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Endocrine Flashcards

1
Q

Paracrine chemicals

A

act local to the site of synthesis, do not travel to distant sites e.g. histamine

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2
Q

Autocrine chemicals

A

act on/in the same cell that synthesises the hormone e.g. cytokines

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3
Q

Exocrine chemicals

A

released from exocrine glands via ducts to the external environment including the GI tract e.g. saliva, sweat, bile

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4
Q

Insulin action on muscle/fat

A

increase gylcogenesis, decreased gluconeogenesis

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5
Q

Peptide or protein hormones

A

composed of chains of amino acids (most common). Water soluble. Insulin, TRH.

are water soluble, transported in solution in the plasma.

  • are vulnerable to degradation before they reach their target.
  • have a short half-life in the plasma, (time taken for [plasma] concentration to fall by a half), usually minutes. Prolonged action therefore requires continued secretion.
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6
Q

Amine hormones

A
  • all derived from one of two amino acids (tryptophan or tyrosine)
  • All from tyrosine apart from melatonin (tryptophan)

dopamine, norepinephrine.

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7
Q

Steroid hormones

A

all derived from cholesterol..
synthesied when needed (lipid soluble and cannot be stored)
are lipophilic, once made they diffuse across the cell membrane into the blood.
-circulate in plasma bound to specific transport plasma proteins (eg thryoxine-binding globulin, or albumin) so have longer half-life, usually hours to days.
-Alter protein synthesis via modifying gene expression thus effect also persists for hours to days.

  • Gonads (testes and ovary) – sex steroids
  • Placenta - hCG, sex steroids
  • Kidney - Vitamin D3
  • Adrenal cortex - corticosteriods
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8
Q

production of insulin

A

The initial peptide hormone produced by ribosomes is large and inactive - preprohormone. Preprohormones contain one or more copies of the active hormone in their amino acid sequence.
Preprohormones are cleaved into smaller units in the endoplasmic reticulum to leave smaller but still inactive proteins called prohormones.
Prohormones are packaged into vesicles in the golgi apparatus, along with proteolytic enzymes which break the prohormone down into active hormone and other fragments.
Hormones and fragments are stored in vesicles in the endocrine cells until release is triggered then all vesicle contents are released into plasma (co-secretion).
Measuring inactive fragments in plasma can be useful clinically e.g. C-peptide in diabetes

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9
Q

epinephrine + TH

A

permissive. TH increases receptors for epinephrine on adipocytes. This increases lipolysis (even though TH doesn’t actually cause lipolysis)

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10
Q

growth hormone + insulin

A

GH impairs the response of insulin by reducing the number of insulin receptors on tissues.

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11
Q

Role of calcium in the body

A

signalling, clotting, apoptosis, skeletal strength, membrane excitability

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12
Q

Hypocalcaemia

A

increases neuronal Na+ permeability leading to hyperexcitation of neurons. In extreme cases causes tetany, if spreads to larynx and respiratory muscles – asphyxiation.

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13
Q

Hypercalcaemia

A

decreases neuronal Na+ permeability which will reduce excitability and depress neuromuscular activity and in extreme cases, trigger cardiac arrhythmias

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14
Q

Calcium Distribution in the Body

A

bones - 99% (hydroxyapatite), intracellular 0.9% (mitochondria + SR), extracellular 0.1%. (50% free, 40% protein bound, 10% anion bound)

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15
Q

high pH on calcium binding

A

Binding capacity is increased under alkalotic conditions. E.g. hyperventiliation

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16
Q

low pH on calcium binding

A

decreased in acidic conditions

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17
Q

osteoblasts

A

bone building cells. lay down a collagen extracellular matrix which they then calcify.

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18
Q

osteoclasts

A

responsible for mobilizing bone.
-They secrete H+ ions (pH ~ 4) to dissolve the calcium salts and also provide proteolytic enzymes to digest the extracellular matrix.

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19
Q

osteocytes

A

in established bone - appear to regulate the others

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20
Q

Parathyroid hormone (PTH)

A

polypeptide hormone produced by the parathyroid glands. responds to drops in Ca. Raises calcium by: stimulating osteoclasts, inhibiting osteoblasts, increasing reabsorption by kidney tubules (decreased excretion), increases renal excretion of phosphate, stimulates kidney to synthesis calcitriol.

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21
Q

Calcitriol

A

steriod hormone. activated D3. produced by vit D3 in the liver and kidneys or by action of UV light. Raises calcium by: binding to receptors in the gut to increase absorption from the gut. (active transport). also has small effects on bone and kidney (but it’s mostly PTH). Also stimulated by prolactin

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22
Q

Calcitonin

A

peptide hormone produced by the thyroid. secreted when Ca is high. acts against this by increasing excretion by the kidneys, and binding to osteoclasts to prevent bone resorption.

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23
Q

cortisol on calcium

A

Cortisol inhibits osteoblasts, increases renal excretion of Ca2+ and phosphate and reduces intestinal absorption of Ca2+. leads to reduced plasma [Ca2+ ] which increases PTH which increases bone resorption. This together with the reduced bone formation can, over time, produce osteoporosis.

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24
Q

insulin and bones

A

Insulin increases bone formation and antagonises the action of cortisol. Diabetics may have significant bone loss

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25
Q

oestrogen and osteoporosis

A
  1. Oestrogen promotes bone formation via oestrogen receptors on osteoblasts. Post-menopausal osteoporosis a major problem.
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26
Q

where is Growth hormone (somatotropin) released

A

anterior pituitary

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27
Q

where are GHRH (growth hormone releasing hormone / somatocrinin) vs GHIH (growth hormone inhibiting hormone / Somatostatin) released

A

hypothalamus

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28
Q

GH

A

somatotropin. peptide hormone.

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29
Q

GHIH + GHRH

A

neurohormones released from the hypothalamus

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30
Q

main actions of GH

A

Growth and development (indirect action)

Regulation of metabolism (direct action)

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31
Q

initial growth is determined by

A

Growth in the foetal period and the first 8-10 months of life is largely controlled by nutritional intake, but thereafter GH becomes the dominant influence on the rate at which children grow.

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32
Q

why do Children with untreated hypothyroidism, or poorly controlled diabetes, have stunted growth despite normal GH levels.

A

GH requires permissive action of thyroid hormones and insulin before it will stimulate growth.

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33
Q

insulin-like growth factor-1 (IGF-1) aka somatomedin C. and where it acts and how is it produced

A

The effect of GH on growth is almost entirely indirect, being achieved through the action of an intermediate known as insulin-like growth factor-1 (IGF-1) aka somatomedin C as it mediates the action of GH.
IGF-1 has structure very similar to pro-insulin, binds to receptors very similar to the insulin receptor and has hypoglycaemic qualities (hence “insulin-like”) although latter action is limited to glucose uptake in muscle. Liver and adipose tissue have few IGF receptors
IGF-I is secreted by the liver, and many other cell types, in response to GH release, and IGF-1 controls GH release through a negative feedback loop.

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34
Q

GH and IGF-I are peptide hormones, but

A

they are transported in the blood bound to carrier proteins.
-~50% of GH is in the bound form. This helps to provide a “reservoir” of GH in the blood which helps to smooth out the effects of the erratic pattern of secretion and extends half-life by protecting from excretion in the urine.

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35
Q

IGF-1 Negative Feedback Loop on GH Release

A
  • IGF exhibits negative feedback on GH release both via inhibiting GHRH (somatocrinin) and stimulating GHIH (somatostatin).
  • Additional negative feedback loop of GH on GH release from somatotrophs in pituitary.
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36
Q

GH/IGF-I effects on bone growth

A

GH stimulates chondrocyte precursor cells (prechondrocytes) in the epiphyseal plates to differentiate into chondrocytes.

  • During the differentiation, the cells begin to secrete IGF-I and to become responsive to IGF-I
  • IGF-I then acts as an autocrine or paracrine agent to stimulate the differentiating chondrocytes to undergo cell division and produce cartilage, the foundation for bone growth.
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37
Q

sex hormone effect on bone growth

A

Epiphyseal plates close during adolescence under the influence of sex steroid hormones, then no further longitudinal growth is possible.

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38
Q

GH and regulation of metabolism (direct effects of GH)

A
  1. Increases gluconeogenesis by the liver.
  2. Reduces the ability of insulin to stimulate glucose uptake by muscle and adipose tissue.
  3. Makes adipocytes more sensitive to lipolytic stimuli.
  4. Increases muscle, liver and adipose tissue amino acid uptake and protein synthesis = anabolic effect

in other words

  1. Mobilises glucose stores, to increase blood [glucose]
  2. Inhibits the action of insulin (by reducing the number of insulin receptors on muscle and adipose tissue) thus augmenting the increased blood [glucose]
  3. Promotes lipolysis, providing a source of energy for most cells of the body, sparing glucose and again augmenting increased blood [glucose]
  4. Promotes amino acid uptake to cells, supporting protein synthesis
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39
Q

When is GH secreted

A

Large quantities of GH are present in pituitaries of both adults and children, with highest rates of secretion occurring in teenage years.

Majority of GH released during first 2 hours of sleep (deep delta sleep). 20X increase in GH secretion in children during this period. General energy requirements low so energy diverted to growth.
GH release during waking hours is low.

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40
Q

Stimuli that increase GHRH (somatocrinin) secretion (increase GH):

A
  1. Actual or potential decrease in energy supply to cells.
    - As well as growth and development, GH is needed for maintenance of tissues and their energy supply.
    - In fasting and hypoglycaemia there is a decrease in substrate supply. In exercise and in the cold, there is an increased demand for energy. All stimulate increase GH.
  2. Increased amounts of amino acids in the plasma, e.g. protein meal.
    - GH promotes amino acid transport and protein synthesis by muscle and liver.
  3. Stressful stimuli e.g. infection, psychological stress
  4. Delta sleep
    - increase in GH in delta sleep may be related to growth spurts in children and adolescents and tissue repair in adults.
  5. Oestrogen and androgens
    - growth spurt in puberty corresponds with sex steroid mediated release of GHRH and resultant increase GH
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41
Q

Stimuli that increase GHIH (Somatostatin secretion)

decrease (GH)

A
  1. Glucose
  2. FFA (free fatty acids)
  3. REM sleep (Subjects deprived of REM sleep have decreased GH secretion)
  4. Cortisol (although inhibitory effect on growth may be more to do with increased protein catabolism, rather than stimulating GHIH release)
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42
Q

thyroid hormones and growth

A

-Thyroid hormones are essential for normal growth, particularly important for development of the nervous system in utero and early childhood.
Effects are permissive to GH/IGF-I.

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43
Q

Cretinism

A

a condition where children are hypothyroid from birth. They have retarded growth because of the loss of TH’s permissive action on GH. They retain infantile facial features = hypothyroid dwarf. GH levels are normal
(Hypothyroid tadpoles never become frogs!)

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44
Q

Gigantism

A
  • Excess GH due to a pituitary tumour before epiphyseal plates of long bones close
  • excessive growth, may be more than 7ft tall (210cm), called pituitary giants.
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45
Q

Acromegaly

A

Excess GH due to a pituitary tumour after epiphyseal plates have sealed.
-Long bones cannot increase so there is no longitudinal growth and no increase in height. However, can still grow in other directions and the characteristic features are enlarged hands and feet.

In adults, feet should NOT get bigger = classic sign of ACROMEGALY

Surgery to remove tumour or somatostatin analogues to treat.

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46
Q

Dwarfism causes

A
  1. A deficiency of GHRH. In this case GH response to administered GHRH may be normal. (Hypothalamic in origin)
  2. GH secreting cells may be abnormal. So, less GH will be produced in response to GHRH. (Pituitary in origin)
  3. End organ is unresponsive to GH (Laron Dwarfism). Individuals may have increased [GH] in plasma. Defective GH receptor prevents IGF-1 release and peripheral tissues cannot respond to growth signal. Loss of IGF-1 inhibition of GH responsible for increase [GH] (remember negative feedback loop!).
  4. Genetic mutations. Pygmies have a genetic mutation that impairs the ability of cells to produce IGF-I in response to GH.
  5. Precocious puberty. Excess GnRH release stimulates puberty via promoting sex hormone release. These children have stunted growth because long bones fuse early under influence of sex hormones.
  6. Hypothyroid children retain infantile features with stunted growth due to loss of permissive effect of TH on GH. Limits bone growth and promotes fat storage. Also severely impacts on neurological development.
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47
Q

Adrenal Medulla (~25%)

A

is a modified sympathetic ganglion (neural tissue) derived from neural crest tissue. Secretes catecholamines, mainly epinephrine (adrenaline), also norepinephrine and dopamine.

Preganglionic sympathetic fibres terminate on specialised postganglionic cells in the adrenal medulla. These postganglionic fibres do not have axons – instead they release their neurohormones (adrenaline) directly into the blood

48
Q

Adrenal Cortex (~75%)

A

is a true endocrine gland derived from mesoderm and secretes 3 classes of steroid hormones, the first 2 of which are of particular importance:

Mineralocorticoids e.g. aldosterone: involved in the regulation of Na+ and K+
Glucocorticoids e.g. cortisol: involved in maintaining plasma glucose
Sex steroids e.g. testosterone

49
Q

Zona glomerulosa

A

mineralocorticoids - aldosterone

50
Q

Zona fasciculata

A

glucocorticoids

51
Q

Zona reticularis

A

sex steroids - testosterone

52
Q

Defects in 21-hydroxylase

A

common cause of congenital adrenal hyperplasia resulting in deficiency of aldosterone and cortisol and associated disruption of salt and glucose balance. Androgen biosynthesis is unaffected so accumulating steroid precursors are channelled into excessive adrenal androgen production.

  1. Lack of 21-hydroxylase inhibits synthesis of cortisol.
  2. This removes the negative feedback on ACTH and CRH release.
  3. Increased ACTH secretion is responsible for enlargement of adrenal glands.
  4. Negative feedback of ACTH on CRH synthesis remains. (an increase in CRH, but not as much as you see of ACTH)

Babies are very ill in a matter of days. (cortisol – BG metabolism, aldosterone – bp management). They also have indeterminate sex on birth.

53
Q

Cortisol

A
  • glucocorticoid hormone (influences glucose metabolism).
  • ~95% of plasma cortisol is bound to a carrier protein, cortisol binding globulin (CBG).

All nucleated cells have cytoplasmic glucocorticoid receptors.

The hormone receptor complex migrates to the nucleus, binding to DNA via a hormone-response element to alter gene expression, transcription and translation.

Cortisol as a glucocorticoid is crucial in helping to protect the brain from hypoglycaemia.
-It has a permissive action on glucagon, which is vital as glucagon alone is inadequate in responding to a hypoglycaemic challenge.

54
Q

Cortisol release

A

Plasma levels of cortisol show a very characteristic pattern.

  • There is a marked circadian rhythm, preceded by a similar pattern of release of ACTH. Cortisol “burst” persists longer than ACTH burst because half-life is much longer.
  • Peak is ~ 6-9am, nadir (lowest level) is ~ midnight.
  • Other fluctuations during the day are due to effects of other stimuli which are related to stress.
55
Q

Actions of cortisol on glucose metabolism (glucocorticoid actions)

A
  1. Gluconeogenesis: Cortisol stimulates formation of gluconeogenic enzymes in the liver thus enhancing gluconeogenesis and glucose production. This is aided by cortisol’s action on muscle:
  2. Proteolysis: cortisol stimulates the breakdown of muscle protein to provide gluconeogenic substrates for the liver.
  3. Lipolysis: similarly, cortisol stimulates lipolysis in adipose tissue which increases [FFA] plasma creating an alternative fuel supply that allows [BG] to be protected while also creating a substrate (glycerol) for gluconeogenesis.
  4. Decreases insulin sensitivity of muscles and adipose tissue.

In all these glucose counter-regulatory effects, cortisol is acting to oppose insulin, not surprisingly excess cortisol is diabetogenic.

56
Q

Additional Actions of Cortisol (non- glucocorticoid)

A
  1. Negative effect on Ca2+ balance: decrease absorption from gut, increases excretion at kidney resulting in net Ca2+ loss. Also increase bone resorption leads to osteoporosis
  2. Impairment of mood and cognition: depression and impaired cognitive function are strongly associated with hypercortisolaemia.
  3. Permissive effects on norepinephrine: particularly in vascular smooth muscle (alpha-receptor effect = vasoconstrictive). Cushings Disease (hypercortisolaemia) is strongly associated with hypertension. Likewise, low levels of cortisol are associated with hypotension.
  4. Suppression of the Immune System: Cortisol reduces the circulating lymphocyte count, reduces antibody formation and inhibits the inflammatory response. Latter effect can be useful clinically e.g. asthma/ulcerative colitis/organ transplant.
57
Q

Aldosterone

A

Aldosterone is mineralocorticoid, which acts on the distal tubule of the kidney to determine the levels of minerals reabsorbed/excreted. Aldosterone increases the reabsorption of Na+ ions and promotes the excretion of K+ ions.

58
Q

Increased aldosterone release

A

stimulates Na+ (and H2O) retention and K+ depletion, resulting increased blood volume and increased blood pressure.

59
Q

Decreased aldosterone

A

leads to Na+ (and H2O) loss and increased[K+]plasma, resulting in diminished blood volume and decreased blood pressure.

60
Q

Hypersecretion of cortisol

A

Cushing’s syndrome/disease
- Hypersecretion is most commonly due to a tumour in:
- adrenal cortex (1o hypercortisolism = Cushing’s syndrome)
or
- pituitary gland (2o hypercortisolism = Cushing’s disease). Most common. Excess ACTH.

Iatrogenic
- Too much cortisol administered therapeutically.

61
Q

Hyposecretion of cortisol

A

much less common than hyper.

Addison’s disease

  • Hyposecretion of all adrenal steroid hormones
  • Due to autoimmune destruction of adrenal cortex
62
Q

Pheochromocytoma

A

-a rare neuroendocrine tumour, found in adrenal medulla which results in excess catecholamines:
increased HR, leading to increase CO, leading to massively increased BP

  • Diabetogenic due to adrenergic effect on glucose metabolism.
  • Responds well to surgery.
63
Q

Withdrawing chronic glucocorticoid treatment

A

Care is required when withdrawing glucocorticoid treatment due to enhanced negative feedback effects of exogenous cortisol.

Additional, therapeutic cortisol enhances the negative feedback on hypothalamus and pituitary reducing release of CRH and ACTH.
Loss of trophic action of ACTH on adrenal gland cause atrophy of gland. Risk of adrenal insufficiency if withdrawal is too fast.

64
Q

Feeding Centre

A

promotes feelings of hunger and drive to eat (a hypothalamic centre)

65
Q

Satiety Centre

A

promotes feelings of fullness by suppressing the Feeding centre. (a hypothalamic centre)

66
Q

Glucostatic theory

A

food intake is determined by blood glucose: as [BG] increases, the drive to eat decreases (- Feeding Centre; + Satiety centre)

67
Q

Lipostatic theory

A

food intake is determined by fat stores: as fat stores increase, the drive to eat decreases (- feeding centre; + Satiety Centre). Leptin is a peptide hormone released by fat stores which depresses feeding activity.

68
Q

Energy output

A

Cellular work – transporting molecules across membranes; growth and repair; storage of energy (eg. fat, glycogen, ATP synthesis).

Mechanical work – movement, either on large scale using muscle or intracellularly.

Heat loss – associated with cellular and mechanical work accounts for half our energy output.

69
Q

Anabolic pathways

A

= Build Up.
-Net effect is synthesis of large molecules from smaller ones, usually for storage purposes.

After eating we enter an Absorptive State where ingested nutrients supply the energy needs of the body and excess is stored. This is an anabolic phase.

70
Q

Catabolic pathways

A

= Break Down.
-Net effect is degradation of large molecules into smaller ones, releasing energy for work.

Between meals and overnight the pool of nutrients in the plasma decreases and we enter a Post-absorptive State (aka Fasted State) where we rely on body stores to provide energy. This is a catabolic phase.

71
Q

Normal range of [BG]

A

4.2-6.3mM (80-120mg/dl)

72
Q

Hypoglycaemia = [BG]

A

< 3mM

73
Q

alpha cells produce

A

glucagon

74
Q

beta cells produce

A

insulin

75
Q

delta cells produce

A

somatostatin

76
Q

insulin secretion from beta cells

A

Insulin dominates the absorptive state. Only hormone which lowers [BG].

beta-cells have a specific type of K+ ion channel that is sensitive to the [ATP] within the cell = KATP channel.

  • When glucose is abundant it enters cells through glucose transport proteins (GLUT) and metabolism increases.
  • This increases [ATP] within the cell causing the KATP channel to close. Intracellular [K+] rises, depolarising the cell.
  • Voltage-dependent Ca2+ channels open and trigger insulin vesicle exocytosis into the circulation.

When [BG] is low, [ATP] is low so KATP channels are open so K+ ions flow out removing +ve charge from the cell and hyperpolarizing it, so that voltage-gated Ca2+ channels remain closed and insulin is not secreted.

77
Q

PRIMARY ACTION OF INSULIN

A

Binds to tyrosine kinase receptors on the cell membrane of insulin-sensitive tissues to increase glucose uptake by these tissues.

In muscle and adipose tissue, insulin stimulates the mobilization of specific glucose transporters, GLUT-4, which reside in the cytoplasm of these cells.
When stimulated by insulin GLUT4 migrates to the membrane and is then able to transport glucose into the cell. When insulin stimulation stops, the GLUT-4 transporters return to the cytoplasmic pool.

Most types of tissue do NOT require insulin to take up glucose, ONLY muscle and fat are insulin dependent.

78
Q

In other tissues glucose uptake is via other GLUT-transporters, which are NOT insulin-dependent.

A

GLUT-1 Basal glucose uptake in many tissues e.g. brain, kidney and red blood cells. GLUT-3 Similar
GLUT-2 beta cells of pancreas and liver

79
Q

The Liver and Glucose Uptake

A

The liver is not an insulin-dependent tissue. Liver takes up glucose by GLUT 2 transporters, which are insulin independent.

Glucose enters down concentration gradient.

However, although insulin has no direct effect on the liver, glucose transport into hepatocytes is affected by insulin status.

80
Q

ADDITIONAL ACTIONS OF INSULIN

A

a) Increases glycogen synthesis in muscle and liver. Stimulates glycogen synthase and inhibits glycogen phosphorylase.
b) Increases amino acid uptake into muscle, promoting protein synthesis.
c) Increases protein synthesis and inhibits proteolysis
d) Increases triacylglycerol synthesis in adipocytes and liver i.e. stimulates lipogenesis and inhibits lipolysis.
e) Inhibits the enzymes of gluconeogenesis in the liver

All of the above are anabolic processes – laying down energy stores – or inhibit catabolism

f) Promotes K+ ion entry into cells by stimulating Na+/K+ ATPase. Very important clinically.

81
Q

Stimuli which increase insulin release

A

Increased [BG]*****

  1. Increased [amino acids]plasma
  2. Glucagon (insulin required to take up glucose created via gluconeogenesis stimulated by glucagon)
  3. Other (incretin) hormones controlling GI secretion and motility e.g. gastrin, secretin, CCK, GLP-1, GIP. Released by ileum and jejunum in response to nutrients. Early insulin release prevents glucose surge when absorption occurs.
  4. Vagal nerve activity
82
Q

vagal activity on insulin

A

Vagal activity stimulates release of major GI hormones, and also stimulates insulin release, therefore meaning that the insulin response to an intravenous glucose load is less than the equivalent amount of glucose administered orally, ie:
i.v. glucose increases insulin by direct effect of increased glucose on beta cells.
Oral loading of same amount of glucose increases insulin by both direct effect on beta cells and vagal stimulation of beta cells, plus incretin effects!

83
Q

Stimuli which inhibit insulin release

A
  1. Low [BG]
  2. Somatostatin (GHIH)
  3. Sympathetic alpha 2 effects
  4. Stress e.g. hypoxia
84
Q

Glucagon

A

Peptide hormone produced by alpha-cells of the pancreatic islet cells in same fashion as all peptide hormones.
Primary purpose is to raise blood glucose. It is a glucose-mobilizing hormone, acting mainly on the liver.

85
Q

Actions of Glucagon

A

Primarily opposes the action of insulin, forming part of the glucose counter-regulatory control system which includes the hormones epinephrine, cortisol and GH. It is most active in the post-absorptive state.

Glucagon receptors are G-protein coupled receptors linked to the adenylate cyclase/cAMP system which when activated phosphorylate specific liver enzymes resulting in:

  • increased glycogenolysis
  • increased gluconeogenesis (substrates: aa’s and glycerol (lipolysis))
  • formation of ketones from fatty acids (lipolysis)

All these processes occur in the liver.

** Net result is elevated [BG]**

Glucagon doesn’t stimulate the breakdown of fat and protein, it just uses the products to make glucose.

86
Q

Amino acids are also a potent stimulus for glucagon secretion. What would happen if it wasn’t?

A

While changes in [BG] have opposite effects on insulin and glucagon:

increase glucose - increase insulin and decrease glucagon
decrease glucose - increase glucagon and decrease insulin

Amino acids in the plasma stimulate release of both insulin and glucagon.
This is an adaptation to adjust for the composition of a meal very high in protein (typical of carnivores!).

A high protein meal with very little carbohydrate -
aas - increase insulin - decrease [BG]
aas - increase glucagon - increase [BG]

If it were not for the effect of aas on glucagon, then the insulin-stimulating effects of aas would result in very low [BG]. This is counteracted by the glucose mobilizing effects of glucagon and so [BG] is maintained.

Most other tissues can readily use FFAs and ketones to produce energy.
In the post-absorptive state, lower insulin levels mean a large mass of tissue, i.e. muscle and fat, cannot readily access glucose and so there is glucose sparing for obligatory glucose users (brain).

87
Q

Stimuli that promote glucagon release

A
  1. Low [BG] (<5mM)
  2. High [amino acids] Prevents hypoglycaemia following insulin release in response to aa.
  3. sympathetic innervation and epinephrine, beta 2 effect
  4. cortisol
  5. stress e.g. exercise, infection
88
Q

Stimuli that inhibit glucagon release

A
  1. glucose
  2. free fatty acids (FFA) and ketones
  3. insulin (fails in diabetes so glucagon levels rise despite high [BG])
  4. somatostatin
89
Q

ANS innervation of islet cells

A

Generally:
increased parasympathetic activity (vagus) increase insulin and to a lesser extent increase glucagon, in association with the anticipatory phase of digestion.

increased sympathetic activation promotes glucose mobilization increases glucagon, increases epinephrine and inhibition of insulin, all appropriate for fight or flight response.

90
Q

Somatostatin (SS)

A

Peptide hormone secreted by D-cells of the pancreas (and hypothalamus aka GHIH).

  • Main pancreatic action is to inhibit activity in the GI Tract.
  • Function appears to be to slow down absorption of nutrients to prevent exaggerated peaks in plasma concentrations.
  • (Synthetic SS may be used clinically to help patients with life-threatening diarrhoea associated with gut or pancreatic tumours).

SS is NOT a counter-regulatory hormone (because it acts on glucagon and insulin to switch them off) in the control of blood glucose, but it does strongly suppress the release of both insulin and glucagon in a paracrine fashion.
-Patients with pancreatic SS-secreting tumours develop the symptoms of diabetes which disappear when the tumour is removed.

Aka GHIH it inhibits secretion of GH from the anterior pituitary.

91
Q

Effect of exercise on [BG]

A
  • The entry of glucose into skeletal muscle is increased during exercise, even in the absence of insulin.
  • Exercise also increases the insulin sensitivity of muscle and causes an insulin-independent increase in the number of GLUT-4 transporters incorporated into the muscle membrane.
  • This effect persists for several hours after exercise and regular exercise can produce prolonged increases in insulin sensitivity.

In non-active muscle, insulin binds to its receptor, which then leads to glucose transporters, GLUT4, migrating to the cell membrane, allowing glucose to enter.

In active muscle, GLUT4 transporters can migrate to the membrane without insulin being present, so exercise causes glucose uptake independently of insulin.
It also increases the sensitivity of the muscle to insulin.

92
Q

Starvation

A

When nutrients are scarce, body relies on stores for energy – when adipose tissue is broken down fatty acids are released.
FFA’s can be readily used by most tissues to produce energy and liver will convert excess to ketone bodies which provides an additional source for muscle and brain!
Important - After a period of starvation, the brain adapts to be able to use ketones.

This serves to “spare protein” which would otherwise be broken down excessively to provide gluconeogenic substrates. (Loss of protein -very weakening, vulnerable to infection). Last store to be depleted in starvation.

93
Q

Ketoacidosis in Diabetes Type 1

A

Diabetes similar to starvation – lack of access to nutrients.

When nutrients are scarce, body relies on stores for energy – when adipose tissue is broken down fatty acids are released. FFA’s can be readily used by most tissues to produce energy and liver will convert excess to ketone bodies which provides an additional source for muscle and brain!

HOWEVER, in poorly controlled insulin-dependent diabetes a lack of insulin depresses ketone body uptake. They build up rapidly in the plasma and because they are acidic create life threatening acidosis (ketoacidosis or ketosis) with plasma pH < 7.1. Death will occur within hours if untreated.
Ketones detectable in urine and produce distinctive acetone smell to breath.

94
Q

Thyroid Hormones (TH)

A

T3 (triiodothyronine) and T4 (thyroxine)

95
Q

Thyroid Gland Structure

Contains 2 cell types:

A
  1. C (clear) cells which secrete calcitonin (Ca2+ regulating hormone).
  2. Follicular cells which support thyroid hormone synthesis and surround hollow follicles.
96
Q

Thyroid follicles

A

Thyroid follicles are spherical structures whose walls are made of follicular cells. Centre of follicle filled with colloid = sticky glycoprotein matrix. Contain 2-3 months’ supply of TH.

97
Q

follicular cells

A

Follicular cells manufacture the enzymes that make thyroid hormones as well as thyroglobulin, a large protein rich in tyrosine residues.

The enzymes and thyroglobulin are packaged into vesicles and exported from the follicular cells into the colloid.

Follicular cells also actively concentrate iodide from the plasma and transport it into the colloid where it combines with the tyrosine residues to form the thyroid hormones.

Both tyrosine and iodide are derived from the diet.

Iodide enters the follicular cells from the plasma via a Na+/I- transporter (symport). The coupling to Na+ enables the follicular cells to take up iodide against a concentration gradient.
Iodide is then transported into the colloid via the pendrin transporter.

98
Q

Thyroid peroxidase (aka thyroperoxidase)

A

Enzymes exocytosed into the colloid, along with the thyroglobulin, catalyses the addition of iodide to tyrosine residues on the thyroglobulin molecule. (In the process iodide loses an electron to become iodine).

Addition of one iodine to tyrosine - MIT (monoiodotyrosine).
Adding a second iodine - DIT (diiodotyrosine).

MIT and DIT then undergo reactions where:
MIT + DIT - triiodothyronine or T3, or
DIT + DIT - tetraiodothyronine or Thyroxine T4.

You can only add up to 2 iodides to tyrosine, after that you have to put the tyrosine’s together.

Reaction catalysed by thyroid peroxidase located on the apical membrane of the follicular cells.

99
Q

Thyroid hormone release

A

In response to TSH, portions of the colloid are taken back up into the follicular cell by endocytosis. Within the cells they form vesicles which contain proteolytic enzymes that cut the thyroglobulin to release thyroid hormones.

Both T3 and T4 are lipid soluble (despite being amine hormones) and so pass across the follicular cell membrane into the plasma where they bind to plasma proteins, mainly thyroxine-binding globulin. Transporter proteins may also be involved in this process as rare mutations in this protein cause major disruption to TH balance.

Both T3 and T4 circulate in the plasma

100
Q

Circulating TH

A

More than 99.8% of T3 and T4 circulates in plasma bound to plasma protein.
Thyroxine Binding Globulin (TBG) has particularly high affinity for T4 releasing it only slowly into the plasma. This partly accounts for the longer half-life of T4:
T4 ~ 6 days; T3 ~ 1 day
Only free hormone exerts an inhibitor effect on TSH and TRH.

101
Q

T3 vs T4

A

Most TH circulates in the form of protein bound T4 ~100nmoles/l, while T3 is only ~2.3nmoles/l (note: free TH is in picomolar range (1000x smaller)).

50x more total (free+bound) T4 in plasma than T3

However, 90% of TH binding to TH receptors inside cells is T3.
The TH receptor has a much higher affinity for T3 than T4 making T3 3-5 times more physiologically active than T4

T4 is deiodinated to T3 by deiodinase enzymes. Around half the T4 is deiodinated in plasma, the remaining fraction being deiodinated inside target cells. The level of deiodinase activity can be altered at different times in different tissues to suit demand.

102
Q

Regulation of Thyroid Hormone Release

A

continuous stable secretion by TRH from hypothalamus.
cold, exercise and pregnancy upregulate.
SS inhibits TSH (TH required for GH action)
glucocorticoids inhibit TSH, and stop conversion of t4 to t3

103
Q

Thyroid Hormone Function

A

TH bind to nuclear receptors in target cells, where they change transcription and translation to alter protein synthesis.

  • raises metabolic rate and promotes thermogenesis, typically through promoting futile cycles of simultaneous catabolism and anabolism.
  • increase hepatic gluconeogenesis, although no effect on BG providing pancreas is releasing adequate insulin (therefore not a counter regulatory hormone)
  • net increase in proteolysis
  • net increase in lipolysis

-critical for growth (lack of TH results in retarded growth)
- stimulates GH receptor expression
essential for brain development in utero (maternal iodine deficiency = congenital hypothyroidism/cretinism)

104
Q

Hyperthyroidism causes

A

Causes
• Graves’ Disease (common) - antibodies produced that bind mimic TSH and continually activate the thyroid gland. Increased release of TH switches off TSH release from anterior pituitary so [TSH]plasma very low. Thyroid gland may be 2-3x normal size due to hyperplasia. Hyperactivity of cells also apparent.
• Thyroid Adenoma (rare) - hormone-secreting thyroid tumour

105
Q

Graves’ Disease

A

antibodies produced that bind mimic TSH and continually activate the thyroid gland. Increased release of TH switches off TSH release from anterior pituitary so [TSH]plasma very low. Thyroid gland may be 2-3x normal size due to hyperplasia. Hyperactivity of cells also apparent.

106
Q

hyperthyroidism Symptoms

A
  1. Increased metabolic rate and heat production
    • weight loss/ heat intolerance
  2. Increased protein catabolism
    • muscle weakness/weight loss
  3. Altered nervous system function
    - hyperexcitable reflexes and psychological disturbances
  4. Elevated cardiovascular function.TH is permissive to epinephrine, beta receptors
    • increased HR/contractile force, high output, cardiac failure
107
Q

Hypothyroidism Causes

A
  • Hashimoto’s Disease - autoimmune attack of thyroid gland
  • Deficiency in dietary iodine – only 50mg/year(!) required but many areas of the world soil has insufficient quantities. Main source of dietary iodine was table salt which was enriched with iodine. But no longer in the UK! Milk, Fish, seafood and seaweed are good sources.
  • Idiopathic – no known cause, may be linked to thyroiditis.
108
Q

Hypothyroidism symptoms

A
  1. Decreased metabolic rate and heat production
    • weight gain/cold intolerance
  2. Disrupted protein synthesis
    • brittle nails/thin skin
  3. Altered nervous system function
    • slow speech/reflexes, fatigue
  4. Reduced cardiovascular function
    • slow heart rate/weaker pulse
109
Q

Goitre

A

Both hypo- and hyperthyroidism are often accompanied by significant enlargement of the thyroid gland
-Termed goitre

  • Goitre formation may be caused by increased trophic action of TSH on thyroid follicular cells (hypothyroidism) or over-activity as a result of autoimmune disease (Graves’ Disease)
  • results in hypertrophy (overgrowth) of thyroid gland
110
Q

Hypothalamus

A

Integration centre for endocrine systems

  • Located at the base of the brain, below the thalamus,
  • Connected to the pituitary via a stalk (infundibulum)
111
Q

Pituitary gland

A

Bean-shaped and bean-sized endocrine gland (~14 mm diameter)

  • Located in a pocket in the sphenoid bone, directly below the hypothalamus
  • Contains 2 distinct types of tissue – anterior and posterior pituitary
112
Q

Hypothalamic-pituitary hormones

A

Both the hypothalamus and the anterior pituitary release tropic and non-tropic hormones (tropic hormones govern the release of another hormone)

  • All hormones released by the hypothalamus are neurohormones.
  • All hormones released by the posterior pituitary are neurohormones (from the hypothalamus).
  • All hormones released by the anterior pituitary are classic endocrine hormones.

Two forms:

  1. Tropic – neurohormones secreted into capillaries travelling to anterior pituitary. Govern release of anterior pituitary hormones
  2. Non-tropic – neurohormones produced in the hypothalamus and travel to posterior pituitary (via axons of hypothalamic neurons) where they are released into blood.
113
Q

Hypothalamus – Anterior Pituitary Axis

A

All hypothalamic tropic hormones bind to receptors on anterior pituitary and stimulate/inhibit release of AP hormones

  • There are at least 5 hypothalamic “releasing hormones”
  • Thyrotropin Releasing Hormone (TRH)
  • Corticotropin Releasing Hormone (CRH)
  • Growth Hormone Releasing Hormone (GHRH)
  • Gonadotropin Releasing Hormone (GnRH)
  • Prolactin Releasing Hormone (PRH)

And 2 hypothalamic “inhibiting hormones”

  • Growth Hormone Inhibiting Hormone (GHIH) aka somatostatin
  • Dopamine aka Prolactin Inhibiting Hormone (PIH)

All are peptides, except dopamine

114
Q

Hypothalamo-hypophyseal portal system

A

Network of tiny vessels which transfer trophic hormones from hypothalamus to anterior pituitary

  • Small numbers of neurosecretory neurons sufficient for control
  • Hormones released from neurosecretory neurons at the median eminence
  • Very small amounts of hormones required
  • Short distance – very rapid and dynamic
115
Q

The anterior pituitary

A

True endocrine organ
Connected to hypothalamus via hypothalamic-hypophyseal portal system (two capillary beds connected in series)
The production of anterior pituitary hormones is controlled by hypothalamus
Hypothalamus does this by producing “releasing” or “inhibiting” trophic hormones, (sometimes called factors), that stimulate or inhibit hormone production from the anterior pituitary e.g. Thyrotropin Releasing Hormone (TRH) stimulates AP to secrete Thyroid Stimulating Hormone (TSH).
6 hormones are released from the anterior pituitary gland, all peptides;
5 of these are also tropic hormones

116
Q

anterior pituitary hormones

A

TSH, ACTH, FSH, FH, GH, prolactin

117
Q

The posterior pituitary

A

stores and releases 2 peptide neurohormones:

  • vasopressin (aka anti-diuretic hormone; ADH)
  • oxytocin

-these are synthesised in magnocellular neurons which have their cell bodies in specific areas of the hypothalamus

  • different subsets make either vasopressin or oxytocin
  • axons project down the infundibulum to posterior pituitary
  • do not synapse with other neurons, their terminals end directly on capillaries

hormones synthesised in the hypothalamus and transported to the nerve terminal in posterior pituitary ready for release
-activity in these neurons results in release of vasopressin or oxytocin directly into the blood stream at the posterior pituitary

Neuro (9 decks)

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