment: lifelong insulin injections (subcutaneous). Insulin cannot be taken orally because it is a peptide hormone and would be digested by proteases in the stomach and small intestine.
• Insulin delivery: multiple daily injections, insulin pens, or insulin pumps (continuous subcutaneous insulin infusion, CSII).
• Monitoring: blood glucose testing (finger-prick blood samples analysed by glucose oxidase biosensors), HbA1c (glycated haemoglobin -- measures average blood glucose over the previous 8--12 weeks).

12.2 Type 2 Diabetes Mellitus (T2DM)

• Cause: insulin resistance (target cells become less responsive to insulin) combined with progressive $\beta$ cell failure.
• Risk factors: obesity (especially visceral fat), sedentary lifestyle, diet high in refined carbohydrates, age, family history, ethnicity (higher risk in South Asian, Afro-Caribbean populations).
• Mechanism: excess adipose tissue releases pro-inflammatory cytokines (TNF-$\alpha$, IL-6) and free fatty acids, which interfere with insulin receptor signalling. The $\mathrm{PI3K}$ pathway is disrupted, reducing GLUT4 translocation to the cell membrane.
• Treatment: lifestyle changes (diet, exercise), oral medication (metformin reduces hepatic glucose production and increases insulin sensitivity), GLP-1 receptor agonists, SGLT2 inhibitors (increase glucose excretion in urine), and eventually insulin if $\beta$ cell function deteriorates.

12.3 Complications of Diabetes

Chronic hyperglycaemia damages blood vessels through several mechanisms:

1. Glycation: glucose binds non-enzymatically to proteins (e.g., haemoglobin to form HbA1c, collagen in blood vessel walls), altering their structure and function.
2. Activation of protein kinase C (PKC): high glucose activates PKC, which increases vascular permeability and promotes inflammation.
3. Polyol pathway: excess glucose is converted to sorbitol by aldose reductase, depleting NADPH and reducing antioxidant capacity (glutathione regeneration). Sorbitol accumulation damages cells.

Microvascular complications:

• Retinopathy: damage to retinal blood vessels, causing blindness.
• Nephropathy: damage to glomerular capillaries, causing kidney failure.
• Neuropathy: damage to peripheral nerves, causing loss of sensation (especially in feet), leading to ulcers and amputations.

Macrovascular complications:

• Atherosclerosis: accelerated formation of fatty plaques in arteries, increasing risk of heart attack and stroke.

warning

Common Pitfall Students often state that "insulin converts glucose to glycogen." This is imprecise. Insulin stimulates the enzyme glycogen synthase (via dephosphorylation) and promotes GLUT4 translocation, which increases glucose uptake into cells. Glycogen synthase catalyses the conversion. Always specify the enzyme or the cellular mechanism, not just the hormone.

13. Control of Blood Sugar: Molecular Mechanisms

13.1 Insulin Signalling Cascade

When insulin binds to its receptor (a receptor tyrosine kinase, RTK) on the target cell membrane:

1. Insulin binds to the $\alpha$-subunits of the receptor, causing the $\beta$-subunits to autophosphorylate (add phosphate groups to their own tyrosine residues).
2. The phosphorylated receptor activates IRS-1 (insulin receptor substrate-1) by phosphorylation.
3. IRS-1 activates PI3K (phosphoinositide 3-kinase).
4. PI3K converts PIP2 to PIP3, which activates PDK1.
5. PDK1 phosphorylates and activates PKB (protein kinase B, also called Akt).
6. PKB phosphorylates multiple targets:
   • GLUT4 vesicles: PKB triggers the translocation of GLUT4 glucose transporters from intracellular vesicles to the cell membrane, increasing glucose uptake (especially in muscle and adipose tissue).
   • Glycogen synthase: PKB inhibits GSK-3 (glycogen synthase kinase-3), which normally inhibits glycogen synthase. The net effect is activation of glycogen synthase, promoting glycogen synthesis.
   • Acetyl-CoA carboxylase: promotes fatty acid synthesis.
   • mTOR pathway: stimulates protein synthesis and cell growth.

13.2 Glucagon Signalling

Glucagon binds to a G-protein-coupled receptor on the target cell (primarily hepatocytes):

1. Glucagon binding activates $\mathrm{G_s}$ protein, which activates adenylate cyclase.
2. Adenylate cyclase converts ATP to cAMP (second messenger).
3. cAMP activates protein kinase A (PKA).
4. PKA phosphorylates targets that promote:
   • Glycogenolysis: phosphorylation of glycogen phosphorylase kinase, which activates glycogen phosphorylase, breaking glycogen into glucose-1-phosphate.
   • Gluconeogenesis: activation of key enzymes (PEP carboxykinase, fructose-1,6-bisphosphatase).
   • Lipolysis: in adipose tissue, PKA activates hormone-sensitive lipase, breaking triglycerides into fatty acids and glycerol.

13.3 Second Messengers Compared

Second Messenger	Produced By	Activated By	Primary Effect
cAMP	Adenylate cyclase	Glucagon, adrenaline ($\beta$-adrenergic)	Activates PKA
cGMP	Guanylate cyclase	Nitric oxide (NO), atrial natriuretic peptide (ANP)	Activates PKG; causes vasodilation
$\mathrm{IP_3}$	Phospholipase C (PLC)	Adrenaline ($\alpha_1$-adrenergic), ADH ($\mathrm{V_1}$ receptors)	Releases $\mathrm{Ca^{2+}}$ from ER
DAG	Phospholipase C (PLC)	Same as $\mathrm{IP_3}$	Activates PKC

14. The Endocrine System: Beyond the Pancreas

14.1 The Adrenal Glands

The adrenal glands sit on top of the kidneys and have two distinct regions:

Adrenal cortex (outer region): produces steroid hormones in three zones:

Zone	Hormone	Function
Zona glomerulosa	Aldosterone (mineralocorticoid)	Increases $\mathrm{Na^+}$ reabsorption and $\mathrm{K^+}$ excretion in the kidneys; increases blood pressure
Zona fasciculata	Cortisol (glucocorticoid)	Increases blood glucose (stimulates gluconeogenesis and glycogenolysis); suppresses the immune system; anti-inflammatory
Zona reticularis	Androgens (e.g., DHEA)	Converted to testosterone and oestrogens in peripheral tissues

Adrenal medulla (inner region): produces adrenaline (epinephrine) and noradrenaline (norepinephrine) -- the "fight or flight" hormones. These are released in response to stress and:

• Increase heart rate and stroke volume.
• Dilate bronchioles (increasing air flow).
• Dilate pupils.
• Stimulate glycogenolysis in the liver (increasing blood glucose).
• Cause vasoconstriction in skin and digestive organs (redirecting blood to muscles and brain).

14.2 The Thyroid Gland

The thyroid gland produces:

Hormone	Target	Function
$\mathrm{T_3}$ (triiodothyronine) and $\mathrm{T_4}$ (thyroxine)	Most body cells	Increases basal metabolic rate (BMR) by stimulating transcription of genes involved in metabolism; promotes protein synthesis; essential for growth and development (especially brain development in infants)
Calcitonin	Bones, kidneys	Lowers blood $\mathrm{Ca^{2+}}$ by inhibiting osteoclast activity and stimulating $\mathrm{Ca^{2+}}$ excretion in urine

Thyroid hormones are produced by iodination of tyrosine residues in thyroglobulin (a protein stored in the thyroid follicle). Iodine deficiency causes the thyroid to enlarge (goitre) as it attempts to produce more $\mathrm{T_3}$/$\mathrm{T_4}$ with insufficient raw material.

Thyroid disorders:

Disorder	Cause	Symptoms
Hyperthyroidism (Graves' disease)	Autoantibodies stimulate the TSH receptor	Weight loss, increased heart rate, anxiety, heat intolerance, exophthalmos (bulging eyes)
Hypothyroidism (myxoedema)	Autoimmune destruction of thyroid (Hashimoto's) or iodine deficiency	Weight gain, fatigue, cold intolerance, slow heart rate, mental slowing
Cretinism	Congenital hypothyroidism	Severe intellectual disability, stunted growth (preventable by newborn screening and early $\mathrm{T_4}$ treatment)

14.3 The Pituitary Gland

The pituitary gland (hypophysis) is the "master gland" located at the base of the brain, connected to the hypothalamus by the infundibulum (pituitary stalk).

Part	Hormones	Function
Anterior pituitary (adenohypophysis)	FSH, LH, ACTH, TSH, GH, prolactin	Stimulates other endocrine glands (FSH/LH $\to$ gonads; ACTH $\to$ adrenal cortex; TSH $\to$ thyroid); GH stimulates growth; prolactin stimulates milk production
Posterior pituitary (neurohypophysis)	ADH (vasopressin), oxytocin	Stores and releases hormones produced by the hypothalamus; ADH increases water reabsorption in kidneys; oxytocin stimulates uterine contraction during labour and milk ejection during breastfeeding

15. Negative Feedback: Detailed Examples

15.1 Blood Glucose: A Complete Feedback Loop

Stimulus: blood glucose rises above 90 $\mathrm{mg\ dL^{-1}}$ (e.g., after a meal).

1. Receptor: $\beta$ cells in the islets of Langerhans detect increased blood glucose (via GLUT2 glucose transporters and glucokinase).
2. Coordination centre: $\beta$ cells are both the receptor and the coordination centre -- they process the information and secrete insulin directly.
3. Effector response: insulin stimulates glucose uptake (GLUT4 translocation), glycogen synthesis, glycolysis, and lipogenesis in target cells.
4. Negative feedback: as blood glucose falls back towards 90 $\mathrm{mg\ dL^{-1}}$, the stimulus to $\beta$ cells decreases, insulin secretion decreases, and the response diminishes.

If blood glucose falls below 90 $\mathrm{mg\ dL^{-1}}$ (e.g., during fasting):

1. Receptor: $\alpha$ cells in the islets of Langerhans detect decreased blood glucose.
2. Coordination centre: $\alpha$ cells secrete glucagon.
3. Effector response: glucagon stimulates glycogenolysis, gluconeogenesis, and lipolysis, raising blood glucose.
4. Negative feedback: as blood glucose rises, glucagon secretion decreases.

15.2 Why Negative Feedback Maintains Stability

Negative feedback is self-limiting: the response produced by the system opposes the original stimulus. As the parameter returns to its set point, the stimulus weakens, the response weakens, and the system stabilises.

However, negative feedback can produce oscillations (overcorrection) if the response is too strong or too slow. For example, in diabetes, insulin injections may cause hypoglycaemia (overcorrection), triggering a counter-regulatory glucagon response, which raises blood glucose too high, requiring more insulin -- a cycle.

15.3 Positive Feedback: When It Occurs

Positive feedback amplifies a change rather than opposing it. It is less common than negative feedback and typically drives processes to completion:

Example	Mechanism	Why It Is Useful
Ovulation	High oestrogen triggers LH surge, which triggers ovulation	Ensures ovulation occurs decisively once the follicle is mature
Blood clotting	Thrombin activates more thrombin (amplification cascade)	Ensures rapid clot formation to prevent excessive blood loss
Childbirth	Oxytocin stimulates uterine contractions, which stimulate more oxytocin release	Drives labour to completion
Action potential	$\mathrm{Na^+}$ influx depolarises the membrane, opening more $\mathrm{Na^+}$ channels	Ensures the action potential is an all-or-nothing event

16. Kidney Failure and Dialysis

16.1 Causes of Kidney Failure

• Acute kidney injury (AKI): sudden loss of kidney function due to dehydration, infection, toxins, or obstruction. May be reversible.
• Chronic kidney disease (CKD): progressive, irreversible loss of kidney function over months to years. Most common causes: diabetes mellitus (diabetic nephropathy), hypertension (damage to glomerular capillaries), glomerulonephritis.

16.2 Consequences of Kidney Failure

• Accumulation of urea and other nitrogenous waste products (uraemia): causes nausea, vomiting, fatigue, confusion, seizures.
• Accumulation of $\mathrm{K^+}$ (hyperkalaemia): can cause cardiac arrhythmias and cardiac arrest.
• Fluid retention (oedema): due to inability to excrete water.
• Acidosis: inability to excrete $\mathrm{H^+}$.
• Anaemia: reduced erythropoietin production (kidneys produce EPO, which stimulates red blood cell production in bone marrow).
• Bone disease: reduced activation of vitamin D (kidneys convert calcifediol to calcitriol, the active form), leading to reduced $\mathrm{Ca^{2+}}$ absorption from the gut.

16.3 Haemodialysis

Blood is taken from an artery, passed through a dialyser (artificial kidney), and returned to a vein.

The dialyser contains:

• Blood compartment: patient's blood flows through.
• Dialysis fluid compartment: dialysis fluid flows in the opposite direction (countercurrent).
• Semi-permeable membrane between the two compartments.

Dialysis fluid composition:

• Same concentration of glucose and salts ($\mathrm{Na^+}$, $\mathrm{K^+}$, $\mathrm{Ca^{2+}}$, $\mathrm{HCO_3^-}$) as normal blood plasma.
• No urea: creates a concentration gradient so urea diffuses from blood to dialysis fluid.
• No excess $\mathrm{K^+}$: allows excess $\mathrm{K^+}$ to diffuse from blood to dialysis fluid.

Dialysis is typically performed 3 times per week for 4--5 hours per session.

16.4 Kidney Transplantation

The best treatment for end-stage renal failure. A donor kidney (from a living relative or a cadaver) is transplanted into the patient's pelvis (the original kidneys are usually left in place).

• Advantages over dialysis: better quality of life, no dialysis sessions required, longer life expectancy.
• Disadvantages: risk of surgical complications; lifelong immunosuppressive medication (to prevent rejection); shortage of donor organs; risk of transplant rejection.

Types of rejection:

• Hyperacute rejection: minutes to hours; caused by pre-existing antibodies against the donor (ABO or HLA mismatch). Prevented by tissue typing.
• Acute rejection: weeks to months; T cell-mediated attack on the transplanted tissue. Treated with immunosuppressants (corticosteroids, ciclosporin).
• Chronic rejection: months to years; gradual loss of function due to chronic inflammation and fibrosis.

warning

Common Pitfall In questions about dialysis, students often state that "urea is actively transported out of the blood." In haemodialysis, urea removal occurs by diffusion down a concentration gradient (dialysis fluid has no urea). No active transport is involved. The patient's own kidneys use both diffusion and active transport; the dialysis machine relies solely on diffusion and ultrafiltration.

24. Communicable and Non-Communicable Diseases

24.1 Types of Disease

Type	Definition	Examples
Communicable (infectious)	Caused by a pathogen and can be transmitted between individuals	Influenza, tuberculosis, HIV/AIDS, malaria, COVID-19
Non-communicable	Not caused by a pathogen and cannot be transmitted between individuals	Coronary heart disease, type 2 diabetes, cancer, asthma, arthritis
Genetic	Caused by inherited or acquired mutations	Cystic fibrosis, Huntington's disease, sickle cell anaemia
Degenerative	Caused by progressive deterioration of tissues or organs	Alzheimer's disease, Parkinson's disease, osteoarthritis
Autoimmune	Caused by the immune system attacking the body's own tissues	Type 1 diabetes, rheumatoid arthritis, multiple sclerosis
Deficiency	Caused by a lack of essential nutrients or enzymes	Scurvy (vitamin C), anaemia (iron), kwashiorkor (protein)
Environmental	Caused by exposure to environmental factors	Asbestosis, silicosis, skin cancer (UV radiation)

24.2 Risk Factors for Non-Communicable Diseases

Disease	Risk Factors	Mechanism
Cardiovascular disease	High LDL cholesterol, hypertension, smoking, obesity, diabetes, physical inactivity, family history, stress	Atherosclerotic plaque formation narrows coronary arteries, reducing blood flow to the heart muscle
Lung cancer	Smoking (90% of cases), radon gas exposure, asbestos, air pollution	Carcinogens in tobacco smoke (e.g., benzopyrene) cause mutations in proto-oncogenes (e.g., RAS) and inactivate tumour suppressor genes (e.g., p53)
Type 2 diabetes	Obesity, physical inactivity, high-sugar diet, family history, ethnicity (South Asian, Afro-Caribbean)	Insulin resistance in target cells; progressive $\beta$ cell failure
Skin cancer (melanoma)	UV radiation exposure (sunburns, tanning beds), fair skin, many moles	UV radiation causes thymine dimers in DNA, leading to mutations
Cervical cancer	HPV infection (human papillomavirus), smoking, early sexual activity, weak immune system	HPV E6 and E7 oncoproteins inactivate p53 and Rb tumour suppressor proteins

24.3 Lifestyle Interventions to Reduce Disease Risk

Intervention	Diseases Reduced
Regular exercise	CVD, type 2 diabetes, obesity, some cancers, osteoporosis
Balanced diet (low saturated fat, high fibre, 5+ portions of fruit/vegetables per day)	CVD, type 2 diabetes, some cancers, constipation
Not smoking	Lung cancer, CVD, COPD, stroke
Reducing alcohol intake	Liver disease, some cancers, CVD, mental health problems
Maintaining healthy BMI (18.5--24.9)	Type 2 diabetes, CVD, osteoarthritis, some cancers

24.4 Epidemiology: Interpreting Data

Correlation vs causation: just because two variables are correlated does not mean one causes the other. There may be a confounding variable that explains both.

Example: a study finds a correlation between coffee consumption and reduced risk of heart disease. Does coffee prevent heart disease?

Possible explanations:

1. Coffee contains antioxidants that protect blood vessels (causation).
2. Coffee drinkers may also exercise more or have healthier diets (confounding).
3. People who are ill may reduce their coffee intake (reverse causation).

Only controlled experiments (randomised controlled trials) can establish causation.

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Diagnostic Test

23. Plant Responses to the Environment

23.1 Tropisms

Tropism	Stimulus	Mechanism	Example
Phototropism	Light (directional)	Auxin redistribution (more auxin on shaded side); auxin promotes cell elongation	Shoots grow towards light
Geotropism (gravitropism)	Gravity	Shoots: auxin accumulates on lower side; in shoots, auxin promotes elongation $\to$ shoots grow up. Roots: auxin accumulates on lower side; in roots, high auxin inhibits elongation $\to$ roots grow down	Shoots grow up; roots grow down
Thigmotropism	Touch	Mechanical stimulation causes differential growth	Climbing plants (tendrils coil around supports)
Chemotropism	Chemical gradient	Pollen tubes grow down the style towards ovary, guided by calcium and chemotropic signals	Fertilisation

23.2 Nastic Movements

Nastic movements are responses to non-directional stimuli (the direction of the response is not related to the direction of the stimulus).

Movement	Stimulus	Mechanism	Example
Thigmonasty (seismonasty)	Touch/mechanical disturbance	Rapid change in turgor pressure in pulvini (swollen leaf bases). Touch triggers $\mathrm{K^+}$ and $\mathrm{Cl^-}$ efflux from cells on one side, causing water loss and cell collapse. This is reversible.	Mimosa pudica (sensitive plant) -- leaves fold when touched
Photonasty	Light/dark	Changes in turgor pressure driven by blue-light receptors. Flowers open during the day (turgid cells in upper petal surface) and close at night (cells become flaccid).	Dandelion flowers, morning glory
Nyctinasty	Darkness	Same mechanism as photonasty but triggered by darkness. Leaves fold up at night, reducing water loss and exposure to herbivores.	Clover, beans

23.3 Leaf Abscission

Leaf abscission (shedding) in autumn is controlled by:

1. Shortening day length triggers a decrease in auxin production and an increase in ethylene production by the leaf.
2. Ethylene stimulates the production of cellulase and pectinase in the abscission zone (a layer of cells at the base of the petiole).
3. These enzymes break down the cell walls in the abscission zone.
4. A protective layer of cork (suberin) forms on the stem side, sealing the wound.
5. The leaf eventually falls.

Before abscission, chlorophyll is broken down (unmasking carotenoids, causing the autumn colour change), and nutrients (amino acids, minerals) are reabsorbed into the stem and stored for winter.

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Diagnostic Test

21. Plant Growth Substances: Quantitative Investigations

21.1 Investigating the Effect of Auxin Concentration on Root Growth

Hypothesis: Auxin stimulates root growth at low concentrations but inhibits it at high concentrations.

Method:

1. Prepare Petri dishes with agar containing different concentrations of IAA (indole-3-acetic acid): 0, $10^{-6}$, $10^{-5}$, $10^{-4}$, $10^{-3}\ \mathrm{mol\ dm^{-3}}$.
2. Place 10 germinated cress seedlings (with radicles of equal length, approximately 5 mm) on each dish.
3. Incubate in the dark at 25 degrees C for 3 days.
4. Measure the increase in radicle length for each seedling.
5. Calculate the mean increase in length for each concentration.
6. Plot a graph of mean increase in radicle length against auxin concentration.

Expected results: a bell-shaped curve. Root growth is stimulated at very low concentrations ($10^{-6}$ to $10^{-5}\ \mathrm{mol\ dm^{-3}}$) but inhibited at higher concentrations ($> 10^{-4}\ \mathrm{mol\ dm^{-3}}$).

21.2 Statistical Analysis: t-Test

To determine whether the effect of auxin on root growth is statistically significant, a t-test can be used:

$t = \frac◆LB◆\bar{x}_1 - \bar{x}_2◆RB◆◆LB◆\sqrt◆LB◆\frac{s_1^2}{n_1} + \frac{s_2^2}{n_2}◆RB◆◆RB◆$

Where $\bar{x}_1, \bar{x}_2$ = mean radicle lengths in the two groups, $s_1, s_2$ = standard deviations, $n_1, n_2$ = sample sizes.

If the calculated $t$ value exceeds the critical value (at $p = 0.05$, with appropriate degrees of freedom), the difference is statistically significant.

Worked Example. Control group ($n = 10$): mean radicle growth $= 12.0\ \mathrm{mm}$, SD $= 2.5\ \mathrm{mm}$. Treatment group ($10^{-4}\ \mathrm{mol\ dm^{-3}}$ IAA, $n = 10$): mean $= 5.0\ \mathrm{mm}$, SD $= 2.0\ \mathrm{mm}$.

$t = \frac◆LB◆12.0 - 5.0◆RB◆◆LB◆\sqrt◆LB◆\frac{2.5^2}{10} + \frac{2.0^2}{10}◆RB◆◆RB◆ = \frac◆LB◆7.0◆RB◆◆LB◆\sqrt◆LB◆\frac{6.25 + 4.00}{10}◆RB◆◆RB◆ = \frac◆LB◆7.0◆RB◆◆LB◆\sqrt{1.025}◆RB◆ = \frac{7.0}{1.012} = 6.92$.

Degrees of freedom $= n_1 + n_2 - 2 = 18$.

Critical value at $p = 0.05$ for 18 df $= 2.10$.

Since $t = 6.92 > 2.10$, the difference is statistically significant. Auxin at $10^{-4}\ \mathrm{mol\ dm^{-3}}$ significantly inhibits root growth.

22. Excretion: The Liver and Kidneys

22.1 The Liver in Homeostasis

The liver plays a central role in homeostasis:

Function	Mechanism
Detoxification	Converts harmful substances (alcohol, drugs, ammonia) into less harmful products. Alcohol $\to$ acetaldehyde (toxic) $\to$ acetate (by alcohol dehydrogenase and aldehyde dehydrogenase). Ammonia $\to$ urea (ornithine cycle).
Storage	Stores glycogen, vitamins (A, D, B12), iron (in ferritin), copper.
Protein synthesis	Syntheses plasma proteins (albumin, fibrinogen, globulins, clotting factors).
Bile production	Produces bile salts (emulsify fats), bilirubin (from haemoglobin breakdown), cholesterol.
Carbohydrate metabolism	Glycogenesis, glycogenolysis, gluconeogenesis.
Lipid metabolism	Synthesises lipoproteins (LDL, HDL), converts excess carbohydrate to fat.
Immune function	Kupffer cells (macrophages in liver sinusoids) phagocytose pathogens and dead red blood cells.

22.2 Bilirubin and Jaundice

When red blood cells are destroyed at the end of their lifespan (approximately 120 days), haemoglobin is broken down:

1. Haemoglobin $\to$ globin (amino acids, recycled) + haem (iron + protoporphyrin).
2. Iron is removed and stored in ferritin.
3. Protoporphyrin is converted to bilirubin (an orange-yellow pigment).
4. Bilirubin is transported to the liver bound to albumin (unconjugated bilirubin, insoluble).
5. In the liver, bilirubin is conjugated with glucuronic acid (conjugated bilirubin, soluble) and excreted in bile.
6. Bacteria in the intestine convert bilirubin to stercobilin (brown pigment in faeces) and urobilinogen (partly reabsorbed and excreted in urine, giving urine its yellow colour).

Jaundice (yellowing of the skin and sclerae) occurs when bilirubin accumulates in the blood (> $50\ \mu\mathrm{mol\ L^{-1}}$). Causes:

• Pre-hepatic: excessive red blood cell breakdown (haemolytic anaemia) produces more bilirubin than the liver can process.
• Hepatic: liver damage (cirrhosis, hepatitis) reduces the liver's ability to conjugate and excrete bilirubin.
• Post-hepatic: obstruction of the bile duct (gallstones, pancreatic cancer) prevents excretion of conjugated bilirubin into the intestine.

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Diagnostic Test

17. Thermoregulation in Ectotherms

17.1 Behavioural Temperature Regulation

Ectotherms cannot generate significant metabolic heat, so they rely on behavioural and physiological mechanisms to maintain their body temperature within an optimal range:

Mechanism	Description	Example
Basking	Exposing the body to direct sunlight to absorb radiant heat	Lizards on rocks in the morning
Shade-seeking	Moving to shade to avoid overheating	Desert lizards retreating to burrows at midday
Posture changes	Flattening the body to increase surface area for heat absorption; curling up to reduce it	Grass snakes flatten to absorb heat; dung beetles form balls
Burrowing	Moving underground where temperatures are more stable	Desert tortoises, scorpions
Colour change	Some reptiles can darken their skin to absorb more heat or lighten it to reflect heat	Bearded dragons, chameleons
Nocturnal activity	Being active at night to avoid daytime heat	Desert geckos, fennec foxes

17.2 Physiological Adaptations in Ectotherms

Adaptation	Mechanism	Effect
Countercurrent heat exchange	Arteries carrying warm blood from the body core run alongside veins carrying cold blood from the extremities; heat is transferred from arteries to veins before reaching the skin	Reduces heat loss at the periphery
Antifreeze proteins	Proteins that lower the freezing point of body fluids by binding to ice crystals and preventing their growth	Found in Antarctic fish (Notothenioids), Arctic insects
Supercooling	Body fluids remain liquid below 0 degrees C by removing ice-nucleating agents	Some amphibians and reptiles can survive partial freezing

17.3 Advantages and Disadvantages of Ectothermy

Advantages	Disadvantages
Much lower energy requirements (no metabolic cost of heating)	Inactive in cold conditions; cannot maintain activity in winter
Can allocate more energy to growth and reproduction	Slower growth and digestion at low temperatures
Can survive longer without food (lower metabolic rate)	Limited geographic distribution (restricted to warmer climates)
Smaller food requirements	Dependence on environmental temperature limits ecological niches

18. The Kidney: Advanced Calculations

18.1 Clearance

Renal clearance measures the efficiency with which the kidneys remove a substance from the blood:

$C = \frac◆LB◆U \times V◆RB◆◆LB◆P◆RB◆$

Where $C$ = clearance ($\mathrm{mL\ min^{-1}}$), $U$ = urine concentration of the substance, $V$ = urine flow rate ($\mathrm{mL\ min^{-1}}$), $P$ = plasma concentration of the substance.

• If clearance $<$ GFR ($\approx 125\ \mathrm{mL\ min^{-1}}$): the substance is partially reabsorbed.
• If clearance $=$ GFR: the substance is neither reabsorbed nor secreted (e.g., inulin).
• If clearance $>$ GFR: the substance is actively secreted (e.g., para-aminohippuric acid, PAH).

18.2 Worked Example: Glucose Clearance

A patient has a blood glucose concentration of $8.0\ \mathrm{mmol\ L^{-1}}$ and a urine glucose concentration of $0\ \mathrm{mmol\ L^{-1}}$ (no glucose in urine).

$C = \frac◆LB◆0 \times V◆RB◆◆LB◆8.0◆RB◆ = 0\ \mathrm{mL\ min^{-1}}$.

This means glucose is completely reabsorbed by the kidneys (no clearance). This is normal -- the kidneys normally reabsorb all glucose from the filtrate.

If the patient has blood glucose of $15\ \mathrm{mmol\ L^{-1}}$ (above the renal threshold of approximately $11\ \mathrm{mmol\ L^{-1}}$), glucose appears in the urine. This occurs in uncontrolled diabetes (glycosuria).

18.3 Filtration Fraction

$\text{Filtration fraction} = \frac◆LB◆\text{GFR}◆RB◆◆LB◆\text{Renal plasma flow (RPF)}◆RB◆ = \frac{125}{650} \approx 0.19 = 19\%$

This means approximately 19% of the plasma passing through the glomerulus is filtered into the Bowman's capsule.

19. Plant Hormones: Experiments

19.1 Auxin and Phototropism: The Went Experiment

Frits Went (1928) demonstrated that auxin is the phototropic hormone:

1. He placed oat coleoptile (shoot tip) on an agar block for several hours.
2. The auxin produced by the tip diffused into the agar block.
3. He placed the agar block asymmetrically on a decapitated coleoptile (the tip had been removed).
4. The coleoptile bent away from the agar block (towards the side without auxin), demonstrating that auxin promotes cell elongation.

19.2 Investigating the Effect of Auxin Concentration on Root Growth

Unlike shoots, roots are inhibited by high concentrations of auxin. The effect of auxin concentration on growth follows a dose-response curve:

Auxin Concentration	Effect on Shoot	Effect on Root
Very low	Little effect	Promotes growth
Low	Promotes growth	Promotes growth (optimal)
Moderate	Promotes growth strongly	Inhibits growth
High	Promotes growth (approaching optimum)	Strongly inhibits growth
Very high	Inhibits growth	Strongly inhibits growth

This difference is exploited in horticulture: synthetic auxins (2,4-D) are used as selective weedkillers. They kill broad-leaved weeds (dicots, which are more sensitive to auxin) but not grasses (monocots, which are less sensitive).

20. Coordination in Plants vs Animals: A Comparison

Feature	Animal Coordination	Plant Coordination
Electrical signals	Nervous system (action potentials)	Action potentials (slow, in some plants)
Chemical signals	Hormones (endocrine system)	Plant hormones (auxin, gibberellin, ethylene, ABA, cytokinin)
Speed of response	Very fast (milliseconds)	Slow (minutes to hours to days)
Type of response	Movement (muscle contraction)	Growth (cell elongation, division)
Receptors	Specialised sense organs (eyes, ears, skin)	Receptors in all cells (hormone receptors)
Adaptability	Highly adaptable (learned responses, memory)	Genetically programmed; limited adaptability
Target specificity	Highly specific (neurons connect to specific effectors)	Less specific (hormones diffuse through tissue)

21. Plant Tropisms and Nastic Movements

21.1 Phototropism

Phototropism is the growth of a plant in response to light. Shoots grow towards light (positive phototropism); roots grow away from light (negative phototropism).

Mechanism (shoots):

1. Auxin (IAA) is produced in the shoot tip (coleoptile).
2. Auxin is transported down the shoot by polar auxin transport (PIN proteins).
3. When light is unilateral (from one side), auxin accumulates on the shaded side of the shoot.
4. The higher auxin concentration on the shaded side stimulates cell elongation (by activating proton pumps, which acidify the cell wall, loosening bonds between cellulose microfibrils, allowing turgor-driven expansion).
5. The shaded side elongates more than the illuminated side, causing the shoot to bend towards the light.

Evidence: Darwin and Darwin (1880) demonstrated that the tip of the coleoptile is sensitive to light; Went (1928) extracted auxin from coleoptile tips and showed it promoted growth.

21.2 Gravitropism

Gravitropism is the growth response to gravity. Roots grow towards gravity (positive gravitropism); shoots grow away from gravity (negative gravitropism).

Mechanism (roots):

1. Statocytes (specialised cells in the root cap) contain amyloplasts (starch-containing organelles) that sediment to the bottom of the cell under gravity.
2. The sedimentation of amyloplasts triggers redistribution of auxin.
3. Auxin accumulates on the lower side of the root.
4. In roots, high auxin concentration inhibits cell elongation (unlike shoots, where it promotes it).
5. The upper side of the root elongates more than the lower side, causing the root to bend downwards.

21.3 Nastic Movements

Nastic movements are non-directional responses to stimuli (e.g., touch, light intensity, temperature):

Movement	Stimulus	Mechanism	Example
Thigmonasty (seismonasty)	Touch	Rapid change in turgor pressure in pulvinus (swollen joint at base of leaflet)	Mimosa pudica (sensitive plant) leaflets fold when touched
Photonasty	Light intensity	Turgor changes controlled by the biological clock	Crocosmia flowers open in light, close in dark
Thermonasty	Temperature	Turgor changes in petal cells	Tulip flowers open in warmth, close in cold

22. Communicable and Non-Communicable Diseases

22.1 Categories of Pathogen

Pathogen Type	Examples	Diseases	Key Features
Bacteria	Mycobacterium tuberculosis, Vibrio cholerae, S. aureus	Tuberculosis, cholera, bacterial meningitis	Prokaryotic; treated with antibiotics; can produce toxins (endotoxins or exotoxins)
Viruses	HIV, influenza virus, SARS-CoV-2, tobacco mosaic virus (TMV)	AIDS, flu, COVID-19, TMV disease in plants	Obligate intracellular parasites; not affected by antibiotics; protein coat + nucleic acid
Fungi	Histoplasma, Candida albicans, Puccinia spp.	Histoplasmosis, thrush, wheat stem rust	Eukaryotic; chitin cell walls; produce spores; treated with antifungals
Protoctista	Plasmodium falciparum, Trypanosoma brucei	Malaria, sleeping sickness	Eukaryotic; often have complex life cycles involving multiple hosts
Helminths (parasitic worms)	Schistosoma mansoni, Taenia solium	Schistosomiasis, taeniasis	Multicellular; complex life cycles; transmitted through contaminated water or undercooked meat

22.2 Disease Transmission

Transmission Route	Example	Prevention
Direct contact (skin, bodily fluids)	HIV, herpes simplex, MRSA	Barrier methods (condoms); hand hygiene; PPE
Waterborne	Cholera, typhoid, dysentery	Clean water supply; sanitation; water treatment (filtration, chlorination)
Airborne (droplets, aerosols)	Influenza, TB, COVID-19, measles	Ventilation; masks; vaccination; isolation of infected individuals
Vector-borne	Malaria (mosquito), dengue (mosquito), Lyme disease (tick)	Vector control (insecticide-treated bed nets, spraying); habitat management; vaccines
Foodborne	Salmonella, E. coli O157, botulism	Food hygiene; proper cooking; pasteurisation; HACCP systems

22.3 Epidemiology

Key terms:

Term	Definition
Incidence	Number of new cases of a disease in a population in a given time period
Prevalence	Total number of cases (new + existing) in a population at a given time
Mortality rate	Number of deaths from a disease per 100,000 population per year
Morbidity rate	Number of people suffering from a disease per 100,000 population per year
Epidemic	A sudden increase in the number of cases of a disease above what is normally expected in a specific area
Pandemic	An epidemic that has spread across multiple countries or continents

22.4 Non-Communicable Diseases: Risk Factors

Disease	Genetic Risk Factors	Lifestyle Risk Factors	Environmental Risk Factors
Coronary heart disease	Family history, FH (familial hypercholesterolaemia)	High saturated fat diet, smoking, physical inactivity, obesity	Air pollution, chronic stress
Type 2 diabetes	Family history, certain ethnicities (South Asian, Afro-Caribbean)	Obesity (especially abdominal), physical inactivity, high sugar diet	socioeconomic deprivation
Lung cancer	BRCA mutations (rare)	Smoking (85% of cases), air pollution	Radon gas exposure, asbestos
Cervical cancer	BRCA mutations, Lynch syndrome	Early sexual activity, multiple sexual partners	HPV infection (vaccine prevents 70% of cases)

23. Diabetes: Detailed Pathophysiology

23.1 Type 1 Diabetes (Autoimmune)

• Cause: autoimmune destruction of $\beta$ cells in the islets of Langerhans in the pancreas. T cells (CD8+ cytotoxic T cells) recognise $\beta$ cell antigens as foreign and destroy the $\beta$ cells. Autoantibodies (anti-GAD, anti-IA-2, anti-insulin) are present in blood.
• Onset: typically in childhood or adolescence (but can occur at any age).
• Pathophysiology: no insulin is produced. Without insulin, glucose cannot enter muscle and adipose cells (via GLUT4 transporters, which require insulin signalling). Blood glucose rises (hyperglycaemia). Cells switch to using fat and protein for energy.
• Symptoms: polyuria (excessive urination, due to osmotic diuresis when blood glucose exceeds the renal threshold of approximately $10\ \mathrm{mmol\ L^{-1}}$); polydipsia (excessive thirst); weight loss (despite increased appetite); fatigue; ketoacidosis (breakdown of fat produces ketones, which lower blood pH; can be fatal if untreated).
• Treatment: insulin injections (or insulin pump); blood glucose monitoring; carbohydrate counting; management of hypoglycaemia (low blood glucose from excess insulin).

23.2 Type 2 Diabetes (Insulin Resistance)

• Cause: insulin resistance (target cells respond poorly to insulin) combined with progressive $\beta$ cell dysfunction. Strongly associated with obesity (especially visceral fat), physical inactivity, and genetic predisposition.
• Onset: typically in adults over 40 (but increasingly in younger people due to rising obesity).
• Pathophysiology: initially, $\beta$ cells produce extra insulin to compensate for insulin resistance. Over time, $\beta$ cells become exhausted and insulin production declines. Blood glucose rises.
• Symptoms: similar to type 1 but often milder and more gradual; may be asymptomatic initially.
• Treatment: lifestyle changes (weight loss, exercise, dietary modification); metformin (reduces hepatic glucose production, increases insulin sensitivity); other oral medications (sulfonylureas, GLP-1 agonists, SGLT2 inhibitors); insulin therapy if $\beta$ cell function is severely impaired.

23.3 Blood Glucose Regulation: Detailed Mechanism

Blood Glucose Level	Pancreatic Response	Mechanism	Effect
High (post-prandial)	$\beta$ cells secrete insulin	Insulin binds to receptors on liver, muscle, adipose cells; activates tyrosine kinase; GLUT4 vesicles fuse with cell membrane (in muscle and fat); activates glycogen synthase; inhibits glycogen phosphorylase	Glucose uptake increased; glycogenesis stimulated; glycogenolysis and gluconeogenesis inhibited; blood glucose falls
Low (fasting/exercise)	$\alpha$ cells secrete glucagon	Glucagon binds to G-protein coupled receptors on liver cells; activates adenylate cyclase $\to$ cAMP $\to$ protein kinase A; activates glycogen phosphorylase; activates phosphoenolpyruvate carboxykinase (PEPCK) for gluconeogenesis	Glycogenolysis stimulated; gluconeogenesis stimulated; blood glucose rises
Normal ($\approx 5\ \mathrm{mmol\ L^{-1}}$)	Both $\alpha$ and $\beta$ cells are relatively inactive	Basal insulin secretion maintains glucose homeostasis	Blood glucose remains stable

warning

Common Pitfall Students often think insulin lowers blood glucose by converting glucose to glycogen in all cells. Insulin promotes glucose uptake primarily in muscle and adipose tissue (via GLUT4). The liver does not require insulin for glucose uptake (it uses GLUT2, which is insulin-independent). Insulin acts on the liver primarily to stimulate glycogenesis and inhibit glycogenolysis and gluconeogenesis.

23.4 Adrenal Glands and Stress Response

The adrenal glands sit on top of the kidneys and have two distinct regions:

Region	Hormone(s)	Function
Adrenal medulla (inner)	Adrenaline (epinephrine), noradrenaline	"Fight or flight" response: increases heart rate, stroke volume, blood pressure; dilates bronchioles; stimulates glycogenolysis in liver; dilates pupils; redirects blood to skeletal muscles
Adrenal cortex (outer)	Mineralocorticoids (aldosterone)	Regulates blood pressure by promoting $\mathrm{Na^+}$ reabsorption and $\mathrm{K^+}$ excretion in the kidneys
	Glucocorticoids (cortisol)	Increases blood glucose (gluconeogenesis, anti-insulin effect); suppresses immune system; anti-inflammatory; peaks in the morning (circadian rhythm)
	Androgens (DHEA)	Converted to testosterone and oestrogen in peripheral tissues

24. The Kidney: Ultrafiltration and Selective Reabsorption

24.1 Structure of the Nephron

Region	Location	Function
Renal (Bowman's) capsule	Cortex	Ultrafiltration: filters blood to form filtrate
Proximal convoluted tubule (PCT)	Cortex	Selective reabsorption: reabsorbs all glucose, all amino acids, approximately 85% of $\mathrm{Na^+}$ and water, approximately 50% of urea
Loop of Henle	Medulla	Countercurrent multiplication: creates a salt gradient in the medulla for water reabsorption
Distal convoluted tubule (DCT)	Cortex	Fine-tuning: reabsorption of $\mathrm{Na^+}$ and $\mathrm{Ca^{2+}}$ (under aldosterone control); water reabsorption (under ADH control)
Collecting duct	Medulla (passes through to papilla)	Water reabsorption (ADH-dependent): water moves out into the hypertonic medulla by osmosis

24.2 Ultrafiltration

Ultrafiltration occurs at the renal corpuscle (glomerulus + Bowman's capsule):

Pressure forces:

• Glomerular hydrostatic pressure ($\approx 55\ \mathrm{mmHg}$): blood pressure in the glomerulus; pushes filtrate out of the blood.
• Capsular hydrostatic pressure ($\approx 15\ \mathrm{mmHg}$): pressure of fluid already in the Bowman's capsule; opposes filtration.
• Blood oncotic pressure ($\approx 30\ \mathrm{mmHg}$): osmotic pressure due to plasma proteins (which are too large to be filtered); opposes filtration.

Net filtration pressure $= 55 - 15 - 30 = 10\ \mathrm{mmHg}$

24.3 Selective Reabsorption in the PCT

Substance	Fate	Mechanism
Glucose	100% reabsorbed	Secondary active transport ($\mathrm{Na^+}$/glucose co-transporter, SGLT2) on apical membrane; facilitated diffusion (GLUT2) on basolateral membrane
Amino acids	100% reabsorbed	Secondary active transport (similar to glucose)
$\mathrm{Na^+}$	$\approx 85\%$ reabsorbed	$\mathrm{Na^+/K^+}$ ATPase on basolateral membrane creates $\mathrm{Na^+}$ gradient; $\mathrm{Na^+}$ enters via co-transporters
Water	$\approx 85\%$ reabsorbed	Follows $\mathrm{Na^+}$ by osmosis (water permeability of PCT is always high)
Urea	$\approx 50\%$ reabsorbed	Diffuses (passive) down its concentration gradient
$\mathrm{K^+}$	$\approx 85\%$ reabsorbed	Passive diffusion and active transport

24.4 ADH and Water Reabsorption

1. Osmoreceptors in the hypothalamus detect increased blood $\mathrm{Na^+}$ concentration (increased osmolarity).
2. The hypothalamus stimulates the posterior pituitary to release ADH.
3. ADH binds to receptors on the collecting duct cells.
4. ADH activates a G-protein coupled receptor $\to$ adenylate cyclase $\to$ cAMP $\to$ protein kinase A.
5. Protein kinase A causes vesicles containing aquaporin (water channel) proteins to fuse with the collecting duct membrane.
6. Water moves out of the collecting duct by osmosis (down the water potential gradient into the hypertonic medulla) and is reabsorbed into the blood.
7. Blood volume and pressure increase; blood osmolarity decreases (negative feedback).

warning

Common Pitfall Students often think that ADH makes the kidneys produce "more urine." In fact, ADH makes the kidneys produce less, more concentrated urine by increasing water reabsorption in the collecting ducts. Without ADH (e.g., in diabetes insipidus), large volumes of dilute urine are produced.

25. Plant Hormones: Detailed Analysis

25.1 Auxin (IAA)

Synthesis: in the shoot tip (apical meristem) and young leaves.

Effects:

• Stimulates cell elongation (in shoots) by activating proton pumps ($\mathrm{H^+}$-ATPase), acidifying the cell wall and activating expansin enzymes that loosen bonds between cellulose microfibrils.
• Inhibits cell elongation (in roots) at high concentrations.
• Inhibits lateral bud growth (apical dominance): the shoot tip produces auxin, which is transported down the stem and suppresses growth of lateral buds. Removing the shoot tip (decapitation) causes lateral buds to grow.
• Promotes root initiation (used in rooting powders for cuttings).
• Promotes fruit development (in some species, unpollinated flowers can be treated with auxin to produce parthenocarpic (seedless) fruit).

25.2 Gibberellin

Synthesis: in young leaves, roots, and developing seeds.

Effects:

• Stimulates stem elongation (by activating genes for enzymes that break down DELLA proteins, which normally repress growth). Dwarf varieties of plants (e.g., dwarf wheat, dwarf peas) have a mutation in gibberellin synthesis or response.
• Stimulates seed germination: gibberellin is produced by the embryo after water imbibition; it diffuses to the aleurone layer of the seed and stimulates the synthesis of amylase (and other hydrolytic enzymes). Amylase breaks down starch into maltose, which is used as an energy source by the growing embryo.
• Promotes bolting (rapid stem elongation) in response to long days (photoperiodism).

25.3 Ethylene

Synthesis: in most plant tissues, especially ripening fruits, senescing flowers, and stressed tissues.

Effects:

• Promotes fruit ripening: ethylene stimulates the production of enzymes (pectinase, cellulase) that soften the fruit wall; converts starch to sugars (sweetening); produces volatile flavour compounds.
• Promotes leaf abscission (leaf fall): ethylene stimulates the production of cellulase in the abscission zone.
• Promotes senescence (ageing) of flowers and leaves.

Commercial application: ethylene gas is used to ripen fruit (e.g., bananas, tomatoes) during transport; 1-methylcyclopropene (1-MCP) is used to inhibit ethylene action and extend shelf life.

25.4 Abscisic Acid (ABA)

Synthesis: in leaves, roots, and stem (mainly in response to stress).

Effects:

• Antagonises gibberellin: inhibits seed germination and maintains dormancy.
• Closes stomata: ABA binds to receptors on guard cells, causing $\mathrm{Ca^{2+}}$ channels to open; $\mathrm{Ca^{2+}}$ influx triggers $\mathrm{K^+}$ and $\mathrm{Cl^-}$ efflux; water follows by osmosis; guard cells become flaccid and the stomata close.
• Promotes bud dormancy in winter.

25.5 Cytokinin

Synthesis: mainly in the roots; transported to shoots via the xylem.

Effects:

• Promotes cell division (cytokinesis).
• Delays leaf senescence (used commercially to extend the shelf life of cut flowers and vegetables).
• Promotes shoot formation in tissue culture (in combination with auxin).
• Promotes bud growth (counteracts apical dominance).

26. Thermoregulation: Detailed Mechanisms

26.1 Endotherm Thermoregulation

Mammals maintain a core body temperature of approximately 36.5--37.5 degrees C (humans: 37 degrees C).

Temperature receptors:

• Peripheral thermoreceptors: in the skin (both warm and cold receptors). Detect changes in external temperature.
• Central thermoreceptors: in the hypothalamus (pre-optic area). Detect changes in blood temperature.

Thermoregulatory centre: the hypothalamus processes information from both peripheral and central thermoreceptors and sends signals to effectors (sweat glands, arterioles, skeletal muscles, hair erector muscles).

Response to Cold	Response to Heat
Vasoconstriction: arterioles in skin narrow, reducing blood flow to the skin surface, reducing heat loss by radiation and convection	Vasodilation: arterioles in skin dilate, increasing blood flow to the skin surface, increasing heat loss
Piloerection: hair erector muscles contract, raising hairs to trap a layer of insulating air	Sweating: sweat glands secrete sweat onto the skin surface; water evaporates, cooling the skin (latent heat of vaporisation)
Shivering: rapid, involuntary contraction of skeletal muscles generates heat from increased metabolic rate	Behavioural: seeking shade, removing clothing, reducing activity
Increased metabolic rate: thyroid hormones (T3, T4) increase basal metabolic rate; brown adipose tissue (BAT) generates heat by uncoupled respiration (UCP1 protein uncouples ETC from ATP synthesis)	Behavioural: seeking sun, wearing lighter clothing
Behavioural: curling up to reduce surface area; seeking shelter; huddling

26.2 Ectotherm Thermoregulation

Ectotherms (reptiles, amphibians, fish, invertebrates) cannot generate significant metabolic heat and rely on external heat sources:

Strategy	Example
Basking in the sun	Lizards orient their bodies perpendicular to the sun's rays to maximise heat absorption; press their bodies against warm rocks
Seeking shade	Moving to cooler areas when body temperature exceeds optimal
Colour change	Some lizards darken in cold weather (absorbs more heat) and lighten in warm weather (reflects heat)
Altering body shape	Horned lizards can expand their body to increase surface area for heat absorption; some snakes coil to reduce surface area
Behavioural adaptations	Nocturnal activity in hot climates (e.g., desert geckos); burrowing to escape extreme temperatures

26.3 The Menstrual Cycle

Phase	Days	Events
Menstruation	Days 1--5	Endometrium breaks down and is shed (if implantation has not occurred)
Follicular phase	Days 1--13	FSH stimulates follicle development in the ovary; follicles secrete oestrogen; oestrogen stimulates endometrium to thicken; oestrogen inhibits FSH (negative feedback) at low concentration; at high concentration, oestrogen stimulates LH secretion (positive feedback)
Ovulation	Day 14	LH surge triggers release of a mature oocyte from the ovary
Luteal phase	Days 15--28	LH stimulates the ruptured follicle to become the corpus luteum; corpus luteum secretes progesterone and oestrogen; progesterone maintains the thickened endometrium; progesterone inhibits FSH and LH (negative feedback); if no implantation, corpus luteum degenerates after approximately 10 days; progesterone and oestrogen levels drop; endometrium breaks down (menstruation)

27. Kidney Failure and Dialysis

27.1 Causes of Kidney Failure

Cause	Mechanism
Diabetes mellitus	Chronic hyperglycaemia damages glomerular capillaries (diabetic nephropathy); progressive loss of filtration function
Hypertension	High blood pressure damages glomerular capillaries over time
Glomerulonephritis	Inflammation of the glomeruli (autoimmune or post-streptococcal)
Polycystic kidney disease	Genetic disorder; fluid-filled cysts progressively destroy kidney tissue
Pyelonephritis	Bacterial infection of the kidneys; can cause scarring

27.2 Symptoms of Kidney Failure

• Accumulation of urea and other nitrogenous wastes (uraemia): fatigue, nausea, vomiting, confusion.
• Accumulation of $\mathrm{K^+}$ (hyperkalaemia): can cause cardiac arrhythmias and cardiac arrest.
• Fluid retention (oedema): swelling of ankles, face, lungs (pulmonary oedema).
• Anaemia: kidneys produce erythropoietin (EPO), which stimulates red blood cell production. Kidney failure reduces EPO.
• Bone disease: kidneys activate vitamin D (calcitriol); kidney failure leads to low $\mathrm{Ca^{2+}}$ absorption, secondary hyperparathyroidism, and bone demineralisation.

27.3 Haemodialysis

Blood is taken from an artery, passed through a dialysis machine (dialyser), and returned to a vein.

Component	Function
Dialysis membrane	Partially permeable membrane; allows exchange of small molecules (urea, $\mathrm{K^+}$, $\mathrm{Na^+}$, $\mathrm{Ca^{2+}}$) between blood and dialysis fluid by diffusion
Dialysis fluid	Contains the same concentration of useful substances ($\mathrm{Na^+}$, $\mathrm{K^+}$, $\mathrm{Ca^{2+}}$, glucose, bicarbonate) as healthy blood; contains no urea (creating a concentration gradient for urea to diffuse from blood to dialysis fluid)
Blood pump	Moves blood through the dialyser
Anticoagulant	Heparin prevents blood clotting during dialysis

Limitations of haemodialysis:

• Requires 3 sessions per week, 4--6 hours per session.
• Does not replace all kidney functions (e.g., erythropoietin production, vitamin D activation).
• Increased risk of infection (via the vascular access site).
• Dietary restrictions (limited $\mathrm{K^+}$, phosphate, fluid intake).

27.4 Peritoneal Dialysis

Dialysis fluid is introduced into the peritoneal cavity (abdomen). The peritoneum acts as the dialysis membrane. Urea and other wastes diffuse from the blood in the peritoneal capillaries into the dialysis fluid, which is drained after several hours.

• Advantages: can be done at home; no machine required; more continuous (gentler on the body).
• Disadvantages: risk of peritonitis (infection of the peritoneum); less efficient than haemodialysis.

27.5 Kidney Transplant

The best treatment for end-stage renal failure. A healthy kidney from a donor (living or deceased) is transplanted into the patient.

• Advantages: restores near-normal kidney function; no need for dialysis; better quality of life and life expectancy.
• Disadvantages: requires lifelong immunosuppression (to prevent rejection); risk of transplant rejection (hyperacute, acute, chronic); shortage of donor organs; surgical risks.
• Tissue matching: ABO blood group compatibility; HLA (human leukocyte antigen) matching; cross-matching (testing for pre-formed antibodies against the donor).

28. Negative and Positive Feedback in Homeostasis

28.1 Negative Feedback

Negative feedback is the primary mechanism for maintaining homeostasis. A change in a variable (e.g., temperature, blood glucose) triggers a response that opposes the change, returning the variable to its set point.

Key features:

• Receptor detects deviation from set point.
• Control centre (e.g., hypothalamus, medulla) processes information.
• Effector produces a response that counteracts the change.
• The system is self-regulating and maintains stability.

Examples already covered: blood glucose regulation (insulin/glucagon); thermoregulation; osmoregulation (ADH); heart rate control.

28.2 Positive Feedback

Positive feedback amplifies a change, moving the variable further from the set point. It is less common than negative feedback and usually leads to a definitive outcome (not a stable state).

Process	Stimulus	Positive Feedback Loop	Outcome
Childbirth (parturition)	Pressure of baby's head on the cervix	Pressure stimulates oxytocin release $\to$ oxytocin causes stronger uterine contractions $\to$ increased pressure on cervix	Birth (the positive feedback loop is broken when the baby is delivered)
Blood clotting	Damage to blood vessel wall	Platelets adhere to damaged site and release clotting factors $\to$ more platelets are attracted $\to$ clot grows	Clot formation (limits further blood loss)
Ovulation	High oestrogen concentration	High oestrogen stimulates LH surge $\to$ LH triggers ovulation (egg release)	Egg released (oestrogen levels then fall, breaking the loop)
Action potential	Depolarisation reaches threshold	Depolarisation opens voltage-gated $\mathrm{Na^+}$ channels $\to$ more $\mathrm{Na^+}$ enters $\to$ more depolarisation	Action potential generated ($\mathrm{Na^+}$ channels then inactivate, breaking the loop)

29. Osmoregulation in Other Organisms

29.1 Marine Fish

Marine bony fish are hypotonic (their internal salt concentration is lower than the surrounding seawater). They face two problems:

1. Water loss by osmosis: water diffuses from the fish into the sea.
2. Salt gain: salts diffuse into the fish from the sea.

Adaptations:

• Drink large quantities of seawater (to replace lost water).
• Active transport of $\mathrm{Na^+}$ and $\mathrm{Cl^-}$ out through the chloride cells in the gills.
• Excrete small volumes of concentrated urine (kidneys retain water).
• Minimal glomerular filtration (reduces water loss in urine).

29.2 Freshwater Fish

Freshwater bony fish are hypertonic (their internal salt concentration is higher than the surrounding freshwater). They face the opposite problems:

1. Water gain by osmosis.
2. Salt loss by diffusion.

Adaptations:

• Do not drink (they are already gaining too much water).
• Absorb salts through the gills (active transport of $\mathrm{Na^+}$ and $\mathrm{Cl^-}$).
• Excrete large volumes of dilute urine (kidneys remove excess water).
• Extensive glomerular filtration.

29.3 Insects

Insects are small and have a large surface area:volume ratio, so they lose water rapidly through their cuticle. Adaptations for water conservation:

• Waxy cuticle: reduces water loss through the body surface.
• Spiracles: can be closed to reduce respiratory water loss.
• Malpighian tubules: excrete nitrogenous waste as uric acid (insoluble; requires minimal water for excretion).
• Rectum: reabsorbs water and ions from the faeces, producing very dry waste.

29.4 Desert Mammals

Adaptation	Example	Mechanism
Concentrated urine	Kangaroo rat	Very long loop of Henle (20x kidney length); produces urine up to 17x more concentrated than plasma
Dry faeces	Koala, desert rodent	Colon absorbs almost all water from faeces
Nasal counter-current heat exchanger	Camel, kangaroo rat	Nasal passages cool outgoing air, condensing water vapour, which is reabsorbed into the body
No sweat glands	Camel	Reduces water loss through the skin
Behavioural	Fennec fox	Nocturnal; burrows during the day; gets water from food

30. The Menstrual Cycle: Hormonal Control in Detail

30.1 Key Hormones and Their Actions

Hormone	Source	Target	Effect
FSH (follicle-stimulating hormone)	Anterior pituitary	Ovarian follicles	Stimulates follicle development; stimulates oestrogen secretion by follicle cells
LH (luteinising hormone)	Anterior pituitary	Ovarian follicles; corpus luteum	Triggers ovulation (LH surge); stimulates corpus luteum to secrete progesterone
Oestrogen	Developing follicle (granulosa cells)	Uterus; anterior pituitary; hypothalamus	Stimulates endometrial thickening; inhibits FSH (negative feedback at low levels); stimulates LH surge (positive feedback at high levels)
Progesterone	Corpus luteum (after ovulation)	Uterus; anterior pituitary	Maintains thick endometrium; inhibits FSH and LH (negative feedback); prevents further ovulation

30.2 The Four Phases

Phase	Days	What Happens	Dominant Hormone
Menstruation	Days 1--5	Endometrium breaks down; bleeding occurs	Low oestrogen and progesterone
Follicular phase	Days 1--13	FSH stimulates follicle development; follicles secrete oestrogen; endometrium thickens	Rising oestrogen
Ovulation	Day 14	High oestrogen triggers positive feedback on anterior pituitary $\to$ LH surge $\to$ follicle ruptures; egg released	Peak LH and oestrogen
Luteal phase	Days 15--28	Corpus luteum forms; secretes progesterone and oestrogen; endometrium maintained for implantation	Progesterone (and oestrogen)

30.3 Feedback Loops

Type	When It Occurs	Hormones Involved
Negative feedback	Most of the cycle (days 1--12, days 16--28)	Oestrogen inhibits FSH and LH; progesterone inhibits FSH and LH
Positive feedback	Day 14 (ovulation)	High oestrogen stimulates LH secretion from anterior pituitary $\to$ LH surge $\to$ ovulation

31. Negative Feedback: General Principles

31.1 Components of a Negative Feedback System

Every negative feedback system has the same components:

Component	Role	Example (Thermoregulation)
Receptor (sensor)	Detects deviations from the set point	Thermoreceptors in skin and hypothalamus detect temperature change
Communication system	Transmits information from receptor to effector	Nervous system (sensory neurones $\to$ hypothalamus $\to$ motor neurones) and endocrine system (ADH, adrenaline)
Effector	Carries out the corrective response to restore the set point	Sweat glands, arterioles, shivering muscles, brown fat
Set point	The ideal value being maintained	Core body temperature: $37.0\degree\mathrm{C}$

31.2 Why Negative Feedback Maintains Homeostasis

Principle	Explanation
Deviation triggers correction	Any change away from the set point activates the corrective mechanism
The further from set point, the stronger the response	Greater temperature deviation $\to$ more sweating, greater vasodilation
Self-limiting	As the set point is approached, the corrective response diminishes (prevents overshoot)
Oscillation around set point	Body temperature, blood glucose, and blood pH all fluctuate slightly around the set point rather than being held at a single exact value

32. Diabetes Mellitus: Pathophysiology in Detail

32.1 Type 1 vs Type 2 Diabetes

Feature	Type 1 Diabetes	Type 2 Diabetes
Cause	Autoimmune destruction of $\beta$ cells in islets of Langerhans	Insulin resistance (target cells become less responsive to insulin); relative insulin deficiency
Onset	Usually childhood/adolescence (but can occur at any age)	Usually adulthood (but increasingly diagnosed in younger people due to obesity)
Insulin production	None (or very little)	Reduced (initially may be normal or even high)
Treatment	Insulin injections (lifelong); blood glucose monitoring; careful diet	Diet and exercise (first-line); oral medication (metformin); may eventually require insulin
Prevalence	~10% of diabetes cases	~90% of diabetes cases
Body weight	Often normal or underweight at diagnosis	Often overweight or obese at diagnosis
Genetic component	Polygenic (HLA-DR3, HLA-DR4 genes increase susceptibility)	Strong polygenic component; lifestyle is a major factor

32.2 Blood Glucose Regulation in Diabetes

Condition	Blood Glucose	Insulin	Glucagon	Mechanism
Normal (after meal)	Rises to ~8 mmol/L then returns to ~5 mmol/L	Increases	Decreases	Insulin stimulates glucose uptake by cells; glycogenesis; glycolysis
Type 1 diabetes (after meal)	Rises to 15--30+ mmol/L; stays high	None	Decreases (but insufficient to compensate)	Glucose cannot enter cells (no insulin); glucosuria (glucose in urine); polyuria; dehydration
Type 2 diabetes (after meal)	Rises higher than normal; takes longer to return to baseline	Increased (but cells are resistant)	Decreases	Cells respond poorly to insulin; glucose uptake is slower and less efficient

32.3 Complications of Poorly Controlled Diabetes

Complication	Cause	Symptoms
Diabetic retinopathy	Chronic hyperglycaemia damages retinal blood vessels	Vision loss; blindness
Diabetic neuropathy	High glucose damages nerve cells (myelinated nerves affected first)	Numbness, tingling, pain (especially in feet); loss of sensation
Diabetic nephropathy	High glucose damages glomerular basement membrane; proteins leak into urine	Kidney failure; need for dialysis or transplant
Cardiovascular disease	Atherosclerosis accelerated by hyperglycaemia	Heart attack, stroke, peripheral vascular disease
Foot ulcers	Combined neuropathy + poor circulation	Slow-healing wounds; infection; gangrene; amputation

33. Kidney Failure and Dialysis

33.1 Causes of Kidney Failure

Cause	Mechanism
Diabetes mellitus	Chronic hyperglycaemia damages glomerular basement membrane (diabetic nephropathy); proteinuria
Hypertension	High blood pressure damages glomerular capillaries; reduced filtration
Glomerulonephritis	Inflammation of glomeruli (often autoimmune or post-streptococcal); damages filtration membrane
Polycystic kidney disease	Genetic (ADPKD, autosomal dominant); fluid-filled cysts enlarge and destroy kidney tissue
Pyelonephritis	Bacterial infection of the kidney; inflammation and scarring

33.2 Haemodialysis vs Peritoneal Dialysis

Feature	Haemodialysis	Peritoneal Dialysis
Location	Hospital or dialysis centre	Patient's home (can be done overnight)
Frequency	3 times per week (4--5 hours per session)	Continuous or nightly (automated)
Mechanism	Blood is pumped through an artificial kidney (dialyser); dialysis fluid on the other side of a partially permeable membrane; diffusion removes urea and excess ions	Dialysis fluid is pumped into the peritoneal cavity (abdomen); peritoneum acts as the exchange membrane; fluid is drained after several hours
Advantages	Efficient; monitored by professionals	More convenient; more continuous; no need for vascular access
Disadvantages	Requires regular hospital visits; risk of infection at access site; dietary restrictions	Less efficient than haemodialysis; risk of peritonitis (peritoneal infection); patient must be trained

33.3 Kidney Transplant

Feature	Description
Source	Living donor (relative or altruistic) or deceased donor (after brain death)
Advantages	Better quality of life; no dialysis required; longer life expectancy; fewer dietary restrictions
Disadvantages	Risk of rejection (immune system attacks the transplanted kidney); lifelong immunosuppressive drugs required; shortage of donors; surgical risks
Tissue matching	ABO blood group must be compatible; HLA tissue typing to minimise rejection risk
Immunosuppression	Drugs such as ciclosporin (inhibits T cell activation); prevents rejection but increases susceptibility to infections and certain cancers

34. Control of Blood Glucose: Detailed Mechanism

34.1 After a Meal (Blood Glucose Rising)

Step	What Happens
1	Blood glucose rises (detected by $\beta$ cells in the islets of Langerhans in the pancreas)
2	$\beta$ cells secrete insulin into the blood
3	Insulin binds to receptors on target cells (liver, muscle, adipose tissue)
4	In liver: insulin stimulates glycogenesis (glucose $\to$ glycogen); inhibits glycogenolysis; stimulates glycolysis
5	In muscle: insulin stimulates glucose uptake (via GLUT4 transporters; insulin triggers vesicle fusion); glycogenesis
6	In adipose tissue: insulin stimulates glucose uptake; promotes triglyceride synthesis (lipogenesis)
7	Blood glucose returns to normal (~5 mmol/L)

34.2 After Fasting/Exercise (Blood Glucose Falling)

Step	What Happens
1	Blood glucose falls (detected by $\alpha$ cells in the islets of Langerhans)
2	$\alpha$ cells secrete glucagon into the blood
3	Glucagon binds to receptors on liver cells (NOT muscle or adipose)
4	In liver: glucagon stimulates glycogenolysis (glycogen $\to$ glucose); stimulates gluconeogenesis (amino acids/lactate $\to$ glucose)
5	Glucose is released into the blood
6	Blood glucose returns to normal

34.3 Adrenaline's Role in Blood Glucose

Adrenaline (from adrenal medulla, during fight or flight response):

Effect	Mechanism
Increases blood glucose	Stimulates glycogenolysis in liver AND muscle; inhibits insulin secretion
Cannot directly raise blood glucose from muscle glycogen	Muscle glycogen is used by the muscle itself (muscle lacks glucose-6-phosphatase, so cannot release free glucose into blood)

35. Thermoregulation: Detailed Mechanisms

35.1 Responses to Cold

Response	Mechanism	Effect
Vasoconstriction	Arterioles in skin constrict (sympathetic nervous system; noradrenaline)	Less blood flows near the surface; less heat lost by radiation
Shivering	Rapid, involuntary contraction of skeletal muscles	Muscle respiration generates heat
Piloerection	Hair erector muscles contract; hairs stand upright	Traps a layer of insulating air next to the skin (more effective in furry animals than humans)
Increased metabolic rate	Thyroid gland secretes more thyroxine; cells respire more	More heat generated from exothermic reactions
Behavioural responses	Curling up; huddling; putting on clothes; moving to a warmer environment	Reduces surface area exposed; reduces heat loss
Non-shivering thermogenesis	Brown fat (brown adipose tissue) is metabolised; uncoupling protein (UCP1) uncouples respiration from ATP production; energy is released as heat	Generates heat without muscle contraction (important in newborns)

35.2 Responses to Heat

Response	Mechanism	Effect
Vasodilation	Arterioles in skin dilate (sympathetic nervous system withdrawal)	More blood flows near the surface; more heat lost by radiation
Sweating	Sweat glands secrete sweat onto the skin surface; water evaporates (high latent heat of vaporisation)	Heat is removed from the body as water evaporates; effective at temperatures above body temperature (when radiation is insufficient)
Flattening of body hair	Hair erector muscles relax; hair lies flat	Removes the insulating layer of air
Behavioural responses	Removing clothes; seeking shade; drinking cold water; fanning	Increases heat loss; cools the body directly

36. Osmoregulation: The Role of ADH

36.1 ADH (Antidiuretic Hormone / Vasopressin)

Feature	Description
Produced by	Hypothalamus (neurosecretory cells)
Released by	Posterior pituitary gland
Target	Collecting ducts in the kidney nephrons
Trigger for release	Increased blood osmolarity (detected by osmoreceptors in the hypothalamus); decreased blood volume/pressure (detected by baroreceptors in the aorta and carotid sinus)

36.2 Mechanism of ADH

Step	What Happens
1	Blood water potential decreases (blood becomes more concentrated, e.g., after sweating or not drinking)
2	Osmoreceptors in the hypothalamus detect the change
3	Neurosecretory cells in the hypothalamus produce ADH; ADH travels down their axons to the posterior pituitary
4	Posterior pituitary releases ADH into the blood
5	ADH binds to receptors on the collecting duct cells
6	Intracellular cascade: ADH activates adenylate cyclase $\to$ cAMP $\to$ protein kinase A $\to$ vesicles containing aquaporin-2 (water channel proteins) fuse with the collecting duct membrane
7	Collecting duct becomes more permeable to water
8	Water is reabsorbed from the collecting duct into the hypertonic medulla (by osmosis) and enters the blood
9	Blood water potential returns to normal (blood becomes more dilute)
10	Negative feedback: osmoreceptors detect the return to normal; ADH secretion decreases

37. The Importance of Homeostasis

37.1 Why Homeostasis Matters

Parameter	Why It Must Be Controlled	Consequence of Loss of Control
Body temperature (37$\degree$C)	Enzymes have an optimum temperature; above 40$\degree$C, enzymes denature; below 35$\degree$C, enzyme activity slows dramatically	Hypothermia: enzyme activity too slow; cardiac arrhythmias; death. Hyperthermia: protein denaturation; seizures; organ failure; death
Blood glucose (~5 mmol/L)	Glucose is the main respiratory substrate for the brain (which cannot use other fuels); very high or very low blood glucose is dangerous	Hypoglycaemia (<3 mmol/L): confusion, seizures, coma, death. Hyperglycaemia (>15 mmol/L): osmotic diuresis, dehydration, ketoacidosis
Blood pH (7.35--7.45)	Enzymes are sensitive to pH; changes in pH alter the charge on amino acid residues, affecting enzyme tertiary structure and active site shape	Acidosis (pH < 7.35): enzymes denature; coma; death. Alkalosis (pH > 7.45): enzymes denature; muscle spasms; arrhythmias
Blood $\mathrm{CO_2}$	High $\mathrm{CO_2}$ lowers blood pH (forms carbonic acid)	Hypercapnia: respiratory acidosis; confusion; coma
Blood pressure	Maintains adequate blood flow to organs (especially brain, kidneys, heart)	Hypotension: inadequate blood flow to brain $\to$ fainting; shock. Hypertension: damage to blood vessels; stroke; heart attack; kidney damage
Water potential of blood	Maintains blood volume and pressure; ensures cells neither shrink nor swell excessively	Dehydration: low blood volume; low blood pressure; kidney damage. Water intoxication: cells swell (including brain cells); potentially fatal

38. Plant Hormones and Growth Responses

38.1 Phototropism

Feature	Description
Stimulus	Unidirectional light
Response	Shoot bends towards the light (positive phototropism)
Mechanism	Auxin is produced in the shoot tip; auxin is transported laterally to the shaded side of the shoot; auxin stimulates cell elongation on the shaded side; the shaded side grows longer; the shoot bends towards the light

38.2 Gravitropism

Feature	Shoots (Positive Phototropism, Negative Gravitropism)	Roots (Positive Gravitropism, Negative Phototropism)
Response to gravity	Grows upwards (away from gravity)	Grows downwards (towards gravity)
Mechanism	Statoliths (amyloplasts, dense starch granules) settle to the bottom of cells; in shoots, auxin accumulates on the lower side; auxin inhibits root cell elongation but stimulates shoot cell elongation	Auxin accumulates on the lower side; auxin inhibits cell elongation in roots; lower side grows less; root bends downwards

39. Communication and Coordination

39.1 Nervous vs Endocrine System

Feature	Nervous System	Endocrine System
Signal type	Electrical impulses (action potentials)	Chemical (hormones)
Transmission speed	Very fast (milliseconds)	Slower (seconds to hours)
Duration of response	Short-lived (seconds to minutes)	Longer-lasting (hours to weeks)
Target	Specific (neurones and muscle/gland cells at synapses)	Widespread (any cell with the correct receptor)
Adaptation	Rapidly adapts to repeated stimuli	Slower to adapt
Examples	Reflexes, sensory processing, motor control	Blood glucose regulation, growth, reproduction, metabolism

39.2 Examples of Integration

Example	Both Systems Working Together
Fight or flight response	Nervous: sympathetic neurones directly stimulate adrenal medulla (fast); Endocrine: adrenaline released into blood (wider, longer-lasting effects)
Blood glucose regulation	Nervous: autonomic neurones can influence insulin/glucagon secretion; Endocrine: insulin and glucagon are hormones
Thermoregulation	Nervous: thermoreceptors detect temperature; hypothalamus sends signals via neurones to sweat glands and muscles; Endocrine: thyroxine regulates basal metabolic rate (long-term temperature regulation)

40. The Role of Negative Feedback in Temperature Control

40.1 Example: Temperature Control Pathway

Component	When Hot	When Cold
Receptor	Thermoreceptors in skin and hypothalamus	Same
Coordination centre	Hypothalamus	Same
Effector 1	Sweat glands activated (evaporative cooling)	Sweat glands inhibited
Effector 2	Arterioles dilate (vasodilation; more blood near surface)	Arterioles constrict (vasoconstriction; less blood near surface)
Effector 3	Body hair lies flat (no insulating air layer)	Body hair erect (traps insulating air layer)
Effector 4	Shivering inhibited	Shivering stimulated (muscle contraction generates heat)

40.2 Why Negative Feedback Is Important

Without negative feedback:

• Enzyme activity would be disrupted by temperature changes.
• Protein denaturation would occur.
• Cellular metabolism would become unpredictable.
• The organism could not maintain a stable internal environment.
• Homeostasis would fail, leading to illness or death.

41. Positive Feedback: When Homeostasis Goes Wrong

41.1 Examples of Positive Feedback

Example	Mechanism	Why It Is Dangerous
Childbirth (normal positive feedback)	Pressure of the baby's head on the cervix stimulates oxytocin release $\to$ uterine contractions $\to$ baby pushed further into cervix $\to$ more oxytocin released $\to$ stronger contractions $\to$ birth	This is a normal, beneficial positive feedback loop
Blood clotting	Damaged blood vessel exposes collagen; platelets adhere and release clotting factors $\to$ more platelets are recruited $\to$ clot grows	Normally controlled by anticoagulant mechanisms; can be dangerous if clotting occurs inappropriately (thrombosis)
Fever (high temperature)	High body temperature increases metabolic rate $\to$ body generates more heat $\to$ temperature rises further	Normally limited by negative feedback (sweating, vasodilation); can spiral out of control in extreme cases (heatstroke)
Hypothermia	Low body temperature reduces metabolic rate $\to$ less heat generated $\to$ temperature falls further	Positive feedback that can be fatal without intervention

42. The Skin and Temperature Regulation

42.1 Skin Structure

Layer	Description	Role in Thermoregulation
Epidermis (outer)	Keratinised stratified squamous epithelium; contains melanocytes (produce melanin for UV protection)	Barrier to water loss; melanin absorbs UV radiation (prevents DNA damage)
Dermis (inner)	Contains blood vessels (capillary loops), sweat glands, hair follicles, sensory receptors, adipose tissue	Blood vessels dilate/constrict; sweat glands produce sweat; hair provides insulation
Hypodermis (subcutaneous fat)	Adipose tissue layer beneath the dermis	Insulation (fat is a poor conductor of heat); energy store

42.2 Sweat Glands

Feature	Description
Type	Eccrine (distributed across the body) and apocrine (armpits, groin)
Mechanism	Sweat (water, $\mathrm{Na^+}$, $\mathrm{Cl^-}$, urea) is produced by coiled secretory portion; secreted onto the skin surface via a duct
Evaporation	Water in sweat evaporates; heat is absorbed from the skin surface (high latent heat of vaporisation); this is the primary cooling mechanism in humans
Control	Sympathetic nervous system stimulates sweat gland secretion

43. Control of Blood pH

43.1 Why Blood pH Must Be Maintained

Normal blood pH: 7.35--7.45.

Enzymes are sensitive to pH changes. A small change in pH can alter the charge on amino acid residues, affecting enzyme tertiary structure and active site shape, reducing or abolishing enzyme activity.

43.2 Buffers in the Blood

Buffer System	Components	How It Works
Carbonic acid-bicarbonate buffer	$\mathrm{H_2CO_3}$ (carbonic acid) and $\mathrm{HCO_3^-}$ (bicarbonate)	Excess $\mathrm{H^+}$ shifts equilibrium: $\mathrm{H^+ + HCO_3^- \rightleftharpoons H_2CO_3 \rightleftharpoons CO_2 + H_2O}$; $\mathrm{CO_2}$ is removed by the lungs (exhaled)
Haemoglobin buffer	Haemoglobin can bind $\mathrm{H^+}$ (acting as a weak acid/base)	Haemoglobin binds $\mathrm{H^+}$ in the tissues (where $\mathrm{H^+}$ concentration is high) and releases them in the lungs (where $\mathrm{H^+}$ concentration is low)
Plasma proteins	Albumin has many carboxyl groups that can accept or donate $\mathrm{H^+}$	Contributes to the buffering capacity of blood

43.3 Respiratory Compensation

Condition	Respiratory Response
Metabolic acidosis (low blood pH; high $\mathrm{H^+}$)	Increased breathing rate (hyperventilation); $\mathrm{CO_2}$ is blown off; the equilibrium shifts to reduce $\mathrm{H^+}$ concentration; blood pH returns towards normal
Metabolic alkalosis (high blood pH; low $\mathrm{H^+}$)	Decreased breathing rate (hypoventilation); $\mathrm{CO_2}$ is retained; the equilibrium shifts to increase $\mathrm{H^+}$ concentration; blood pH returns towards normal

44. Plant Hormones (Auxins)

44.1 Auxin (IAA)

Feature	Description
Full name	Indole-3-acetic acid (IAA)
Site of synthesis	Shoot tip (apical meristem); young leaves
Transport	Polar (unidirectional) -- moves from shoot tip downwards through parenchyma cells; transported via auxin efflux carriers (PIN proteins)
Mechanism	Promotes $\mathrm{H^+}$ ion secretion into cell wall $\to$ lowers pH $\to$ activates expansin enzymes $\to$ loosens cell wall $\to$ cell takes up water by osmosis $\to$ cell elongates

44.2 Effects of Auxin

Effect	Mechanism
Cell elongation (in shoots)	Acid growth hypothesis: auxin stimulates proton pumps; low pH activates expansins that break cross-links in cellulose microfibrils
Apical dominance	Auxin from the apical bud inhibits lateral bud growth; removing the apical bud allows lateral buds to grow (pruning)
Root initiation (at high concentrations)	Synthetic auxins (IBA, NAA) used as rooting powders for cuttings
Abscission (at very high concentrations)	Promotes ethylene production, which triggers leaf/fruit fall
Weedkillers	Synthetic auxins (2,4-D, MCPA) selectively kill broad-leaved weeds (dicots are more sensitive than grasses/monocots)

45. Gibberellins

45.1 What Are Gibberellins?

Gibberellins are a group of plant hormones that stimulate growth, particularly stem elongation, seed germination, and flowering.

Feature	Description
Discovery	First identified from a fungus (Gibberella fujikuroi) that caused "foolish seedling" disease in rice (excessive stem elongation)
Site of synthesis	Young leaves, roots, and developing seeds
Transport	Not polar (can move in both directions through xylem and phloem)

45.2 Effects of Gibberellins

Effect	Mechanism / Evidence
Stem elongation	Stimulates cell division and cell elongation in the internodes; dwarf varieties of plants (e.g., peas, maize) have a genetic defect in gibberellin synthesis; applying gibberellic acid restores normal height
Seed germination	In some seeds (e.g., barley), gibberellin is produced by the embryo and diffuses to the aleurone layer; it stimulates the aleurone layer to produce amylase; amylase breaks down starch in the endosperm to maltose for the growing embryo
Flowering	In long-day plants (e.g., lettuce, spinach), gibberellins can substitute for the long-day photoperiod and induce flowering
Fruit development	Applied to grapes to produce larger, seedless fruits; stimulates fruit set and growth

46. Ethylene

46.1 What Is Ethylene?

Ethylene (ethene, $\mathrm{C_2H_4}$) is a gaseous plant hormone that is involved in fruit ripening, leaf fall (abscission), and stress responses.

Feature	Description
Nature	Gas at room temperature; can diffuse through air between plants
Site of synthesis	Ripening fruits; senescing (aging) leaves; damaged tissues
Transport	Diffuses through air spaces in plant tissue; no specific transport mechanism needed

46.2 Effects of Ethylene

Effect	Mechanism / Application
Fruit ripening	Stimulates the conversion of starch to sugars; breaks down cell walls (softening the fruit); stimulates the production of volatile compounds that give ripe fruit its aroma
Positive feedback	Ripening fruit produces ethylene; ethylene stimulates neighbouring fruit to ripen (this is why one rotten apple spoils the whole bunch)
Leaf fall (abscission)	Ethylene stimulates the production of cellulase enzymes in the abscission zone; cellulase breaks down the cell walls in this layer, causing the leaf to detach
Stress response	Produced in response to flooding (waterlogging), drought, pathogen attack, and physical damage
Commercial use	Bananas are picked green and shipped; ethylene gas is applied on arrival to trigger ripening; ethylene inhibitors (e.g., 1-MCP) are used to delay ripening during storage

47. Abscisic Acid (ABA)

47.1 What Is Abscisic Acid?

Abscisic acid (ABA) is a plant hormone that inhibits growth and is primarily involved in stress responses (drought, cold, salinity) and seed dormancy.

Feature	Description
Site of synthesis	Leaves, stems, and green fruits
Transport	Phloem (non-polar; can move in any direction)
Primary role	Stress hormone; also maintains seed dormancy

47.2 Effects of ABA

Effect	Mechanism
Stomatal closure (drought response)	ABA is produced in response to water stress; transported to guard cells; causes $\mathrm{K^+}$ ions to leave guard cells; water follows by osmosis; guard cells become flaccid; stomata close; reduces water loss by transpiration
Seed dormancy	High ABA levels in seeds maintain dormancy (prevent germination until conditions are favourable); ABA levels decrease and gibberellin levels increase when conditions for germination are right (water, warmth, oxygen)
Bud dormancy	ABA accumulates in buds in autumn; prevents bud growth during winter; levels decrease in spring (allowing bud break)
Wilting response	In rapidly wilting plants, ABA triggers stomatal closure within minutes; this is one of the fastest hormonal responses in plants

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