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Flashcards in Endo (General) Deck (501):
1

2

which are the 2 most common  endocrine disease

diabetes melltius

thryoid disease

 

3

what's the difference between primary and secondary endocrine disorder

a primary endocrine disorder: the defect is in the cells that secrete the hormones.

secondary disorder is lack of hormone or its receptor - there is too much or too little tropic hormone.

4

where is the pituitary gland found 

in the sella turcica just below the optic chiasm 

  • The pituitary gland is located behind the eyes on a stalk, known as the infundibulum, at the base of the brain (below the third ventricle, hypothalamus and the optic chiasm). The pituitary gland is enclosed within the sphenoid bone.
  • The pituitary is physically connected to the hypothalamus through the pituitary stalk; it is also connected functionally by the hypophyseal portal circulation and supraoptic-hypothalamic tract.

5

what's the relationship between hemianopias and pituitary tumours

 

Pituitary tumours put pressure on the optic chiasm and lead to hemianopia.

because the pituatary gland sits in a pit in the midline just above the optic chiasm, tumours press on this and cause deficits in the periphery of visual fields

6

describe the development of, and the anatomy of the pituitary gland

Divided into the anterior lobe (adenohypophysis) and the posterior lobe (neurohypophysis)

The anterior pituitary develops from an upgrowth of the lining of the mouth (Rathke’s pouch) and the posterior lobe develops from downward growth of the diencephalon (neural).

The anterior pituitary is much larger, and forms a cup around the posterior pituitary

7

describe the formation of the posterior lobe of the pituitary gland

as the 3rd ventricle forms it pushes the tissue down to form the neural portion of the adult pituitary gland

this becomes the NEUROHYPOPHYSIS (posterior lobe) 

8

describe the function of the posterior pituitary 

The posterior lobe of the pituitary gland is controlled by magnocellular neurons that project from the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus.

Axons project into the posterior pituitary gland along the hypothalamic-hypophyseal tract. 

secretes hormones including oxytocin and vasopressin (ADH).

9

what are neurophysins

Neurophysins are carrier proteins that transport the hormones along the axons of magnocellular neurons to the posterior pituitary, these are also synthesised in the PVS and SON as they are parts of the precursor molecules.

10

describe how oxytocin and vasopressin are released from the pituitary 

These hormones are synthesised in the PVN and SON of the hypothalamus, and then transported along the magnocellular neurons to the posterior pituitary.

The posterior pituitary stores oxytocin and vasopressin within axon terminals, until hypothalamic neurons fire and cause the hormones to be released into the blood via the inferior hypophyseal artery.

 

11

describe the function of the anterior pituitary

Secretions of the anterior lobe are also controlled by neuronal factors secreted from the hypothalamus.

Releasing hormones are synthesised in the PVN, they then travel down magnocellular neurons (aided by neurophysins), which terminate in the external layer of the median eminence.

From here the hormones pass into the primary capillary plexus, through the hypophyseal portal veins and into the secondary capillary plexus in the anterior pituitary.

These releasing hormones reach their target cells in the anterior pituitary and stimulate protein synthesis and secretion either through AC-cAMP-PKA-CREB or PLC/IP3/Ca pathways. Hormones are then released into general circulation.

12

what does the hypophyseal portal system consist of 

primary capillary plexus

hypophyseal portal veins

secondary capillary plexus

13

list the hormones (not releasing hormones) secreted by the anterior pituitary 

growth hormone (GH)

thyroid stimulating hormone (TSH)

 adenocorticotropic hormone (ACTH)

follicle-stimulating hormone (FSH)

luteinising hormone (LH) 

prolactin (PRL).

14

list the releasing hormones secreted by the hypothalamus

growth hormone releasing hormone (GHRH) - 44aa

 growth hormone inhibiting hormone (GHIH)

 thyrotropin releasing hormone (TRH) - 3aa

 corticotropin releasing hormone (CRH) - 41aa

 gonadotrophin releasing hormone (GnRH) - 10aa

 prolactin inhibiting hormone (PIH)

15

how is prolactin release controlled

There is currently no known releasing factor for prolactin, however it appears to be under dominant negative control, where dopamine is the main inhibitory factor

After the pituitary stalk is damaged, the first effect will be increased prolactin levels.

16

describe the histology of the adenohypophysis, and what is seen with a H&E stain

The bulk of adenohypophysis is the pars distalis, composed of winding cords of epithelial cells flanked by vascular sinusoids.

H&E stain reveals three cell types amongst the epithelial cells, this reflects differences in hormonal content; acidophils, basophils, chromophobes

17

which colour do acidophils stain with H&E, and what kind of cells are they (and what hormones do they produce)

stain red/orange

they're cells that contains polypeptide hormones

1. somatotrophs - produce GH

2. Lactotrophs - produce prolactin

18

which colour do basophils stain with H&E, and what kind of cells are they (and what hormones do they produce)

stain blue

they're cells that contain glycoprotein hormones:

1. thyrotropes - thyroid stimulating hormone

2. gonadotropes - LH or FSH

3. corticotropes - adrenocorticotrophic hormone

19

which colour do chromophobes stain with H&E, and what kind of cells are they (and what hormones do they produce)

stain very poorly

they're cells that have minimal or no hormonal content

 Many of the chromophobes may be acidophils or basophils that have degranulated and thereby are depleted of hormone

Some chromophobes may also represent stem cells that have not yet differentiated into hormone-producing cells.

20

what is the function of thyrotrophs

secrete TSH

TSH stimulates thyrotrophs to produce TSH, it also stimulates prolactin release from lactotrophs

21

what is the function of gonadotrophs

to release LH, and FSH 

these stimulate steroid biosynthesis and germ cell maturation in the gonads 

22

what is the function of corticotrophs

to release ACTH (Adrenocorticotrophic hormone)

 stimulates steroid biosynthesis in adrenal cortex 

23

what is the function of somatotrophs

release somatotrophin aka GH

to stimulate growth bia IGF-1 (insluin-like growth factor)

24

what is the function of lacotrophs

produce lactin

this stimulates lactation 

25

describe the structure of TSH, LH and FSH

heterodimeric glycoproteins 

 they have identical alpha sub-units and differing beta sub-units that confer speciality

26

describe the structure of ACTH

ACTH is a 39aa peptide produced by the post-translational processing of POMC gene (pro-opiomelanocortin)

Other products include alpha-melanocyte stimulating hormone (MSH) and beta-endorphin.

27

describe the structure of GH and prolactin (PRL)

GH and prolactin are peptides with similar structures and both have internal disulphide bonds at equivalent positions

They are able to stimulate each other’s receptors (homologus receptors)

28

describe the intermediate pituitary lobe

(remnant of the hollow of the anterior pituitary forming around the posterior pituitary)

Pars intermedia is closely associated with pars nervosa (posterior) and separated from pars distalis (anterior) by the hypophyseal cleft.

MSH is the main hormone secreted from pars intermedia.

In adulthood, pars intermedia is either very small or entirely absent.

29

describe the control of the synthesis and secretion of anterior pituitary hormones 

under dual control of;

1. hypothalamic releasing hormones 

2. hypothalamic inhibitory factors 

these hypothalamif factors are synthesised in the parvicellular neurones and are screted at the median eminence of the 3rd ventricle 

30

describe the role of Thyrotrophin Releasing Hormone (TRH)

stimulates thyrotrophs to produce TSH

 it also stimulates prolactin release from lactotrophs

31

describe the role of Gonadotropin-Releasing Hormone (GnRH)

stimulates gonadotrophs to produce LH and FSH (gonadotrophins)

32

describe the role of Corticotropin Releasing Hormone (CRH)

stimulates corticotrophs to produce ACTH

33

describe the role of Growth Hormone Releasing Hormone (GHRH)

stimulates somatotrophs to produce GH

34

what are the 2 pathways by which hypothalamic releasing hormones work 

35

describe the dual control pathway of GH secretion

36

what is the rule regarding the control of the anterior pituitary, and what is the exception to that rule

anterior pituitary stimulated by hypothalamic releasing hormones (& may be suppressed by hypothalamic inhibitory factors)

Prolactin appears to be under dominant negative control by dopamine (from arcuate nucleus) ∴ stimulus = less inhibition

37

describe and give examples of the short-loop negative feedback in the anterior pituitary

stimulus to anterior pituitary is controlled by negative feedback loops within the pituitary itself.

LH and FSH decrease frequency and amplitude of GnRH impulses.

GH suppresses subsequent synthesis and secretion of GHRH

38

describe and give examples of the long-loop negative feedback in the anterior pituitary

these are hormone signals arising from outside of the hypothalamo-pituitary complex. Examples include the thyroid, gonadal and adrenal axes;

1. effects of gonadal steroids on GnRH - LH and fSH act on gonads which stimulate production of steroids which feedback on GnRH signal

2. effects of corticosteroids on CRH - ACTH acts on adrenal glands to produce corticosteroids which feedback to hypothalmus to turn off CRH

39

sumarise the Hypothalamo-pituitary-thyroid (HPT) Axis

40

summarise the Hypothalamo-pituitary-gonadal (HPG) Axis:

41

summarise the Hypothalamo-pituitary-adrenal (HPA) Axis:

42

describe how chronic stress override endocrine negative feedback mechanisms

Higher centres of brain can over-ride hypothalamopituitary drive to endocrine axes

Over-rides negative feedback on CRH and ACTH - causing hyperactivity in adrenal axis (increased cortisol)

 the hyperacitivty in the adrenal axis causes ;

1. Loss of GnRH (so stress is a contraceptive)

2. Loss of GHRH (so stress effects growth potential)

43

list some causes of funcational disconnections of the pituitary gland

1. cranial trauma - interrupt flow between hypothalamus and pituitary - stops releasing hormones and injure neuronal axis. also pituitary stalk commonly injured therefore loss of protection 

2. Pressure on the pituitary stalk, usually secondary to pituitary tumour, which causes occlusion of the hypophyseal portal circulation.

3. cytokines from inflammation or infection.

4. midline defects e.g. septo-optic dysplasias 

5. defects in migration of hypothalamic neurones e.g. Kellman's syndrome 

 

44

describe Kallman's syndrome

There is no migration of hypothalamic neurons and they end up in the nose causing anosmia (inability to perceive odor).

There is also hypogonadism, infertility and inability to start puberty.

45

which part of the pituitary does irradiation effect the most

Anterior pituitary cells are  sensitive to irradiation, causing progressie loss of cell function.

Somatotrophs (GH) are most sensitive.

46

name 2 examples of funcation pituitary tumours

very rare

1. prolactinomas

2. ACTH-hypersecretion

47

describe the effects of prolactinomas

Functional pituitary tumours

They're very rare. They secrete prolactin.

They cause infertility by supressing the HPG axis

Prolactinomas can be shrunk to an operable size by administering a dopamine agonist (bromocriptine)

48

describe the causes of ACTH hypersecretion

 

either from pituitary corticotrophs as in Cushing's disease

or ectopically from small cell lung tumours 

49

describe the effects of ACTH secretion in Cushing's disease

caused by hypersecretion of ACTH from adrenocorticotrophic anterior pituitary tumours, which are insensitive to cortisol negative feedback

 Patients will also be hyperpigmented with acanthosis nigricans (thickened dark patches of skin around groin and neck)

50

why is ectopic ACTH not supressed by cortisol

e.g. from small cell lung tumours

in HPA (Adrenal) axis cortisol suppresses CRH and this in turn supresses stimulus to ACTh synthesi and secretion

ectopic ACTh secretion isn't dependent on CRH and so will not be supressed by cortisol (which only supresses endogenous ACTH)

51

describe the effects of GH hypersecretion

Hypersecretion of GH from pituitary somatotrophs causes bones and cartilage to grow in infants causing gigantism

 In adulthood the epiphyseal plates have fused, thus only cartilage grows causing acromegaly

52

describe the effects of TSH hypersecretion

very rare 

most measurements of raised TSH reflect under-active thyroid gland or assay errors

53

describe the structure of oxytocin

Oxytocin is a nine amino acid peptide that is synthesized in hypothalamic neurons

 Oxytocin is also secreted from a few other tissues, including the ovaries and testes

Oxytocin differs from ADH in two of the nine amino acids

 Both hormones are packaged into granules and secreted along with carrier proteins called neurophysins

54

describe the role of oxytocin in the stimulation of milk ejection

55

 how does the suckling reflex causes milk ejection

baby suckles → stimulates mechanoreceptors in mammilary gland tissue → signal to hypothalamus and stimulate release of oxytocin and prolactin

oxytocin caused increases milk ejection (via ducts)

prolacin causes ncreased milk production 

56

describe the role of oxytocin in uterine smooth muscle contractions at birth

57

describe the role of oxytocin on the establishment of maternal behaviour

58

describe 2 neural reflexes that mediate oxytocin secretion

1. suckling reflex - The act of nursing or suckling is relayed within a few milliseconds to the brain via a spinal reflex arc. These signals impinge on oxytocin-secreting neurons, leading to release of oxytocin

2. the Fergusson reflex - released during labour to stimulate contraction of uterine smooth muscle, this is a positive feedback loop

59

how can crying stimulate lactation in mothers

strong neural reflexes, which release prolactin as a result of baby’s cry and mechanical stimulation

60

describe the structure of hydrophilic hormones

they're peptide/protein hormones

Rendered water-soluble by virtue of the polar peptide bonds and/or the polar amino-acid side-chains (catecholamines are hydrophilic hormones because they possess numerous polar hydroxyl groups)

The water-solubility of glycoprotein hormones is increased further by the additional presence of N-linked and/or O-linked carbohydrate chains

Prostaglandins, while lipid derivatives, are rendered hydrophilic by the presence of a carboxylic acid group

unable to pass through the hydrophobic core of the plasma membrane

THEREFORE, to influence the activity of intracellular enzymes, the binding of hydrophilic hormones to their cell surface receptors must initiate a transmembrane signalling pathway that typically involves second messengers and protein kinase/phophatase enzymes

61

describe the structure of hydrophobic hormones

  • In general, these are non-polar molecules, often comprising cyclic carbon structures which may be derivatives of:
    • cholesterol (as for the steroid hormones)
    • tyrosine (as in the case of the thyroid hormones).
    • or derivatives of the fat-soluble vitamins, A & D.
  • Hydrophobic hormones can diffuse across the plasma membrane to interact directly with intracellular receptors
  • In the unbound state, these receptors can be located either in the cytoplasm or in the nucleus (dependent on the precise identity of the receptor)
  • In either event, ligand-activated receptors must translocate into the nucleus and dimerise in order to bind to DNA and exert their actions as ligand-dependent transcription factors, either increasing or decreasing the rate of transcription of target genes

62

give examples of hydrophobic hormones

Steroid hormones – progesterone, cortisol, aldosterone, testosterone, oestradiol

Thyroid hormones – thyroxine, MIT, T4, T3

fat-soluble vitamins

63

how are the the plasma concentration of a peptide/protein hormone or catecholamine controlled

at both the level of hormone synthesis and at the level of secretion.

64

describe the relationship between rate of secretion and rate of synthesis of hydrophilic hormones

their rate of secretion is directly proportional to the rate of their synthesis

65

which kind of hormone is heaptic metabolism more relevant to

more important for the clearance of hydrophobic than hydrophilic hormones

66

Where (in a target cell) might you find the receptor for a hydrophobic hormone?

nucleus

cytosol

67

In general, how do hydrophilic hormones affect metabolism?

Activation of transmembrane signal transduction pathways – generation of second messengers – activation of protein kinases and or phosphatases – phosphorylation/ dephosphorylation of enzymes

68

In general, how do hydrophobic hormones affect metabolism?

Activation of intracellular receptors – "ligand-dependent transcription factors" – bind to DNA and affect the level of expression of target genes (including enzymes)

69

Suggest 3 possible reasons why the homeostatic relationship between X and Y might fail:

1. defect in synthesis and/or secretion of hormone X

2. defect in action of hormone X

3. defect in the ability of the gland that synthesises hormone X to respond to the solute Y

70

Suggest 4 possible reasons why the negative feedback between hormones "C" and "B" might fail

1. Defect in the synthesis of hormone "C"

2. Defect in the secretion of hormone "C"

3. Defect in the cellular response(s) to hormone "C"

4. Ectopic production of hormones "A" and/or "B" outside the normal endocrine axis.

71

Assume that hormone "C" acts to increase the concentration of "S".

Explain what would happen to the concentration of the stimulatory hormone "A" and of the solute/ion "S" if a mutation in the receptor for hormone "C" were to render the patient resistant to the actions of this hormone?

Loss of negative feedback by hormone "C" would lead to increased concentration of hormone "A" Loss of stimulatory action of hormone "C" would allow concentration of the solute "S" to fall

72

Which of the factors listed above (if any) is NOT relevant in determining the concentration of the steroid hormone, progesterone?

Rate of secretion – since steroids are hydrophobic such that rate of secretion (by diffusion) is determined by the rate of synthesis

73

Indicate how each of these have to change in order to decrease the concentration of a hydrophilic hormone

74

gove exmaples of hormones sensed by nuclear receptors

 steroid and thyroid hormones

75

why are nuclear recetpors classified as transcription factors 

because they have the ability to directly bind to DNA and regulate the expression of adjacent genes

76

how does ligand binding to nuclear receptor affect gene expression

ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up-regulation or downregulation of gene expression.

77

describe what happens when ligands bind to type 1 nuclear receptors

Ligand binding to type I nuclear receptors in the cytosol results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HREs)

Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat)

78

give examples of type 1 nuclear receptors 

androgen receptor

oestrogen receptors

glucocorticoid receptor

progesterone receptor

79

descibe the domans of nuclear receptors

N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 in the E-domain to produce a more robust upregulation of gene expression.

DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers that binds to specific sequences of DNA called hormone response elements (HRE)

Hinge region: Thought to be a flexible domain that connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution

Ligand binding domain (LBD):  The structure of the LBD is referred to as an alpha helical sandwich fold in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread")The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling".Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand

C-terminal domain: Highly variable in sequence between various nuclear receptors.

80

how do type 2 nuclear receptors work

Type II receptors, in contrast to type I, are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA

In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins

 Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins

Additional proteins including RNA polymerase are then recruited to the NR/DNA complex that transcribes DNA into messenger RNA

81

what's the function of type 3 nuclear receptors

referred to as orphan receptors - have no known endogenous ligands

 Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity

 These receptors hence may function as metabolic sensors

82

what's the function of type 4 nuclear receptors

Bind as monomer or dimers but only a single DNA binding domain of the receptor binds to single half site.

83

how are hydrophilic hormones found in the plasma

Hydrophilic hormones can dissolve in the plasma without needing transport by binding proteins, although there are exceptions (about half of the catecholamines are loosely bound to plasma albumin).

84

describe the difference between endocrine, paracrine, autocrine, and juxtacrine hormones

Endocrine - Act on cells far from the site of release. Are secreted into the blood. Only target cells express the receptor, e.g. insulin and adrenaline

Paracrine - Act on nearby cells only. They diffuse in the interstitial fluid and are rapidly inactivated by local enzymes, e.g. histamine

Juxtacrine - The hormone is either bound to the membrane (this requires physical contact between cells) or the hormone is secreted into the extracellular matrix

Autocrine - Act on the cell that released the hormone, e.g. T-cells and interleukin-2

85

describe the basic structure of hormone receptors

86

name and give examples of the 4 types of hormone receptors

87

explain the generalised signal transuction process

1. Hormone is released. The hormone may enter into the bloodstream in order to reach targets all over the body, or may only be released into the tissue fluid, to reach nearby cells

2. Hormone binds to receptor on plasma membrane of cell. Hormone binding induces a conformational change in the receptor's cytosolic region that alters its function

3. This causes an increase in the concentration of second messenger inside the cell, which amplifies the hormone effect

4. Effectors in the cytosol, which may be pumps, enzymes or gene transcription factors are stimulated or inhibited by the 2nd messenger

5. The signalling pathway is shut down. Effectors return to original state, and messengers are removed or become ineffective.

 

88

describe what generally happens when a hormone binds a g-protein coupled receptor

Hormone-bound receptor causes the exchange of GDP for GTP, activating the Gα subunit. The (dissociated) Gα subunit then interacts with an enzyme, until it hydrolyses the GTP to GDP, becoming inactive again (takes seconds to minutes)

89

which kind of responses are g-protein coupled receptors involved in

They are involved in responses to hormones, neurotransmitters, odours, tastes, and light

90

describe the 4 groups of G alpha sybunits ate their actions

Gs - activates adenylyl cyclase, increasing [cAMP]
Gi - inhibits adenylyl cyclase, reducing [cAMP]
Gq - activates phospholipase C, increasing [DAG], [IP3] and [Ca++]
Gt - activates retinal cyclic GMP phosphodiesterase

91

whcih specific part of the g-protein coupled receptor interacts with the g-protein alpha subunit

The 3/4 and 5/6 cytosolic loops

92

what's the role of the Gβγ in g-protein coupled hormone receptors

may alter specificity of receptor-G-protein binding (help determine which receptors interact with which g-protein)

co-operate in transduction

 shut the pathway down

93

describe what happens when adrenaline binds at the β-Adrenergic Receptor

the β-Adrenergic Receptor activates Gs alpha

PKA has 2 catalytic and 2 regulatory subunits

  1. Adrenaline comes, binds to receptor, changes conformation of the 3,4 5,6 loops à now they’re able to interact with g-protein
  2. Cause g-protein to drop GDP and pick up GTP from inside cell à changes shape of Gs alpha subunit which can therefore no longer bind to beta and gamma subunits which go away
  3. The alpha subunit interacts with the adenylate cyclase and activates it (AC only active as long as it binds to the Gs alpha subunit)
  4. The AC now active can convert ATP into cAMP
  5. cAMP binds to PKA, and releases the catalytic subunits which then phosphorylate lots of different proteins

94

describe the activation of the heterotrimeric G-protein at the molecular level 

Switch II is hidden by the βγ subunits. switch 2 forms a alpha helix

the extra phsophate from GTP stabilises the helical switch 2

The stabilised switch II interacts and activates adenylyl cyclase

When the GTP is hydrolysed, switch II becomes disordered.

95

what's the effect of vibrio cholerae toxin on the heterotrimeric g-protein

it inhibits the ability of Gs α to breakdown GTP into GDP 

THEREFORE: Overactive adenylyl cyclase in enterocytes of intestine - responsible for watery diarrhoea

96

describe how PKA is able to alter metabolic pathways both long-term and short term

The binding of 4 x cAMP to the two R subunits causes them to dissociate from the catalytic subunits, activating them.

SHORT TERM: Protein kinase A phosphorylates several enzymes, such as hormone-sensitive lipase (+), acetyl CoA carboxylase (-), glycogen synthase (-)

LONG TERM: it also phosphorylates the transcription factor CREB (+).

Protein kinase A is thus able to immediately alter metabolic pathways, and have longer term effects via gene transcription

97

describe the structure of PKA

Protein kinase A, an R2C2 heterotetramer, is a serine/threonine kinase.


It recognises the consensus sequence:Arg,Arg,X,Ser/Thr,Z
The regulatory subunits have the sequence: Arg,Arg,Gly,Ala,Ile
 

98

what are the effects of the cAMP/PKA pathway on the liver (and which are the relevant hormones)

adrenaline, NA, glucagon

to increase glycogenolysis and gluconeogenesis

99

what are the effects of the cAMP/PKA pathway on the adipose tissue (and which are the relevant hormones)

adrenaline and ACTH

increases lipolysis

100

what are the effects of the cAMP/PKA pathway on the ovarian follicles (and which are the relevant hormones)

FSH, LH

Increased synthesis of oestrogen and progesterone

101

what allows our cells to be so sensitive to small concentrations of hormones

1. The adrenaline:receptor complex is able to catalyse GDP:GTP exchange on multiple G-proteins.
Each activated Ga subunit can only bind to one adenylyl cyclase.

2. Each active adenylyl cyclase can catalyse the formation of many molecules of cAMP.
It take 4 molecules of cAMP to activate 2 x PKA subunits.

3. Each active PKA subunit can phosphorylate many proteins.

102

describe receptor enzymes

These receptors have an extracellular ligand-binding domain, and an enzyme active site on the intracellular section, connected by a single transmembrane segment.

  1. Many of these enzymes are tyrosine kinases (RTKs), e.g. the insulin receptor.
  2. There are also some with serine/threonine kinase activity.
  3. Another group have guanylyl cyclase activity (convert GTP to cGMP)

In these receptors, ligand binding either activates the enzyme activity, or brings it in proximity to its target.

103

describe receptor tyrosine kinases 

These functions as dimers, with an extracellular hormone-binding domain, and an intracellular protein tyrosine kinase domain.

Upon binding of hormone (many are growth factors), RTK monomers cross-phosphorylate each other.

Phosphorylation of the RTK makes it a site of attachment for proteins with SH2 domains, or PTB domains - localising proteins at the membrane.

For the insulin receptor, cross-phosphorylation causes the kinase to become fully active.

104

describe how the epidermal growth factor works 

1. Binding of EGF to each EGFR monomer induces a structural change that allows the monomers to dimerize. Proximity of the cytosolic domains allows cross-phosphorylation


2. Tyrosine-phosphates act as docking sites for Grb-2, which is attached to Sos


3. Sos catalyses the exchange of GDP for GTP on membrane-bound Ras, activating it


4. GTP:Ras binds and activates Raf, a membrane-bound protein kinase

 

5. A series of protein kinases are phosphorylated and activated, resulting in the phosphorylation of several transcription factors, altering their activity.

105

what is Sos and how does it work

Sos is a guanine nucleotide exchange factor (GEF)

it catalyses the exchange of GDP for GTP on the Ras protein

But only when it has been recruited to the membrane via Grb-2.
 

106

what is Ras, and how does it differ to heterotrimeric G-proteins

Ras is a small G-protein. Unlike the heterotrimeric G-proteins, Ras is monomeric

Ras also has a slower GTPase activity than heterotrimeric G-proteins

The GTPase activity can be greatly increased by GAPs (GTPase activating proteins)

Ras:GTP binds to, and activates, Raf

107

describe why some EGFR signalling can cause cancer

EGFR is overexpressed in some epithelial cancers.

In this case, a small amount of receptor can dimerize in the absence of ligand.

Since the tyrosine kinase activity is already present, this is enough to initiate signal transduction, thereby sending an inappropriate 'grow and divide' signal to the cell.

A therapeutic antibody can be used totargets the extracellular domain of the receptor, sterically blocking the ability of the receptor to dimerise.

This has been successfully used in colorectal cancers.

108

describe how insulin receptor signalling works

1. Binding of insulin to the dimeric receptor forces the PTK domains together, followed by cross-phosphorylation.
2. The first round of cross-phosphorylation fully activates the kinase activity, and is followed by more cross-phosphorylation.
3. These phosphorylated tyrosine residues act as docking sites for IRS-1 (insulin receptor substrate 1), which gets phosphorylated.
4. Phosphorylated IRS-1 can bind PI-3K (phosphoinositide-3 kinase), which, now located at the membrane, phosphorylates PIP2 at position 3, forming PIP3 (phosphatidylinositol-3,4,5 trisphosphate).
5. PIP3 allows both PDK1 (phosphoinositide-dependent kinase-1) and PKB (protein kinase B) to associate with the membrane via their PH (pleckstrin homology) domains.
6. Phosphorylated PKB dissociates from the membrane and phosphorylates its target proteins

109

which pathway pathway is responsible for GLUT4 translocation?

the insulin receptor signalling pathway

110

why is IRS-1 described as a docking protein

as it can bind many proteins, including Grb-2 (thereby activating the MAPK pathway)

111

where is IRS-1 normally found

IRS-1 is already associated with the membrane due to its PH domain, which can bind PIP2. Once phosphorylated, it can dissociate from the insulin receptor

112

 

There are other proteins that can assemble at the phosphorylated insulin receptor, including IRS-2, a homologous protein.

Insulin is therefore capable of simultaneously stimulating numerous pathways, involving short-term and long-term effects

113

what is TGF-β, and what is its role

The TGF-β family is a large family of proteins involved in regulating development

These signalling proteins normally prevent proliferation of most mammalian cells by inducing synthesis of proteins that inhibit the cell cycle

Most mammalian cells secrete at least one TGF-β isoform, and have receptors on their surface

Bone morphogenetic protein (BMP7 - a TGF B) induces bone formation in cultured cells and is now used clinically to strengthen bone fractures

TGF-β proteins also play a role in tissue organisation, promoting expression of extracellular matrix proteins and adhesion molecules

114

explain how TGF-β causes activation of its receptor

TGF-β binds to TBR-II, whose serine/threonine kinase activity is constitutively active.

This allows it to bind to TBR-I, and phosphorylate its glycine-serine rich (GS) domain, activating the S/T kinase activity.

TBR-I can then phosphorylate a class of transcription factors called R-Smads.

Upon phosphorylation, two R-Smads and a Co-Smad form a heterotrimer, and the nuclear localisation signals are also exposed.

In the nucleus, the heterotrimer interacts with transcription factors to cause expression of particular target genes.

115

describe why the link between TGF-β and cancers

The TGF-β receptor pathway often inhibits growth in cells.

Loss of either TBRI or TBRII function due to inactivating mutations is found in many human tumours.

These tumours are resistant to growth inhibition by TGF-β.

Mutations in the Smad proteins also prevent TGF-β signalling, most human pancreatic cancers contain a deletion in Smad4 (a Co-Smad).

116

describe the structure of cytokine receptors

Cytokines are a family of small (~160 aas) signalling molecules, with a characteristic arrangement of four alpha helices, controlling the growth and differentiation of a number of cells.

Cytokine receptors do not have an intrinsic enzyme activity, rather they recruit an enzyme.

The receptors all have a tyrosine kinase called JAK bound to their cytosolic domains, which phosphorylate transcription members of the Signal Transduction and Activation of Transcription (STAT) family.

Although cytokine receptors can activate other pathways, e.g. the MAPK pathway, the JAK/STAT pathway is normally only activated by cytokines.

117

what is erythropoietin

Erythropoietin is a cytokine released by the kidney in response to low oxygen

It stimulates the transcription of genes in erythroid progenitors that prevent them from undergoing apoptosis, and stimulate them to differentiate into erythrocytes (RBCs)

The use of supplemental erythropoietin to increase the level of erythrocytes in the blood is banned in international athletic competitions

The use of supplemental erythropoietin is also dangerous, as the surplus erythrocytes can clot small blood vessels. Several athletes have died of stroke during exercise due to erythropoietin doping

118

describe how the erythropoietin receptor works

1. A JAK2 kinase with low activity is bound to the cytosolic domain of EpoR

2. Epo simultaneously binds two EpoRs, bringing the JAK kinases close enough for each to phosphorylate the 'activation lip' of the other. This lowers the Km of the kinase for its substrate, activating it

3. The JAK kinases phosphorylate the receptors allow STAT5 to bind (via SH2 domains), and also get phosphorylated

4. The phosphorylated STAT5s dissociate from the receptor, dimerise, exposing a nuclear localisation sequence

5. The STAT5 dimer enters the nucleus and its DNA-binding domain binds to specific DNA regulatory sequences to control the expression of target genes

119

describe how the JAK/STAT Pathway is switched off, and the importance of this

SHP1 is a phosphotyrosine phosphatase,that binds the phosphorylated receptor and dephosphorylates JAK kinase, inhibiting the pathway when cytokines are no longer binding to the receptor

A mutant version of the erythropoietin receptor was discovered in an athlete that caused them to have higher levels of RBCs than normal, despite unusually low levels of erythropoietin

This mutant receptor was missing some of the tyrosines normally phosphorylated during signal transduction

The receptor was able to bind and activate STAT5, but was unable to bind the SHP1 phosphatase, resulting in increased intracellular signalling in the erythroid progenitor cells, and more RBCs than usual

120

what are the 2 main functions of the pancreas

exocrine - acinar cells. and these screte into ducts and channels which carry products outside of body/into body cavities (salivary glands, sweat glands, pancreas mammillary glands etc)

endocrine - islets of langerhans

121

describe the anatomical position of the pancreas

Lies deep in the stomach

Tail is close to spleen

Head is encircled by duodenum

122

which 3 parts does the pancreas consist of 

LOBULES: acinar cells that secrete enzymes & fluid

DUCTS: intercalated ducts joint to form pancreatic duct - this fuses with common bile duct before emptying into the duodenum

ISLETS OF LANGERHANS: dedicated to endocrine function 

123

describe the nerve supply of the islets of langerhans

Sympathetic adrenergic input: Splanchnic nerve – from coeliac plexus

Parasympathetic cholinergic input: Vagus nerve

124

list the types of cells found in the islets of langerhans

α cells - Glucagon

β cells - Insulin

δ cells - Somatostatin

PP cells - Pancreatic polypeptide

125

describe the structure and formation of insulin

126

what is the function of prohormone convertases 1 and 2

to cleave pro-insulin to produce insulin, and proglucagon into glucagon

127

what does preproglucagon give rise to

Processed by prohormone convertases 1 and 2

Differential processing in alpha cells vs L-cells

glucagon in the alpha cells of the pancreas

GLP1, GLP2 in L-cells

128

what's the paracrine role of somatostatin

suppresses insulin and glucagon

129

what is the role of pancreatic polypeptide

Secreted after eating and suppresses appetite

130

what is the role of Islet Amyloid PolyPeptide (IAPP or amylin)

appears to supress insulin secretion

131

summarise the actions of inulin and glucagon with respect to hypo and hyperglycaemia 

132

list the factors that stimulate insulin secretion

  • EATING A MIXED MEAL: ↑Glucose , Amino acids, Gut hormones released postprandially - (GLP-1, GIP = INCRETINS)
  •  Glucagon
  • AUTONOMIC INNERVATION: Acetylcholine . Alpha1 adrenergic receptors, Beta2 adrenergic receptors

133

list the factors that inhibit insulin secretion

↓ Glucose

• Somatostatin - intraislet pancreatic somatostatin, Gastric somatostatin

• Alpha2 adrenergic receptors (species dependent)

134

describe the process fo insulin secretion (from glucose uptake)

  1. Glucose sitting outside the cell is brought to the pancreas, it enters cell via GLUT2
  2. It undergoes glycolysis and releases atp → Rise in ATP:ADP ratio and this leads to closure of ATP-sensitive potassium channel
  3. Leads to accumulation of potassium and depolarisation there à leads to opening of voltage-gated calcium channel which lets calcium in
  4. Calcium binds to the storage granules which contain insulin → degranulation → fusion of vesicles with cell membrane → release

135

list the factors that stimulate and those that inhibit insulin secretion

136

list the factors that stimulate somatostain secretion

137

describe the roles of Endocrine vs Paracrine Somatostatin

138

describe the role of insulin in carbohydrate metabolism 

↑ blood [ glucose ] stimulates release of Insulin:

• Facilitates entry of glucose to tissues, especially in: Liver, Muscle, Adipose

• Stimulates the liver to store glucose in the form of Glycogen

139

which is the organ that can either take up or release glucose

liver

140

what is glucose disposal, and what are the 2 kinds 

it's the rate of uptake into peripheral tissue

it can be either inslin mediated, or non-inlsulin mediated mediated

Insulin mediated: Skeletal muscle + adipose tissue

 Non-insulin mediated: CNS + other tissues

141

how does insulin facilitate glucose uptake

facilitated diffusion via hexose transporters such as GLUT4 (major transporter in muscle, adipose)

in the absence of insulin GLUT4 stored in cytoplasmic vesicles

when insulin comes along you get fusion of vesicles and Insertion of glucose transporters in plasma membrane

142

describe the structure of hexose transporters

143

where is SGLUT1 expressed, and what are its characteristics

Intestinal mucosa, kidney tubules

 

Cotransports one molecule of glucose or galactose along with two sodium ions

Does not transport fructose.

144

where is GLUT-1 expressed, and what are its characteristics

Brain, erythrocyte, endothelial cells, fetal tissues

 

Transports glucose (high affinity) and galactose, not fructose

145

where is GLUT-2 expressed, and what are its characteristics

Liver, pancreatic beta cell, small intestine, kidney

 

Transports glucose, galactose and fructose.

A low affinity, high capacity glucose transporter

serves as a "glucose sensor" in pancreatic beta cells

146

where is GLUT-3 expressed, and what are its characteristics

Brain, placenta and testes

 

Transports glucose (high affinity) and galactose, not fructose.

The primary glucose transporter for neurons.

147

where is GLUT-4 expressed, and what are its characteristics

Skeletal and cardiac muscle, adipocytes

 

The insulin-responsive glucose transporter

High affinity for glucose

148

where is GLUT-5 expressed, and what are its characteristics

Small intestine, sperm

 

Transports fructose, but not glucose or galactose

149

describe the effects of insulin on the liver

150

what are 2 factors that stimulate glycogen reserve breakdown

absence of insulin

and

presence of glucagon

151

what happens to cells as blood [glucose] drops

Many cells become unable to take up glucose and switch to alternative fuels for energy eg. FA

Neurones need constant supply of glucose

152

how is fed glucose utilised

153

how is fasting glucose made and utilised

154

what's the role of Glycogen Synthase & Glycogen Phosphorylase in breakdown of glycogen

Both enzymes can be converted between active and less active forms using a system of protein kinases:

PKA phosphorylates and activates PKB, which activates GP

PKA phoshorylates and inactivates GS, which prevents cycling of glucose-1-P ⇒ Glycogen breakdown

155

explain the glycogen synthase/glycogen phosphorylase coordination

156

summarise the effects of phosphorylation on anabolism vs catabolism 

 ANABLOSIM = PHOSPHATASES (insulin)

CATABOLISM = KINASES (glucagon)

 

Insulin DEPHOSPHORYLATES By activating PHOSPHATASES This leads to net glycogen synthesis

Glucagon PHOSPHORYLATES By activating KINASES This leads to net glycogen breakdown

157

explain the process by which Glucagon Switches ON Glycogen Phosphorylase

158

describe the 2 ways in which Glucagon Switches OFF Glycogen Synthetase (GS)

159

describe the 2 ways by which Insulin Switches ON Glycogen Synthetase (GS)

160

describe the effects of insulin and glucagon on the liver

161

what are the important effects of insulin on lipid metabolism 

1. Promotes synthesis of fatty acids in the liver

2. Inhibits breakdown of fat in adipose tissue

Therefore from a whole body perspective, insulin has a fat-building effect

162

describe insulin's effect on TAG

ANABOLIC - Increases net TAG synthesis:

1. Activates acetyl-CoA carboxylase to generate malonyl CoA and therefore fatty acids

2. Inactivates hormone-sensitive lipase (HSL)

163

describe glucagon's effects on TAG

CATABOLIC - Stimulates net breakdown of TAG stores (spares glucose)

1. Inactivates acetyl-CoA carboxylase

2. Activates hormone-sensitive lipase (HSL)

164

describe how Glucose metabolism linked to Lipogenesis

• Pyruvate enters citric acid cycle – citrate can exit for FA biosynthesis (role for acetyl-CoA)

• Glycolysis generates α-phospho-glycerate – backbone of TAG

• Pentose phosphate pathway generates reduced cofactors for FA biosynthesis

165

explain glucagon's effect on Acetyl-CoA Carboxylase

166

describe insulin's effect on Acetyl-CoA Carboxylase

167

explain Hormone Sensitive Lipase's role in FA synthesis

168

why do glucagon and glucocorticoids upregulate HSL

To increase fat metabolism, to spare plasma glucose 

169

what is diabetes

A metabolic disorder of multiple aetiologies

Chronic hyperglycaemia

Disturbances of carbohydrate, fat and protein metabolism

Resulting from defects in:

insulin secretion

insulin action

or both

170

outline the 2 main types of diabetes

Type 1 Diabetes

ß-cell destruction

Absolute lack of insulin

Type 2 Diabetes

Defective insulin secretion (ß-cell dysfunction)

Insulin resistance

Relative lack of insulin

171

other than T2DM and T1DM, list some other types of diabetes

Maturity onset diabetes of the young (MODY)

Gestational diabetes

Other types of diabetes: Pancreatic / Endocrine / Drugs / Other genetic syndromes

172

describe continuum of diabates

173

list the signs and symptoms of diabates

Weight loss

Polydipsia (drinking too much)

Polyuria (too much urine)

Lethargy & general malaise

Recurrent infections (often skin or urine)

In type 2 often NO symptoms

174

outline the WHO criteria for the diagnosis of diabetes

175

what is Hb1AC

RBCs containing HB are exposed to glucose in the blood, and glucose enters RBCs via GLUT1

if it's not used for glyoclysis this glucose sticks to HB in non-enzymatic reaction (glycosylation) and this happens at the N-terminus of the Beta chain

 

The higher the glucose the faster the glycosylation - Normally 4-6%

Reflects average blood glucose over ~90 days

176

describe impaired glucose tolerance

Patient has trouble metabolising glucose 

  • stage of impaired glucose regulation
  • fasting plasma glucose < 7.0 mmol/L
  • 75g OGTT 2-hour value > 7.8 but < 11.1

177

describe impaired fasting glycaemia (IFG)

Patient has trouble controlling glucose even when they haven't eaten

  • fasting plasma glucose > 6.1 mmol/L but < 7.0
  • OGTT needed to exclude diabetes

178

how are and IGT and IFG managed, and why

Risk ↑ for CV disease ± diabetes IGT

2-5% per year progress to diabetes

Early treatment may reduce progression to diabetes:

  • Healthy eating advice / weight management / exercise effective in slowing progression
  • Metformin useful but less effective

Annual OGTT or HbA1c to diagnose diabetes

179

list the goals of diabates management

Manage symptoms

Prevent acute and late complications

Improve quality of life

Avoid premature diabetes-associated death

Provide an individualised approach

180

list 5 chronic complications of diabates

nephropathy - vessles in kidnyes start shutting off and cause renal failure

erectile dysfunction is an indication of: blood flow, nerve function and cardiovascular disease

181

briefly outline T2DM and its causes

Strongly linked to increase in obesity

182

what are the core defects of T2DM

1. ß-cell malfunction

2. Insulin resistance

183

outline treatments of T2DM

  • Diet and exercise Weight loss
  • Bariatric surgery?
  • Oral hypoglycaemic agents;
    • Sulphonylureas, metformin
    • Gliptins, thiazolidinediones, gliflozins
  • GLP-1 analogues
  • Insulin therapy

184

how can surgery be useful in treating diabetes/obesity

  • decrease in levels of glycated Hb (Hb1AC)
  • drop in fasting plasma glucose
  • patients can be on less diabetic medications 
  • drop in BMI

185

fill in this table for T2DM care strategy

186

in T2DM treatment, why do we give a lower limit of 6.5 for glycaemia levels

because hypoglycaemia kills faster than hyperglycaemia 

187

list 3 ways to monitor glycaemic control

188

briefly outline the 'patahology' of T1DM

Generally < 30 yrs

Beta cell destruction

↓insulin

Need insulin to survive

Absence of insulin causes ketogenesis

Ketoacidosis kills

189

list the factors that lead to T1DM

190

what is the treatment for T1DM

INSULIN

 

1-3 insulin injections/day of the same insulin

Multiple daily injections (4-5) with different insulins

Continuous subcutaneous insulin infusion (‘ pump ’)

191

what's the purpose of insulin anaolgues

Created to alter pharmacokinetics meaning alter how quickly the insluin appears in the blood

192

list the 3 kinds of insulin analogues

  1. inhibit hexamerisation → more rapid acting
  2. bind albumin → slow acting, longer lasting
  3. form insoluble depots under skin → ultra slow acting

193

describe this insulin Time-action curve

purple - works immediately

pink - inconvenient as when you eat blood sugar too high and then when the insulin arrives (late) the blood sugar goes down even more and so you get hypoglycaemia

dark blue - prolonged action

194

describe regimen tailor-made insulin

195

describe gestational diabetes mellitus 

During pregnancy - Macrosomia, resp distress, early delivery

macrosmia = larger baby normally caesarean needed

Resolves after delivery but may recur w/subsequent pregnancies

Risk factors: Obesity, family history T2DM, prev GDM

↑future risk of T2DM, hypertension

TREATMENT: Insulin, metformin Rx

196

describe MODY

Different genetic background to T2DM as it's monogenic T2DM is polygenic)

Strong family history of diabetes - autosomal dominant

Diabetes develops at an early age (<25 years)

6 genes identified so far: GCK, HNF1α, HNF1β, HNF4α, IPF1, NeuroD (not autoimmune - defect in insulin sceretion)

TREATMENT: Diet or tablets (don't treat with insulin)

197

list 4 causes of pancreatic diabates

surgery

pancreatitis 

cystic fibrosis (defects in endo and exocrine secretions)

tumours

198

list 2 causes of endocrinopathy-caused diabetes

Cushing's

acromegaly

199

list 3 drugs that carry risk of drug-induced diabetes

Glucocorticoids

thiazide diuretics

 ß blockers

200

list some genetic causes of diabetes 

MODY

Myotonic dystrophy, DIDMOAD

Insulin resistance syndromes

201

describe the pathophysiology of T1DM

202

describe the histological changes in a diabetic pancreas in T1DM vs T2DM

203

what are the effects of Lack of insulin in Type I Diabetes patient

Glucose transport and utilization reduced → ↑glucose

Lack of insulin → unopposed ↑glucagon

↑protein breakdown, ↑glycogenolysis, ↑gluconeogenesis, ↑hepatic glucose output, ↑lipolysis ↑ketogenesis (increased ketogenesis because TAGs broken down into FAs+ glycerol and FAs used to make ketone bodies)

Patient becomes catabolic

Becomes dehydrated because of polyuria

Progressive deterioration → decompensation, diabetic ketoacidosis, coma

 

204

how would a graph of plasma glucose concentrations of diabetics vs non-diabetics look

205

summarise the metabolic disturbances in T1DM

206

what are the 2 main characteristics of T2DM

Insulin resistance

ß-cell malfunction

207

why is T2DM described as a Complex Metabolic Disorder

involves a bunch of conditions

208

describe the mechanisms of insulin resistance 

209

describe the pathogenesis of T2DM

Often revealed by Long-term complications

210

explain the Interaction of genes, obesity and environment in T2DM

211

describe how dysfunctional adipose tissue can cause T2DM

adipose tissue can send distress signals (via cytokines which attract inflammatory cells - t-cells, macrophages etc) when it's no longer able to cope ⇒ presence of inflammatory cells leads to state of chronic inflammation throughout the body 

adipose tissue expams to accumulate the fat in subcutaneous tissue AND in visceral organs (lesser extent)

where the body can't store fat anymore in its normal deposits it starts putting it elsewhere (Ectopic fat) ⇒ this can be in the liver causing fatty liver disease or in the heart linked to cardiovascular disease or in the muscles or pancreas (in pancreas it leads to defects in insulin secretion 

212

list some complications of diabetes 

• Increased incidence of cardiovascular disease

• Peripheral vascular disease

• Renal disease (microangiopathy)

• Retinal disease (microangiopathy)

• Lens opacity (cataracts)

• Neuropathy (impaired nerve conductance): Autonomic (bladder, stomach, blood vessels, erections), Sensory, Motor

• Skin infections (gangrene, thrush and other yeasts)

• Osteoarthritis

213

describe the process of glycation of proteins in hyperglycaemia

Excess glucose increases glycation of Hb

 We use HbA1c as a easily accessible measure of glycaemia

HbA1c reflects average glycaemia over past 90 days or so (dependent on red blood cell life)

214

describe how increased glucose/lipids can cause nephropathy, neuropathy, retinopathy, atherosclerosis

215

describe the role of SOD (Superoxide dismutase) and how this is altered in diabetes

SOD's role is to detoxify free radicals and generate H2O2, which is disposed of in one of 2 ways:

1. catalse: H20 +O2

2. glutathione: H2O

BUT in diabetes we glycate SOD which inhibits the enzyme and so we get accumulation of free radicals which damage the cell

216

what causes increased oxidative stress in diabates, and why can that contribte to insulin resistance and β-cell dysfunction?

the increase in oxidative stress causes an internal inflammatory response linked to both insulin resistance and β-cell dysfunction

217

explain the effects of hyperglycaemia on the sorbitol pathway

When glucose levels are high, sorbitol and fructose accumulate in the cells since they diffuse relatively slowly and they aren't absorbed

This causes osmotic effects (water drawn into cells) which may damage cells such as lens cells and nerve cells

218

what causes retinopathy in diabetes

glycation of basement membrane, exudation, bleeding

219

what causes cataracts in diabetes

accumulation of polyols in lens

220

what causes neuropathy in diabetes

glycation of BM, blood supply to nerves blocked

221

what causes skin infections in diabetes

poor blood supply leads to poor healing, high glucose levels encourage pathogenic growth

222

what can you see here

223

what can you see here

224

what differences can you see in the retina of someone with Diabetic retinopathy vs normal 

225

what causes foot infections in T2DM

High levels of glucose make a rich medium for organisms infecting the skin

 Contributed to by damage to small blood vessels

 Sensory neuropathy leads to foot numbness and damage e.g. from ill-fitting shoes

226

what's the relation between T2DM and risk of cardiovascular disease

227

what's the relation between T2DM complications and HbA1c

228

how can T2DM cause heart attack

infiltration of the intima muscles with macrophages which produce cytokines which lead to proliferation of the smooth muscle layer underneath and they accumulate cholsterol and become called FOAM CELLS

these foam cells produce athersclerotic lesions which grown into the lumen of the blood vessel

when it grows large enough it blocks the flow of blood through the cessel

in a coronary vessel this leads to angina

when the clot ruptures and causes a thrombus you get a heart attack

229

3 ways in which diabetes can cause athersclerosis

Impaired Endothelial function:

↓NO production, therefore greater arterial contraction and reduced blood flow

Also increased platelet activation due to lack of NO

Modification of lipoproteins: 

LDL particles oxidised/glycated

Macrophages have receptors for AGE

Take up modified LDL to form ‘foam cells’

Proliferation of smooth muscle cells:

Macrophage activation

Chemokine release

230

Lowering HbA1c by 1% significantly reduces risk of

Diabetes-related death

Myocardial infarction

Microvascular complications

Peripheral vascular disease

231

What is the optimum HbA1C?

• It is not true that the lower you go the better things are

• ‘Normal’ HbA1c of <6.5% (<48 mmol/mol):

  • is difficult to achieve without causing hypos
  • may be associated with ↑mortality

• We aim for 6.5-7.5% (48-59 mmol/mol)

• Quality of life is paramount

232

Compare the effects of insulin and glucagon on the following processes. Put arrows on either side of the list to represent an increase, a decrease or no effect.

233

 Diabetes is a disease that affects an increasing proportion of the population, now of the order of ____ %. The majority of diabetics have the ____________ onset form also known as Type ___ diabetes or by the abbreviation ____________ . Diabetes may be due to a decrease in the secretion of the hormone _______________ , a hormone secreted by the______________ , or due to a ______________sensitivity to it. The latter condition may be treated by drugs such as __________________________________. The acute effects of diabetes result from increased concentrations of _________________ in the blood, leading to the symptoms of______________________ , _______________ and ultimately to ______ , after which death will ensue if not treated. In uncontrolled diabetes, there are also profound changes in lipid metabolism with large increases in the concentrations of _______________________ and _________________________________ . Oxidation of the former may give rise to the formation of ________________________________ with consequent decreases in the pH of the blood. In diabetes, protein metabolism is also affected and the most obvious symptom is ___________________ . Treatment of uncontrolled diabetes may be achieved by use of the hormone isolated from another species, usually the ________ . Recombinant human hormone is available, but gives rise to ______________ _______________  in a minority of patients

Diabetes is a disease that affects an increasing proportion of the population, now of the order of 5-7 %. The majority of diabetics have the late onset form also known as Type 2 diabetes or by the abbreviation NIDDM. Diabetes may be due to a decrease in the secretion of the hormone insulin, a hormone secreted by the pancreas, or due to a reduced sensitivity to it.

The latter condition may be treated by drugs such as biguanides. The acute effects of diabetes result from increased concentrations of glucose in the blood, leading to the symptoms of glycosuria, polyuria and ultimately to coma, after which death will ensue if not treated.

 In uncontrolled diabetes, there are also profound changes in lipid metabolism with large increases in the concentrations of non esterified fatty acids and triacylglycerols. Oxidation of the former may give rise to the formation of ketone bodies with consequent decreases in the pH of the blood. In diabetes, protein metabolism is also affected and the most obvious symptom is muscle wasting.

Treatment of uncontrolled diabetes may be achieved by use of the hormone isolated from another species, usually the pig. Recombinant human hormone is available, but gives rise to reactive hypoglycaemia in a minority of patients

234

someone presents with T2DM

He is emaciated due to loss of muscle and body fat. Possibly drowsy. Most likely an insulin - dependent diabetic Tests should be made to test for blood or urinary glucose and ketone bodies Immediately the breath should be smelt to see if is sweet Plasma insulin levels should be measured K + and bicarbonate should be determined to assess the need for correction of blood pH with bicarbonate. Has been treated successfully with insulin

235

What is the relevance of these chemical reactions to diabetes?

This can lead to the glycation of enzymes and structural proteins, irreversibly if AGEPs are formed

 Underlies many long term effects of diabetes

236

What does this reaction have to do with the differences in the retinas on the displayed photographs?

Lead to modifications (glycation) in the basement membranes of capillaries in the eye and other tissues

Formation of exudates due to overproduction of these glycoproteins and increased permeability and weakness

Bleeding into vitreous humour occurs - blindness

237

what part of the eye, other than the retina, could be affected by this reaction

Crystallin in lens glycated causing cataract

238

Why is the following reaction relevant to diabetes?

This is the sorbitol pathway found in liver and other tissues. Increased glucose concentrations increase this minor pathway by a mass action effect

Since the transport systems in most cells are slow for sorbitol and fructose, they tend to accumulate and cause osmotic disturbances.

239

How could this reaction influence cellular function in tissues outside the liver?

In sensitive cells such as the nerves, the osmotic effects cause cell damage and contribute to neuropathy, although other factors including protein glycation play a role

 They can cause distortion of the lens cells and also contribute towards problems with vision.

240

These days, few diabetics die after their condition has been diagnosed. However, they are at risk from other diseases that affect the non-diabetic population. This includes increased risk of _________ disease , the leading cause of death also among non-diabetics.

The elevated glucose concentrations leads to the _________ of proteins in which the amino acid residue _________ is modified by glucose reversibly to form a _________ base.

Further chemical reactions give rise to the formation of Amadori products and ultimately to the irreversible cross-linking of proteins and the formation of AGEP which is an abbreviation for ___________________________.

Examples of circulating proteins that may be modified by glucose to the first stage, are the complexes that carry cholesterol around in the blood and are known as __________________.

These may become cross-linked to proteins in the extracellular matrix of the arterial wall and are then recognised by receptors known by the abbreviation_________ on _________, a cell type that internalises the total protein complex, leading to pathological changes in the artery wall know as _________.

These days, few diabetics die after their condition has been diagnosed. However, they are at risk from other diseases that affect the non-diabetic population. This includes increased risk of cardiovascular disease , the leading cause of death also among non-diabetics.

The elevated glucose concentrations leads to the glycation of proteins in which the amino acid residue lysine is modified by glucose reversibly to form a Schiff's base.

Further chemical reactions give rise to the formation of Amadori products and ultimately to the irreversible cross-linking of proteins and the formation of AGEP which is an abbreviation for advanced glycation end products.

Examples of circulating proteins that may be modified by glucose to the first stage, are the complexes that carry cholesterol around in the blood and are known as low-density lipoproteins.

These may become cross-linked to proteins in the extracellular matrix of the arterial wall and are then recognised by receptors known by the abbreviation RAGE on macrophages, a cell type that internalises the total protein complex, leading to pathological changes in the artery wall know as atherosclerosis

241

Pancreas arises from dorsal and ventral outgrowths of ______. These outgrowths arise from the ______. 

endoderm

foregut

242

In neonate, islets are highly vascularised and receive both sympathetic and parasympathetic neural inputs from the following nerves respectively:

sympathetic nerve =

 parasympathetic nerve  = 

sympathetic nerve = splanchnic nerve

 parasympathetic nerve  =  vagus nerve

243

What proportion of the normal pancreas (% by mass) is endocrine tissue?

2%

244

How many amino-acid residues are there in total in:

 human insulin?

 human C-peptide?

glucagon ? 

 somatostatin ?

 human insulin: 51 amino acids

 human C-peptide: 35 

glucagon: 29 amino acids

 somatostatin: 14

245

How is insulin packaged prior to secretion?

Hexamers co-ordinated by Zn – surrounded by C-peptide

246

list some factors that increase insulin release

Increased [ glucose] 

Increased [ free amino-acids] 

Increased [ GI hormones] 

Increased [ glucagon ] 

Noradrenaline (at low conc.)

 Acetylcholine

247

list some factors that decrease insulin release

Decreased [ glucose ]

Pancreatic somatostatin

Gastric somatostatin 

Noradrenaline (at high conc.)

Adrenaline

248

Which of the following statements accounts for the phenomenon of insulin -mediated glucose disposal (IMGD) into skeletal muscle and adipose tissue?

A. insulin increases the synthesis of GLUT1

B. insulin increases the synthesis of GLUT4

C. insulin increases the insertion of GLUT1 into the plasma membrane

D. insulin increases the insertion of GLUT4 into the plasma membrane

D. insulin increases the insertion of GLUT4 into the plasma membrane

249

Insulin stimulates the synthesis of glycogen by glycogen synthetase whereas glucagon inhibits the activity of this enzyme. State two mechanisms via which glucagon inactivates glycogen synthetase:

1. Stimulates phosphorylation via cAMP-dependent kinase / PKA

2. Inhibits dephosphorylation by phosphoprotein phosphatase (secondary to stimulation of glycogen phosphorylase a)

250

Insulin stimulates the synthesis of fatty acids via polymer acetyl CoA carboxylase whereas glucagon inhibits the activity of this enzyme.

State three similarities between the control of acetyl CoA carboxylase and glycogen synthetase:

1. Inactivated by phosphorylation – activated by dephosphorylation

2. Both activated by insulin – insulin inhibits phosphorylation by cAMP-dependent kinase / PKA

3. Both inactivated by glucagon – glucagon increases phosphorylation by cAMP-dependent kinase / PKA

In addition, insulin stimulates activation of both enzymes by increasing activity of phosphoprotein phosphatase

251

Which protein kinase is inhibited by insulin but stimulated by glucagon to mediate antagonistic effects on the activity of glycogen synthetase?

cAMP-dependent kinase / PKA

252

which cells form the pancreatic islets of Langerhans

Some cells, which bud off from the pancreatic ducts, proliferate to form the pancreatic islets of Langerhans

253

how is recombinant insulin made

The two cDNA sequences encoding the α- and β-chains of insulin are translated in E.coli, isolated, purified and chemically combined with the 3 disulphide bonds at the appropriate molecular positions

254

the magnitude of the insulin response to oral intake of protein reflects the combined effects of the rise in plasma amino-acids and the increased levels of gastrin, secretin and CCK

255

list and explain 3 characteristic features of T1DM

hyperglycaemia - Lack of insulin action means glucose is not taken up and stored in muscle, liver and fat which causes increased circulating blood glucose levels

ketoacidosis - Muscle, liver and fat turn to other energy sources such as fatty acid. Increases production of acetyl CoA - condensed into ketone bodies which acidify the blood

osmotic diuresis - High circulating levels of glucose eventually overcome the ability of the kidneys’ glucose reabsorption systems so that glucose spills into urine

256

list and explain 2 characteristic features of T2DM

osmotic diuresis - High glucose levels in the urine combined with a high excretion of H+ as a result of the acidity, water flows into the bladder

Advanced Glycation End Products (AGEP) - When present at high levels in the circulation the glucose can covalently link to proteins in the blood or on walls of blood vessels, a process known as glycation

257

list some autoantibodies found to be associated with T1DM

islet cell autoantibodies (ICA)

insulin (IAA)

glutamic acid decarboxylase (GAA or GAD)

protein tyrosine phosphatase (IA2 or ICA512)

 

The number of antibodies, rather than the individual antibody, is thought to be most predictive of progression to overt diabetes

258

approximately 50% of the genetic risk for T1DM can be attributed to the HLA region

The highest risk HLA-DR3/4 DQ8 genotype has been shown to be highly associated with beta-cell autoimmunity

259

list some possible treatments for T1DM

Islet transplantation – some success but limited by availability of islets

Artificial islets approved in 2012

Immunosuppressive therapy of those at risk – in trial

Prophylactic injections of insulin or other preventative agents in those at risk of diabetes may delay onset of diabetes

260

what's the role of autoantibodies in the pathogenesis of T1DM

Although the role of autoantibodies in the pathogenesis of the disease is debated, their presence indicates a dysregulation of the humoral immune response

Circulating autoantibodies to beta cell antigens are present in the majority of patients with Type 1 DM. These autoantibodies can be detected before and at time of clinical diagnosis of disease

261

how do Anti-idiotypic antibodies regulate both autoantibody binding and their levels?

neutralizing autoantibodies

inhibiting the secretion of autoantibodies

 

 

here is an equilibrium between autoantibodies and their anti-idiotypic antibodies, preventing autoimmunity

B lymphocytes that produce autoantibodies function as autoantigen presenting cells. Inhibiting their binding to autoantigen by anti-idiotypic antibodies may prevent development of autoimmune disease

262

what's the main factor distinguishing T2DM from T1DM

Circulating levels of insulin distinguish T2 from T1DM.

 

Patients invariably have normal or excessive circulating levels insulin - pancreas is not completely destroyed. β-cells lose the ability to secrete insulin with progression

Severe insulin resistance is associated with accumulation of amyloid plaques in the β cells. May contribute to the death of pancreatic cells

Importantly most T2’s do not have islet cell antibodies. Suggests destruction of pancreas by non-immune mechanisms in T2DM

263

what are the different ways in which we can prevent IGT progression to DM

Lifestyle interventions aimed at weight loss of 5-10% of with moderate aerobic exercise such as brisk walking for 150 minutes a week are the most effective

Effective pharmacologic interventions include metformin, acarbose and orlistat

Although thiazolidinediones, such as rosiglitazone, can decrease the rate of progression to diabetes, they pose a significant risk of fluid overload and heart failure

264

Where does insulin resistance first arise

Insulin resistance arises first in muscle and fat and then at later stages in the liver

265

describe the (molecular) development of insulin resistance

266

describe the effects of insulin resistance of FAs, BP, androgen levels

n insulin resistance there is increased release of fatty acids into the circulation and then reconversion of these acids by the liver into triacylglycerols which are recirculated as VLDL in high concentrations (dyslipidaemia)

The high levels of insulin have other consequences – e.g. stimulation of some cells of the sympathetic nervous system leading to hypertension

n some cases it may increase androgen production by ovaries which contributes to the hormonal disturbances seen in PCOS – which may include masculinisation

267

describe the Glucose-stimulated Insulin Secretion mechanism

Glucose homeostasis relies critically on detection of variations in blood glucose concentrations by pancreatic beta cells, and their subsequent timely release of the appropriate amount of insulin

Glucose sensing by pancreatic beta cells requires glucose uptake and metabolism through the glycolytic pathway

 Activation of the Krebs cycle and oxidative phosphorylation generates ATP, and the increase in the ATP to ADP ratio induces plasma membrane depolarization by closing an ATP-dependent K+ channel

This leads to the opening of voltage-dependent Ca2+ channels, and the entry of calcium then triggers insulin granule exocytosis

Glucose uptake by beta cells is catalyzed by the low affinity, high-capacity glucose transporter GLUT2

GLUT2 expression is markedly down-regulated in conditions in which glucose-stimulated insulin secretion is lost

Feeding mice a high-fat diet, which is known to dysregulate insulin secretion, and is associated with a reduction of GLUT2 expression at the plasma membrane

In Fanconi–Bickel syndrome, caused by mutation of GLUT-2 often present with postprandial hyperglycemia and reduced insulin levels

Humans have in addition GLUT-1 and GLUT-3, which may compensate for the absence of GLUT-2

268

list some genes associated with MODY

MODY patients often present early in life

269

what is mitochondiral diabetes, causes, prevelance, and symptoms

Families with heritable form of diabetes inherited from mother with a variable penetrance

Caused by mutations in mitochondria (hence maternal transmission)

Accounts for 1-2% of all diabetes

 Often misdiagnosed as either T1 or T2DM

When mutant mitochondria predominate - oxidative capacity is reduced. In β-cells this results in reduced capacity to secrete insulin in response to glucose as insulin secretion is linked to glycolysis

Symptoms: e.g. muscle weakness, deafness, neurological problems and lactic acidosis, Maternally inherited diabetes and deafness (MIDD)

270

what is gestational diabetes

Severe insulin resistance caused by hormonal changes and metabolic stress of pregnancy

In women with low insulin secretory capacity this can result in a form of diabetes

Affects 2% of pregnancies of non diabetic women

Symptoms normally disappear after birth but 60% of these women go on to develop diabetes in later life

271

list some similarities and differences between T2DM and MODY

Similarities: no Islet cell antibodies, 0 cell destruction

Differences: patients age, autosomal dominant inheritance, no association with obesity

272

name some genes responsible for the different types of MODY

MODY1: Caused by mutations in Hepatic Nuclear Factor 4a (HNF-4a). Estimated to cause 1% of MODY. Insulin secretion normal at birth but decreases dramatically with age

MODY2: Caused by mutations in glucokinase thus affecting glucose sensing in pancreas. Estimated to cause 15% of MODY. Insulin secretion impaired at birth but remains relatively stable

MODY3: Caused by mutations in Hepatic Nuclear Factor 1a (HNF-1a). Estimated to cause 70% of MODY. Insulin secretion normal at birth but decreases dramatically with age

MODY4: PDX-1 transcription factor in 0 cells involved in regulating insulin gene expression. Estimated to cause 1% of MODY

MODY5: HNF 10 transcription factor. Estimated to cause 1% of MODY

MODY X: Estimated to cause 11% of MODY

273

Rare Conditions Which Have Similar Symptoms to Type-2 Diabetes

Antibodies to insulin receptor or to insulin

Mutations in insulin receptor (these can cause Leprechaunism)

 Glucagonomas

274

what is the effect of hyperthyroidism on diabetes

There is an increased occurrence of insulin resistance and diabetes in hyperthyroid patients – the reason is unclear

 

275

what is the effect of acromegaly and GH on diabetes

Around 60% of acromegalics are insulin resistant and around 20% are diabetic

GH acts as a counter regulatory hormone as shown by the fact that administration of growth hormone in normal subjects causes insulin resistance in insulin target tissues (very similar pattern to that seen for glucocorticoids)

growth hormone deficient children are hypoglycaemic

GH has no effect on insulin secretion

276

what is the effect of glucocorticoids on diabetes

Excess glucocorticoids from either endogenous sources (usually a tumour) or from exogenous administration clearly can induce severe insulin resistance and even frank Type-2 diabetes

The effects are mainly by causing insulin resistance in insulin target tissues

cell function is normal and there is a rise in compensatory insulin release

The diabetes is usually reversible if steroid levels are reduced

The mechanism may be an effect on IRS1 by decreasing the level of tyrosine phosphorylation of the protein

277

what is the effect of adrenaline on diabetes

Adrenaline counteracts the effects of insulin and also blocks insulin secretion

Excess adrenaline induced by conditions such as phaeochromocytoma or by exogenous adrenaline administration will stimulate breakdown of glucose stores in cells and decrease the ability of the body to clear glucose from the blood

Like glucorticoids, adrenaline is reported to decrease the tyrosine phosphorylation of IRS1

278

why can T1DM occur with other autoimmune conditions (and which)

Because it's an autoimmune disease, type 1 diabetes can occur along with other autoimmune diseases such as hyperthyroidism from Grave's disease or the patchy decrease in skin pigmentation that occurs with vitiligo

279

Signs of an emergency with type 1 diabetes include:

Shaking and confusion

Rapid breathing

Fruity smell to the breath

Abdominal pain

 Loss of consciousness (rare)

280

There are four main kinds of injectable insulin

The type of insulin you use will depend on your individual needs and lifestyle:

Short-acting insulin: e.g. Actrapid: soluble insulin starts working within 30 to 60 minutes and lasts six to eight hours. Insulin analogues start working within 15 minutes and last for up to five hours. Examples are insulin aspart, insulin lispro and insulin glulisine

Intermediate-acting insulin: isophane insulin starts working after one to two hours and lasts 10 to 14 hours. Examples are Humulin I and Insulatard

 Long-acting insulin: these start working after one to two hours and last for up to 24 hours. Examples are insulin zinc suspension, protamine zinc insulin, and the insulin analogues insulin glargine and insulin detemir. The latter two insulins are now the most widely used long-acting insulins

 Biphasic insulins : mixtures of short-acting and intermediate-acting insulins in different proportions, such as 30/70, 50/50. Examples are NovoMix 30, Humulin M3, Insuman comb and Humalog Mix25.

281

There are three common insulin regimes

Twice daily doses of short- and intermediate-acting insulin

These are given before breakfast and before the evening meal

The short-acting doses cover the insulin needs of the morning and evening

 The intermediate-acting doses cover the afternoon and overnight

The pre-mixed insulin injections are convenient for this type of dosing

Three times a day dosing

Short-acting and intermediate-acting insulin before breakfast

Short-acting insulin before the evening meal

Intermediate-acting insulin before bed

Moving the second intermediate-acting dose to before bedtime gives better coverage of the overnight period

Multiple daily doses

Short-acting insulin is used before each main meal

 An intermediate or long -acting insulin is used before bedtime to give coverage overnight

There are other types of regimes - for example diabetes in some older people can be adequately controlled with a single daily injection of long-acting insulin

282

when are we likely to use pump treatment of diabetes

Pump treatment is sometimes used in young people with diabetes

It involves a constant drip-feed of insulin throu gh a needle in the skin and extra insulin doses with meals

he feed is controlled by a small portable pump called an infusion pump

This treatment is now becoming more common where good blood glucose control cannot be obtained by multiple daily injections of insulin, or where hypoglycaemia is a major problem with injections of insulin

Multiple injections are increasingly being favoured, because they give the most flexibility and are most capable of mimicking natural insulin release

283

how do we measure patient compliance in diabetes

There is a correlation between A1c levels and average blood sugar levels as follows

 While there are no guidelines to use A1c as a screening tool, it gives a physician a good idea that someone is diabetic if the value is elevated

Right now, it is used as a standard tool to determine blood sugar control in patients known to have diabetes

284

what test do we give patients when the diabetes diagnosis is uncertain

A Glucose Tolerance Test

• The patient fasts overnight

• The patient rests during the test

• Smoking is not permitted

• A fasting glucose sample is taken

• A glucose solution is given by mouth (75g in 300ml water)

• Blood and urine samples are taken after 2hours

285

what is GH's role in hypoglycaemia 

when we're lacking energy GH has a role to preserve cognitive functions so it stops fat cells and muscles taking up the glucose via inuslin mediation and so it blocks some of insulin's actions to keep glucose in circulation to keep our brain functioning

286

what are possible OGTT results

287

Which of the following options is the single best way to determine whether there was an insulin secretory defect?

A. Absence of insulin

B. Absence of C-peptide

C. Presence of antibodies to β-cells

D. A and B

E. B and C

E. B and C

C-peptide is made in the same molar concentrations as insulin and because it's the shortest sequence it has an betterimmunogenic detection system than insulin 

we wouldn't measure insulin!!

288

Which form of Diabetes Mellitus is the most likely diagnosis from the following finding?

• Normal to high insulin

• Normal C-peptide

• No β-cells antibodies

• Aged 45

• Female

Type II DM

 

not gestational because of age, and not MODY because of age too

mitochondrial is very rare so not likely

not T1DM because normal c-peptide and is usually diagnosed earlier in life

289

Which form of Diabetes Mellitus is the most likely diagnosis from the following finding?

• Normal to high insulin

• Normal C-peptide

• No β-cells antibodies

• Aged 18

• Male

• Normal weight

• Mother normal

• Affected father

• No deafness

MODY

because young and normal weight

 

290

what does IFG mean

glucose values are at the top end of the normal range

291

when would you diagnose someone with IGT

raised levels of glucose seen after a glucose tolerance test showing abnormal glucose metabolism

292

We can gain an insight into how glucose metabolism has been regulated over a period of several weeks by measuring circulating levels of which factor?

Haemoglobin HA1c

293

We can gain an insight into how much insulin was secreted over a period of several days by measuring levels of which circulating factor?

C-peptide

294

The mechanism by which insulin resistance is manifested (not via dysfunction of glucose transport) on the proteins downstream of insulin binding, are called?

Insulin receptor substrates (IRS)

295

Tissues become less sensitive to insulin because of an increase in?

Lipolysis

the more you breakdown lipids the more FAs there'll be in circulation and high FA levels reduce insulin sensitivity

296

Diabetes might also be induced by interactions with other endocrine systems. In Cushing syndrome an excess of which circulating factor will cause insulin resistance?

Cortisol

297

Diabetes might also be induced by interactions with other endocrine systems. In Polycystic Ovarian Syndrome (PCOS) an excess of which circulating factor will cause insulin resistance?

Androgen

298

Diabetes might also be induced by interactions with other endocrine systems. In phaeochromocytomas an excess of which circulating factor will cause insulin resistance?

Epinephrine (Adrenaline)

299

Diabetes might also be induced by interactions with other endocrine systems. In acromegaly an excess of which circulating factor will cause insulin resistance?

Growth Hormone

300

You might recognise Maturity Onset Diabetes of the Young (MODY) by which of the following findings?

A. Young age and absence of obesity

B. Clear genetic inheritance

C. Normal to raised C-peptide levels

D. Absences of beta cell antibodies

`

E. All of the above

301

You might recognise Mitochondrially-Induced Diabetes Mellitus by which of the following findings?

A. Impaired glucose tolerance inherited from the maternal line

B. Reduced mitochondrial activity and deafness

C. Increased exercise tolerance

D. Both A and B

E. A, B and C

D. Both A and B

302

Which of the following options is used to treat Type 1 Diabetes Mellitus?

A. Dietary restriction

B. Sulphonylureas

C. Biguanides

D. Thiazolidinediones

E. None of the above

E. None of the above

303

In type 1 diabetic treatment insulin injections are used to bring about required metabolic changes. Select the best option for their mechanism of action?

A. Decreases glucose metabolism and suppresses gluconeogenesis

B. Decreases glucose metabolism and stimulates glycolysis

C. Decreases glucose metabolism and suppresses glycolysis

D. Increases glucose metabolism and suppresses gluconeogenesis

E. Increases glucose metabolism and stimulates gluconeogenesis

D. Increases glucose metabolism and suppresses gluconeogenesis

304

Summary Diabetic Treatment T1 T2

Type 1 • Insulin replacement

Type 2 (& other insulin resistance): • Insulin sensitizers • Diet and lifestyle • Co-morbidities • Other hormones • CHD

305

Where is GH secreted from, stored and released

GH is secreted from the somatotroph cells in the anterior pituitary

GH is stored and released from preformed granules

10% of pituitary dry weight

306

talk about the chemistry of GH

A single chain protein

2 disulphide bonds

2 forms: 22 kD (major)  OR 20 kD (minor)

Half-life = 15 mins

Similar to prolactin

307

what's similar about Somatostatin and GH (structure and mechanism)

Both GHRH (10aa) and somatostatin (14aa) are small hypothalamic peptides

Both act on G-protein coupled receptors on somatotrophs:

• GHRH activates adenylyl cyclase

• Somatostatin acts via an inhibitory G protein to inhibit adenylyl cyclase

308

which hormones sensitise somatotrophs to GHRH, and what does this cause

Androgens & oestrogens

This accounts for the pubertal rise in GH and the growth spurt

309

give exmaples of Metabolic products which influence GH release

Amino acids such as arginine stimulate GH release

 Glucose and free fatty acids suppress GH release

310

give 3 examples of factors that inhibit GH and 3 that stimulate

Inhibit GH: Cortisol • Glucose • Free fatty acids

Stimulate GH:  Arginine • Thyroid hormones • Gonadal hormones

311

how does GH promote growth and anabolism

via the GHR

both directly by tyrosine kinase activation and indirectly via IGF-1

312

which receptor superfamily is the GH receptor a part of

The GHR is a member of the cytokine receptor superfamily

313

explain the mechanism by which GH binds GHR

Binding of the hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane

Activated JAK2 phosphorylates the GHR on tyrosine residues, which in turn recruits members of the signal transducer and activator of transcription (STAT)

 STAT dimerization and translocation to the nucleus to modulate target gene transcription such as IGF-1 and SOCS (suppressor of cytokine signaling)

SOCS terminate the GH signal cascade

 

GH receptors must dimerise to get the functionality

Site 1 binding causes twist in other receptor so they come together, and brings the signaling molecules closer in the transmembrane area

Once the receptor is activated it activates a cascade of kinases called JAK

When GH binds it activates an intracellular mechanism to activate JAK2, which activates a downstream signaling pathway called the STAT signal à activated STAT can dimerise and translocate into the nucleus where they can activate a cascade of events

Once the receptor has been activated for amount of time it activated SOCS to turn off the GH signaling through that receptor

Lots of GH can desensitise its receptor

 

314

which syndromes are associated with insensitivity to GH vs excessive GH

Insensitivity to GH (Laron syndrome) can result from mutations in the GHR, whereas excessive activation results in gigantism and acromegaly

315

In humans there are 2 groups of receptors respond to GH:

Lactogenic receptors: both GH + PRL activate

Somatogenic receptors: only GH activates

316

how do we treat GH deficient children

Must treat GH deficient children with human GH

317

what are the physiological actions of GH

METABOLIC:

• Decreases glucose metabolism – opposing insulin

• Increases lipolysis

• Increases protein synthesis (anabolic)

• (increases milk yield in cows)

OTHER:

• Increases IGF production from liver etc

• Increases chondrocyte and cartilage formation

• INDIRECT ACTIONS via IGF-I

• GROWTH PROMOTION

• Clonal expansion of chondrocytes

• Growth of bones, soft tissue & viscera

318

describe the structure of IGF-1 vs insulin

319

describe the Major Role Of GH In Transforming Fibroblasts

320

describe how GH and IGF-1 act on the growth plate

321

when does GH become the most important factor for growth

GH is the dominant endocrine regulator of growth. However, for the first year, growth is largely dependent on nutrition as significant GH receptors appear at 7 months of age

322

when and why does growth stop

When puberty ends: Sex steroids have increased:  androgens in boys,oestrogens in girls

These close the growth plates and growth stops

323

what is aromatase, and when would you want to inhibit it

324

describe 2 methods we use to measure GH

1. immunoassay: ELISA (Enzyme Linked Immunosorbent Assay) since GH is a 22kDa protein

• Large-scale routine use

• Very precise and sensitive

• Does not measure biological potency directly - doesn't measure if GH active or not

2. bioassays:

• Used to measure potency of new batches of recombinant GH

• Rarely used to check bioactivity of patient GH

insensitive + imprecise

• in vitro/ immortalised target cells/ hGH receptor

• colorimetric/ luminescent responses via reporter genes

325

what are the 6 ways (not methods!!) in which we can measure growth

1. height vs age

2. rate of growth vs age

3. bone age/maturation

4. pubertal stages

5. height vs chronological age (population)

6. SD score

326

how do we measure growth in height vs age for less than 2yrs and more than

less than: supine length (lying down) 

more than: standing height, using a stadiometer, careful positioning, reproductible, repeat regularly

plot height vs years graph 

327

how do we measure growth in rate of growth vs age 

328

how do we measure growth through bone age/maturation 

329

how do we measure growth through pubertal stages 

• Delayed or precocious puberty?

• Assessed by staging : Pubic and auxillary hair, Development of boy’s external genitalia, Girl’s breast development

TANNER'S STAGE: pubertal maturation described in terms of sequences 

330

describe boy's tanner stage: development of external genitalia

Stage 1: Prepubertal

Stage 2: Enlargement of scrotum and testes; scrotum skin reddens and changes in texture

Stage 3: Enlargement of penis (length at first); further growth of testes

Stage 4: Increased size of penis with growth in breadth and development of glans; testes and scrotum larger, scrotum skin darker

Stage 5: Adult genitalia

331

describe girl's tanner stages: breast development

Stage 1: Prepubertal

 Stage 2: Breast bud stage with elevation of breast and papilla; enlargement of areola

Stage 3: Further enlargement of breast and areola; no separation of their contour

Stage 4: Areola and papilla form a secondary mound above level of breast

Stage 5: Mature stage: projection of papilla only, related to recession of areola

332

Tanner stages: Boys and girls - pubic hair stages:

1.Prepubertal (can see velus hair similar to abdominal wall)

2.Sparse growth of long, slightly pigmented hair, straight or curled, at base of penis or along labia

3.Darker, coarser and more curled hair, spreading sparsely over junction of pubes

4.Hair adult in type, but covering smaller area than in adult; no spread to medial surface of thighs

5.Adult in type and quantity

333

how do we measure growth with height vs chronological age (population)?

Appropriate reference population must be used

 Generations change, linked to improved nutrition and economic conditions

334

how do we measure growth with SD score?

a normalised system derived from the position of an individual on the population chart showing height v age i.e. Assessment 5

 

SD score = (observed – mean height )

SD for that age and sex

Normal SDS scores lie between –2 and +2

So we’d quote the SD and expect the normal population to lie within 2SDs of the mean (50th percentile)

335

describe the GH axis

GHRH is released from the hypothalamus à travels down the pituitary stalk to bind to the GHRH receptor which is on the surface of the somatotroph cells and stimulates them to produce and secrete growth hormone

 

We also have somatostatin neurons (anterior to GHRH neurons) and they also secrete their products into the median eminence à down pituitary stalk and binds to the somatostatin receptors on the somatotroph cell, and that inhibits GH secretion

 

Ghrelin (from stomach) is known to regulate GH secretion. Releases GH from anterior pituitary through its own receptor

 

The main growth actions in the body are mediated by IFF-1, causes a range of pastnatal body growth

So GH produces growth via its receptor but also through indirect actions such as IGF-1

 

IGF-1 and GH feedback through the normal negative feedback systems to control own secretion at both the pituitary and the hypothalamic level

336

what does GH need in order for it to be turned on

transcription facotr PIT1

337

Why does a one-off GH sample not tell you anything

because of the pulsatile release

338

where is the The human GH/ chorionic somatomammotropin (CS) locus

chromosome 17

GH-N is expressed preferentially in the somatotropes of the anterior pituitary, while GH-V and the CS genes are expressed in the syncytiotrophoblasts of the placenta

HS I and II are pituitary specific

 HS IV is placenta specific, and HS III and V are found in both pituitary and placenta but nowhere else

HS (hypersensitivity sites) are areas where gene transcription initiate

339

what is involved in the clinical observation in management of patients with growth disorders

Patient history: rule out multiple non-endocrine causes eg respiratory/ cardiac/ renal problems

Appearance: proportionate growth?

Anthropometric measurements: growth velocity/ bone ge/ pubertal stages etc

340

how do we usually Measure serum GH:

by immunoassay

Need 0.5 ml blood ⇒ Send to Chemical Pathology for immunoassay

 

341

describe the secretion pattern of serum GH, and how do we then test for serum GH

Pulsatile secretion

24 hr profile, taking blood samples every 20 mins

major peaks during sleep stages 3 or 4

delayed sleep/ delayed rise in GH

cannot interpret a single random sample

24 hr profile inconvenient for patient and lab

342

what abnormalities do these 2 graphs indicate

1st one shows classic idiopathic GH deficiency - absent or only feeble peaks

2nd one shows GH excess - continuous secretions of high GH, with absent pulsatility

343

what is the use of Dynamic Function Tests for GH secretion, and explain the types

Widely used: Deals with the problem of irregular secretion, two kinds

(a) Provocative tests

(b) Suppression tests

344

what happens to GH secretion with age

declines with age, during and after the 3rd decade of life

345

how do we measure IGF-1 levels

by immunoassay

not as widely used as GH measurements

confined to specialist centres

346

when do we measure IFG binding proteins

measured in specialist centres FOR DIFFICULT CASES

reasearch (not routine)

 

347

what GH did we use before as treatment, and what do we use now

nitially GH replacement was in the form of cadaveric pituitary GH as GH from other species does not stimulate growth in humans

The development of Creutzfeldt-Jakob disease (a degenerative brain disorder) in those who were treated with hGH produced in this way, led to the discontinuation of all products derived from the human pituitary gland

This has led to development of artificial (recombinant) hGH (rhGH) to treat children with growth disorders since 1985

An alternative approach to height augmentation employs agents that impede puberty and, in particular, oestrogen production (in both sexes), which is responsible for ultimate epiphysial fusion such as gonadotropin-releasing hormone agonists and, more recently, aromatase inhibitors

These approaches have been used as sole treatments or in various combinations, with varying efficacy and safety

348

list some Key points for diagnosis of classic idiopathic GH deficiency

• Proportionate growth/ normal appearance

Truncal obesity/ immature face

 Low rate of growth: low SD score

 No or poor GH response to an ITT provocation test

Nil or feeble peaks in a 24hr profile

 Low IGF1

349

how would we treat classic idiopathic GH deficiency

350

what condition does a GH-resistant patient have, and list some key points for diagnosis

laron syndrome

• Rare, autosomal recessive condition

• Very low SD score/ growth velocity

• Proportionate growth but with a very immature face

• NORMAL GH LEVELS

• Low IGF-1

351

describe the mechanism for Laron Syndrome

352

treatment for Laron Syndrome

ALL WE CAN DO IS MANAGE SYMPTOMS REALLY

Defective GH receptors:

• Recombinant hGH not effective

• Trials with recombinant IGF-1

Note: one patient described with partial deletion in gene for IGF-1:

• Severe intrauterine growth retardation

• Post-natal growth failure

• Sensorineural deafness/mental retardation/GH resistance

353

what dpes achondroplasia involve, and what is it due to

• Disproportional growth failure

• Short limbs

• Normal GH

• No response to GH treatment

• Defective chondrocyte growth in growth plates ⇒ Leads to short long bones and limbs

• Due to defective receptors for fibroblast growth factor (FGF)

• Therefore not responsive to GH as GH is not the problem

354

what does coeliac disease involve

355

what is the effect of Hypothyroidism on growth

356

effect of Juvenile Cushing’s Syndrome on growth

357

effect of Pseudohypoparathyroidism on growth

358

Turner's syndrome patient appearance

XO. the designation of a cell in an individual in whom only one sex chromosome is present. Either the other X or the Y chromosome is missing so that each cell is monosomic and contains a total of 45 chromosomes. All XO individuals are females with Turner's syndrome

359

what is Precocious Puberty

• Early sexual maturity

• Initially rapid growth

• But growth stops early

• Premature epiphyseal fusion

DUE TO: have enough calroies so GnRH signal get sturned on

360

effect of delayed puberty on growth

• Puberty after 15 years

• 1:50 prevalence

• M:F ratio is 6:1

• Growth slows around year 10

• Height falls below 3rd centile

• Bone age delayed by 2 years

• LH/FSH low

• GH normal

• Catch-up growth occurs

• Reaches full growth potential

361

what do we treat with OXANDROLONE, and what are its actions

delayed puberty

• Anabolic steroid

• Weak androgen

• Cannot be aromatised to oestrogen

• Therefore does not advance bone age or lead to growth plate closure. So does not shorten pre-pubertal window of time

• Stimulates growth of boys with pubertal delay: increases natural GH

• Lower doses used for girls

362

what does Anorexia Nervosa involve

• Prevalence 1:100 for females

• Hypothalamic turn-off  

• Low GnRH release

• Fasting GH and cortisol raised

363

effects of Intrauterine Growth Retardation

• Low birth weight

• Placental insufficiency?

• Poor catch-up growth

364

effects of Cranial Irradiation on growth

• E.g. for leukaemia or brain tumours

• Pituitary particularly radiation sensitive

• Low GH

365

which chronic illnesses impact growth the most?

Congenital heart disease

• Chronic obstructive or infective pulmonary disease

• Chronic renal failure

366

effects of Psychosocial Deprivation on growth?

• Emotional and social upheaval

• Hypothalamic turn-off

• Lack of GHRH

367

what is excessive GH secretion before puberty called, and describe the growth velocity compared to normal

gigantism

Prolonged pre-pubertal linear growth period prior to an exaggerated growth spurt

Results in excessive height attainment

368

what is the delayed puberty in gigantism due to

compromised pituitary function due to somatotroph compression of other pituitary cells in the restricted space of the sella turcica giving reductions in other pituitary functions

369

what causes the excessive GH secretion in gigantism

Due to a benign tumour of the somatotrophs

 Autonomous, unregulated, non-pulsatile GH secretion

 Note incidence of pituitary tumours: PRL > ACTH > GH

 LH / FSH / TSH very rare

370

how is gigantism diagnosed, and how is it treated (+complications of treatment)

Poor prognosis if untreated

Easily recognised syndrome.

The high SD score should be picked up in childhood and the tumour, which can be imaged with an MRI scan, removed surgically

After surgery:

• In some cases impaired endocrine function can recover, if the normal but compressed pituitary tissue has been preserved

• For others, difficulties in growth, development and sexual maturation may persist. Careful replacement therapy needed for a normal life

371

why is there no icreased height in acromegaly

post-puberty

No increased height possible because of oestrogen closure of growth plates

372

describe acromegaly onset

nsidious in onset

pituitary tumours in 25% at post mortem – usually stain for prolactin

373

which hormones altered in acromegaly, and what effects does this have

Raised GH causes raised IGF1

Gives rise to:

• Proliferation of bone, cartilage and soft tissues + increase in size of other organs

• Enlarged hands and feet, jaw protrusion and dental malocclusion

374

why does acromegaly increase risk of DM

Raised GH opposes insulin

 Increased risk of diabetes mellitus with associated symptoms:

• Polydipsia / polyuria / recurrent urinary tract infections / retinopathy / neuropathy

375

Acromegaly treatments

• Somatostatin analog (octeotride)

• Dopamine agonist (bromocriptine)

• Mutated GH which prevents receptor dimerisation/ activation

Surgical: • Transphenoidal route guided by MRI scan usually

• Transfrontal route if tumour is large

Radiotherapy: • Conventional supervoltage: slow effect in tumour reduction: often results in eventual hypothyroidism

376

what tends to be the cause of pituitary tumours

Mutations in classic oncogenes and tumor-suppressor genes are rarely associated with pituitary tumours

In fact, most mechanisms of endocrine tumourigenesis differ significantly from those associated with haematological malignancies and non-endocrine tumours

Instead, tumourigenesis is promoted by hormones and growth factors that are implicated in pituitary development

377

when do we use GH for children

• Growth hormone deficiency in children

• Growth hormone use following cranial irradiation

• Small for gestational age (SGA)

• Growth delay in children with chronic renal failure

• Turner Syndrome

• Prader-Willi Syndrome

378

when do we use GH for adults

Growth hormone deficiency continued into adulthood

379

what controls growth in the foetus, and what controls it in an infant

foetus: IGF-2

infant: nutrition rather than GH/ IGF-1 most important during year 1

380

describe the life-time growth velocity (+causes)

 

Postnatal growth rapid (15cm/y)

 Declines by 3 to a plateau (6cm/y)

At puberty GH/IGF-1 rise - get growth spurt

Oestrogens close the growth plates at the end of puberty in boys and girls

After puberty GH steadily declines throughout adult life resulting in :

• The "somatopause"?

• Central adiposity

• Decreased muscle mass

381

Growth hormone receptor-deficient people (Laron Syndrome) do not get two of the major diseases of aging, cancer and diabetes

Therefore GH activity in adults who are beyond their growing years may be harmful!

382

what's the formula for working out SD score

standard deviation score = (observed height - mean height for age and sex)/ SD for that age and sex

normal values then lie between -2 and +2

383

signs and symptoms of acromegaly

The Head • Large tongue • Interdental separation - separation of teeth due to alveolar bone growth • Prominent supraorbital ridge • Prognathism - growth of the mandible leading to a jutting jaw • Visual field defects • Goitre - due to generalised visceral enlargement • Headaches

The Body • Galactorrhoea • Hirsuties

• Heart failure • Generalised organomegaly - increase in size of heart, kidney, spleen, liver etc. • Hypertension • Impotence • Amenorrhoea

The Limbs • Increase in size of hands and feet • Tight-fitting rings • Carpal tunnel syndrome • Proximal myopathy • Arthropathy • Oedema

 

The most common presenting complaint is that of a change in appearance. This is can be seen by studying old photographs

Acromegaly usually presents as a subtle disease with the clinical features developing over many years

Some patients may present with galactorrhoea as in some tumours, both somatotrophin and prolactin are secreted

 Approximately a quarter of acromegaly patients have an impaired glucose tolerance due to the increased gluconeogenesis produced by the growth hormone.

384

4 tests for diagnosis of acromegaly

An important test in the diagnosis of acromegaly is the glucose tolerance test. The patient is given a 75g glucose meal, and blood tests are taken at half-hourly intervals. In a normal patient the growth hormone levels will be suppressed, but in the acromegaly patient the growth hormone levels are unsuppressable

 Another unique test that can be used in the diagnosis of acromegaly is by the administration of TRH. This is a unique test as only in acromegaly will there be a doubling of the blood levels of growth hormone

Another test that is routinely done is the blood level of the somatomedins (IGF-1), which will almost always be raised in acromegaly

Imaging is obviously a very important part of the diagnosis. A routine plain radiograph of the skull will show an enlarged pituitary fossa in approximately 70% of patients with acromegaly. The best way to identify the tumour is by using a CT scan or an MRI scan

385

list some risks of obesity

T2DM

Hyperinsulinaemia

glucose intolerance

hypertension and stroke

coronoary heart disease

some cancers - breast, endometrial, ovarian, gall bladder, colon

obese people often suffer from metabolic syndrome - a group of risk factors that typically occur together, and increase the risk for coronary artery disease, and T2DM

these risk factors include central obesity, high BP, dyslipidaemia, hyperglycaemia, mild chronic inflammation 

386

describe the lethal tellow mutant mouse obesity model

mouse has ectopic expression of the agouti protein due to a deletion in the promotor

expression of this protein antagonises some neurons, and disrupts their function 

these neurons normally act to inhibit feeding behaviour, but in the mutant mice this is inhibited

387

describe the obese mouse obesity model

this mouse doesn't express the product of the ob gene: leptin

leptin is primarily secreted by the adipocytes, circulating levels reflect body fat

leptin acts on hypothalamus to depress apetite AND affects insulin signalling (absence causes insulin resistance)

if you give them leptin you see a dramatic reduction in weight, also seen in humans whose obesity is caused by chromosomal mutations causing leptin deficiency

BUT IN MOST OBESE HUMANS leptin levels are high, and they appear to show leptin resistance which may be due to decreased uptake across BBB

388

describe the diabetic obese mouse obesity model

doesn't express prodcut of db gene: so no leptin receptor (form that's invovled in signalling)

same phenotype as obese mouse

adminstering leptin however does NOT treat the obesity here

 

389

describe the traditional view of adipose tissue during fed vs fasting state 

fed: insulin stimulates glucose uptake which is used to synthesise TAGs. these are stored in large droplet for later use

fasting: low insulin or adrenaline stimulates lipolysis of stored TAG,a dn the released NEFA enter plasma as fuelf or other tissues

SO ADIPOSE TISSUE WAS SEEN SIMPLY AS A WAY OF STORING ENERGY FOR LATER USE

390

Describe the insulin signalling pathway in adipocytes (for immediate responses)

391

describe the insulin signalling pathway in adipocytes (proliferative effects)

392

how does brown adipose tissue stimulate heat 

non-shivering thermogenesis

upon stimulation by NA (beta 3 receptor) lipolyiss and FA oxidation are activated 

the proton gradient generated by the ETC is then waster via UCP1

 

393

describe some differences between white and brown adipose tissue

in brown, the TAG droplets are multilocular, the mitochondria are larger, and higher in density

it's highly innervated by the SNS, and the capillary network is denser (to distribute the heat around the body) 

394

describe the development of adipose tissue from stem cell to mature adipocyte 

395

which is the transcription factor necessary for adipogenesis

PPARy

an increase in adipogenesis is associated with smaller adipocytes, less ectopic deposition (in muscle, liver), and improved insulin sensitivity 

PPARy is also needed for maintenance of the adipocyte's differentiation 

 

396

what are thiozolidinediones, and what's their effects

synthetic ligands to PPARy (trasncription factor required for adipogenesis)

they increase adipogenesis 

they have been shown to increase insulin sensitivity, lower plasma glucose, and alter the secretory profile of adipose tissue away from the pro-inflammatory direction 

397

what are lipodystrophies, effects, symptoms and treatment

clinical disorders, often involving lipoatrophy or selective loss of adipose tissue from some regions

genetic or acquired

patients often have aspects of metabolic syndromes; dyslipidaemia, hypertension, insulin resistance

some symtpoms can be alleviated by adminstering adipocytokines such as leptin or adiponectin 

lipodystrophies highlight the benefit of adipose tissue

398

what happens in familial partial lipodystrophy 3, symptoms and cause?

progressive, gradual loss of subcutaneous adipose tissue from extremities, normally begining at puberty

increased deposition of TAG in muscles & liver

hypertriglyceridaemia, low HDL, severe insulin-resistance leading to diabtetes and othe rmetabolic irregularities 

caused by mutations of the gene coding for PPARy (2 mechanisms, on another card)

 

399

describe the 2 mechanisms by which familial partial lipodystrophy 3 causes mutation of gene coding for PPARy

1. DOMINANT NEGATIVE: the faulty copy is expressed, and translocates to the nucleus but interacts with PPARy-binding proteins, inhibiting the activity of the wild-type OR binds to the DNA-binding sites but doesn't increase expression and outcompetes the wild-type PPARy       ⇒ more difficult to stimulate cells to become adipocytes 

2. HAPLOINSUFFICIENCY: due to the non-functional allele, there's only 50% expression of a functional gene product so that the normal effects of PPARy on gene expression are greatly reduced ⇒ idek

400

how can PPARy mutations cause obesity

mutated PPARy2 (mutation disrupts phosphorylation site for MAPK) is overactive and so stimulates MORE differentiation of pre-adipocytes to adipocytes and so subjects would have greater obesity, but lower fasting insulin levels

401

describe the distriubution of adipose tissue

402

what are possible effects of high visceral adipose tissue

visceral adipose tissue drains directly into the portal vein to the liver

VAT is hyperlipolytic, resistance to insulin signalling --> causing liver insulin resistance

insulin resistance in the liver causes it to increase production of VLDL and glucose

403

difference between hyperplasia and hypertrophy

hyperplasia is an increase in cell number, and is a relatively healthy way to increase TAG storing capacity 

hypertrophy is an increase in cell size, and is associated with several problems 

adipokines secreted by smaller adipocytes are anti-inflammatory and also insulin-sensitising, but those secreted by larger adipocytes are pro-inflammatory, also insulin-desnsitising, more cell death which = recruiting macrophages 

404

how do leptin levels change?

leptin secretion increases with overfeeding, fluctuates in response to feeding in response to insulin; increasing with overfeeding and decreases with fasting 

FUNCTION: decrease food intake and increase energy expenditure

obese people have high leptin

405

give one reason why diets high in fat or fructose are associated with obesity  

they don't increase leptin secretion as they don;t stimulate insulin production

406

describe the levels of leptin in an obese person centrally and peripherally

high plasma levels

low in CSF (+decrease hypothalamic response to leptin) 

leptin can cross BBB via saturable transport mechanism

407

what is metreleptin, describe 3 uses 

recombinant methionyl human leptin 

1. lipodystrophy - normalises fat and carb metabolism, increases insulin secretion & sensitivity

2. obesity: not as effective, but may cause weight loss with amylin

3. weight loss maintenance: could be used in future to counteract decrease in resting metabolic rate, and help maintain weight lost

 

408

list some effects of leptin (outside of metabolism)

has a role in immunity and immune system development 

it's a chemoattractant, and the high levels secreted by adipocytes in obesity MAY be responsbile for macrophages' infiltration of adipose tissue

also has effect on reproductive system

409

what is adiponectin

hormone, normally found in high levels in plasma

only secreted by mature adipocytes

plasma levels LOWER in obesity, and also in large adipocytes

expression depends on PPARy, and inhibtied by TNF-α

410

what are low levels of adiponectin associated with

hyperinsulinaemia

insulin resitance

future T2DM risk

 

411

how can we increase levels of adiponectin

dieting

excercise

synthetic ligands to PPARy, such as thiozolidinediones

412

how does adiponectin act on muscle, and how does it act on the liver

muscle has a receptor AdipoR1 and adiponectin causes an increase in glucose uptake, an dincreases beta oxidation which is a cause of the decrease in muscle lipid stores, and this increases inuslin insensitivity

liver has AdipoR2 and also has improved insulin sensitivity in response to adiponectin, decreasing liver gluconeogenesis and plasma glucose

 

413

describe the anti-inflammatory actions of adiponectin

inhibits TNF-α secretion by monocytes and macrophages 

414

what kind of inflmmation in obesity, and what causes it?

mild but chronic inflammation

may be due to hypoxia in expanding adipose tissue, or high levels of FFA stimulating Toll-like receptors

many inflammatory markers are high in plasma, including CRP, IL6, serum amyloid

adipose tissue produces IL6, IL8, IL1, TNF-α, IL1β, chemokines, etc

THESE PROTEINS STIMULATE IMMUNE RESPONSES, recruiting immune cells and stimuilating maturation (of immune cells)

these proteins also inhibit preadipocyte maturation

severity of chronic inflammation correlates well with the size of visceral adipocytes 

415

give examples of anti and pro-inflammatory proteins (in obesity)

ANTI-INFLAMM: IL-10 and aidponectin, both produced less as obesity increases

adiponectin inhibts activation of macrophages, and stimulates them to produce anti-inflammatory cytokines e.g. IL-10

PRO-INFLAMM: Leptin, IL-6, angiotensin, TNF-α, all increased in plasma of obese people

1/3rd of circulating adipose IL-6 is produced by adipose tissues, levels predict onset of T2DM. also inhibits adiponectin expression

IL-6 makes the liver make inflammatory proteins such as CRP

RAAS is also overactive in obese people

416

what are crown-like structures

 

macrophages are typically clustered around individual adipocytes forming CLSs

CLSs always found around dead adipocytes that have undergone necrosis (inflamm) rather than apoptosis (non-inflamm)

adipocyte death was increased with the size of the adipocytes, even in lean individuals

infilitrating macrophages may then secrete large amounts of pro-inflammatory cytokines - infiltration has been show to occur BEFORE hyperinsulinaemia 

417

how does inflammation lead to insulin resistance in obesity

saturated FAs e.g. can inhibit this pathway 

Inflammatory signalling pathways interacting with, and inhibiting components of the insulin signalling pathway, e.g. by serine phosphorylation of IRS (making it more difficult to start up this pathway shown)

418

why do we get exctopic lipid deposition in obesity?

inability of subcutaenous tissues to handle the load of fat storage so TAG storage spills over into visceral adipose tissue, skeletal muscle and liver

this extopic deposition can lead to an increase in other compounds such as ceramide that alter signalling pathways 

419

how does adiponectin decrease ectopic lipid storage in muscle

it activates AMPK which favours FA oxidation in skeletal muscle via AdipoR1

thsi decreases ectopic lipid sotrage in muscle and increases its sensitivity to insulin

420

how does adiponectin decrease hyperglycaemia

it decreases expression of PEPCL and G6Pase (involved in glucoconeogenesis)

421

how is adiponectin anti-inflammatory

it opposes the action of TNF-α

422

Give an example of an anti-inflammatory drug that's able to reduce insulin resistance 

aspirin

423

give examples of vasoconstrictors and vasodilators produced by the endothelial cells lining blood vessels

vasodilators: NO, prostacyclin

vasoconstrictors: ROS, endothelin-1, RAAS components

424

how does leptin contribute to hypertension

425

how does inflammation contribute to hypertension

426

describe how the RAAS is involved in hypertension

427

describe adinopectin's role in CVD and hypertension

428

describe adiponectin levels in cancer patients

v.low

and hypoadiponectinaemia is marker for aggressive phenotype

also adiponectin can supress cell proliferation, stop cell growth and favour apoptosis 

 

429

how can adipose tissue facilitate cancer development

produces growth factors that stimulate angiogenesis (blood vessels develop that supply the tumour)

also leptin is an agiogenesis promotor and it acts with VEGF (produced by macrophages that infiltrate chronically inflamed adipose tissue)

TNF-α can be angiogeneic at low levels, and IL-6 increases expression of VEGF

Leptin is a chemoattractant for monocytes and macrophages and  

430

describe the mechanism by which tumour cells metastisize via circulation

431

what's the blood supply to the thyroid gland

external carotid

subclavian artery 

BLOOD SUPPLY IS IMPORTANT AS IT IS AN ENDOCRINE GLAND

432

describe the anatomy of the thyroid gland

433

what are the parathyroid glands, and where are they in relation to the thyroid

4 parathyroid glands attached to posterior surface of thyroid

Sense Ca AND Secrete PTH

434

describe the morphology of the thyroid gland

follicles (made up of follicular epithelial cells) surround a centre filled with a substance called colloid

C-cells are found betweent he follicles, and these make calcitonin

 

435

how do underactive follicles look like

436

how do overactive follicles look like

437

describe the embryological development of the thyroid gland

arises from an outpouch between the anterior 2/3s and posterior 1/3rd of the tongue 

the ball of cells migrats downwards and forwards, and gets to its final position at 12 weeks

this is dependent on transcription factors such as PAX8 

during this time the thyroid can leave bits of itself behind and we occasionaly see these as embryological remnants

438

list some embryological abnormalities of the thyroid gland

439

what does this show

it's a section of normal thyroid

follicles lined by cuboidal epithelium, containing colloid

 

440

what does this show

normal thyroid: colloid (thyroglobulin) stained red

colloid in lumen

441

what kind if stain is used here, and describe what it shows

Normal thyroid: immunofluorescent stain using anti-thyroid autoantibodies from a hypothyroid patient

 

furry edge to thyroid peithlium as they have villi

442

which 2 hormones does the thyroid make, and by which cells

THYROID FOLLICLES → T4 and T3

 C-CELLS → Calcitonin

443

what is calcitonin

Peptide hormone

Antagonises PTH: ↓Ca (when plasma concn too high)

Probably not significant in human Ca metabolism

444

why is high blood flow important for the thyroid

4-6 ml / min / g thyroid tissue i.e. twice that of the kidney!

High blood flow important for:

1. delivery of Iand TSH

2. to export T3 and T4 

445

what is responsible for the audible "bruit" of an overactive thyroid gland

the high blood flow

446

describe the vascularisation of the thryoid gland

447

summarise the process by which TH is made in the epithelial cells

448

what stimulates thyroid epithelial activity

TSH 

449

what effects does TSH stimulation have

450

what are the raw materials required for the synthesis of TH

tyrosines and iodide

451

describe tyrosines' role in TH

• Glycoprotein scaffold called thyroglobulin

• Synthesized by thyroid epithelial cells

• Secreted into the lumen of the follicle

• Colloid is a pool of thyroglobulin

• 1 thyroglobulin = 134 tyrosines

• Only a handful of these are actually used to synthesize T4 and T3

452

describe iodide's role in TH

• Avidly taken up from blood by thyroid epithelial cells

• Via sodium-iodide symporter or "iodine pump".

• Once inside the cell, iodide is transported into the lumen of the follicle along with thyroglobulin via pendrin

453

describe the role of thryoid peroxidase in TH synthesis

1. thyroglobulin contains a bunch of tyrosine molecules

2. organification: TP attached iodide to tyrosine rings (reaction catalysed by TP using H2O2 - made seperately in the cell using O2 + NADPH)

3. So you get either DIT or MIT (2 or 3 iodides)

4. coupling: take the ring from one structure and stick it onto the other to make a 2-ringed structure; 2 DITs makes T4, and DIT+MIT makes T3

454

describe how the accumlating THs are released from colloid into blood

455

how do tyrosines and iodides get into the colloid

TSH from blood binds it receptor on the thryoid epithelial cell, which stimulates the cell to:

1. import Na+ and I- into the cell via NIS

2. iodide exported via pendrin to follicle lumen 

at the same, the cell is stimulated to produce thyroglobulin which is secreted into the colloid pool 

456

what impacts TSH secretion/levels

negative feedback via T4/T3

457

what are the normal levels of circulating TH

0.3 – 4.5 mU/L

 

Total T4 = 60 – 150 nmol/L

 Total T3 = 1.2 – 2.9 nmol/L

458

what percentage of the total [TH] is physiologically active

0.1% because this isn't bound to protein and so is free to get across cell membranes

459

give the amounts of free T3 and T4

Free T4 is 9-22 pmol/L

 

Free T3 is 3-6 pmol/L

460

describe how TH is transported in the blood

 

99.9% bound to proteins;

1. thyroxine binding protein

2. transthyreitin

3. albumin

0.1% free

461

which of the TH is more bioactive

T3

462

describe 5 physiological actions of thryoid hormone

1. Increase basal metabolism - goes to mostyl generating heat

2. Promote growth and development (with GH)

3. Cardiovascular

Positively chronotropic

inotropic

4. CNS:  

Regulates alertness

Development of fetal brain

5. Modulate actions of other hormones

Insulin – antagonistic

Adrenaline – synergistic: ↑lipolysis, glycogenolysis, ↑HR

GH releasing hormone – ↓secretion (via negative feedback)

TRH – ↓secretion and release (TRH to release TSH - so negative feedback)

463

describe how T3/T4 effect gene transcription

T4 is the circulating prohormone for T3, and T4 is deiodinated to from T3 which acts on nulcear receptors 

464

explain the effects of D1/2/3 on T3/T4

465

Name the 3 cellular actions of T4/T3

 

differentiation

growth

energy

466

what kind of receptors are thryoid hormone receptors

nuclear receptors

members of the steroid-thyroid hormone receptor family 

bound to DNA in their resting state 

467

explain how TH is actively repressed in transcription in resting state

at resting state the THR is bound to TRE (thryoid respons element) alongside RXR 

RXR+THR are bound to a complex of repressors (SMRT,NCoR) 

this complex is bound to HDAC which chnages the formation of chromatin on the DNA and causes the DNA to bind owund up in histones which actively represses it

468

explain the role of TH in active transcription

when T3 binds, the complex of THR+RXR swaps the repressor complex for co-activators (SRC-1, PACF etc)

these co-activators mediate interactions with the basic transcription complex: RNA pol II and it's accessory factors TATA andTBA etc 

because HDAC has been kicked off histones can be acetylated which opens up the chromatin so DNA opens up 

it's ready to be transcribed 

469

describe TH role in permissive transcription

this is the state in between active repression and active transcription

involves the absence of RXR and THR 

But you can still have a co-activator complex and you get a half-way state where the genes are transcribed at a lower level than they would be if they were actively transcribed 

 

470

what are the 2 types of alpha hormone receptor

ASK SOMEONE TO EXPLAIN THE SLIDE

471

how exactly does TH influence basal metabolism

mitochondria can transcribe some genes, and t3 binfd THR on some mitochondria and influences the basal metbaolism rate 

472

list the different functions of TH

473

how does an increase in fat activate TH

increase fat leves = increased [leptin]

this stimulates the body to increase basal metabolism to burn more fat by:

1. acting directly on adipose tissue

2. activating sympathetic system

474

describe T3's effects on the mitochondria

T3 also targets the mitochondria directly:

Regulates energy metabolism directly

Increases nuclear expression of key regulatory factors such as PGC-1 , nuclear respiratory factor (NRF-1), mitochrondrial RNA polymerase (Polrmt), mitochondrial basal transcription factor (Tfam)

Binds truncated TR 1 in mitochondria triggering copying of mtDNA

Binds AdNT (adenine nucleotide transporter) to promote ‘proton leak’ and heat generation

475

what kind of results would you expect to see with hyperthyroidism (T3, T4, TSH levels)

high T3

high T4

very low TSH

this is because the high T3 and T4 feedback on the pituitary and supress TSH 

476

list the signs and symptoms of hyperthyroidism

477

list some clinical feature of hyperthyroidism, general to thyrotoxicosis

478

list some clinical feature of hyperthyroidism, specific to graves disease

479

list some causes of hyperthyroidism

Graves’ disease (most common)

Multinodular goitre or Toxic adenoma (2nd most common)

Thyroiditis: subacute, Hashimoto, De Quervain

Ectopic TSH: hCG in early pregnancy, recombinant TSH

Drugs: Amiodarone, Exogenous iodine (JodBasedow), Thyroxine!

Ectopic thyroid tissue: metastases from thyroid carcinoma, struma ovarii

Pituitary disease: TSHoma

480

briefly describe Grave's disease

481

describe how you get thyrotoxicosis in graves disease

you have TSH-R antibodies which bind the TSH-R and stimulate it, producing T3/T4

TH feedback on pituitary which reduces TSH release, but antibody stimulation persists as it's not subject to negative feedback

482

describe the relapsing/remitting in Grave's disease

TSH-R Abs do not always stimulate

TSI = Thyroid stimulating antibodies

TBII = TSH-R binding inhibitory immunoglobulins

later on in disease progression, some patients start producing TBII which just blocks (without stimulating) the receptor therefore leading HYPOthyroidism

483

describe the immunology of Grave's disease

484

what does Polyglandular autoimmune syndrome type II involve

  1. Type 1 DM - autoimmune attack on Beta cells
  2. Addison’s disease - autoimmune attack on adrenal cortex
  3. Pernicious anaemia - autoimmune attack on gastric parietal cells
  4. Vitiligo - autoimmune attack on melanocytes in skin
  5. Hypoparathyroidism - autoimmune attack on parathyroid glands

485

describe how thyroid eye disease develops

TSI bind to orbital muscle Ag ⇒ Inflammatory cell infiltrate, secretion of cytokines ⇒ cytokins cause fibroblast proliferation ⇒ Fibroblasts secrete Glycosaminoglycans (BABY NAPPY) ⇒ Oedema due to water retention (pushes eyes forwards), fibrosis

486

name the 2 diagnostic tests for hyperthyroidism

Thyroid autoantibodies

Thyroid scintigram (not used much now)

487

describe the thyroid autoantibody test

a diagnostic test for hyperthyroidism

Anti Thyroid peroxidase (TPO) and Anti Thyroglobulin (TG) are non-specific and insensitive

Anti TSH-R Abs: specific for Graves’ disease (95%)

488

describe the thyroid scintigram test

a diagnostic test for hyperthyroidism

inject Tc-99m pertechnetate (radioactive label) then scan under gamma camera

489

what test was used here, and describe what you see

 

Thyroid scintigram

Thyroid uptake in Graves vc MNG (Multinodular Goiter);

GRAVES: outline normally shaped, and uptake even

MNG: tracer unevenly distriubuted with lumps in some places 

490

what does this scan show

tracer concentrated in one lump, and the rest of the gland is supressed because TSH is supressed therefore the rest of thyroid is inactive

491

what does this scan indicate and why

thyroiditis (release of all TH in gland --> causing the thyrotoxicosis)

as poor upatke, and also can see iodine overload 

492

list the 2 classes of medical treatment (drugs) for hyperthyroidism, and where do they act

Antithyroid drugs (PTU, carbimazole)

Lugol’s iodine

 

ACT ON THYROID PEROXIDASE ENZYME

493

what are Antithyroid drugs useful for, name 2 examples

PTU, carbimazole

Useful for Graves’ disease (50% remit at 18 months)

Toxic MNG/adenoma will not remit

Rash/urticaria/arthralgia (up to 10%)

Agranulocytosis (0.2%)

494

what is Lugol’s iodine useful for

blocks production of T4/T3 by Wolff-Chaikoff effect (give someone overload of iodine therefore switching off the gland)

Effective for 10 days

Then becomes hyperthyroid (Jod-Basedow effect)

495

which 3 conditions seen here?

496

outline radioiodine treatment

497

when would we use surgery in the treatmeant of hyperthyroidism

In patients who are unable to take drugs or RAI

Large goitre

498

list some complications of surgery in treatment of hyperthyroidism

499

what kind of results would you expect to see in someone with primary hypothyroidism

low T4

low T3

high TSH

500

in which kind of thryoid disease can goitres occur

either hypo or hyperthyroidism

501

list some signs and symptoms of hypothyroidism