Homeostasis in mammals

Homeostasis is the maintenance of a relatively constant internal environment despite changes in the external environment. The internal environment includes the tissue fluid that bathes the body's cells, and the blood plasma from which it is derived. The key variables under homeostatic control are:

• Blood glucose (~5 mmol dm⁻³)
• Core body temperature (~37°C in humans)
• Blood water potential (~−7 kPa, equivalent to ~290 mOsm)
• Blood pH (~7.4)
• Blood ion concentrations (Na⁺, K⁺, Ca²⁺, etc.)

Why homeostasis matters. Enzymes have narrow optimum ranges of temperature and pH; outside these, they denature and lose function. Cells lose water by osmosis if blood becomes hypertonic, or swell and burst if it becomes hypotonic. A reliable internal environment allows the body to operate efficiently regardless of external conditions.

Negative feedback is the central mechanism. It has four components:

1. Set point — the normal value of the variable.
2. Receptor — detects the variable and any deviation from the set point.
3. Coordinator — usually the brain or an endocrine gland; receives information from the receptor and decides on a response.
4. Effector — a cell or organ that produces the corrective response.

A deviation triggers a response that opposes the change. Once the set point is restored, the receptor stops firing and the effector switches off. The opposite deviation triggers an opposite response.

Positive feedback is the rare opposite: a deviation triggers a response that enhances the change. Used for short-lived 'committed' processes (childbirth contractions, blood clotting, action potential generation), but not for steady-state homeostasis.

Blood glucose is held close to 5 mmol dm⁻³ by two opposing hormones secreted by the islets of Langerhans of the pancreas.

β-cells (beta cells) make up ~70% of each islet and secrete insulin when blood glucose rises (after a meal). Glucose enters β-cells via the GLUT2 transporter; it is metabolised to raise intracellular ATP, which closes ATP-sensitive K⁺ channels, depolarises the cell, opens voltage-gated Ca²⁺ channels and triggers insulin exocytosis.

Insulin's actions on target cells:

• Muscle and adipose cells: insulin binds its receptor → tyrosine kinase cascade → vesicles containing GLUT4 transporters fuse with the cell surface membrane. With more GLUT4 in the membrane, glucose enters by facilitated diffusion much faster, lowering blood glucose.
• Liver cells: insulin activates glycogen synthase → glucose-6-phosphate → glucose-1-phosphate → glycogen (glycogenesis). Stored glycogen is the body's short-term carbohydrate reserve. Insulin also inhibits glycogenolysis and gluconeogenesis.
• Adipose tissue: excess glucose is converted to fat (lipogenesis).
• All target cells: insulin promotes anabolic processes (protein synthesis, fat storage).

α-cells (alpha cells) make up ~20% of each islet and secrete glucagon when blood glucose falls (between meals, during exercise, in stress). Glucagon binds its receptor on liver cells and activates:

• Glycogen phosphorylase → glycogenolysis (glycogen → glucose-1-phosphate → glucose-6-phosphate → glucose). Glucose is exported to the blood.
• Gluconeogenesis: synthesis of new glucose from non-carbohydrate sources (lactate, glycerol, amino acids).
• Lipolysis in adipose tissue.

Adrenaline (from the adrenal medulla, during 'fight-or-flight') has similar glucose-raising effects in liver and muscle, mediated by cyclic AMP. It is important during exercise and stress.

The two opposing hormones (insulin and glucagon), released by two opposing cell types in the same organ, exemplify perfect negative feedback control.

Diabetes mellitus is a condition in which blood glucose cannot be controlled and rises to dangerous levels (hyperglycaemia). It comes in two main forms:

Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM).

• Cause: an autoimmune disease. The body's own immune system attacks and destroys the β-cells of the islets of Langerhans, so little or no insulin is produced. Genetic predisposition (HLA genes) + environmental trigger (often viral infection).
• Onset: usually in childhood / adolescence; appears suddenly.
• Treatment: lifelong insulin injections (or continuous infusion pump). Insulin is recombinant human insulin made in genetically modified bacteria or yeast. Doses are matched to carbohydrate intake; regular blood glucose monitoring.

Type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM).

• Cause: insulin resistance — target cells have fewer insulin receptors or impaired signalling, so insulin cannot lower blood glucose. β-cells initially compensate by producing more insulin but eventually become exhausted. Strongly linked to obesity, poor diet (high refined sugar / saturated fat), lack of exercise and ageing. Genetic component too.
• Onset: usually in middle / older age; develops slowly. The proportion of younger / overweight people with Type 2 is rising.
• Treatment: starts with diet (low refined carbohydrate, high fibre, weight loss) and exercise. Drugs (e.g. metformin — reduces hepatic glucose output; sulphonylureas — stimulate residual β-cells). Bariatric surgery in obese patients can reverse Type 2. Insulin injections may be needed eventually.

Symptoms (both types). Hyperglycaemia; polyuria (excess urine — glucose in filtrate exceeds the SGLT2 transporter capacity, drags water osmotically); polydipsia (excess thirst); fatigue; weight loss; blurred vision; slow wound healing. Untreated Type 1 may develop ketoacidosis (cells starved of glucose break down fat → ketones acidify blood).

Long-term complications. Damage to small blood vessels (retinopathy → blindness; nephropathy → kidney failure; neuropathy → peripheral nerve damage); cardiovascular disease; foot ulcers (poor healing).

Prevention. Type 1 cannot currently be prevented. Type 2 can be largely prevented by maintaining healthy weight, balanced diet and regular physical activity.

Mammals are endotherms — they maintain a roughly constant core body temperature (~37°C in humans) independent of the environment. Control is centred on the hypothalamus, which acts as a thermoregulatory centre.

Detection.

• Peripheral thermoreceptors in the skin detect external temperature.
• Central thermoreceptors in the hypothalamus detect blood temperature.

When core temperature deviates from the set point, the hypothalamus coordinates effectors via the autonomic nervous system (fast responses) and the endocrine system (slower responses).

In a cold environment — reducing heat loss + increasing heat production.

• Vasoconstriction of skin arterioles: smooth muscle in arteriole walls contracts; less blood reaches surface capillaries; shunt vessels direct flow deeper. Less heat radiated.
• Erection of hairs: arrector pili muscles contract, raising hairs and trapping insulating air. (Modest in humans — 'goosebumps'.)
• Sweating ceases: no evaporative cooling.
• Shivering: rapid involuntary contractions of skeletal muscle generate metabolic heat (the contraction does little mechanical work, but inefficiency means most of the chemical energy becomes heat).
• Thyroxine release (over hours / days): hypothalamus → TRH → anterior pituitary → TSH → thyroid → thyroxine → raises basal metabolic rate.
• Adrenaline release (short term, minutes): adrenal medulla → adrenaline → raises metabolic rate and stimulates glycogenolysis in muscle / liver.
• Behavioural responses: curling up, huddling, seeking shelter, putting on clothing.

In a hot environment — increasing heat loss + decreasing heat production.

• Vasodilation of skin arterioles: more blood at surface; more heat radiated; skin flushes pink.
• Hairs lie flat: arrector pili relax; less insulation.
• Sweating: sweat glands secrete sweat onto skin; evaporation absorbs latent heat of vaporisation (~2.4 kJ per gram of water). Humans have ~2-4 million eccrine sweat glands.
• No shivering.
• Thyroxine release falls → lower BMR.
• Behavioural responses: spreading limbs, removing clothing, seeking shade, panting (in dogs / cats — exposes the moist tongue to evaporative cooling).

Adaptations across species.

• Cold-adapted (polar bear, Arctic fox): thick fur, blubber, small extremity surface area, countercurrent heat exchanger in limbs.
• Heat-adapted (camel, fennec fox): tolerate larger temperature swings, conserve water, long thin limbs, large ears for radiation.

Failure of thermoregulation. Hyperthermia (T > 40°C) — enzymes denature; can be fatal. Hypothermia (T < 35°C) — metabolism slows; cardiac arrhythmias; can also be fatal. Both override normal homeostatic correction at extreme deviations.

Each kidney is bean-shaped, ~12 cm long in humans, and lies in the abdomen on either side of the spine. It receives blood from the renal artery (a branch of the abdominal aorta) and returns blood via the renal vein.

A cross-section shows three regions:

• Cortex (outer): contains all Bowman's capsules, glomeruli, proximal convoluted tubules and distal convoluted tubules. Densely packed with these tubule sections and capillaries.
• Medulla (middle): contains the loops of Henle and collecting ducts, running in parallel as medullary pyramids. The medulla has a steep solute gradient (Na⁺, urea) increasing from cortex to inner medulla.
• Pelvis (inner): a funnel-shaped cavity that collects urine from the collecting ducts and passes it to the ureter, which carries urine to the bladder for storage and eventual excretion.

Blood supply. Renal artery → afferent arterioles → glomerular capillaries → efferent arterioles → peritubular capillaries (around PCT, DCT) and vasa recta (around loop of Henle) → renal vein. About 1.1 L of blood passes through each kidney per minute — together the kidneys receive ~25% of cardiac output despite being small.

Each kidney contains ~1 million nephrons (functional units). Long-loop nephrons (with loops reaching deep into the medulla) are crucial for producing concentrated urine.

Each nephron has five regions, each with a distinct function:

1. Bowman's (renal) capsule + glomerulus — ultrafiltration. The Bowman's capsule is a cup-shaped invagination of squamous epithelium that surrounds the glomerulus — a knot of capillaries. Blood enters via the wider afferent arteriole and exits via the narrower efferent arteriole, creating high hydrostatic pressure. Fluid is forced through three filtration layers:

• Fenestrated capillary endothelium (with small pores).
• Basement membrane — a meshwork of collagen IV and glycoproteins acting as the molecular sieve (~70 kDa cutoff).
• Podocytes of Bowman's capsule, with foot-processes (pedicels) leaving narrow filtration slits.

What passes (filtrate): water, glucose, amino acids, urea, creatinine, Na⁺, K⁺, Cl⁻, HCO₃⁻. What stays (blood): red blood cells, white blood cells, platelets, plasma proteins.

Filtration rate ≈ 125 cm³ min⁻¹ in both kidneys = ~180 L per day.

2. Proximal convoluted tubule (PCT) — selective reabsorption. Cuboidal epithelium with microvilli on the apical surface (vast surface area) and many mitochondria (for active transport). ~80% of the filtrate is reabsorbed here, including:

• Glucose and amino acids — 100% reabsorbed by Na⁺ co-transport (SGLT1 / SGLT2): Na⁺ moves down its gradient (the gradient is maintained by basolateral Na⁺/K⁺ ATPase), dragging glucose / amino acid in with it.
• Na⁺ ~80% reabsorbed by Na⁺/K⁺ ATPase and co-transport.
• Water ~80% reabsorbed by osmosis through aquaporin-1.
• HCO₃⁻ reabsorbed; H⁺ secreted (acid-base balance).
• Some urea passively reabsorbed.

After the PCT, the filtrate is isotonic with the blood.

3. Loop of Henle — sets up the medullary solute gradient. A hairpin loop descending into the medulla and returning to the cortex. Different permeabilities along its length:

• Descending limb: thin, permeable to water but not to Na⁺. Water leaves by osmosis into the salty medulla; filtrate becomes more concentrated as it descends.
• Ascending limb: thick, impermeable to water; actively pumps Na⁺ and Cl⁻ out into the medulla. Filtrate becomes more dilute as it ascends.

This countercurrent multiplier continually exchanges water and Na⁺ at opposite ends of the loop, building a steep gradient in the medulla — Na⁺ can reach 1200 mmol dm⁻³ in the inner medulla (vs ~140 in blood). The vasa recta capillary loop runs parallel to the loop of Henle and preserves the gradient.

The medullary gradient is the driving force for water reabsorption in the collecting duct.

4. Distal convoluted tubule (DCT) — fine-tuning ions and pH. Cuboidal cells with many mitochondria. Controlled by:

• Aldosterone (adrenal cortex) — promotes Na⁺ reabsorption and K⁺ secretion.
• H⁺ secretion — fine pH adjustment.

5. Collecting duct — water reabsorption under ADH control. The duct passes back through the salty medulla. Its water permeability depends on ADH (antidiuretic hormone):

• High ADH → aquaporin-2 inserted in apical membrane → water moves out into the salty medulla by osmosis → small volume of concentrated urine.
• Low ADH → few aquaporins → water cannot escape → large volume of dilute urine.

Net result. Of ~180 L of filtrate per day, only ~1.5 L is excreted as urine. The kidney is a remarkable water-conservation organ.

Why high pressure? The afferent arteriole is wider than the efferent arteriole. Blood enters the glomerulus faster than it can leave, so it accumulates under pressure — typically 50-55 mm Hg (much higher than in other capillary beds, ~20 mm Hg). This drives fluid out of the capillary.

The three filtration barriers (in order from blood to filtrate):

1. Capillary endothelium. Glomerular capillaries are uniquely fenestrated — they have small pores in their wall, allowing plasma to pass but retaining red and white blood cells and platelets.

2. Basement membrane. A thin layer of meshwork made of collagen IV and glycoproteins (laminin, heparan sulphate proteoglycans). The mesh has effective pores ~5 nm in size. This is the molecular sieve — molecules larger than ~70 kDa (mainly plasma proteins) cannot pass. The negative charge on the heparan sulphate also repels negatively charged proteins.

3. Podocyte slits. Podocytes are specialised epithelial cells of Bowman's capsule. Their long branching extensions wrap around the capillary, and even finer projections (pedicels / foot processes) interdigitate, leaving narrow filtration slits (~30 nm wide). Slit diaphragms made of nephrin further regulate what passes.

What is filtered (small molecules). Water, glucose, amino acids, urea, creatinine, ions (Na⁺, K⁺, Cl⁻, HCO₃⁻, phosphate).

What is retained. Red blood cells (~7 μm), white blood cells (~10 μm), platelets (~2 μm), plasma proteins (~70 kDa cut-off — albumin 67 kDa is right at the edge; very small amounts may leak through).

Pathology. Damage to the basement membrane (e.g. in glomerulonephritis) allows proteinuria (protein in urine) or haematuria (blood in urine). These are routine markers of kidney disease.

Filtration rate. Both kidneys together filter ~125 cm³ min⁻¹ = 180 L per day. Most is reabsorbed; only ~1% (~1.5 L) is excreted as urine.

Osmoregulation is the control of blood water potential (water content). Negative feedback loop:

1. Detection. Osmoreceptors in the hypothalamus monitor blood water potential. They are sensitive neurosecretory cells:

• When blood water potential falls (dehydration), water leaves the osmoreceptors by osmosis → they shrink → fire impulses more frequently.
• When blood water potential rises (overhydration), water enters them → they swell → fire less.

2. ADH release. Hypothalamic neurosecretory cells have axons that project into the posterior pituitary. Activated osmoreceptors trigger these cells to release stored antidiuretic hormone (ADH, also called vasopressin) into the bloodstream.

3. Action on the collecting duct (and DCT). ADH binds to V2 receptors on the basolateral membrane of cells lining the collecting duct. Binding activates a cyclic AMP (cAMP) signalling cascade.

4. Aquaporin insertion. The cAMP cascade triggers intracellular vesicles containing aquaporin-2 water channels to fuse with the apical (lumen-side) membrane. The apical membrane becomes much more permeable to water.

5. Water reabsorption by osmosis. Filtrate in the collecting duct passes through the salty medulla, which has a very low water potential (due to the Na⁺ gradient set up by the loop of Henle). With aquaporins present, water moves out of the filtrate by osmosis down its water potential gradient, through the duct cells and into the vasa recta capillaries. Urine becomes more concentrated and reduced in volume.

6. Reverse response. When blood water potential rises (overhydration), osmoreceptors stop firing; ADH secretion falls; aquaporins are removed from the apical membrane by endocytosis; the duct becomes nearly impermeable to water; large volumes of dilute urine are produced.

Negative feedback. As water re-enters the blood (or as excess water is lost), blood water potential returns to its set point. The loop is self-regulating.

Diabetes insipidus is the failure of this system:

• Cranial diabetes insipidus: no ADH produced (pituitary damage). Treated with synthetic ADH (desmopressin).
• Nephrogenic diabetes insipidus: collecting duct does not respond to ADH (receptor / aquaporin gene defect). Treated with low-salt diet and thiazide diuretics. Either form causes huge urine output (~10-20 L per day) and extreme thirst.

ADH and alcohol. Alcohol inhibits ADH release — which is why alcoholic drinks cause polyuria and contribute to next-day dehydration.

ADH and stress. Severe blood loss / very low blood volume also stimulates ADH release (via baroreceptors in the carotid sinuses), as ADH also constricts blood vessels (hence its alternative name 'vasopressin'), helping to maintain blood pressure.