Flashcards in Endocrinology: Pancreas and Adrenal glands Deck (57)
1) Zona glomerulosa (15%)
2) Zona fasciculata (75%)
3) Zona reticularis (10%)
The zona glomerulosa, an indistinct layer lies just beneath the capsule of the adrenal gland and produces the mineralocorticoid, aldosterone.
The zona fasciculata and the zona reticularis (that surrounds the adrenal medulla) produce glucocorticoids (cortisol) and androgens (dehydroepiandrosterone – DHEA and
its sulphate) respectively.
DHEAS and androstenedione are relatively inactive hormones. Both fasciculata and reticularis layers are ACTH-responsive. Hormones are produced ‘on demand’ – they are not stored.
Corticotrophin releasing hormone (CRH) is
released from hypothalamic neurones in response to neural stimuli (e.g. circadian rhythm, stress) into the hypothalamic-hypophyseal portal venous system and stimulates adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary.
ACTH causes secretion of cortisol and other steroids from the adrenal cortex. Rising levels of glucocorticoid inhibit the synthesis and release of CRH and ACTH within minutes. The main effect of ACTH is at the cholesterol-pregnenolone conversion which occurs within minutes.
A more chronic effect of ACTH stimulation involves growth and DNA and RNA synthesis within adrenocortical cells. ACTH deficiency causes atrophy of the adrenal glands.
Functional ‘atrophy’ of the HPA axis may persist for
weeks or months after chronic administration of therapeutic glucocorticoids.
Circadian rhythm is generated by a ‘pacemaker’ in the hypothalamus. ACTH is secreted in pulsatile bursts at different times of the day which leads to the normal diurnal variation of plasma ACTH and cortisol. Levels are highest in the morning about the time of waking and lowest around midnight. Disease, surgical trauma, and psychological stress can all cause modification or loss of normal diurnal variation.
Mechanism of action of cortisol
In the plasma over 90% of cortisol is carried bound
to proteins, mainly cortisol binding globulin or, to albumin.
Protein binding allows uniform distribution
of hormone to cells of the target tissues. Free, unbound cortisol is biologically active; it enters the cells and binds with a glucocorticoid receptor.
The hormone receptor complex translocates to the nucleus, binds to DNA and regulates gene expression. In the liver, this causes an increase in protein synthesis: in most other tissues cortisol has a catabolic effect.
Effects on intermediary metabolism
In the liver, glycogen formation and gluconeogenesis is increased by activation of glucose-6-phosphatase and release of gluconeogenic amino acids from skeletal muscle.
Cortisol enhances the gluconeogenic actions of glucagon and catecholamines. Glucose uptake and utilisation is reduced in peripheral tissues. In fatty tissue there is increased lipolysis that results in the production of glycerol and free fatty acids. The fatty acids are then incorporated into the gluconeogenic process within the liver.
In glucocorticoid excess there is hyperinsulinaemia
almost certainly due to the effect of cortisol on glucose metabolism.
In disorders of glucocorticoid excess there is redistribution of body fat manifest as progressive, central obesity, the limbs are spared, often being wasted due to muscle breakdown.
Effects on central nervous system
Glucocorticoids influence sleep patterns and mood.
In excess, appetite is increased and there can be sleep disturbance. In early stages, cortisol excess is associated with a feeling of wellbeing which can progress to severe psychosis or depression.
Effects on musculoskeletal and connective
In excess, glucocorticoids cause osteopaenia as a result of inhibition of fibroblastic activity and decreased bone formation. Bone changes include vertebral body collapse, fractures and avascular necrosis – especially of the femoral head.
Children with cortisol excess show growth retardation, often severe. Many of the ‘classic signs’ of hypercortisolism are due its catabolic effects on muscle (wasting, myopathy), skin and connective tissue (thin, friable skin, poor wound healing, striae and an increased tendency to bruise).
Immunological effects of glucocorticoids:
• Effect on cells
— lymphocyte, monocyte, eosinophil reduction in blood
— increase in circulatory polymorphs
— inhibition of accumulation of inflammatory cells
— inhibition of lymphocyte production
Immunological effects of glucocorticoids:
• at sites of inflammation
• effects on cell function
— inhibition of prostaglandin synthesis
— inhibition of interleukins
— inhibition of T cell proliferation
In excess, glucorticoids have a mineralocorticoid action, hypertension is common, hyponatraemia and hypokalaemia are common in patients on intravenous fluid therapy.
The association of chronic cortisol excess with peptic ulcer disease is not understood.
This is confirmed firstly by loss of the normal diurnal
variation – as indicated by elevated midnight and
morning plasma cortisol levels and/or an increase in
24-hour urinary free cortisol excretion.
Secondly, by loss of ACTH regulation of cortisol levels as indicated by the failure of cortisol to suppress after an oral dose of dexamethasone (a potent corticosteroid).
In this way Cushing’s syndrome (excess circulating cortisol) is confirmed. The next step is to determine whether the cortisol excess is ACTH dependent or ACTH independent.
ACTH levels and diagnosis
If ACTH levels are low (ACTH independent), this suggests primary adrenal disease and an abdominal CT or MRI will usually confirm abnormal adrenal morphology (adenoma or carcinoma).
If ACTH levels are normal or elevated (ACTH dependent) pituitary disease (Cushing’s disease) must be distinguished from ectopic ACTH production (e.g. small cell lung cancer) by further biochemical studies and cross-sectional imaging.
This may be due to adrenal disease, i.e. primary
adrenal insufficiency. Adrenocortical reserve is
tested by the administration of synthetic ACTH
(Synacthen); the cortisol response is then measured.
Secondary adrenal insufficiency (hypopituitarism)
is distinguished from tertiary adrenal insufficiency
(CRH deficiency) by giving CRH and measuring the
Tests of the stress response assess the hypothalamic component of the axis and, therefore, potentially, the complete HPA axis. A satisfactory rise in plasma cortisol and ACTH in response to insulin-induced hypoglycaemia indicates a normally functioning axis.
Aldosterone is a mineralocorticoid and the other main product of the adrenal cortex. It is produced in the zona glomerulosa and is predominantly under the control of the renin-angiotensin mechanism. ACTH, hyponatraemia,
hyperkalaemia play a minor role in aldosterone
Decreased renal blood flow (haemorrhage, renal artery narrowing, dehydration) increases plasma renin levels.
Renin is produced in the juxtaglomerular apparatus
of the renal cortex and is released by three main
• Reduction in renal perfusion pressures via
baroreceptors in the afferent arterioles;
• Renal sympathetic nerve activity; and
• Sodium concentration in tubular fluid sensed by
the macula densa.
Renin cleaves angiotensinogen, which is secreted
by the liver, to form angiotensin I.
Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE) mainly in the lungs.
Angiotensin II cleavage produces Angiotensin III. All have inotropic and vasoconstrictive actions.
Angiotensin III has greater activity than angiotensin II for stimulating aldosterone synthesis but only 20% of the pressor activity.
Angiotensin II and III increase aldosterone production. Aldosterone binds to a receptor in its target tissues and promotes active sodium transport and excretion of potassium. Its secretion results in sodium retention and increased plasma volume.
Treatment of hypertension
The treatment of hypertension may include the use
of two drugs that modify mineralocorticoid physiology.
1) The first, spironolactone, is an aldosterone antagonist– it competes for the aldosterone receptor sites – and is, therefore, used as a K+ sparing diuretic and in hyperaldosteronism.
2) The second, a group of drugs inhibiting
the angiotensin converting enzyme – ACE inhibitors.
3) One of their most potent effects is vasodilatation within the kidney – especially in the efferent arterioles of the glomerulus. They are effective in patients with renal hypertension and in diabetic patients with hypertension,
promoting a more favourable outlook for diabetic
However, a reduction in efferent
arteriolar tone and a fall in intraglomerular pressure
may be associated with adverse outcome, i.e. acute renal failure in patients with renal artery stenosis.
Investigating mineralocorticoid status
Primary hyperaldosteronism is associated with hypokalaemia.
High plasma aldosterone levels and a suppressed plasma renin activity in association with an increased urinary potassium excretion confirm the biochemical diagnosis.
Cross-sectional imaging and selective venous catheterisation of adrenal veins to identify aldosterone gradients can confirm the morphological abnormality.
In secondary hyperaldosteronism (congestive heart failure, cirrhosis, nephrotic syndrome,
and renal artery stenosis) the high aldosterone is associated with a high plasma renin activity.
Isolated adrenal hypoaldosteronism is rare.
Sex hormone secretion
DHEA, DHEAS and androstenedione are converted to biologically active metabolites – dihydrotestosterone testosterone – in peripheral tissues.
In men testosterone is mainly produced in the testis; in women by peripheral conversion. ACTH plays a role; plasma androgens parallel the circadian rhythm of cortisol.
Very small amounts of oestrone and oestradiol are secreted. In premenopausal women most oestrogens are produced by the ovary.
The peripheral conversion of androgens to oestrogens in adipose tissue by aromatase enzymes accounts for circulating oestrogen levels in men and post-menopausal women.
Addisons disease: Primary causes
Addison’s disease, a cause of primary adrenocortical insufficiency was described in the mid-19th century when the commonest cause of the condition was tuberculosis which is now rare.
Other causes include metastatic cancer (lung, breast), haemorrhage into the adrenals (anticoagulants, meningococcal septicaemia), and an autoimmune disorder – polyglandular autoimmune syndrome.
Addisons disease: Secondary causes
Secondary insufficiency is due to hypopituitarism resulting from destructive lesions of the pituitary (tumour, TB, histoplasmosis, hypophysitis, infarction) or cerebral trauma.
Addisons disease: Tertiary causes
The most common cause of tertiary insufficiency is exogenous pharmacological glucocorticoid therapy which results in suppression of ACTH production.
Other causes include tumour and cranial irradiation. After cure of Cushing’s syndrome (ACTH dependent or ACTH independent) adrenocortical tissue will be suppressed as occurs following exogenous steroid treatment.
Symptoms and signs of adrenal insufficiency
Signs and symptoms do not appear until 90% of cortical tissue is destroyed. In the acute scenario there will be hypotension, shock, nausea and vomiting.
Abdominal pain, confusion, fever, electrolyte imbalance and hypoglycaemia can occur. Immediate treatment with intravenous fluids and parenteral hydrocortisone is necessary.
In addition to those symptoms and signs described
above, patients may have facial plethora, acne,
hirsutism, thirst, urinary tract calculi, a loss of bone
density and glucose intolerance or frank diabetes.
Chronic primary adrenal insufficency
In patients with chronic primary adrenal insufficiency, symptoms and signs of glucocorticoid, mineralocorticoid, and in women, androgen deficiency may be present. These include malaise, weakness, weight
loss and anorexia. Abdominal pain and gastrointestinal symptoms are common. The striking feature of primary adrenal insufficiency will be skin pigmentation (and pigmentation of mucosa). This arises because
ACTH shares a shared subunit sequence with melanocyte stimulating hormone and binds to its receptors.
Adrenal insufficiency treatment
Replacement therapy with hydrocortisone and
fludrocortisone is required. Patients with secondary
and tertiary insufficiency usually maintain adequate
mineralocorticoid function. Any patient on (or with a
recent history of) long-term glucocorticoid treatment
(including some topical steroid-containing preparations) will almost certainly have suppressed ACTH levels or limited functional reserve. They will be at risk of an acute adrenal crisis when subjected to stress – such as an emergency or elective surgical procedure.
These patients will need additional perioperative
glucocorticoid cover and careful evaluation of hydration, serum electrolytes and blood pressure.
When Cushing’s syndrome is confirmed and the
cause identified, definitive treatment is indicated.
Adrenocortical adenoma or carcinoma is treated
Malignant disease of the adrenal
cortex has a poor prognosis; the tumours are often
large, locally invasive and have metastasised before
the diagnosis is made.
Nodular adrenal hyperplasia
may require bilateral adrenalectomy. Patients with
Cushing’s disease are treated with pituitary surgery
Medical treatment with:
1) Metyrapone (blocks the final step in cortisol synthesis)
2) ketoconazole (acts mainly on the initial step of cortisol synthesis) is used prior to surgery in some
patients and when pituitary surgery fails.
3) Bilateral adrenalectomy is sometimes required in patients with ACTH dependent Cushing’s if surgical treatment is unsuccessful or, a source of ectopic ACTH cannot be identified. Hyperpigmentation (Nelson’s syndrome) may develop in patients with Cushing’s disease with continued ACTH production after bilateral adrenalectomy.
4) Patients must be maintained on cortisol (and
fludrocortisone after bilateral adrenalectomy) after
successful treatment of hypercortisolism until biochemical tests confirm full recovery of the HPA axis.
Bilateral adrenalectomy is without effect in terms of
adrenomedullary hypofunction. Autonomic failure or
neuropathy is especially important in diabetes mellitus. There may be severe problems with postural hypotension; the symptoms of hypoglycaemia may be masked.
This is usually (80%) caused by a unilateral adrenal
adenoma, i.e. Conn’s syndrome, most of the remaining cases by bilateral hyperplasia of the zona glomerulosa.
Primary hyperaldosteronism accounts for at least
1% of cases of hypertension. The syndrome is associated, with hypertension (due to Na+ and water retention), hypokalaemia and metabolic alkalosis (caused by the intracellular shift of H!, and a loss of H+ in the kidney).
Symptoms include headache, muscle weakness,
tiredness and polyuria. Medical treatment with
spironolactone is indicated.
Primary hyperaldosteronism: Treatment
Adrenalectomy is indicated for patients with an adenoma when hypertension proves difficult to control or, when side effects of medical treatment are severe.
Bilateral adrenalectomy is not used in the treatment of bilateral hyperplasia.
Virilising and feminising tumours are rare and usually malignant. Congenital adrenal hyperplasia (CAH) is an inherited disorder of cortisol synthesis.
Signs of androgen excess in adrenal disease are due to androgenic cortisol precursors or DHEAS.
The adrenal medulla (10% of adrenal mass) mainly
comprises of chromaffin cells. Pre-ganglionic sympathetic nerve fibres contribute to the splanchnic nerves that innervate the adrenal medulla.
The chromaffin cells synthesise catecholamines–adrenaline and noradrenaline from tyrosine via dopa and dopamine to noradrenaline and thence adrenaline. Once produced, the hormones are stored as granules – causing the typical appearance of the chromaffin cells. The
medulla produces adrenaline (‘epinephrine’) predominantly and, to a much lesser extent, noradrenaline (‘nor-epinephrine’).
Catecholamine release from chromaffin cells occurs as a result of cholinergic discharge from synapses of the preganglionic sympathetic nerve fibres.
Hypoglycaemia, anoxia, pain, haemorrhage
and many other factors stimulate the release of adrenaline and noradrenaline. On release, catecholamines are taken up by sympathetic nerve endings, excreted by the kidneys or, converted to inactive metabolites by monoamine oxidase and catechol 0-methyltransferase enzymes. Resultant breakdown products – hydroxy methyl mandelic acid (VMA), metanephrines and normetanephrines – are excreted in urine.
Catecholamine mode of action
Table pg 471
Catecholamines mediate their effects through alpha
and beta adrenergic receptors. Each is divided into two subgroups; the receptors are widely distributed the adrenergic response is dependent on the receptor type present within the tissue.
Adrenaline and noradrenaline are agonists of alpha receptors which mediate vasoconstriction; phentolamine and phenoxybenzamine
are alpha receptor antagonists (alpha blockers).
Alpha1 receptors are postsynaptic; activation results in smooth muscle contraction, i.e. uterus and blood vessels.
Alpha2 receptors are found widely on platelets and
within the nervous system; on presynaptic sympathetic neurones – where activation inhibits noradrenaline release – and on cholinergic neurones within the gut; activation inhibits acetylcholine release. Insulin secretion is reduced.
CNS Alpha 2 receptors mediate vasoconstriction.
Beta1 receptors are found in cardiac tissue
and, when stimulated, cause a rise in the force and
rate of myocardial contraction.
Beta 2 receptors, when stimulated, generally cause smooth muscle relaxation and glycogenolysis: they are found in blood vessels, the uterus and the bronchioles.
Noradrenaline is a potent agonist of Beta 1 receptors, but a weak agonist of Beta 2 receptors.
Propanolol is a non-selective " receptor
antagonist (beta blocker). Metoprolol is a selective
Beta 1 receptor antagonist. Beta 3 receptors are found in fat and are associated with increased lipolysis.
Investigating elevated catecholamines
In clinical practice, the possibility of excess catecholamine secretion is investigated by the measurement of any combination of urinary VMA, urinary metanephrines, normetanephrines and fractionated catecholamines in a 24-hour collection.
Plasma catecholamines and metanephrines are not assessed in routine diagnostic testing. When hypersecretion of catecholamines is confirmed, CT or MRI is used to localise the catecholamine secreting tumour.
123I-MIBG (metaiodobenzylguanidine) scintiscan confirms that a mass seen on cross-sectional imaging is a phaeochromocytoma.
1) Phaeochromocytoma is a rare tumour. It arises
in the adrenal medulla (90%) or in extra adrenal
chromaffin tissue of the sympathetic nervous system (paraganglioma).
2) The tumour can occur at any age
as a sporadic tumour or as part of an inherited syndrome such as:
a) MEN 2
b) von Hippel Lindau disease
c) Neurofibromatosis Type1
d) Familial Paraganglioma syndromes
Symptoms and signs of phaeochromocytoma
The symptoms of phaeochromocytoma include headache, sweating, palpitations, anxiety and
Signs include hypertension (90%), tachycardia,
hyperglycaemia, occasionally as acute cardiovascular collapse.
Catecholamine secretion may be intermittent
or continuous; it may be provoked by drugs such
as glucagon or opiates. Phaeochromocytoma may be multiple, bilateral, malignant.
1) Surgery is the treatment of choice.
2) Anaesthesia and or manipulation of the tumour can cause profound cardiovascular responses due to catecholamine secretion; the physiological response must be fully controlled before surgery is performed.
3) Prior to operation the patient is given an alpha blocker at increasing dose until signifi cant postural hypotension occurs indicating alpha blockade is complete.
4) A beta blocker is used if the patient develops a tachycardia but only when alpha blockade is adequate because of the risk of hypertensive crisis.
5) Once the tumour is removed, unopposed vasodilatation may require that a large volume of intravenous fluid is given to fill the expanded vascular compartment.
6) Hypoglycaemia may occur.
Insulin is formed from the conversion of preproinsulin to proinsulin in the endoplasmic reticulum of the beta cell.
Proinsulin consists of an amino-terminal
beta chain, a carboxy-terminal alpha chain and a connecting peptide, C-peptide.
Within the endoplasmic reticulum, proinsulin is exposed to peptidases which excise the C-peptide, generating insulin. Insulin is stored in secretory granules. When the beta cell is stimulated,
it is secreted by exocytosis and diffuses into islet
capillary blood. C-peptide is also secreted, but has no known biological activity.
Insulin is released into the portal circulation; half
will be removed by the liver. Insulin is unbound in
the plasma; it has a short half-life of approximately
five minutes and is predominantly broken down in the kidney. Patients with developing end-stage diabetic nephropathy usually require less insulin than before the nephropathy developed.
1) Glucose is the most important stimulus to insulin
2) Carbohydrate ingestion or a rise in the blood sugar is associated with a rise in circulating insulin.
3) A fall in blood sugar levels to the lower end of the normal range is associated with rapid fall in insulin secretion and levels.
4) Amino acids stimulate insulin release, as do some fatty acids. Alpha-adrenergic stimulation also reduces insulin secretion.
5) Insulin has a direct inhibitory effect on the pancreatic alpha (glucagon-producing) cells, i.e. a paracrine action. Reduced insulin secretion causes increased glucose production and decreased utilisation and is associated with a rise in blood glucose levels.
Insulin action: cell surface
Insulin receptors are found on the cell membranes
of fat, liver and muscle cells. When insulin binds to
the receptor, the receptor-insulin complex undergoes autophosphorylation which then stimulates glucose transporter systems permitting diffusion of glucose into the cell.
It is known that the insulin-receptor complex becomes incorporated into the cell. Once inside the cell the complex is broken down; whether
the insulin then remains active or is simply metabolised and broken down is not known.
Insulin action: Intracellularly
Insulin activates the transport of glucose, potassium
ions and amino acids, promotes glycogen synthesis and glycolysis and inhibits glycogenolysis and gluconeogenesis.
Insulin and muscle
Within muscle insulin, independent of glucose
metabolism, favours the uptake of amino acids
into skeletal muscle and proteins.
Insulin and fat
Insulin acts on fat cells in several ways: it increases glucose transport into the cells and thus increases triglyceride synthesis; it induces lipoprotein lipase activity which acts to break
down circulating chylomicrons to free fatty acids and glycerol – these in turn are taken up by fat cells and reconverted back again to triglycerides.
Insulin also inhibits the breakdown of triglycerides within adipocytes.
Insulin and electrolytes
Insulin reduces extracellular K+ levels by producing
an intracellular shift of K+. This property of insulin is
used in the treatment of hyperkalaemia – for example, in acute renal failure, shock and septicaemia – an infusion of insulin and glucose lowers the extracellular K+ concentration. A low K+ concentration inhibits insulin
secretion – thus any condition, or drug therapy,
which results in a low K", may cause deterioration in blood sugar control.
Glucagon, a polypeptide molecule of 29 amino acids is produced by the pancreatic alpha cell and has a major role in the control of blood glucose causing a rise in the blood sugar. The most potent stimulus to glucagon release is hypoglycaemia. It is secreted into the hepatic portal circulation and rapidly activates glycogenolysis and gluconeogenesis and the production of ketone bodies. Glucagon inhibits glycolysis. Glucagon secretion is suppressed by high glucose levels in blood, increased insulin and somatostatin levels. It is increased by catecholamines, cortisol and growth hormone.
Somatostatin is produced in the delta cells of the
pancreatic islets. It is also produced in the gut and
found widely in brain tissue where it regulates growth hormone and TRH. It has a suppressive paracrine effect on glucagon and insulin. Somatostatin analogues are used to reduce pancreatic exocrine secretions in patients with pancreatic fistulae.
Pancreatic polypeptide (PP) is produced by PP cells; its physiological role is unknown. It is produced by some pancreatic endocrine tumours; blood levels of PP are used for screening patients with MEN 1 for pancreatic endocrine tumours.
This is uncommon except in patients treated with insulin for diabetes. Because glucose is essential for central nervous system function there are regulatory mechanisms to ensure blood glucose levels are maintained within a physiological range. Low glucose levels are associated with inhibition of insulin. Conversely, glucagon, adrenaline, growth hormone and cortisol secretion lead to a rise in blood sugar.
Hypoglycaemia may be fasting/drug mediated (insulin, sulphonylureas, alcohol), illness (hepatic disease, renal disease, sepsis), hormone defi ciency (cortisol), endogenous hyperinsulinism (insulinoma), autoimmune disorders or reactive (post-prandial).
Reactive hypoglycaemia after gastric drainage procedures is well recognised and is of importance in surgical practice. The stomach drains rapidly after a meal, presenting the small bowel with a high carbohydrate load: rapid absorption of carbohydrate occurs and high levels of insulin are produced with resultant hypoglycaemia. This problem is known as ‘dumping’.
Symptoms of hypoglycaemia
Patients with a low blood sugar level present with
similar symptoms regardless of the cause (autonomic effects and neuroglycopaenia).
Autonomic manifestations include sweating, hunger
and parasthesiae (cholinergic mediated), tremor, palpitations and tachycardia (catecholamine mediated).
Diabetic patients with an intact autonomic nervous
system rely on these early symptoms to warn of
developing hypoglycaemia. Diabetics with autonomic neuropathy may not be aware of impending hypoglycaemia. Brain deprivation of glucose (neuroglycopaenia) is manifest as confusion, drowsiness, speech difficulty, double vision, incoordination, unusual behaviour and other severe effects that may include seizure coma and death. Patients may also have malaise
including nausea and headache.
Treatment of hypoglycaemia is urgent. If the patient
is conscious, then oral glucose may be given; if unconscious, intravenous glucose should be given, i.e. 50 mL of 50% dextrose over two to three minutes. The unconscious diabetic at home should be given glucagon by a family member if it is feasible to do so.
Failure to treat severe hypoglycaemia urgently may result in death or permanent brain damage. Unconscious patients who present to hospital with no evidence of trauma and patients with intermittent attacks of impaired consciousness – for example, patients alleged to have ‘temporal lobe epilepsy’ – should have glucose estimations done during an attack. They may have an insulinoma.
1) Diabetes mellitus
2) Cushing’s syndrome (including corticosteroid treatment)
Some drugs are associated with impaired glucose tolerance, e.g. thiazide diuretics.
1. symptoms and random plasma glucose
> 11.1 mmol/l (>200 mg/dl);
2. fasting plasma glucose > 7.0 mmol/l (>126 mg/dl)
3. 75 g OGTT, 2-hour plasma glucose > 11.1 mmo/l
Type 1 diabetes
The pathogenesis of Type 1 diabetes includes genetic and environmental factors; susceptibility to type I diabetes is linked to certain HLA antigen alleles. In some individuals, a viral infection such as Coxsackie or mumps, which are known to be ! cell toxic, may initiate the disease.
There is strong evidence that Type 1 diabetes is a cytokine mediated autoimmune disease.
Type 2 diabetes
Type 2 diabetes is more common than Type 1 disease; it has a genetic component (an increased risk of the disease in family members), environmental factors (obesity and calorie intake) also contribute to its pathogenesis.
Type 2 diabetes is associated with peripheral
insulin resistance, hyperinsulinaemia and subsequent failure of beta cell function.
Type 2 diabetes varies from an asymptomatic
disorder diagnosed on routine examination to an
acute presentation precipitated by intercurrent
illness. Hyperosmolar non-ketotic coma is the
most severe hyperglycaemic consequence of Type 2 diabetes and is characterised by marked hyperglyaemia (usually "50 mmol/l) and dehydration, without significant ketosis and acidosis. It usually occurs in middle-aged or elderly patients, two-thirds of whom have previously undiagnosed diabetes. Precipitating causes include infection, diuretics and consumption
of large quantities of glucose rich drinks.
Treatment of patients with Type 1 diabetes includes
insulin and diet; in Type 2 diabetes, weight reduction, diet, oral hypoglycaemic agents, insulin, alone or in combination.
Oral hypoglycaemic agents
The oral hypoglycaemic drugs include sulphonylureas that act by stimulating insulin secretion from the beta cells of the pancreas and the biguanides, which appear to block hepatic gluconeogenesis and slightly improve insulin sensitivity.
Other oral agents include:
inhibitors of alpha glucosidase that reduce carbohydrate absorption; the thiazolidinediones which act on the nuclear receptor PPARgamma to reduce insulin resistance and improve tissue sensitivity to insulin; and the postprandial
glucose regulators which increase insulin
secretion after meals.