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Ovid: Oxford Handbook of Medical Sciences

Editors: Wilkins, Robert; Cross, Simon; Megson, Ian; Meredith, David Title: Oxford Handbook of Medical Sciences, 1st Edition Copyright ©2006 Oxford University Press, 2006, except ‘Clinical aspects’ section of Chapter 2 (Copyright by Keith Frayn) > Table of Contents > Chapter 9 – Endocrine organs Chapter 9 Endocrine organs Overview General principles The endocrine system is one of the major control systems that use chemical messengers. Endocrinology is the study of the endocrine system. Hormones are chemical messengers released from a cell to influence the activity of another/the same cell via a receptor. Hormones are normally present in very low concentrations (10-12–10-7M) in the blood/ extracellular fluid.

  • Endocrine glands are a well-defined collection of endocrine cells
  • Diffuse endocrine systems: many hormone-producing cells are not aggregated in glands, but dispersed (e.g. in the gut)
  • Neuroendocrine systems: some neurones release hormones into both the bloodstream and into the CNS.

Classical endocrine action is when a chemical messenger (the hormone), released by a cell, is transported, via the bloodstream, to its target cell. This is now known to be much too narrow a concept because hormones act via various routes:

  • Neuroendocrine: the hormone is released from a neurone into the bloodstream
  • Paracrine: the hormone acts on local cells via the extracellular fluid
  • Autocrine: the hormone acts on the cell producing the hormone.

Major roles and characteristics The endocrine system promotes survival of the species by:

  • Promoting survival of the individual
    • Effects on development, growth, and differentiation
    • Help in preservation of a stable internal environment—homeostasis (but this is often disturbed short term for long-term gain)
    • Responds to an altered external environment—especially emergency ‘stress responses’
  • Control of the processes involved in reproduction.

Proteins/peptides/glycopeptides (hydrophilic) are translated on the rough endoplasmic reticulum and secreted by either the regulated pathway (e.g. insulin, prolactin) or the constitutive pathway (cytokines, growth factors). The original translation product (the prohormone) is usually processed proteolytically to yield the active hormone(s). Some endocrine cells produce more than one active peptide hormone, in varying amounts. Stored in large amounts in intracellular granules, but some peptides (e.g. growth factors and cytokines) are not stored. Steroids (hydrophobic e.g. testosterone, estrogen) are synthesized rapidly on demand (not stored) from cholesterol, via enzymes in the mitochondria and smooth endoplasmic reticulum. Bioactive amines (hydrophilic e.g. adrenaline, dopamine) are produced from tyrosine via intracellular enzymes. They are stored in large amounts in intracellular granules. Thyroid hormones (hydrophilic e.g. thyroxine) are iodothyronines produced by iodination and coupling of tyrosyl residues in a protein (thyroglobulin) which are then released by proteolysis. Large amounts of iodinated thyroglobulin, (the precursor for thyroid hormone synthesis), but not the free hormone, are stored in the thyroid. However, the blood contains a large reservoir of protein-bound thyroid hormone. P.572
Major Systems The pituitary gland (OHCM6 p.318) Pituitary structure The pituitary gland is situated beneath the hypothalamus of the brain, in a depression, (the pituitary fossa or sella turcica), of the skull. The human pituitary comprises anterior and posterior lobes. The anterior pituitary consists of distinct endocrine cell types which produce and secrete the various hormones. The posterior pituitary is formed by the axons and terminals of magnocellular neurosecretory neurones originating in the hypothalamus. Pituicytes (a type of glial cell) surround and support the terminals. The posterior pituitary hormones are synthesized in the hypothalamus, packed into granules, transported down the axons, and released, by exocytosis, into the systemic veins. Anterior pituitary Thyroid stimulating hormone (TSH)

  • Actions: TSH acts in the thyroid. It stimulates T3 and T4 production; increases iodine uptake by the thyroid; and stimulates thyroid growth
  • Control: TSH release is stimulated by thyrotrophin-releasing hormone (TRH) from the hypothalamus and is inhibited by T3 and T4 negative feedback. Secretion of TRH is stimulated by cold and by stress, via the CNS.

Adreno corticotropic hormone (ACTH) Polypeptide hormone cleaved from the prohormone, proopiomelanocortin (POMC).

  • Actions: stimulates production and therefore secretion of cortisol from the cortex of the adrenal gland. ACTH also produces some increase in adrenal sex steroids and stimulates growth of the adrenal cortex. Melanocyte-stimulating hormone (MSH) is also cleaved from POMC and stimulates pigmentation of skin via actions on melanocytes
  • Control: secretion of ACTH is increased by stress. Secretion is pulsatile with a diurnal rhythm (high at 7.00am, low at midnight). Release of ACTH is stimulated by corticotropin releasing hormone (CRH) from the hypothalamus, inhibited by glucocorticoid negative feedback.

Gonadotrophins Luteinizing hormone (LH), Follicle-stimulating hormone (FSH)

  • Actions: female—LH and FSH control growth and development of follicles; ovulation; synthesis of sex steroids by the ovary; growth and secretion of the sex steroid progesterone by the corpus luteum. Male—LH controls testosterone production by the Leydig cells; FSH stimulates the Sertoli cells and sperm production
  • Control: hypothalamic—LH and FSH release is stimulated by hourly pulses of gonadotrophin-releasing hormone (GnRH) during reproductive life; inhibited by sex steroid estrogen negative feedback. However, switch to ‘positive feedback’ triggers LH surge at ovulation. Cyclical variations in LH and FSH in menstrual cycle. In males, LH release is inhibited by negative feedback from testosterone; ovarian peptides (inhibin and follistatin) inhibit FSH.

Prolactin (PRL) Secreted by lactotroph cells.

  • Actions: principal role in preparation for lactation (p.622). PRL stimulates the development and growth of secretory alveoli in the breast and milk production. PRL also inhibits the reproductive system at the level of the gonads and pituitary (causes ‘lactational amenorrhoea’ in women after delivery of baby)
  • Control: secretion of PRL is increased by suckling. PRL release is inhibited by dopamine from the hypothalamus. PRL synthesis is stimulated by circulating estrogen.

Growth hormone (GH)

  • Actions: stimulates long bone and soft tissue growth, both via stimulating the release of IGFs (insulin-like growth factors) from the liver and by direct actions. It is essential for growth after two years postnatal, but only promotes growth if sufficient nutrition is available. GH also exerts complex actions on metabolism (amino acid, fatty acid, glucose). GH has insulin-like effects to promote amino acid uptake by liver and muscle and, therefore, promotes protein synthesis. However, if GH is chronically increased, it has anti-insulin effects. It is one of the hormones that switches metabolism away from glucose use and toward increased oxidation of fat (e.g. in starvation)
  • Control: secretion is increased via the hypothalamus by hypoglycaemia, stress, and exercise. Hypothalamic factors that regulate GH release are growth hormone-releasing hormone (GHRH) which stimulates and somatostatin which inhibits GH release. Systemic control is via negative feedback by GH at the hypothalamus.

Posterior pituitary Antidiuretic hormone (ADH) or vasopressin

  • Actions: increases water reabsorption by acting in collecting ducts of kidney (V2 receptor) and vascular pressor effects constricting peripheral arterioles and veins (V1)
  • Control: osmotic—sensitive to 1% increase from normal plasma OP of 285mOsm. Sensed by hypothalamic osmoreceptors. Also sensitive to decreases in blood volume or blood pressure.


  • Actions: causes contraction of uterine myometrium in childbirth and contraction of breast myoepithelium to eject milk
  • Control: stretch of cervix/vagina during parturition (the Ferguson reflex); suckling—stimulation of the nipple causes the milk ejection reflex.

Pathology—pituitary tumours (OHCM6 p.320)

  • Hormonal effects: hormone-secreting and non-secreting tumours—effects depend on cell type
  • Mechanical effects: effects on vision via pressing on optic chiasm.

Pituitary adenomas (OHCM6 p.320) The pituitary gland is composed almost entirely of cells which make hormones. Thus, a benign tumour of this gland—an adenoma—will often make the same hormone as its cell of origin, but the production of that hormone will not be under the control of the hypothalamus and will usually be produced in excess. Thus, very small tumours in the pituitary, only a few millimetres in diameter, can have extensive effects on the rest of the body. Pituitary adenomas arise predominantly in the anterior pituitary which constitutes about 80% of the pituitary volume. Before the development of immunohistochemistry, the cells in the pituitary were labelled according to their staining properties with various dyes, but this produced confusing names that were not obviously linked to their function (e.g. chromophobe adenoma). These terms may appear in some literature but it is better to refer to the cells by their products, (e.g. growth hormone). The effects of pituitary adenomas will be specific to the hormones which they produce:

  • Adenomas of growth hormone (GH) producing cells
    • Pituitary gigantism if occurring before puberty when the epiphyseal plates are still open and long bones can grow
    • Acromegaly if after puberty, with disproportionate growth of the bones in the jaw, hands, and feet
  • Adenomas of adrenocorticotrophic hormone (ACTH) producing cells
    • Cushing’s syndrome (p.582)
  • Adenomas of prolactin producing cells
    • Galactorrhea, amenorrhea, loss of libido, infertility
  • Adenomas of thyroid stimulating hormone (TSH) producing cells
    • A rare (1%) cause of hyperthyroidism.

Adenomas of the other hormone producing cells (such as follicle-stimulating hormone and luteinizing hormone producing cells) in the anterior pituitary can occur, but they are much less common than those listed above. Sometimes pituitary adenomas do not produce hormones but they expand within the confined space of the sella turcica and cause pressure atrophy of the remaining pituitary with resultant deficiencies of all the pituitary hormones. This leads to end endocrine organ deficiencies such as hypothyroidism, hypoadrenalism, etc. Since the pituitary gland is confined in the pituitary fossa, with the only space available for expansion being superior to this, then structures above it may be compressed by pituitary adenomas. The optic chiasma lies immediately above the pituitary fossa, so a pituitary adenoma may cause pressure atrophy on this with a resultant defect in the lateral fields of vision—a bitemporal hemianopia. P.575
The thyroid Lies anterior to the 2nd–4th rings of the trachea and the lateral lobes extend up on either side of the trachea and larynx. Control of thyroid hormone production and secretion

  • Epithelial cells of the thyroid (follicular cells) are arranged into follicles around a lumen filled with colloid. The cuboidal follicular cells synthesize thyroglobulin which is released into the colloid
  • C cells (parafollicular cells), which release the peptide hormone calcitonin (p.593), are located in the base of the follicle epithelium
  • Production requires iodide. A sodium/iodide symporter on the basal membrane of follicular cells traps and pumps in iodide from the plasma
  • A thyroperoxidase enzyme on the apical plasmalemma oxidizes the iodide to iodine, iodinates tyrosyl residues in the thyroglobulin, and couples tyrosyl residues to produce the thyroid hormones T4 (thyroxine) and T3 (tri-iodothyronine) still bound in the thyroglobulin and, hence, inactive
  • Thyroid stimulating hormone stimulates endocytosis of colloid and its digestion by lysosomes, to free T4 and T3
  • Iodine deficiency can prevent formation of T4 or T3, whereas excess iodine inhibits thyroid activity
  • The main thyroid product (T4) is not the metabolically active hormone. Metabolism of T4 to produce active T3 occurs primarily in the liver by type I (5′)-deiodinase.

Mechanism of action of thyroid hormones

  • Thyroid hormones are transported into cells and T3 acts on nuclear receptors (TRs) which act on response elements (TREs) in gene promoters
  • This interaction results in stimulation or inhibition of the production of many different mRNAs and, therefore, proteins. Sensitivity to T3 is regulated via the number of TRs.

Effects of thyroid hormones

  • Thyroid hormones act on almost every tissue of the body but have little metabolic effect in the brain, spleen, or testis. They act to increase the basal metabolic rate which increases O2 use and heat production
  • Stimulate production of Na+/K+ ATPase (which uses 20–45% of all ATP)
  • Stimulate RNA polymerase I and II activity and, thereby, production of many proteins; stimulates protein degradation; when T3 is excessive, degradation > production
  • Potentiate β adrenoceptor effects, on glycogenolysis, gluconeogenesis; potentiates insulin effects, increasing glycogenesis and glucose usage
  • Stimulate cholesterol breakdown and synthesis; increase number of LDL receptors on cell surface and enhances lipolysis
  • Stimulate production of β adrenergic receptors and TRH receptors
  • P.577

  • Affect cardiovascular system to increase cardiac output, rate, force, SBP; but DBP falls because of vasodilatation
  • Stimulate gut motility
  • Stimulate bone turnover (breakdown > synthesis)
  • Increase speed of muscle contraction.

Developmental effects

  • Lungs: stimulates surfactant production and lung maturation (with glucocorticoids)
  • CNS: essential for postnatal growth of CNS; stimulates production myelin, neurotransmitters, axonal growth
  • Bone: stimulates linear growth by effects on chondrocytes
  • Stimulates normal development, maturation, and eruption of teeth, hair, epidermis.

Thyroid dysfunction Goitre (swelling of the thyroid) Causes

  • Iodine deficiency
  • Grave’s disease
  • A tumour—may be functioning (i.e. secreting T4 and T3) or non-functioning.

Hyperthyroidism (high T3) (OHCM6 p.304) Causes

  • Grave’s disease—auto-antibody with stimulatory activity when it binds to the TSH receptor on thyroid cells
    • most common cause of hyperthyroidism
  • Pituitary adenoma producing thyroid stimulating hormone
  • Tumours of thyroid follicular cells can produce large amounts of T4 and T3
  • Iatrogenic—overadministration of thyroxine.


  • Increased basal metabolism rate—weight loss (despite increased appetite), increased resting heart rate and ‘bounding’ pulse, heat intolerance, increased sympathetic drive, eye protrusion
  • Atrial fibrillation.

Hypothyroidism (low T3) (OHCM6 p.306) Causes

  • Deficiency of iodine in diet—rare since introduction of iodinized table salt and greater distribution of seafood
  • Hashimoto’s thyroiditis—organ-specific autoimmune disease with destruction of thyroid epithelial cells
  • Pituitary hypofunction with lack of production of TSH—non-functioning pituitary adenoma, Sheehan’s syndrome
  • Iatrogenic—surgical removal of thyroid, damage of thyroid by radioactive iodine, antithyroid drugs
  • Thyroid hormone resistance—a number of genetic defects in the thyroid hormone receptor reduce hormone binding. The subject is hypothyroid but will have normal levels of plasma hormone.


  • In the neonate—cretinism leads to gross deficits in CNS myelination and stunting of postnatal growth
  • In the adult: myxoedema—decreased basal metabolic rate (tiredness, lethargy, weight gain), slow mentation, hypothermia, constipation.

The adrenal gland The adrenal gland comprises an inner medulla that secretes the catecholamines, noradrenaline and adrenaline, and an outer cortex that secretes steroid hormones. The adrenal glands are located just medial to the upper pole of each kidney. Structure The adrenal medulla is made up of chromaffin cells packed with granules which store large amounts of adrenaline and noradrenaline. The adrenal cortex is made up of sheets of cells surrounded by capillaries and arranged in three zones: the outer zona glomerulosa which makes aldosterone; middle zona fasciculata which makes cortisol; and inner zona reticularis which makes small amounts of androgens. Adrenal medulla

  • Actions: preparation for emergency physical activity. The adrenal medulla contributes 10% of the total sympathetic nervous system response to stress and so, thus, is not vital. (p.597)
  • Receptors: adrenaline and noradrenaline act at adrenergic receptors (p.240)
  • Stimuli: any stressful stimuli which activate the sympathetic nervous system (e.g. low blood pressure, haemorrhage, pain, low blood glucose, exercise, surgery, asphyxia)
  • Pathology: tumours of the adrenal medulla (phaeochromocytoma) constantly secrete catecholamines causing hypertension, tremor, anxiety, forceful heartbeat.

Adrenal cortex (OHCM6 p.310) Cortisol

  • Actions: provides protection of the body in prolonged stress—primarily to preserve glucose for the brain. Exerts widespread actions on many tissues (p.598)
  • Receptors: glucocorticoid receptors (GR) are present in almost all cells. GRs are located in the cytoplasm of cells and migrate to the nucleus to regulate gene transcription when cortisol binds
  • Control of output
  • Abnormal function: Cortisol insufficiency—Addison’s disease (OHCM6 p.312); cortisol excess—Cushing’s syndrome (OHCM6 p.310).

Aldosterone (regulation of body sodium and fluid volume)

  • Receptors: Mineralocorticoid (MR) receptors are present in the nuclei of only a few cell types—kidney collecting tubule epithelia, salivary and sweat glands
  • Actions: In the kidney, aldosterone regulates ion transport in the kidney collecting tubules in order to stimulate reabsorption of Na+ in exchange for secretion of K+, H+, NH+3. There is a 2hr lag in the response to aldosterone as MR effects are via stimulating transcription of the Na/K ATPase protein. In salivary and sweat glands, aldosterone regulates ion transport to retain sodium
  • P.581

  • Control of output: the renin—angiotensin system (p.594)
  • Abnormal function: Hypoaldosteronism (in adrenal failure) results in sodium loss, low blood volume, and low blood pressure. Hyperaldosteronism (OHCM6 p.314) (Conn’s syndrome) results in excess sodium retention, water retention, and increased blood pressure. Spironolactone (an aldosterone antagonist) is used as an anti-hypertensive.

Adrenal androgens (DHEA) DHEA (dehydroepiandrosterone) is produced and released from the adrenal cortex zona reticularis. DHEA is a weak androgen which is a very minor component of adrenal secretions. P.582
Cushing’s syndrome (OHCM6 p.310) Definition Excess glucocorticoid hormones in the body, from whatever source. Mechanisms (Fig. 9.1)

  • Pituitary adenoma producing excess adrenocorticotrophic hormone (ACTH) because it no longer responds to the normal homeostatic feedback loop. The excess ACTH then stimulates the adrenal cortex to produce excess glucocorticoid hormones. This is also known as Cushing’s disease
  • Adenoma of the adrenal cortex which has become autonomous from the pituitary—adrenal feedback loop and produces excess glucocorticoids
  • Excess ACTH administered by the medical profession or produced endogeneously by a tumour (such as small cell lung cancer)
  • Excess glucocorticoid steroids, (e.g. prednisolone) administered by the medical profession. This was the most common mechanism for a few decades, since steroids were powerful drugs that could control severe allergic and inflammatory processes such as asthma or rheumatoid arthritis. Fortunately, more specific drugs are now available for some conditions, (e.g. asthma) and in others, ‘steroid-sparing’ immuno suppressants, (e.g. azothioprine) are used to reduce the risk or magnitude of Cushing’s syndrome.

Complications of Cushing’s syndrome

  • Diabetes mellitus
  • Proximal muscle weakness
  • Decreased immunity to infections
  • Osteoporosis
  • Truncal obesity
  • Hirsutism
  • Depression, psychosis.
Fig. 9.1 Mechanisms of Cushing’s syndrome. Arrows indicate either an excess of ACTH or glucocorticoids.

Hyperaldosteronism (OHCM6 p.314) Definition Excess production of the aldosterone hormone by the adrenal cortex. Causes

  • Primary
    • Adrenal cortical adenoma with autonomous production of aldosterone
    • Primary adrenal cortical hyperplasia
  • Secondary: normal response to activation of the renin—angiotensin system
    • Congestive heart failure
    • Decreased renal perfusion, (e.g. renal artery stenosis), so the juxtaglomerular apparatus senses a lack of perfusion and produces more renin
    • Hypoalbuminaemia—and, thus, reduced osmotic pressure within the vascular system so reduced plasma volume and reduced renal perfusion
    • Pregnancy—estrogen induces increased plasma renin substrate.


  • Sodium and water retention with potassium excretion leading to hypertension and hypokalaemia
  • In primary hyperaldosteronism, renin levels will be low (useful in the diagnostic process).

The endocrine pancreas Structure—the Islets of Langerhans

  • The islets are diffusely distributed throughout the pancreas
  • Islets comprise insulin cells (β cells), glucagon cells (α cells; somatostatin cells—(δ cells), and pancreatic polypeptide (PP) cells
  • The endocrine pancreas regulates the availability of metabolic substrates.

Plasma glucose concentrations The ‘normal’ morning fasting blood glucose concentration is 4–5mM and rises up to 8mM after a meal. Hypoglycaemia (<3mM) causes: dizziness, confusion, hunger, convulsions, coma; sympathetic activation. Hyper-glycaemia >8mM glucose causes osmotic effects; if >10mM glucose is lost in urine with water (excess urine production = diabetes)—thirst, abnormal glycation of proteins. Insulin Synthesis A protein hormone from the prohormone, proinsulin, cleaved to insulin + C peptide in secretory granules. Insulin comprises two chains linked by two S-S bonds; stored with zinc in granules. Mechanism of insulin secretion

  • Glucose enters the beta cell (diffusion is facilitated by the glucose transporter 2, GLUT 2)
  • Metabolism of the glucose in the β cell produces ATP
  • ATP closes ATP-dependent potassium channels present in the beta cell membrane, which in turn depolarizes the β cell
  • Depolarization causes Ca2+ entry; this in turn stimulates exocytosis of insulin
  • Sulphonylurea drugs inhibit the ATP-dependent K+ channels and promote insulin release.

Mechanism of insulin action

  • The insulin receptor is a tyrosine kinase-linked receptor
  • Phosphorylation of insulin receptor substrate (IRS) proteins occurs which activates intracellular signalling cascades.

Insulin promotes anabolism and controls use of metabolic substrates

  • Acts to lower elevated plasma glucose
  • Controls transport of glucose and amino acids into many types of cell
  • Directs the use of glucose and amino acids and augments their oxidation to ATP
  • Increases protein synthesis and inhibits proteolysis
  • Supports growth and proliferation of many cell types.

Specific actions: p.124 Pathology

  • Diabetes mellitus Type I (insulin-dependent diabetes)—no insulin secretion as result of autoimmune destruction of β cells. Treatment with insulin (OHCM6 p.292)
  • Diabetes mellitus Type II (maturity onset, obesity-associated, non-insulin dependent (NIDDM)) (OHCM6 p.294)
    • Early stages: peripheral resistance to insulin as downregulation of insulin receptors—leads to increased plasma insulin; disordered insulin secretion. Treatment: regulation of diet (no sugary foods), stimulation of insulin release by sulphonylurea drugs which bind to and inhibit the K+-ATP channel subunit
    • Later stages: pancreatic amyloid formation and islet destruction occurs; insulin treatment may be necessary
  • Insulinoma—unregulated hypersecretion of insulin by tumour of β cells.

Glucagon Peptide hormone that protects against a lack of metabolic substrates.

  • Synthesis: produced as prohormone, proglucagon, then cleaved to glucagons in secretory granules
  • Produced: by α cells of the pancreatic islets
  • Release: increased in response to low plasma glucose. The mechanism of release is poorly understood. α cells do have ATP-sensitive K+ channels; fall in insulin inhibition
  • Actions: virtually all in the liver (via Gs, cAMP); protects against hypoglycaemia
    • When low plasma glucose
    • When high amounts of protein ingested or when high demand for glucose (e.g. exercise).

Effects in the liver depend on the concentration of glucagon in the plasma:

  • Low amount of glucagons—stimulates glycogenolysis
  • Medium amount of glucagons—stimulates gluconeogenesis
  • High secretion of glucagons—stimulates lipolysis, fatty acid oxidation, ketogenesis.

NB Synergism with other hormones involved in metabolic control: catecholamines, glucocorticoids, growth hormone all stimulate liver conversion of glycogen to glucose. Somatostatin Peptide hormone made in δ cells of pancreas. • Actions: Inhibits the secretion of both insulin and glucagons (paracrine action); role in the physiology of the islets is as yet uncertain. P.586
Diabetes mellitus (OHCM6 pp.292–9) Diabetes mellitus is, as yet, an incurable condition that is diagnosed as a chronic increase in blood glucose levels—hypergylcaemia. The condition is broadly divided into two types, depending on the underlying cause:

  • Type 1 diabetes (OHCM6 p.292) (formerly ‘insulin-dependent diabetes mellitus’—IDDM) is caused by an inability to synthesize sufficient insulin—the hormone responsible for stimulating uptake of glucose into cells. Insulin is usually synthesized in β-cells of the Islets of Langerhans in the pancreas, but they are destroyed by an autoimmune response early in the life of susceptible individuals (onset usually occurs before children reach 10 years of age). The trigger for this response is believed to be due to an environmental stimulus in individuals with a genetic predisposition to the condition. Although the child of a parent with type 1 diabetes is at increased risk of developing the disease, the risk is relatively small (<2% if the mother is affected, <6% if the father is affected) unless both parents have the disease, in which case genetic counselling should be sought.
  • Type 2 diabetes (OHCM6 p.294) (formerly ‘non-insulin-dependent diabetes’—NIDDM) includes a wide range of disorders that develop over many years, often later in life, ultimately leading to hyperglycaemia. In cases where a specific cause can be identified, reduced secretion of insulin or a reduction in the effectiveness of insulin to facilitate uptake of glucose into cells (so-called insulin resistance) is implicated. However, up to 98% of cases are ‘idiopathic’, meaning that no specific cause has been identified.

There is a far clearer genetic link to type 2 than to type 1 diabetes, with people of Asian or Afro-Carribean ethnic origin, and those with a family history of diabetes or gestational diabetes at increased risk of developing the disease. Furthermore, there are a number of rare inherited diseases, including MODY (dominantly inherited type 2 diabetes), mitochondrial diabetes, and insulin-resistant diabetes (due to genetic defects in the insulin receptor [type A] or autoimmune destruction of the receptor [type B]). An increasingly prominent risk factor for diabetes is obesity, probably due to downregulation of insulin receptors in response to increased insulin production (hyperinsulinaemia). The rise in prevalence of obesity in Western countries is thought to be responsible for the emergence of childhood type 2 diabetes. Gestational diabetes is a specific term relating to pregnant women who are diagnosed with hyperglycaemia during routine plasma glucose tests at ~28 week gestation. Blood glucose levels typically return to normal within 6 weeks of birth, but the condition may be indicative of a predisposition to type 2 diabetes later in life for both mother and child. Babies of mothers with gestational diabetes are often born overweight because of the growth-stimulating effects of increased foetal insulin secretion in response to high glucose levels derived from the mother. P.587
Complications of diabetes (OHCM6 p.296) The major complications associated with persistent hyperglycaemia relate to the cardiovascular system. Broadly, the effect of diabetes on the cardiovascular system can be divided into microvascular complications in the eyes, kidneys, and nerves, and complications pertaining to the major arteries, including coronary artery disease, stroke, and peripheral vascular disease. The principle cause of most, if not all, of these complications is diabetes-induced hypertension, although glycation of haemoglobin is also crucial in microvascular disease. The precise mechanism by which persistent hyperglycaemia induces hypertension has yet to be fully elucidated, but increased generation of reactive oxygen species and the associated dysfunction of protective endothelial effects are believed to be important. Diagnosis (OHCM6 p.292, 294) Diabetes is notoriously difficult to diagnose: patients generally present having suffered weight loss, but other symptoms include tiredness, dry mouth, ketoacidosis (overaccumulation of ketones in the blood and urine as a by-product of the metabolism of lipids that are used as a substitute fuel for energy instead of glucose which is poorly absorbed by cells in the absence of insulin), and, in more advanced cases, foot or leg ulcers and sepsis. Routine screening of patients’ plasma and urine has improved diagnosis. Patients with suspected diabetes are subjected to an oral glucose tolerance test in which they fast for 12hr, after which a baseline blood sample is taken. Patients are then given an oral load of 75g of glucose; a second sample is taken 2hr after the oral glucose load. Generally accepted limits for diagnosis of diabetic patients are given in Table 9.1 and patients whose glucose levels are elevated but do not exceed the threshold for full-blown diabetes are said to have impaired glucose tolerance.

Table 9.1 Limits for diagnosis of impaired glucose tolerance and diabetes mellitus
  Glucose concentration (mmol/l
Venous plasma Venous whole blood Capillary whole blood
Impaired glucose tolerance
Fasting sample: <7.0 <6.1 <6.1
2 hr sample after glucose load: ≥7.8<11.1 ≥6.7<10.0 ≥7.8<11.1
Diabetes mellitus
Fasting sample: ≥7.0 ≥6.1 ≥6.1
2 hr sample after glucose load: ≥11.1 ≥10.0 ≥11.1
1. A ‘casual’ plasma sample (i.e. taken without regard for time of last meal) of ≥11.1 mmol/l can also be indicative of diabetes but usually needs to be confirmed by a glucose tolerance test or by repeating on another day.
2. In the absence of symptoms, a positive glucose tolerance test might have to be supported by elevated glucose levels at a second timepoint (e.g. ≥11.1 mmol/l at 1 hr).

Treatment (OHCM6 p.295, 297) Impaired glucose tolerance and mild gestational diabetes are often treated through changes in diet and lifestyle, in an effort to avoid exacerbating the problem through high carbohydrate intake and weight gain. A similar approach is often used in patients where obesity is a primary cause of diabetes but is supplemented with drugs that stimulate insulin secretion, such as sulphanylureas and meglitidine analogues. Ultimately, however, these patients and their non-obese counterparts, as well as patients with type 1 diabetes are commonly prescribed insulin to alleviate the symptoms. The peptide nature of insulin prevents the use of an oral preparation, requiring patients to inject subcutaneously immediately prior to meals. The inherent danger of this form of treatment is that, should a patient fail to eat after injecting, blood glucose can fall fatally low (hypoglycaemia). Ultimately, diabetes is an incurable condition; treatments aim to improve the lifestyle of patients and to reduce the risk of serious diabetes-related conditions. P.589
Gastrointestinal hormones

  • Functions: GI hormones, with the enteric and autonomic nervous systems, integrate and co-ordinate the mechanisms which move, digest, and absorb the various meals that are ingested. They control GI tract exocrine and endocrine secretion, motility, growth, and blood flow
  • Routes: hormones released from gut endocrine cells act via endocrine, paracrine, neurocrine routes, and possibly also via the gut lumen. Peptides are also released from nerves of the enteric nervous system
  • Gut endocrine cells are part of the GI tract epithelium, variably positioned in crypts or villi; hormone is secreted basally; most have sensory microvilli on an apex open to the gut lumen. Most gut hormones are peptides produced from larger precursors, so different molecular forms of the hormones are found.


  • Distribution: G cells of gastric antrum crypts; some duodenal cells
  • Synthesis: produced as prohormone preprogastrin, cleaved to progastrin and, in turn, to gastrin
  • Stimuli
    • Luminal protein digestion products (especially tryptophan, phenylalanine; also calcium, beer, wine, coffee)
    • Vagus, via acetylcholine and gastrin-releasing peptide
    • Distension of stomach
    • Hypercalcaemia (as in hyperparathyroidism)
  • Inhibitors
    • Inhibited by stomach pH < 2.5; alkali short term has little effect; long term causes hyperplasia
    • Inhibited by somatostatin (local negative feedback)
  • Actions
    • Stimulates gastric acid secretion (direct and indirect, via histamine H2 receptor); stimulates parietal cell growth
    • Stimulates pepsin secretion; (also water and electrolyte secretion in liver, pancreas, intestine)
    • Stimulates antral motility, mucosal blood flow
    • Trophic to body of stomach
  • Pathology: gastrinoma (usually in pancreas) causes repeated peptic ulceration due to high acid and pepsin secretion.


  • Distribution: enterochromaffin-like (ECL) cells of stomach wall
  • Synthesis: from histidine by histidine decarboxylase
  • Stimuli: vagal stimulation, gastrin
  • Actions: local paracrine action stimulates gastric acid (HCl) secretion by parietal cells via H2 receptors (hence the use of H2 receptor antagonists for treatment of peptic ulcerations).


  • Distribution: S cells, from duodenum to distal ileum; in neck region of intestinal glands
  • Stimuli: acid in proximal duodenal causing lumen pH < 4.5; inhibited by somatostatin
  • Actions
    • Stimulates pancreatic secretion of HCO-3 and water—this washes pancreatic enzymes into the gut
    • Stimulates liver secretion of HCO-3 and water into bile
      • Potentiates CCK; calcitonin and PTH secretion.

Cholecystokinin (CCK)

  • Distribution: I cells in the duodenum and jejunum
  • Stimuli: protein and fat digestion products in duodenum
  • Actions
    • Stimulates secretion of pancreatic enzymes and potentiates action of secretin
    • Stimulates contraction of gall bladder
      • Inhibits gastric emptying; increases small bowel transit
      • High levels potentiate secretion of calcitonin
    • In CNS, CCK is linked to satiety (the feeling that one has had enough to eat).

Hormones influencing calcium, phosphate, and bone Ca2+ has very important extracellular effects on excitable tissues and blood clotting; it is also an essential component of bone.

  • Hypocalcaemia (OHCM6 p.694) (i.e. total Ca2+ <1.2–1.5 mM)—very dangerous
    • Increases neuronal membrane excitability by increasing sodium permeability causing tetany (involuntary nerve-induced spasm of skeletal muscles)
    • Heart QT is increased (‘prolonged QT’) and heart failure may occur
  • Hypercalcaemia (OHCM6 p.696)—only dangerous in the long term
    • Decreases neurone excitability
    • Calcium salts are rather insoluble, so urinary stones and tissue calcification occurs
    • Attempts to secrete excess calcium via urine causes polyuria, which leads to dehydration and exacerbates the problem.

A fall in plasma Ca2+ is therefore more dangerous, short term, than a rise; endocrine control mechanisms reflect this. Amounts of calcium in the body (OHCM6 p.694)

  • The main controlled parameter is plasma-ionized Ca2+—1.2mM. Plasma contains 2.5mM total (2.4–2.6mM); 50% is ionized
  • Total body calcium: normal adult contains 25 moles (1kg) of calcium
  • Bone calcium: 1% (250mmole) is rapidly exchangeable; 99% is hydroxyapatite bound to collagen—slowly exchangeable. Interstitial fluid calcium is freely exchangeable with plasma calcium.


  • 85% in the skeleton as hydroxyapatite; 15% in soft tissues
  • Plasma: phosphate 0.2mM; varies widely with age, sex, diet.

Hormone control of calcium and phosphate PTH (parathyroid hormone) (OHCM6 p.308) Principal control; essential for life.

  • Effects
    • PTH, a peptide hormone, is secreted from the parathyroid glands in response to falling plasma Ca2+
    • PTH restores low plasma Ca2+ to normal and causes increased phosphate loss
    • Kidney: PTH inhibits Na-phosphate co-transport and phosphate reabsorption in the kidney; phosphate loss causes an increase in Ca2+ mobilization
      • Increases Ca2+ reabsorption in the distal kidney tubule and collecting duct (independent of Na+)
      • Increases activity of 1 alpha-hydroxylase and production of the active vitamin D metabolite 1,25(OH)2D3 (calcitriol)
    • Bone: normal intermittent secretion of PTH is necessary for healthy bone growth and remodelling
    • P.593

    • Rapid effects: stimulates Ca2+ flux from bone across osteoblasts which lay down new bone and line the bone surface; PTH reorganizes osteoblasts so that they become separated to allow: calciumef flux from matrix; and access of osteoclasts (which break down bone). In the long term, osteoclasts are activated via osteoblasts (protein synthesis needed) which break down bone; excess PTH limits growth of osteoblasts and bone matrix synthesis, causes destruction of bone
  • Pathology: Ca2+ is disturbed, especially when PTH is insufficient
    • Deficiency: hypoparathyroidism (OHCM6 p.308)—low plasma Ca2+, tetany; pseudohypoparathyroidism—resistance to PTH due to receptor defect (PTH levels are normal or increased)
    • Excess hyperparathyroidism (tumours) (OHCM6 p.308)—raised plasma Ca2+, bone destruction, urinary stones, sluggish CNS.

Vitamin D and its metabolites Increases whole body calcium. Synthesized in skin from cholesterol. UV light converts a cholesterol derivative to colecalciferol = vitamin D3. In the liver, 25-hydroxylase produces 25(OH)D3. In the kidney, 1α-hydroxylase converts 25(OH)D3 to 1,25(OH)2D3. Also some dietary intake of D3 (egg yolks, fish oils).

  • Effects of 1,25(OH)2D3: via nuclear receptors which regulate transcription
    • Intestine: increases uptake of Ca2+ via synthesis of the calcium binding protein, calbindin
    • Kidney: facilitates conservation of calcium and phosphate for growth and repair
    • Bone: necessary for the action of PTH; inhibits synthesis of collagen by osteoblasts; action on osteoclasts to increase bone breakdown and increase Ca2+ loss
  • Pathology: in both deficiency and excess of vitamin D, serum Ca2+ is approximately normal
    • Deficiency: children—rickets (OHCM6 p.700); renal rickets; vitamin D-resistant rickets; adults—osteomalacia
    • Excess—vitamin D poisoning which leads to symptoms of hypocalcaemia (see above).

Calcitonin (OHCM6 p.694) Principal function is to prevent hypercalcaemia and excessive bone breakdown. Peptide hormone produced by C cells of thyroid and secreted in response to serum Ca2+ above normal range.

  • Effects: prevents hypercalcaemia by effects on bone. Causes acute reduction in plasma phosphate, uptake to bone
    • Bone: decreases activity of osteoclasts; inhibits mineral/matrix reabsorption; greatest effect when bone resorption is rapid (e.g. in the young)
    • Gut
      • Meal related—helps to control rise in plasma Ca2+ due to absorption, also inhibits absorption
      • Pregnancy/lactation related—protection against demands of foetus/infant
    • Kidney and intestine: pharmacological doses affect ion fluxes
  • Pathology
    • Deficiency: compensation by changes in PTH
    • Excess: uncontrolled secretion from ‘medullary’ carcinoma of thyroid(OHCM6 p.516).

Other sites of hormone production Adipose tissue: leptin

  • Production: produced in fat cells throughout the body
  • Stimuli: constitutive release parallels the accumulation of fat; correlates with body:mass index; reflects the availability of metabolic substrates
  • Actions:
    • Acts on receptors in basal hypothalamus; inhibits neuropeptide Y action in hypothalamus and influences many other neuro-transmitters involved in feeding behaviour
    • Decreases appetite (signals satiety)
    • Increases energy expenditure, sympathetic activity
    • Decreases insulin secretion
    • Mutations in leptin (ob) protein or receptor are a rare cause of human gross obesity; leptin resistance may be involved in human obesity
    • Effects on reproductive system, signalling an adequate reserve of metabolic fuels for reproduction
    • Probably evolved to protect against starvation (‘thrifty genotype’).

Heart: atrial natriuretic peptide (ANP)

  • Production: produced by atrial myocytes
  • Stimuli: atrial dilatation (i.e. increased venous return, right heart failure OHCM6 p.136)
  • Actions:
    • Stimulates loss of sodium (and water) in urine, probably by effect on glomeruli
    • Inhibits renin—angiotensin—aldosterone system
    • Reduces blood pressure (reduces venous return and depresses cardiac output).

Kidneys: erythropoietin

  • Production: glycoprotein produced by epithelial cells of glomeruli
  • Stimuli: reduced oxygen saturation of the blood; androgens, β-adrenergic stimulation
  • Actions: stimulates production of erythrocytes in the bone marrow.

Renin—angiotensin system Renin is an acid protease produced by juxtaglomerular cells in the afferent arterioles of glomeruli, in response to sodium depletion, hypotension, dehydration, poor renal artery blood flow, sympathetic stimulation. This cleaves plasma angiotensinogen to angiotensin I, which is then cleaved by angiotensin-converting enzyme (in the lungs) to the active angiotensin II, which stimulates aldosterone secretion, thirst, and vasoconstriction. P.595
Stress The stress response Stress Any change/event that either disrupts, or threatens to disrupt, homeostasis to an unusual degree. Stressor Any severe disturbance.

  • Acute stressors: extreme heat/cold, blood volume depletion by heavy bleeding, dehydration, hypoglycaemia, pain, surgical procedures, toxins from a bacterial infection, severe exercise, sleep deprivation
  • Chronic stressors: may be obvious or more subtle e.g. chronic infection, chronic pain, housing problems, marital problems, financial worries, difficulties at work, commuting.

The stress response

  • The stress response is, at least in the short term, counter-homeostatic. It raises blood pressure, blood sugar, ventilation, etc.
  • The purpose of these changes is to prepare the body to meet an emergency situation. It has evolved in order to allow the individual to survive the emergency, and return to normal homeostasis when the stress is no longer present
  • It involves a short-term alarm reaction; and a more long-lasting resistance reaction

The hypothalamus controls and co-ordinates the stress response via its actions on the autonomic nervous system and the endocrine systems. It receives inputs from:

  • The brain stem e.g. from nucleus tractus solitarius; non-specific from raphe, locus coeruleus
  • Higher centres fornix from hippocampus; amygdala; orbito-frontal and septal cortex; dorsomedial and midline thalamic nuclei convey potentially stressful information from the external world, the internal organs, and the ‘psyche’.

The acute alarm reaction The acute ‘alarm reaction’ (fight-or-flight) involves hypothalamic control by activation of:

  • CNS outputs
  • The sympathetic nervous system and adrenal medulla.

The responses are immediate and mobilize the body’s resources for immediate physical activity, and cause arousal of the cerebral cortex. CNS outputs

  • Increased respiratory rate/depth; increased cardiac output via cardiovasular centre and ANS
  • Secretion of CRH to activate the pituitary adrenal axis
  • Secretion of ADH to conserve body water
  • Arouses the cerebral cortex by stimulation of the locus coeruleus and widespread central release of noradrenaline
  • Blunts pain by release of endorphins and enkephalins.

Sympathetic activity Increased sympathetic activity causes changes which:

  • Increase the circulation
  • Increase availability of energy substrates (promote catabolism)
  • Decrease non-essential activities.

These changes include:

  • Increased heart rate, force of heart contraction—increases supply of O2 and substrates to where they are most needed
  • Vasodilatation of muscle vascular beds—preparation for intense physical exertion
  • Vasodilation of the adrenal vasculature
  • Vasoconstriction of visceral and skin arteries and veins—redistributes blood away from organs that do not have an immediate role; contraction of veins reduces pooling of blood

NB No constriction of heart, lung, cerebral blood flow

  • Dilation of respiratory tract by relaxing smooth muscle—permits greater O2, and CO2 exchange
  • Increased sweat production—‘cold sweat’, but then improves heat loss if physical exertion
  • Decreased secretion from the GI tract; decreased GI motility, closes sphincters
  • Increased glycogenolysis—from adrenaline (β); reduction of insulin and increase of glucagon secretion
  • Decreased insulin causes reduced use of glucose by muscle and fat, conserving glucose for the brain (muscle runs on glycogen, free fatty acids)
  • Pupil dilation, eyelid retraction, accommodation for distant vision
  • Increased activity of preganglionic sympathetic nerves stimulates the adrenal medulla to release adrenaline which supplements and prolongs all the above reactions; it also causes increased liver glycogenolysis—mobilizes glucose to avoid risk of brain hypoglycaemia
  • Stimulates hormone-sensitive lipase—mobilizes free fatty acids for use as energy substrates by many organs.

The resistance response If the stress is more long-lasting, more prolonged effects of the acute response and more chronic responses occur to produce the resistance reaction. These involve the slower results of the sympathetic nerve stimulation and actions of various hormones that are more prolonged than those of the catecholamines. Sympathetic nerves stimulate juxtaglomerular cells of the kidney. This results in the production of angiotensin II which both causes vascular constriction and also stimulates mineralocorticoid (aldosterone) release which:

  • Increases Na+ reabsorption which causes water retention, maintains a high BP, and counteracts fluid loss
  • Increases elimination (exchange) of H+ ions (accumulate as a result of the increased catabolism).

Glucocorticoids (e.g. cortisol)

  • Metabolic substrate metabolism Cortisol stimulates metabolism of:
    • Carbohydrates—stimulates glucose production; opposes insulin actions
    • Lipids—stimulates lipolysis and ketogenesis (results in redistribution of fat to trunk if fatty acids are in excess)
    • Proteins—stimulates gluconeogenesis
  • Cardiovascular effects:
    • Maintains the circulation via increased myocardial contraction; increases vascular tone
    • Maintains plasma volume by preventing increased vascular permeability
  • Skeletal muscle: maintains ability to give sustained contractile responses
  • Ion control: promotes Na+ retention and K+ excretion (actions at mineralocorticoid receptors when cortisol is high— p.00).
  • In the CNS: varied effects on mood and behaviour
  • Haemopoiesis: increases red blood cell production, so enhances oxygen-carrying capacity of blood
  • Inflammatory response immune system: immunosuppressive actions:
    • Inhibits leukocyte translocation from blood to sites of tissue damage or infection
    • Stimulates lymphocyte destruction
    • Glucocorticoid selective drugs are used therapeutically to treat inflammatory diseases such as asthma and eczema (e.g. prednisone, betamethasone) but have some mineralocorticoid effects
  • Reproduction and lactation: inhibits, in part by inhibition of LH and PRL, release from the anterior pituitary gland (pregnancy is a non-essential metabolic drain on resources).

Hypothalamic TRH Stimulates the release of TSH and, therefore, thyroid hormones. Thyroid hormones increase the metabolic rate and the catabolism of glucose, fats, and proteins (p.576). Note In starvation (which is a particular form of stress), glucocorticoids reduce the conversion of T4 to T3 in the liver, blunting the catabolic response. Hypothalamic GHRH GHRH stimulates the release of GH which, when secreted in a prolonged manner (normally it is secreted in short pulses every 4–6hr), causes:

  • Increased liver breakdown of fats to fatty acids and glycerol
  • Increased liver conversion of glycogen to glucose.

By these means, the resistance reaction allows the body to continue fighting a stressor long after the effects of the acute alarm reaction. It produces the energy and circulatory changes required for the performance of strenuous tasks, fighting infection, avoiding fatal haemorrhage. If there is greatly increased metabolism, blood glucose returns nearly to normal during the resistance reaction as input = output; blood pH is controlled by the kidney. However, blood pressure remains raised because of retention of water. When the stress is prolonged

  • Within the hypothalamus, CRF, glucocorticoids, opioid peptides reduce GnRH secretion—avoid risk of pregnancy and a further drain on metabolic resources
  • In the hippocampus, glucocorticoids act on glucocorticoid receptors to modify emotional reactions—induce mild euphoria, diminishing the psychic effects of the stress.

Chronic stress at different ages

  • In utero: the stress of undernourishment leading to low birth weight is associated with a significant increase in hypertension, diabetes mellitus, and lower life expectancy
  • Childhood: chronic stress in childhood is associated with retarded growth
  • Aged: the morning peak of cortisol occurs earlier in the aged; the cortisol response to the stress of an operation is also prolonged.

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