Endocrinology Flashcards

Question

Which key anatomical structure lie close to the thyroid gland?

Answer 1

The thyroid gland is very close to other very important structures. There are two (superior and inferior) parathyroid glands on the back of each lobe of the thyroid, which produce the parathyroid hormone responsible for calcium metabolism. The thyroid is also in close proximity to the recurrent laryngeal nerve, the nerve supplying vocal cords. Operations to remove the thyroid gland (thyroidectomy) must be done very delicately as they risk damage to both the recurrent laryngeal nerve and the parathyroid glands.

Answer 2

Embryologically, the thyroid gland originates from midline of the pharynx (near the base of the tongue). A thyroglossal duct then develops, descending from the tongue down, before dividing into two lobes. The duct then disappears leaving the Foramen caecum, an embryological remnant, seen as a very small dot at the back of the throat. The thyroid arrives at its final position within the neck by week 7 of gestation, after which the actual gland develops.

Answer 3

The colloid is found at the centre of follicles, adjacent to follicular cells. Within each follicular cell, is a nucleus and lysosomes. Blood vessels lie in close proximity to the follicular cells, whose cell membrane contains a Thyroid Stimulating Hormone receptor (TSH-R). 1) The TSH arrives through the systemic circulation, via the blood, and binds specifically to TSH-R on the follicular cell. 2) Simultaneously, sodium (Na+) and iodide (I-) ions arrive via the blood, entering the follicular cell via the sodium-iodide co-transporter. 3) The iodide ions are taken in cross the follicular cell and they go through the transporter on the other side of the cell, and into the colloid. 4) When TSH binds TSH-R, a prohormone called thyroglobulin (TG) is released and enters the colloid, whilst the thyroid peroxidase enzyme (TPO) is also activated. This enzyme is important in the production of the thyroid hormone as it acts alongside hydrogen peroxide to catalyse the two iodination reactions in the colloid. 5) In the first iodination reaction, iodide ions are oxidised to yield iodine (catalysed by TPO+H2O2). 6) The iodine is then reacted with TG, in a second iodination reaction (catalysed by TPO+H2O2), to give monoiodotyrosine (MIT) and diiodotyrosine (DIT). 7) MIT and DIT, joined together by a coupling reaction (catalysed by TPO+H2O2), give thyroid hormone (T3 and T4), still bound to TG. 8) The thyroid hormone then enters the cell where, in lysosomes, the protein bonds are broken down, allowing T3 and T4 to enter the bloodstream and leave TG behind.

Answer 4

Tyrosine is an amino acid with an aromatic ring, of which there are ~100 tyrosine residues, but only ~20 have the capability of being iodinated, meaning that an iodine group can be added to them.

Answer 5

3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT) can be produced by iodinating tyrosine. Joining 3-monoiodotyrosine (MIT) and 3,5-diiodotyrosine (DIT) by a coupling reaction gives 3,5,3’-tri-iodothyronine (T3), which is the active thyroid hormone. Joining DIT with another DIT gives a different type of coupling reaction producing 3,5,3’,5’-tetra-iodothyronine (T4), also known as Thyroxine.

Answer 6

Essentially, the only difference between the T3 and T4 is the absence of the iodide group at position 5’ in T3.

Answer 7

Thyroxine (T4) is the main prohormone product of the thyroid gland, only being deiodinated by deiodinase enzymes to T3, its bioactive metabolite form, providing almost all of the thyroid hormone activity in target cells. Only 20% of circulating T3 comes directly from secretion from the thyroid gland, the remaining 80% comes from the deiodination of T4. Reverse T3 is an inactive form of T3 that occurs when T4 is deiodinated at the position.

Answer 8

The vast majority of thyroid hormone is transported in the blood, bound to plasma proteins. 70-80% of thyroid hormone is bound to the plasma protein Thyroid-binding Globulin (TBG). 10-15% of thyroid hormone in the blood is bound to the plasma protein Albumin. Some thyroid hormone is also bound to Prealbumin/Transthyretin. Only 0.05% of T4 and 0.5% of T3 is unbound, meaning that they are free to act as bioactive agents in the target tissues.

Answer 9

T3 and T4 effect gene expression by entering the cell within the target tissue, through their respective receptors. The T4 is deioidinated by deiodinase enzymes, within the cell, converting it to the active thyroid hormone T3. T3 then enters the nucleus, containing the Thyroid Responsive Element (TRE), binding to the Thyroid Hormone Receptor on its surface. This allows it to alter gene expression, by activating or repressing gene transcription.

Answer 10

Cretinism is a condition of untreated congenital hypothyroidism, arising from either a complete lack of a thyroid gland or a lack of any thyroid hormone that functions or poorly developed thyroid hormone. Babies with the condition appear unhappy, drowsy and quite puffy. A heel prick test is done at 5 days of age, allowing a few drops of blood to be removed. The blood can then be used to detect Phenylketonuria (PKU), an inborn error of metabolism, as well as for a measurement of TSH, to determine the presence of an under active thyroid. A high level of TSH could suggest congenital hypothyroidism and thankfully lifelong thyroid hormone replacement treatment is available. When the baby is in utero, thyroid hormone, from the mother, crosses the placenta, protecting it while it is growing. Hence, the thyroid hormone deficiency only becomes apparent when the baby is delivered.

Answer 11

Autoimmune damage to the thyroid reduces its ability to produce T4 and T3, and as a result thyroxine levels drop; hence, the anterior pituitary is stimulated to release TSH, causing its levels to climb.

Answer 12

The thyroid hormone increases basal metabolic rate, meaning the amount of energy or calories that every cell in the body requires to function. It also effects metabolism by increasing glucose absorption, glycogenolysis, gluconeogenesis and fat metabolism. As well as this, the thyroid hormone can also affect the sympathetic nervous system, by potentiating the reactions of catecholamine and thus raising cardiac output. It also has effects on the gastrointestinal (GI) tract and the maturation of the CNS, as well as bone maturation.

Answer 13

The half-life of T4 is ~7 days ad ~2 days for T3.

Answer 14

The Hypothalamus-pituitary-thyroid axis is important because it allows the production of thyroid hormone to be controlled by negative feedback. The TRH released from the hypothalamus tells the anterior pituitary to release TSH, which is released into circulation. It the acts on the thyroid gland to stimulate the release of T3 and T4, and when there's sufficient T3 and T4, signals are sent back to both the hypothalamus and anterior pituitary, switching them off. Somatostatin, produced in the hypothalamus, can inhibit the production of TSH. Large quantities of iodide can inhibit the production of T3 and T4, known as the Wolff-Chaikoff effect. In fact, potassium iodide is sometimes used to treat hyperthyroidism.

Answer 15

Women are more predisposed to thyroid disorders (4:1 ratio) than men, as their immune systems have had to evolve to carry babies, who carry a wide range of antigens, that women are exposed to. This had made their immune systems slightly different to men’s and thus more predisposed to autoimmune diseases, such as thyroid disorders.

Answer 16

The incidence of hypothyroidism and hyperthyroidism is exactly the same.

Answer 17

The most common forms of autoimmune thyroid disease are Hashimoto's thyroiditis, usually associated with hypothyroidism, and Graves' disease, usually associated with hyperthyroidism, but in rare cases can also cause hypothyroidism.

Answer 18

The presence of one autoimmune disease increases the risk of others. For instance, patients with vitiligo or pernicious anaemia, which are other autoimmune conditions not specifically related to thyroid, are going to be more at risk of developing autoimmune thyroid disease than the general population.

Answer 19

Levothyroxine is a synthetic tablet of T4 that can be deiodinated in exactly the same way and to produce T3.

Answer 20

Levothyroxine is mainly prescribed for hypothyroidism, but it is also prescribed for hyperthyroidism.

Answer 21

For hyperthyroidism, anti-thyroid drug, called Carbimazole, can be prescribed, that stops any production of thyroid hormone. Hence, a “block and replace” regimen is used, wherein, a high dose of Carbimazole is used, to block all thyroid hormone production, then Levothyroxine is given to replace the thyroid hormone lost.

Answer 22

The amount of Levothyroxine given depends on the amount of TSH and T4 found during the blood test. In a patient presents with hypothyroidism high TSH and low T4 levels would be expected. A prescription of levothyroxine would be given, and ~ 3 months later blood tests would be repeated. At that stage, hopefully, the thyroid hormone levels have gone and the TSH levels have come back into the normal range. The most common dose of Levothyroxine is ~ 100 micrograms but may be lower in very elderly patients or those at risk of ischemic heart disease. It is usually administered orally and only in emergency situations, like a myxoedema coma, that intravenous thyroid hormone replacement is considered.

Answer 23

Complications and side effects of Levothyroxine are very rare. Minor complications arise when the thyroid hormone replacement is overdone, which may cause weight loss and headaches. A major complication may be tachycardia (a rapid heart rate, which may cause a heart attack, but these are incredibly rare.

Answer 24

T3 is not usually prescribed to patients as there's no evidence that it works any better than T4, and it is much more expensive to manufacture. Additionally, target tissues have your deiodinase capable of deiodinating T4 into T3. However, there are reports in the literature that combining both T3 and T4, may cause some people feel to better. However, patients may render themselves thyrotoxic and symptoms such as: palpitations, tremors, anxiety. This is because, often when you give T4 and T3 together TSH may be suppressed as anterior pituitary thyrotroph cells are switched off, due to an excess of thyroid hormone.

Answer 25

Graves' disease is an autoimmune disease that causes antibodies to bind and stimulate the TSH receptor in the thyroid, causing the whole gland to enlarge and nodules that appear for no specific reason. Normally TSH receptors in follicular cells, in the thyroid, are stimulated by the arrival of TSH from the anterior pituitary, but antibodies can develop that bind and stimulate this receptor. This results in the TSH receptor being activated, resulting in the overproduction of T4 and T3, causing a smooth toxic multi nodular goitre. Other antibodies bind to muscles behind the eye, causing Exophthalmos (bulging eyes), whilst others stimulate the growth of soft tissue on shins causing Pretibial myxoedema.

Answer 26

Untreated hypothyroidism is an endocrine emergency that often presents symptoms of anxiety, dry eyes, heat intolerance, myopathy (muscle weakness), mood swings, diarrhoea and palpitations. Clinical features include a smooth goitre, a smooth enlargement of your thyroid gland, weight loss, tremoring hands, exophthalmos (bulging eyes) and pretibial myxoedema (thick, red skin).

Answer 27

The adrenal glands are located above the kidneys.

Answer 28

The left adrenal gland connects to the left adrenal vein , which drains into the renal vein. The right adrenal artery connects to the right adrenal vein, which drains into the inferior vena cava (IVC). Both adrenal glands are supplied by many (57) arteries, but each is supplied by only one adrenal vein.

Answer 29

In the centre of each adrenal gland, lies the adrenal medulla, composed of neuroendocrine/chromaffin cells. Outside the adrenal medulla, lies the adrenal cortex, composed of 3 different layers: 1) Zona reticularis: a thin layer, surrounding the adrenal medulla 2) Zona fasciculata: a thick layer, surrounding the zona reticularis 3) Zona glomerulosa: the outer most layer of the adrenal gland

Answer 30

The adrenal medulla is derived from the ectodermal exclusively secretes catecholamines. 80% of the catecholamine that it secretes is adrenaline/epinephrine. The remaining 20% is noradrenaline/norepinephrine, “nor-“ meaning without a methyl group. Catecholamines are stored in the cytoplasmic granules and released in response to acetylcholine (Ach) from preganglionic sympathetic neurons.

Answer 31

1) Tyrosine is the precursor for these catecholamines. Oxidising (add O2) tyrosine produces dihydroxyphenylalanine (DOPA). 2) Decarboxylating (removing CO2) DOPA produces dopamine, which is important for blood pressure control. 3) Dopamine is then converted to noradrenaline/norepinephrine. 4) Methylating (adding “-CH3” methane group) noradrenaline/norepinephrine produces adrenaline/epinephrine.

Answer 32

Adrenaline/epinephrine plays a role in blood pressure control, as well as the “fight or flight” response, as it causes heart rate to increase, as well as sweating.

Answer 33

The adrenal cortex makes three groups of steroids. The zona glomerulosa makes mineralocorticoids, the key one in humans being aldosterone. The zona fasciculata makes glucocorticoids, which mainly impact glucose metabolism, such as cortisol, as well as some sex steroids, such as androgens (“male” sex hormones) and oestrogen (female sex hormone). However, most sex hormones come from the sex organs (the ovaries and testes).

Answer 34

The zona fasciculata is so much larger than the zona glomerulosa, as there is much more cortisol in blood than aldosterone. Cortisol is measured in nanomoles per litre (nmol/L) whereas aldosterone is measured in picomoles per litre (pmol/L), as there is 100x more cortisol in circulation, than aldosterone. The zona reticularis is disappearing in humans, but also contributes to the production of cortisol.

Answer 35

When the adrenal cortex is magnified, a capsule can be seen on the outside. The zona glomerulosa and zona fasciculata look very similar under direct microscopy, until they’re stained which allows the difference in their cellular structures to be better seen.

Answer 36

The precursor of all adrenal cortex secretions is cholesterol, so a steroid is a hormone which is based on the cholesterol molecule. Cholesterol traditionally has numbers, which are used to label the enzymes that convert cholesterol into the steroids hormones.

Answer 37

An enzyme is a protein that catalyses a specific reaction and there are many different enzymes. Specific enzymes catalyse the synthesis of particular alterations to a molecule.

Answer 38

A fall in blood pressure is detected by: 1) Decreased renal perfusion pressure (normally associated with decreased arterial blood pressure). 2) Increased renal sympathetic activity (direct to Juxtaglomerular apparatus cells which secrete renin) 3) Decreased sodium (Na+) load to the top of the loop of Henle (Macula Densa cells, above which sit the Juxtaglomerular apparatus cells).

Answer 39

When blood pressure is high, renin is suppressed, but when blood pressure begins to fall, renin is released into the circulation. Renin acts by switching on a cascade that converts a basic protein called Angiotensinogen, produced in the liver, into the protein Angiotensin I. Angiotensin Converting Enzyme (ACE) then converts this to Angiotensin II. Angiotensin II regulates aldosterone release from the adrenal glands, by switching on the 5 enzymes in the zona glomerulosa needed to produce aldosterone from cholesterol.

Answer 40

1) When making aldosterone (a mineralocorticoid), the cholesterol side chain is cleaved off, by the cholesterol side-chain cleavage enzyme (P450scc), forming pregnenolone. 2) Pregnenolone is then dehydrogenated (oxidised) in position 3, containing the “-OH” group, to a ketone called progesterone, by the enzyme 3beta-hydroxysteroid dehydrogenase (3b-HSD). Progesterone is generally a hormone that comes from the ovary, but it also a precursor of other steroids, in the adrenal gland. 3) Progesterone is then hydroxylated (“-OH” group added), in position 21, using the enzyme 21 Hydroxylase, forming the hormone 11 deoxycorticosterone. 4) 11 deoxycorticosterone is itself then hydroxylated in position 11, forming corticosterone, by the enzyme 11 hydroxylase. 5) Finally, corticosterone is hydroxylated in position 18, using the enzyme 18 hydroxylase, to form aldosterone.

Answer 41

Aldosterone stimulates sodium (Na+) reabsorption in the distal convoluted tubule and the cortical collecting duct of the kidneys (as well as in sweat glands, gastric glands and the colon): 1) Sodium leaves the urine filtrate, while aldosterone switches on sodium/potassium-ATPase. 2) This causes potassium (K+) to be excreted into the urine filtrate, as sodium and water are reabsorbed into the blood. 3) This raises the blood volume, thus maintaining blood pressure, for instance after being stabbed.

Answer 42

Cortisol is a stress hormone, helping to maintain survival by changing the energy is used.

Answer 43

It has weak mineralocorticoid effects, but has several metabolic effects, including: 1) Peripheral protein catabolism (break down) 2) Hepatic gluconeogenesis 3) Increasing blood glucose concentration 4) Fat metabolism (lipolysis in adipose tissue) 5) Enhanced effect of glucagon and catecholamines (adrenaline) It also has some renal and cardiovascular effects, such as: 1) Excretion of water load, to maintain blood pressure 2) Increased vascular permeability

Answer 44

1) When making cortisol (a glucocorticoid), the cholesterol side chain is cleaved off, by the cholesterol side-chain cleavage enzyme (P450scc), forming pregnenolone. 2) Pregnenolone is then dehydrogenated (oxidised) in position 3, to a ketone called progesterone, by the enzyme 3beta-hydroxysteroid dehydrogenase (3b-HSD). 3) Progesterone is then hydroxylated in position 17, using the enzyme 17 Hydroxylase, forming the hormone 17 hydroxy-progesterone. 4) 17 hydroxy-progesterone is itself then hydroxylated in position 21, forming 11 deoxycortisol, by the enzyme 21 hydroxylase. 5) Finally, 11 deoxycortisol is hydroxylated in position 11, using the enzyme 11 hydroxylase, to form cortisol.

Answer 45

Cortisol plays an important role for waking up in the morning, when its levels in the body are highest. Its levels fluctuate throughout the remainder of the day, and are lowest at midnight, creating a circadian rhythm.

Answer 46

Cortisol is regulated by the Adrenocorticotropic Hormone (ACTH), from the anterior pituitary gland. This allows a negative feedback loop on the hypothalamo-pituitary-adrenal axis, as cortisol supresses ACTH production in the anterior pituitary and Corticotrophin-releasing Hormone (CRH) production in the hypothalamus.

Answer 47

Addison’s disease is an autoimmune disease where the immune system destroys the adrenal cortex, resulting in primary adrenal failure. This leads to cortisol and aldosterone deficiency. Lack of cortisol or aldosterone also leads to low blood pressure, as salt is lost, which can be fatal if left untreated. Tuberculosis of the adrenal glands in the most common cause of Addison’s disease worldwide. Addison’s disease often coexists with autoimmune vitiligo (white patches of skin).

Answer 48

1) Patients with Addisonian crisis are usually rehydrated with saline. 2) They are then given some sugar in the form intravenous dextrose, to prevent hypoglycaemia, which could be due to glucocorticoid deficiency. 3) Patients can also be given hydrocortisone or another glucocorticoid, such as Prednisolone a glucocorticoid analogue.

Answer 49

Pro-opio-melanocortin (POMC) is a large precursor protein that is cleaved to form a number of smaller peptides, including ACTH, Melanocyte-stimulating hormone (MSH) and endorphins. Thus, when the adrenal gland fails and the anterior pituitary gland begins secreting lots of (ACTH), MSH, which causes pigmentation of the skin (tanning), is simultaneously also overproduced.

Answer 50

Cushing’s syndrome is a condition that occurs when the body retains too much cortisol, or other glucocorticoid, causing its metabolism to change. This condition is normally caused by either a tumour of the adrenal gland or a tumour on the pituitary gland. These tumours don't grow and spread around the body, but rather, they grow as a tiny little round dot (nodule) that looks harmless but releases a lot of excess cortisol or ACTH. The nodules can be surgically removed, but this is not easy.

Answer 51

There are 4 possible causes of Cushing’s syndrome: 1) Prolonged ingestion of steroids by the mouth (common), such as Prednisinone, wjich suppresses the immune system 2) Pituitary dependent Cushing’s disease (pituitary adenoma) 3) Ectopic ACTH (lung cancer), lung cancer cells can start to express random genes such as ACTH 4) Adrenal adenoma or carcinoma

Answer 52

The clinical signs of Cushing’s syndrome include: interscapular fat pads, thin skin (protein converted to fat), bruise (thin blood vessels made of protein), centripetal obesity, red striae/stretch marks (protein not being made at the same rate as fat, causes blood to leak under the skin), impaired glucose tolerance (diabetes), high blood pressure, proximal myopathy (muscle weakness), round/moon faces (excess fat in cheeks) and poor wound healing.

Answer 53

The majority (99%) of calcium (Ca2+) in the body is found in the skeleton, 1% is found intracellularly and 0.01% found extracellularly. In the extracellular component, plasma accounts for ~ 2.5 mmol/L. 45% of the calcium in the plasma, is ionised (so unbound), and is the biologically active form of calcium. 45% of the remaining 55% of calcium is bound to plasma proteins (e.g. albumin) and 55% bound to anions (e.g. bicarbonate phosphate or lactate).

Answer 54

There are two hormones that are important for increasing calcium, and also regulating phosphate. One is parathyroid hormone (PTH), which is secreted by the parathyroid glands and the other is Vitamin D, which can either be synthesised in the skin in response to sunshine or taken in via the diet. These two hormones are the major regulators of calcium and phosphate in the body through their effects on the kidneys, on bone and on the gut.

Answer 55

One hormone, calcitonin, works to decrease calcium. It is secreted by parafollicular cells in the thyroid gland. It is not essential in calcium regulation as there are no negative effects if the parafollicular cells are removed (e.g. thyroidectomy).

Answer 56

When serum calcium levels are high, parafollicular cells sense that and release calcitonin, which helps reduce the concentration of circulating extracellular calcium. Calcitonin has a very limited effect and is thought to work in 2 ways. It works by the bone to reduce osteoclast activity, causing less calcium to be reabsorbed from bone, and thus serum calcium levels to fall. Calcitonin also works by promoting calcium excretion from the kidneys.

Answer 57

There are two sources of Vitamin D. Ergocalciferol (Vitamin D2) is obtained from the diet (e.g. oily fish) and Cholecalciferol (Vitamin D3) is synthesised in the skin in response to sunshine. There is a very slight structural difference between them.

Answer 58

When sunshine, UVB light, shines on the skin it stimulates a series of steps. First, the UVB light is converted to 7-dehydrccholesterol, to pre-Vitamin D, and then to a precursor of Vitamin D3. This precursor is then taken from the skin, to the blood supply, where it is joined by Vitamin D2 from the diet and on to the liver. To become biologically active, D3 then undergoes two hydroxylation steps. The first hydroxylation step occurs in the liver, by the enzyme 25-hydroxylase, producing 25-hydroxycholecalciferol. This is then taken to the kidney where the essential second Vitamin D activating hydroxylation step occurs. The second hydroxylation step uses the enzyme 1 alpha-hydroxylase to convert 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol (calcitriol). Calcitriol is the biologically active form of vitamin D in the body, regulating calcium and phosphate.

Answer 59

1,25-dihydroxycholecalciferol (calcitriol) is very difficult to measure in the blood stream, as it is very unstable. So, to measure body stores of Vitamin D, 25-hydroxycholecalciferol, the inactive precursor, is used instead.

Answer 60

Calcitriol (1,25-dihydroxycholecalciferol) regulates its own synthesis, by having a negative feedback loop with the enzyme 1 alpha-hydroxylase, in the kidney. This acts to reduce the activity of that enzyme and reduce calcitriol production.

Answer 61

1,25-dihydroxycholecalciferol (Vitamin D3/ calcitriol), works in several ways. It works on the bone by increasing calcium reabsorption, from bone. Calcitriol also increases calcium and phosphate (PO4 3-) reabsorption from the kidney. Calcitriol also increases calcium and phosphate absorption from the gastrointestinal tract (gut).

Answer 62

The parathyroid glands do not secrete thyroid hormones and are not involved in their regulation, but they do regulate calcium and phosphate balance. They're called parathyroid glands because of where they are situated anatomically, at the back of the thyroid gland. There are four parathyroid glands: 2 above and 2 below.

Answer 63

Parathyroid hormone (PTH) is secreted from specific cells on parathyroid glands called chief cells. Parathyroid hormone is a peptide hormone that is secreted as a large, inactive peptide precursor called pre-pro-parathyroid hormone (pre-pro-PTH). The precursor peptide is then cleaved to produce the active hormone PTH. When G-protein coupled calcium sensing receptors on chief cells detect changes in circulating calcium concentration, the amount of PTH secreted is changed.

Answer 64

The amount of PTH secreted is inversely proportional to serum calcium. When serum calcium is high, calcium binds the G-protein coupled calcium sensing receptors, found on the chief cells in the parathyroid glands, inhibiting PTH secretion. When serum calcium is low, then less calcium binds to the G-protein coupled calcium sensing receptors, so more PTH is secreted, to bring extracellular calcium concentrations back to normal.

Answer 65

PTH increases calcium reabsorption from bone. PTH also increases calcium reabsorption from the kidney, ensuring that less calcium is excreted in the urine, but increases phosphate excretion in the kidney. PTH also increases 1 alpha-hydroxylase activity, the enzyme that helps make active 1,25-dihydroxycholecalciferol/Vitamin D3/calcitriol. More calcitriol means more calcium and phosphate absorption from the gastrointestinal tract (gut). In this way, the phosphate excreted as urine in the kidney, can be replaced by phosphate reabsorbed from the gut.

Answer 66

There are two cells that can be found in bone: osteoblasts and osteoclasts. Osteoblasts work to build bone whereas osteoclasts work to consume bone, releasing powerful digestive enzymes through that dissolve bone to release calcium. The effects of calcitriol on bone depend on the levels of serum calcium.

Answer 67

Osteoblasts contain PTH receptors on their surface. When serum calcium is low, PTH binds to the receptors, stimulating the osteoblasts to produce osteoclast activating factors/OAFs (e.g. RANKL: receptor activator of nuclear factor kappa-B ligand). These special factors stimulate osteoclasts, resulting in an increase in calcium reabsorption from the bone.

Answer 68

Osteoblasts contain calcitriol receptors on their surface. When serum calcium is low, calcitriol binds to the receptors, stimulating the osteoblasts to produce osteoclast activating factors/OAFs (e.g. RANKL: receptor activator of nuclear factor kappa-B ligand). These special factors stimulate osteoclasts, resulting in an increase in calcium reabsorption from the bone. However, if serum calcium levels are normal, then calcitriol can actually work to build up bone, favouring osteoblast rather than osteoclasts.

Answer 69

Once PTH increases serum calcium a negative feedback loop inhibits PTH secretion in the parathyroid glands. PTH increases 1,25-dihydroxycholecalciferol (calcitriol) synthesis via 1 alpha-hydroxylase in the kidney. This is a two-way street which allows PTH secretion to also be inhibited, by negative feedback, once calcitriol reaches certain levels.

Answer 70

Fibroblast Growth Factor 23 (FGF23) is a hormone that is important for the regulation of phosphate. FGF23 reduces phosphate levels in the circulation in two ways. Normally phosphate is reabsorbed from the filtrate, and into the proximal convoluted tubule (PCT) of the kidney by a special sodium-phosphate co-transporter. First, it inhibits phosphate entering the PCT via the co-transporter, meaning that more phosphate is excreted in the urine. The second way is that it lowers serum phosphate levels, is by inhibiting calcitriol production, which increases phosphate reabsorption from the gut.

Answer 71

Hypercalcemia occurs when serum calcium levels are too high and conversely, hypocalcaemia occurs when serum calcium levels are too low. In order to have an action potential generated in nerves or skeletal muscles, a sodium (Na+) influx is required across the cell membrane. Hypercalcemia causes calcium to block the influx of sodium, leading to less membrane excitability. In contrast, hypocalcaemia enables a greater sodium influx and thus more membrane excitability.

Answer 72

Hypocalcaemia sensitises excitable tissues, leading to signs and symptoms such as; paraesthesia (tingling, particularly around the hands, mouth, feet and lips), convulsions, arrhythmias (heart rhythm problems) and tetany (muscles contract but can't relax after) A mnemonic to remember this is: CATs go numb.

Answer 73

Chvostek’s sign is used as evidence of hypocalcaemia. The facial nerve is tapped just below the zygomatic arch (cheek bone), which would be irritable and sensitised in hypocalcaemia, due to more membrane excitability. Twitching of the facial muscles on that side indicates hypocalcaemia.

Answer 74

Trousseau’s sign is the second sign of hypocalcaemia. Inflating the blood pressure cuff for a couple of minutes induces carpopedal spasms (finger spasms). The patient’s muscles contract but cannot then relax again, a marker of neuromuscular irritability.

Answer 75

Low PTH levels result in hypoparathyroidism. This could be down to several reasons, including damaging parathyroid glands during neck surgery, autoimmune conditions, magnesium deficiency (magnesium is required to produced PTH), congenital conditions (parathyroid glands agenesis) and Vitamin D deficiency.

Answer 76

Vitamin D deficiency can be due to many different reasons. One reason is insufficient exposure to sunlight (UVB light), thus producing insufficient cholecaficerol (Vitamin D3). Another cause could be the malabsorption of ergocalciferol (Vitamin D2) from the diet, celiac disease. Liver disease could be another cause, as the liver is important for the first hydroxylation step. Renal (kidney) disease could be a cause as the second hydroxylation step is essential for calcitriol production. Very rarely, congenital vitamin D receptor defects, could be the cause.

Answer 77

Rickets is a condition caused by Vitamin D deficiency in children. The lack of bone mineralisation leads to “soft” and bones. In adults, because their skeletons are more formed, Vitamin D deficiency manifests itself as osteomalacia. Adults with osteomalacia are more predisposed to fractures and proximal myopathy (muscles of the thighs become particularly weak).

Answer 78

Hypercalcemia results in reduced neuronal excitability and atonal muscles (loss of muscle strength), as there's more calcium competing with sodium, causing a reduced sodium influx, to generate action potentials. The key signs and symptoms of hypercalcemia are: 1) Kidney stones (nephrocalcinosis) are caused by deposits of calcium in the kidneys. 2) Abdominal moans due to anorexia, nausea, dyspepsia (heartburn), constipation and pancreatitis (inflammation of the pancreas). 3) Psychic groans are caused fatigue, depression, impaired concentration, altered mentation and coma (usually when calcium levels >3 mmol/L).

Answer 79

Hypercalcaemia is caused by primary hyperparathyroidism. This is characterised by the overproduction of PTH, usually due to a parathyroid adenoma. Usually negative feedback loops, when serum calcium is too high, inhibits PTH, but this is not the case in primary hyperparathyroidism. Often, certain cancers which metastasise to bones have a high calcium level because they produce local factors to activate osteoclasts, thereby increasing calcium from the bone. An excess of Vitamin D, often caused by an excess of Vitamin D supplements ingested, can also lead to hypercalcaemia.

Answer 80

Glucose is an important energy substrate. This is particularly true for the CNS, if blood glucose falls much below normal levels of 4-5mmol/L (hypoglycaemia), then cerebral function is increasingly impaired. If blood glucose concentration falls below 2mmol/L, unconsciousness, coma and ultimately death can occur as a result. Conversely, high glucose levels (hyperglycaemia) can cause damage to the microvasculature (e.g. blindness caused by changes to tiny arteries in the retina or ischemic heart disease). Persistent hyperglycaemia results in diabetes mellitus.

Answer 81

Glucose is very closely regulated by a feedback system. The hormones that help increased blood glucose levels are glucagon (secreted by alpha cells in the pancreas gland), cortisol (secreted by the adrenal glands), growth hormone (secreted by the pituitary gland), catecholamine (secreted by the adrenal glands). Insulin is the only hormone that helps to decrease blood glucose levels.

Answer 82

Diabetes mellitus prevalence is increasing worldwide. In the UK, around 7% of people are affected with diabetes mellitus. A person with diabetes mellitus is 34% more likely to die relative to an age-matched control without diabetes. ~10% of the NHS budget is spent on diabetes mellitus and its associated complications, this translates to ~£11 billion/annum and more than £1,000,000/hour.

Answer 83

Type 2 diabetes is the most prevalent form of diabetes, accounting for ~90% of diabetes mellitus cases. Type 1 diabetes accounts for ~10% of cases and maturity onset diabetes of the young (MODY) account for ~1-2% of cases.

Answer 84

The pancreas gland is a retroperitoneal structure, sitting in the retroperitoneal space. The pancreas gland measures roughly12-15 cm in length. The pancreas is divided into 4 regions: the head, the neck, the body and the tail, the body is the largest of the 4 regions. The head is itself subdivided into 2 areas: the uncinate process and the head proper. Insulin producing beta-cells are thought to be evenly distributed throughout the pancreas, but different structural portions play slightly different roles.

Answer 85

Most of the pancreas gland (98%), generates exocrine secretions (amylase, lipase and protease) via ducts to the small intestine, where they are needed for digestion. These exocrine secretions are generated by cells celled exocrine acinar cells. The remaining 2% of the pancreas is composed of small clumps of cells called islets of Langerhans, which are involved in glucose regulation. The islets of Langerhans, which only make up 2% of the pancreas gland, receive 15% of the blood supply. Across the whole pancreas gland, there is ~3 million islets of Langerhans.

Answer 86

There are 3 different types of cells present within the islets of Langerhans: alpha cells (30%), beta cells (60%) and delta cells (~10%). Alpha cells secrete glucagon, beta cells secrete insulin and delta cells secrete somatostatin. Within the islets can also be found pancreatic polypeptide producing cells.

Answer 87

The cells and hormones within the islets of Langerhans don't act independently but work together to create a balance and ensure that glucose levels are maintained. The islets cells communicate between each other via paracrine communication. This is facilitated by gap junctions, which allow small molecules to pass directly between the different types of cells and tight junctions, which create small intracellular spaces.

Answer 88

Glucagon increases blood glucose, whereas insulin reduces blood glucose and stimulates growth and development. In fact, in utero insulin acts alongside insulin-like growth factor 2 (IGF-2), to maintain foetal growth and development. Somatostatin, secreted by delta cells in the islets of Langerhans, keeps insulin and glucagon levels balanced, by a process akin to negative feedback.

Answer 89

Physiological changes occur in response to increased plasma glucose concentration. This is to ensure that the glucose levels do not continue to rise beyond physiological values and persistently stay elevated. Blood glucose goes up following a meal, stimulating beta cells to produce insulin. The somatostatin negative feedback loop inhibits the overproduction of insulin (leading to hypoglycaemia), but a bit of glucagon is simultaneously produced by alpha cells. Amino acids in meals have a direct stimulatory effect on beta cells, leading to an increased production of insulin. Gastrointestinal (GI) hormones and parasympathetic nervous system activity will also increase insulin secretion by beta cells. The sympathetic nervous system will have an inhibitory effect on the beta cells mediated by its alpha-adrenergic pathways but will have a lesser stimulatory effect mediated by its beta-adrenergic pathways.

Answer 90

Insulin causes: the build-up glycogen (rapidly mobilised form of glucose) stores in the liver by glycogenesis, the increased breakdown of glucose by glycolysis and the increased uptake of glucose to cells via GLUT4. GLUT4 is part of a glucose transporter protein family and is predominantly expressed within skeletal muscles and adipocytes. In a resting state, when insulin levels are relatively low, most of the GLUT4 is actually intracellular and is only transported to the cell membrane in response to insulin. Insulin also increases amino acid transport, in the liver, leading to an increase in protein synthesis. Insulin also causes a decrease in the rate of breakdown of fat (lipolysis) and increases the rate of fat built up (lipogenesis).

Answer 91

Insulin binds to the alpha-subunit, the extracellular domain, on insulin receptors (e.g. GLUT4). This causes a conformational change in the tyrosine kinase domains of the beta-subunits, allowing glucose to travel through the cell membrane and be taken up by the cell.

Answer 92

Physiological changes occur in response to reduced plasma glucose concentration. This is to ensure that the glucose levels do not continue to fall, thereby compromising energy/substrate delivery. Following a reduction in plasma glucose levels, alpha cells are stimulated to secrete glucagon, which inhibits any insulin from being secreted by beta cells. The somatostatin negative feedback loop inhibits the overproduction of glucagon (leading to hyperglycaemia). Certain types of amino acids and certain types of gastrointestinal (GI) hormones also have a stimulatory effect on the alpha cells. Both the parasympathetic nervous system and the sympathetic nervous system, mediated by its alpha-adrenergic pathways, will have a stimulatory effect on the alpha cells.

Answer 93

There are 3 main mechanisms by which glucagon acts. Glucagon increases the rate of breakdown of fat by lipolysis, which in turn allows glucose to be released by gluconeogenesis, thus increasing plasma glucose levels. Glucagon also increases amino acid transport into the liver, which helps increase the rate of gluconeogenesis. Glucagon also increases the rate of breakdown of glycogen reserves in the liver, by hepatic glycogenolysis, thereby increasing the concentration of plasma glucose.

Answer 94

GLUT2 is the is the receptor found on beta cell membranes, and it is not insulin sensitive. Rather, it has a very high affinity for glucose, so the concentration of plasma glucose is therefore reflected by the intracellular glucose concentration of the of the beta cell. 1) When glucose passes across the GLUT2 transporter, it is converted to glucose-6-phosphate, the first stage of glycolysis. This step is mediated by glucokinase (hexokinase IV), which is the main glucose sensor. Glucokinase, unlike other hexokinases found in the body, is not subject to negative feedback, meaning that glucose-6-phosphate does not inhibit glucokinase activity. 2) This allows continual conversion of glucose into glucose-6-phosphate, which is then converted down the glycolysis pathway into ATP. Extracellular glucose levels = intracellular glucose levels = intracellular ATP produced. 3) ATP then closes potassium gated channels on the surface of the beta cell, preventing the extracellular efflux of potassium. 4) The relative increase in intracellular potassium leads to membrane depolarisation, which opens calcium voltage gated channels. 5) This leads to an influx of calcium, which promotes insulin secretion by the beta cell.

Answer 95

Insulin is stored as proinsulin in beta cells. When calcium stimulates insulin secretion, proinsulin undergoes proteolytic cleavage, forming C-peptide and insulin, as products.

Answer 96

Insulin is a phenomenally unstable compound, so although there are ways of measuring it, C-peptide levels are measured instead, as it can be seen as a marker of endogenous insulin reserves.

Answer 97

The gastrointestinal “incretin” effect is observed when glucose is ingested. It relates to the physiological changes that occur in the body as a result of different modalities of administering glucose. When glucose is administered either intravenously or orally, the trends in plasma glucose levels are similar, with both modes causing a plasma glucose concentration peak after around 45 minutes, before plasma glucose levels begin to fall. However, whilst intravenous glucose causes a similar concentration of insulin to be secreted in relation to the increased plasma glucose concentration, glucose administered orally causes a much greater concentration of insulin to be secreted relative to the increased plasma glucose levels.

Answer 98

Glucagon-like peptide 1 (GLP-1), is a gastrointestinal tract (gut) hormone, secreted in response to nutrients in the gut. It is the transcription product of the pro-glucagon gene, which is itself mainly formed from L-cells, found in the distal gut. GLP-1 stimulates insulin secretion and suppresses glucagon secretion and increases satiety (feeling of fullness). It has a relatively short half-life as it is rapidly degraded by the enzyme dipeptidyl peptidase-4 inhibitor (DPPG-4 inhibitor). The hormone is now used as a treatment for type 2 diabetes.

Answer 99

Insulin resistance causes the first phase insulin release response to be to be overproduced to compensate for the excess glucose. When a heathy individual ingests glucose, their insulin levels increase drastically causing their blood glucose levels to decrease and stay down. However, in type 2 diabetes the whole system is then blunted, beta cells are then unable to produce enough insulin to counteract the high blood glucose levels. As a result, the glucose level stays up, and travels into parts of the body contain GLUT1, GLUT2 and GLUT3 transporters, as they are all insulin independent.

Answer 100

When blood glucose levels increase, the two main actions of insulin are decreasing hepatic (liver) glucose output, by encouraging glycogenesis and gluconeogenesis, and increasing muscle uptake of glucose. As there is plenty of glucose in circulation, alternative energy sources are not needed, so insulin inhibits both proteolysis and lipolysis. Decreasing lipolysis results in decreased ketogenesis (production of ketone bodies from fat molecules).

Answer 101

Glucose enters cells via glucose transporters, a very important one being the GLUT4 glucose transporter. GLUT4 is commonly found in myocytes (muscle cells) and adipocytes (fat cells) and is very highly insulin responsive. GLUT4 lies in vesicles and is recruited and enhanced by insulin to sit in the cell membrane.

Answer 102

GLUT4 is composed of a hydrophobic component on the outside and a hydrophilic component on the inside, allowing a 7-fold increase in glucose uptake into various cells.

Answer 103

Myocytes (muscle cells) contain a lot of protein. In the fed state, where blood glucose levels are high, insulin is released, as protein is no longer need as a fuel source. Protein breakdown is therefore inhibited by insulin, whilst proteogenesis (amino acids to protein) is promoted by insulin, growth hormone (GH) and insulin-like growth factor 1 (IGF-1). When gluconeogenic amino acids are needed elsewhere, the amino acids leave the muscle cells and enter the liver, a process promoted by cortisol. Insulin also inhibits the process of oxidative phosphorylation in the mitochondria of myocytes.

Answer 104

During the fasting state, the liver takes up gluconeogenic amino acids released by proteins in myocytes, a process enhanced by glucagon, as alternative energy sources are needed. In the fed state, insulin stimulates the amino acids to be converted into proteins and stored within the liver. At the same time, insulin also inhibits gluconeogenesis (conversion of amino acids into glucose), thereby reduce hepatic glucose output. Conversely, in the fasting state glucagon encourages the breakdown of protein into amino acids, and alongside cortisol, encourages gluconeogenesis, thereby increasing hepatic glucose output.

Answer 105

In the short term, energy comes from carbohydrates, which are stored in the liver and muscle. Within ~16 hours of prolonged fasting, carbohydrate energy stores become depleted. Protein, which makes up about 20% of fuel stores, then begins to be used as the alternative energy source, lasting ~15 days. The biggest energy store in the body is fat, taking 30-40 days to be depleted.

Answer 106

Eating causes an increase in triglycerides in the blood stream. Triglycerides are fairly large molecules, so can't be taken up directly by adipocytes. Thus, they must be broken down first. They are broken down, by insulin activated lipoprotein lipase (LPL), into non-esterified fatty acids (NEFA) and glycerol (GLY), which can then be taken up by adipocytes. In the fed state, glucose can be taken up by GLUT4 transporters on the cell membrane of adipocytes, another process encouraged by insulin. Glucose and insulin, in the adipocyte, promote the GLY and NEFA to be converted back into triglycerides for storage. Insulin simultaneously inhibits the breakdown of those triglycerides. However, in the fasting state, with low glucose ad insulin levels, triglycerides are able to breakdown to glycerol and NEFA, encouraged by growth hormone (GH) and cortisol. GLY and NEFA can then be released from the adipocytes and taken up into the liver.

Answer 107

Glycerol can be taken up by the liver, where it can be stored as triglycerides, during the fed state. In the starving state, if a glucose output from the liver is required, glycerol will then be converted into glucose by gluconeogenesis, thereby increasing hepatic glucose output (HGO). Hepatic gluconeogenesis accounts for 25% of HGO after a 10 hour fast.

Answer 108

There is a separate hepatic portal circulation, which allows the blood to go straight from the heart to the gastrointestinal tract. There, any nutrients can be picked up and taken straight to the liver for processing. Insulin can also be released straight into the hepatic portal circulation, meaning that when there is an increase in blood glucose levels, insulin can be released quickly to target cells.

Answer 109

Most tissues in the body can utilise, glucose, ketones and non-esterified fatty acids (NEFA), as fuel. However, the brain is incapable of using NEFA as fuel. This makes it unique among body tissues. The brain mostly uses glucose, which is the preferred energy source, and if need be, it can use ketone bodies, but it can never use NEFA.

Answer 110

Ketone bodies are produced when non-esterified fatty acids, produced by adipocytes, are taken up by the liver. In the fed state, insulin inhibits the breakdown of NEFA, in the liver, into ketone bodies (e.g. Acetyl CoA, Acetoacetate, Acetone + 3OH-B). However, in the prolonged fasting state, glucagon encourages the breakdown of NEFA to produce ketone bodies, in the liver. The ketone bodies are then released from the liver. This is why it is so worrying for a patient to have high blood glucose and ketone body levels, as the two should never coincide, in a healthy individual.

Answer 111

In the fed state, glucose can enter the liver the GLUT4 transporters, with the help of insulin. Insulin also encourages the conversion of glucose to glucose-6-phosphate and then to glycogen, for storage. However, in the prolonged fasting state, glucagon will encourage the breakdown of glycogen into Glucose-6-phosphate. This can then be converted into glucose and released from the liver. The process of generating glucose from glycogen stores, in the liver, is hepatic glycogenolysis.

Answer 112

In the fed state, glucose is taken up by myocytes (muscle cells), a process encouraged by insulin, here it can be stored as glycogen. However, in a prolonged starving state, glucose uptake, by myocytes, is inhibited by inhibited by growth hormone (GH) and glucagon. The glycogen stores in the myocyte are then converted into glucose, which can then be converted into Acetyl CoA, to be used by mitochondria within the myocytes, as the glucose cannot be released back into circulation. Myocytes can also use non-esterified fatty acids (NEFA) as another energy source.

Answer 113

In the fasting state, there is a low insulin-to-glucagon ratio, normally glucose levels are maintained between 3-5.5 mmol/L. Non-esterified fatty acid (NEFA) levels increase and amino acid levels increase initially but are eventually used up in a prolonged fast. Proteolysis, lipolysis and hepatic glucose output (HGO) from glycogenolysis and gluconeogenesis, all increase. Muscle cells use NEFA from lipids, while the brain uses glucose and later ketone bodies. Ketogenesis increases in a prolonged fasting state.

Answer 114

In the fed state, insulin is initially released, referred to as the first phase insulin release from stored insulin. This is then followed by a slower insulin release, referred to as the second phase. This leads to a high insulin-to-glucagon ratio. Insulin release stops hepatic glucose output (HGO) and decreases both gluconeogenesis and proteolysis. However, it does increase glycogen storage, protein synthesis and lipogenesis.

Answer 115

Diabetes mellitus is diagnosed when you have 1 positive test + symptoms, or 2 positive tests of: 1) A high fasting glucose concentration (>7.0 mmol/L) 2) A high random glucose level (>11.1 mmol/L), 3) An oral glucose test (i.e. fasting glucose, 75g glucose load and 2-hour glucose) 4) A high HbA1c (>48 mmol/mol), which gives an average of glucose over the last three months

Answer 116

Type 1 diabetes mellitus (T1DM) is an autoimmune condition that eventually leads to T cell mediated destruction of insulin producing beta cells in the pancreas. This continual destruction of beta cells goes eventually leads to absolute insulin deficiency.

Answer 117

If the pancreas is unable to produce any insulin, this leads to proteinolysis, increased hepatic glucose output (HGO), which can lead to polyuria (frequent urination), nocturia (urination at night) and polydipsia (excessive thirst), and lipolysis. Prolonged lipolysis can cause non-esterified fatty acids (NEFA) to be converted into ketone bodies. This can lead to diabetic ketoacidosis, which is a serious acute complication.

Answer 118

1) High glucose concentrations cause the kidney threshold (10mmol/L) to be reached, glucose diffuses into urine, causing an osmotic diuresis (water move into the urine), leading to polyuria and nocturia. 2) The polydipsia is caused by the water lost in urine needing to be replaced regularly, due to plasma osmolarity.

Answer 119

The common signs and symptoms of T1DM include weight loss, hyperglycaemia, glycosuria with osmotic symptoms (e.g. polyuria, nocturia and polydipsia) and ketone bodies in the blood and urine.

Answer 120

In clinical practise, there are some useful diagnostic tests used to distinguish between type 1 and type 2 diabetes. T1DM is normally associated with: 1) The presence of antibodies (GAD and IA2) 2) C-peptide (correlates to low insulin levels) 3) Ketones

Answer 121

One of the major challenges that people with T1DM have, is their reliance on exogenous insulin for treatments. Taking exogenous insulin allows the non-functioning insulin secreting beta cells in the pancreas, to be bypassed, however taking too much exogenous insulin can induce hypoglycaemia, very low blood glucose levels. This is due to the fact that too much insulin can halt hepatic glucose output (HGO), causing blood glucose levels to fall. As the mechanism for inhibiting insulin production does not function, the exogenous insulin simply remains in circulation, continuously decreasing blood glucose levels.

Answer 122

When blood glucose levels start dropping, some hormones (e.g. glucagon, catecholamines, cortisol and growth hormones) are secreted to stop blood glucose levels dropping too low. They do this by increasing hepatic glucose output (HGO), through increased glycogenolysis and gluconeogenesis, they also increase lipolysis for an additional alternative energy source. Although this mechanism does exist in those with T1DM, their bodies have a reduced ability to recognise hypoglycaemia and recurrent episodes of hypoglycaemia could cause the body to increase the threshold for when the counter regulatory response kicks in.

Answer 123

The autonomic (initial) signs and symptoms of hypoglycaemia include sweating, palpitations, pallor, shaking and hunger. As glucose drops further signs and symptoms become neuroglycopenic (affecting the brain) and include slurred speech, poor vision, seizures confusion and potentially loss of consciousness.

Answer 124

Severe hypoglycaemia is a medical emergency as is defined as an episode where a person needs third party assistance to be treated.

Answer 125

Jelly babies are often given to patients suffering from an episode of hypoglycaemia as they are quick acting carbohydrates (glucose).

Answer 126

A 1mg intramuscular (IM) injection of glucagon is given to unconscious patients suffering from a severe episode of hypoglycaemia.

Answer 127

Insulin resistance plays a major role in the pathophysiology of type 2 diabetes mellitus (T2DM). Insulin resistance resides in the liver, muscle and adipose tissues, so all metabolic sides and all arms of intermediary metabolism that involves glucose and fatty acids. Unlike T1DM, in T2DM, there is generally enough insulin in circulation to suppress ketogenesis and proteolysis.

Answer 128

1) When insulin binds to insulin receptors, the PI3K-Akt pathway is activated, resulting in a range of metabolic actions (e.g. glucose and fat metabolism). Insulin resistance resides within this pathway, but even though insulin is not working as it should, the body compensate by producing more insulin, helping to maintain blood pressure within the normal range. In this way, an individual can have insulin resistance without having diabetes for quite a long time, until the body can no longer cope, and blood glucose levels begin to increase. 2) When insulin binds to the insulin receptor, another pathway called them MAPK pathway, responsible for the growth and proliferation action of insulin, is also activated. There is no insulin resistance residing within this pathway, when an individual has insulin resistance, peripheral insulin concentration. This causes side effects which can lead to problems such as high blood pressure.

Answer 129

Systemic insulin resistance can lead to a multitude of problems, including hypertension (BP > 135/80 mmHg), increased waist circumference in both men and women, high fasting glucose associated with prediabetes (>6.0 mmol/L), inflammatory states and increased energy expenditure.

Answer 130

T2DM presents with hyperglycaemia, obesity, dyslipidaemia (abnormal conc. of lipids in blood), fewer osmotic symptoms than T1DM, insulin resistance, later development of insulin deficiency and further complication.

Answer 131

Complications of T2DM can cause: 1) Retinopathy - problems with eyes (one of the leading causes of blindness in the UK) 2) Nephropathy - renal failure and end stage renal impairment requiring dialysis 3) Neuropathy – problems with nerves leading to amputations 4) Cardiovascular issues – problems with microvasculature leading to strokes and myocardial infarctions.

Answer 132

There are several risk factors associated with T2DM, including: age, high BMI, ethnicity (Asians often high-risk category), polycystic ovary syndrome (PCOS), family history and inactivity.

Answer 133

T2DM is managed through diet, oral medication, structured education and perhaps insulin later in life.

Answer 134

There are various dietary recommendations associated with T2DM, including total calories control, so reducing calories as fat and refined carbohydrate, but increasing calories as complex carbohydrate. Increase soluble fibre but decrease sodium.

Answer 135

T1DM is managed by: 1) Using exogenous insulin (basal-bolus regime), a long acting insulin injection once or twice a day and a quick acting insulin injection 3 times a day before eating 2) Self-monitoring glucose with finger prick testing at least four times a day 3) Structured education 4) Different technologies to help people self-manage (e.g. insulin pumps and continuous glucose monitoring technologies)

Answer 136

There are different education programmes available: 1) Dose Adjustment For Normal Eating (DAFNE), which is specific for T1DM education 2) Diabetes Education and Self Management for Ongoing and Newly Diagnosed (DESMOND) course, which is specific for T2DM education

Answer 137

This is caused by pancreatic beta-cells dysfunctioning, owing to lipotoxicity, glucotoxicity and resistance to incretins (intestinal hormones that stimulate insulin secretion). Peripheral hormones (e.g. kidneys, liver and muscle) become insulin resistant, leading to reduced glucose uptake from blood, excessive glucose reabsorption by the kidney and increased gluconeogenesis, leading to hyperglycaemia.

Answer 138

1) Genetic abnormalities 2) Ectopic lipid accumulation 3) Mitochondrial dysfunction 4) Inflammation 5) Endoplasmic reticulum stress

Answer 139

The severity and duration of hyperglycaemia determines the risk of microvascular complications such as, retinopathy, nephropathy and neuropathy.

Answer 140

Macrovascular complications usually result from dislipidaemia, hypertension, hyperglycaemia and inflammation, and include: 1) Myocardial infarction 2) Peripheral vascular disease 3) Stroke

Answer 141

A BMI >25 is the single most important risk factor, however the prevalence of T2DM has increased dramatically in China and India, despite the low prevalence of obesity. This may be explained by different fat-versus-muscle-mass ratios, different fat tissue distribution and a greater severity of beta-cell failure.

Answer 142

Metformin is generally the preferred initial medication for treating type 2 diabetes, unless there's a specific reason not to use it, as it allows the body to better respond to insulin and decreases hepatic glucose output (HGO). Metformin is effective, safe as it does not cause hypoglycaemia, inexpensive and does not cause weight gain, unlike other diabetes medications. Serious side effects from metformin are exceedingly rare, occurring only in 1 in 10,000 people.