Endocrine

Question 1

What functions does the hypothalamic-pituitary axis regulate?

Answer 1

Regulates the functions of; thyroid, adrenal, osmoregulation, reproductive glands, growth and milk production and secretion

Question 2

Describe the structure of the pituitary and what is the other name?

Answer 2

Hypophysis, consists of an anterior (adenohypophysis) and a posterior (neurohypophysis) lobe. The hypothalamus is connected to the pituitary by a thin stalk called infundibulum

Question 3

What tissue makes up the posterior pituitary? What does this secrete and where do they act?

Answer 3

The neurohypophysis is made of neural tissue. The posterior pituitary is a collection of axons, whose bodies are in the hypothalamus. This secretes neuropeptides (as they are secreted from nerve cells) anti-diuretic hormone (acts on kidney and arterioles) and oxytocin (Brest and uterus).

Question 4

What tissue makes up the posterior pituitary? What does this secrete and where do they act?

Answer 4

The neurohypophysis is made of neural tissue. The posterior pituitary is a collection of axons, whose bodies are in the hypothalamus. This secretes neuropeptides (as they are secreted from nerve cells) anti-diuretic hormone (acts on kidney and arterioles) and oxytocin (Brest and uterus).

Question 5

Where are the cell bodies of the neurons which secrete ADH and oxytocin located ?

Answer 5

The cell bodies are located in the supraotic and paraventricular nuclei of the hypothalamus. The neuropeptide hormones are produced by both, but ADH is mainly secreted by supraoptic while oxytocin by the paraventricular nuclei

Question 6

What is the adenohypophysis, what tissue is it made of and why?

Answer 6

It is the anterior pituitary and it is made of endocrine cells - the gland derives from the primitive foregut, hence the endocrine cells

Question 7

What is the adenohypophysis, what tissue is it made of and why?

Answer 7

It is the anterior pituitary and it is made of endocrine cells - the gland derives from the primitive foregut, hence the endocrine cells

Question 8

What 7 hormones does the anterior pituitary secrete?

Answer 8

1) thyroid stimulating hormone (tsh)
2) follicular stimulating hormone (fsh)
3) leutenising hormone (LH)
4) growth hormone
5) prolactin
6)adenocorticotroic hormone ACTH)
7) melanocyte stimulating hormone

Question 9

How do the hypothalamus and anterior pituitary communicate ?

Answer 9

In both neuronal and endocrine manner. They are linked by the hypothalamic-hypophyseal portal blood vessels

Question 10

Why does the hypothalamus have its own portal venous system?

Answer 10

The hypophyseal portal vessels allow the hypothalamus to communicate directly with the anterior pituitary. This allows it to;
1) release high concentrations of hypothalamic hormones that are delivered directly to the anterior pituitary
2) the hypothalamic hormones are isolated from the systemic circulation

Question 11

What is the the TRH-TSH-thyroid system

Answer 11

thyroid releasing hormone (trh) is released from the hypothalamus-> secreted into the hypothalamic-hypophyseal portal vessels -> reaches anterior pituitary and stimulated thyroid stimulating hormone secretion (tsh) -> tsh enters systemic circulation and delivered to thyroid gland -> T3 released

Question 12

Of the 6 anterior pituitary hormones, which are secreted by the same cell type? Which one is it?

What are the other cell types the secrete the other hormones ?

Answer 12

FSH and LH are both secreted by gonadotrophs

TSH - Thurotrophs
ACTH- corticotrophs
GH- somatotrophs
Prolactin - lactotrophs

Question 13

What are pituitary hormone families ? Which ones are there

Answer 13

Hormones of the anterior lobe are organised in families based on their structural and functional homology.
1)TSH, FSH and LH family
2) acth family
3) GH and prolactin are a family

Question 14

Define the structure of the FSH, LH and TSH family ?

Answer 14

They are composed of alpha and beta subunits. The alpha are all the same and transcribed from the same gene -> inactive component. The beta subunit is different and is the active unit . These are glycoproteins

Question 15

What are POMC

Answer 15

Pro-opiomelanocortin; this is the common precursor for the hormones in the ACTH (anterior pituitary ) family

Question 16

What hormones are included in the acth family ?

Answer 16

ACTH, Gama and beta lipoprotein, beta-endorphin, and melanocyte stimulating hormone

Question 17

What is somatotropin ?

Answer 17

This is growth hormone. Growth hormone is synthesised by somatotrophs of the anterior pituitary

Question 18

What signal is needed for the release of growth hormone?

Answer 18

Growth hormone releasing hormone (GHRH) is released from the hypothalamus (hypothalamic releasing hormone) which results in growth hormone release from the anterior pituitary

Question 19

What is the pulsatile release of growth hormone and how does this change through life?

Answer 19

GH is released throughout life in pulses every 2 hours. The biggest pulse is 1h post falling asleep.
GH release increases in early childhood. There is a massive release in puberty, induced in females by oestrogen and in males by testosterone. These the decline throughout adult hood

Question 20

What are potent physiological changes that inhibit of growth hormone release suppression ?

Answer 20

Hypoglycaemia and starvation

Question 21

Draw the regulation of growth hormone secretion pathway

Answer 21

Question 22

What controls release of growth hormone and how

Answer 22

The hypothalamus has two pathways which control release;
1) growth hormone releasing hormone (ghrh)
2) somatostatin

Ghrh acts on somatotrophs of the anterior pituitary and stimulate synthesis and secretion of GH

Somatostatin is released by the hypothalamus and acts on the anterior pituitary to inhibit growth hormone release

Question 23

What negative feedback mechanism regulate growth hormone release ?

Answer 23

1)GHRH inhibits its own secretion via an ultrashort negative feedback loop
2) somatomedins (byproduct of GH action) on target tissue inhibit secretion of GH by the anterior pituitary
3) GH and somatomedins stimulate somatostatin release by the hypothalamus

Question 24

What are the main effects of growth hormone metabolically and what are the key receptors?

Answer 24

Direct effect; skeletal muscle, adipose tissue, liver growth. These are mediated by tyrosine kinase-associated receptors

Indirect; mediated by somatomedins; main role is the production of IGF-1. IGF’s act through intrinsic tyrosine kinases

Question 25

What are the main actions of growth hormone;

Answer 25

1) diabetogenic or anti-insulin effect-> increased gluconeogenesis in the liver. Lipolysis is also induced. Both increase BG 2)increased protein synthesis; stimulate DNA->RNA->PROT in nearly all organs 3) increased linear growth: alters cartilage metabolism, bone growth etc via protein synthesis

Question 26

Define growth hormone deficiency;

Answer 26

Children; causes dwarfism, late puberty, mild obesity. Affects every downstream pathway Adults;

Question 27

Define growth hormone excess?

Answer 27

Acromegaly: growth hormone decreasing adenoma. If before puberty-> giganteism due to excess linear growth at the physeal plate After puberty-> once bone plates have closed and linear growth is not possible we see organomegally, tongue, hand and foot growth, insulin resistance and glucose intolerance

Question 28

What is the role of prolactin and what concentration level is it found at

Answer 28

Development of breasts, inhibition of ovulation and stimulation of milk production. Low levels in males and non preganant females. Pregnancy causes a surge

Question 29

Describe the synthesis of ADH and oxytocin

Answer 29

Neuropeptides produced in the posterior pituitary and are synthesised in the supraoptic (ADH neurons) and paraventricular nuclei (oxytocin) of the hypothalamus. Each produces the other hormone but to a lesser concentration. Synthesised as pre-prohormones, which are converted to progormones in the golgi in the hypothalamus. These are packed into vesicles that travel down the axons to the posterior pituitary where they are cleaved into the hormones

Question 30

How are neuropeptides of the posterior pituitary secreted

Answer 30

When an action potential travels down the body to the axon in the posterior pituitary

Question 31

What is the response of the posterior pituitary to an increase in serum osmolarity

Answer 31

Increased osmolarity (decreased water content) the anterior pituidary secretes and to diuretic hormone

Question 32

What is the function of ADH?

Answer 32

ADH acts on the principal cells of the late distal tubule and collecting duct to increase water absorbtion, thus decreasing osmolarity Also increases vascular tone by binding vascular V1 receptors

Question 33

What is another name for ADH?

Answer 33

Vasopressin

Question 34

What are the 9 stimulators factors for ADH?

Answer 34

1) Increased serum osmolarity 2) decreased ECF 3) angiotensin II 4) pain 5) Nausea 6) hypoglycaemia 7) Nicotine 8) Opiates 9) antineoplastic drugs

Question 35

What are the 4 inhibitors of ADH ?

Answer 35

1) Decreased serum osmolarity 2) ethanol 3) alpha adrenergic agonist 4) ANP

Question 36

How is ADH secreted in response to serum osmolarity?

Answer 36

Increased osmolarity -> sensed by baroreceptors in the anterior hypothalamus -> action potentials initiated in cell body of the ADH neurons -> depolarisation wave propagates down the nerves to the posterior pituitary-> posterior pituitary releases ADH

Question 37

How is ADH released in response to hypovolemia or ECF volume contraction

Answer 37

Decrease of ECF by >10% results in BP drop sensed by baroreceptors of the left atrium, carotid artery and aortic arch->the vagus communicates this to the hypothalamus-> results in ADH increase

Question 38

What are the actions of ADH?

Answer 38

1) increase in water permeability of the principal cells of the late distal tubules and collecting ducts - ADH binds V2 receptor->adenylate cyclase (via Gs GPCR)->cAMP ->upregulated aquaporin 2 (AQP2) deposition in the membrane 2) contraction of vascular smooth muscle (hence name vasopressin). - ADH-> V1 receptor-> phospholipase C (via Gq protein) -> IP/Ca2+ -> vascular smooth muscle contraction.

Question 39

What are the actions of ADH?

Answer 39

1) increase in water permeability of the principal cells of the late distal tubules and collecting ducts - ADH binds V2 receptor->adenylate cyclase (via Gs GPCR)->cAMP ->upregulated aquaporin 2 (AQP2) deposition in the membrane 2) contraction of vascular smooth muscle (hence name vasopressin). - ADH-> V1 receptor-> phospholipase C (via Gq protein) -> IP/Ca2+ -> vascular smooth muscle contraction.

Question 40

What are the main pathophysiologic changes associated with ADH?

Answer 40

- central diabetes insipidus; failure of the posterior pituitary to secrete ADH -> collecting ducts become impermeable and urine cannot be concentrated -> urine diluted and body fluids become concentrated (hyperNa and osmolarity). ADH levels are low - nephrogenic diabetes insipidus; principal cells of the collecting duct do not respond to ADH due a defect in V2 recepto, Gs protein or adenylate cyclase. Same effect as above - however, ADH levels are elevated -syndrome of inappropriate ADH (SIADH); excessive ADH is secreted from an autonomous site (eg Oat cell carcinoma of the lung). Excessive ADH causes excessive water reabsorbtion by collecting duct diluting body fluid (low osmolarity and low Na) and urine is inappropriately concentrated

Question 41

What are the treatments for ADH pathologies

Answer 41

- central diabetes insipidus; treated with ADH analogue dDAVP - nephrogenic diabetes insipidus; thiazide diuretics - inhibit Na reabsorbiton in early distal tubule preventing urine dilution at this site - decrease GFR (less water filtered, less excreted) - increase Na excretion cause secondary ECf volume contraction - SIADH; giving ADH antagonist Demeclocycline or water restriction

Question 42

What stimulus’s stimulate oxytocin secretion and milk let down ?

Answer 42

Cervix dilation, suckling, smell/sight/sound of the infant,

Question 43

What are inhibitors of oxytocin ?

Answer 43

Opioids (inc endorphins)

Question 44

How does suckling result in oxytocin release ?

Answer 44

Sensory receptors in the nipples transmit signals to the spinal cord via afferent neurons. This ascends the spinothalamic tract to the brain stem, and up to the paraventricular nucleus of the hypothalamus

Question 45

What are the effects of oxytocin release ?

Answer 45

- milk ejection; Oxytocin ->contraction of the myoepithelial cells lining these ducts forcing the milk into the large duct - uterine contraction At low concentrations it causes forceful contraction of smooth muscles of the uterus

Question 46

What are the full names for T3 and T4

Answer 46

T3;triidothyronine T4; tetraidothyridine or thyroxine

Question 47

In what percentage is T3 and T4 excreted and which one is the metabolically active ?

Answer 47

90% of what is excreted is T4, although T3 is metabolically more active. The T4 is usually converted into the tissues into T3

Question 48

What is rT3?

Answer 48

Reverse T3 and it has no biological activity

Question 49

Describe the layout of the cells that produce the cells that produce thyroid hormones

Answer 49

Follicular epithelial cells of the thyroid gland are arranged in follicles. The cells have a basal membrane facing the blood and an apical membrane facing the follicular lumen. The lumen is full of colloid which is composed of newly synthesised thyroid hormones attached to thyroglobulin

Question 50

What happens when the thyroid gland is stimulated ?

Answer 50

The colloidal hormone is absorbed into the lumen by endocytosis

Question 51

What is the molecular structure of a hormone

Answer 51

Steroid + peptide+amine

Question 52

what are the 3 clases of hormones? What are they synthesized from? which is the most common?

Answer 52

Peptides and protein hormones -> sysnthesised from amino acids steroid hormones ->derived from cholesterole Amine hormones -> derived from tyroside Most hormones are peptide

Question 53

what are the role of the nucleous, ribosomes, endoplasmic reticulum and golgi in peptide hormone synthesis?

Answer 53

Nucleous; DNA->mRNA Ribosomes mRNA-> pre-prohormone Endoplasmic reticulum pre-prohormone->prohormone Golgi Pro-hormone-> homone (packed in secretory vescicles)

Question 54

why, for medicine, has is it convinient that hormones are synthesised from DNA?

Answer 54

Because the gene on the DNA for most hormones have been cloned, and then inserted into cell cultures. This has allowed for the artificial synthesis of the hormones

Question 55

what organs synthesise and secrete steroid hormones?

Answer 55

gonads, adrenal cortex, corpus luteum, placenta

Question 56

which are the main steroid hormones?

Answer 56

Cortisol Aldosterone estradiol estriol progesterone testosterone 1,25 dihydroxycholecalciferole

Question 57

which are the main amine hormones

Answer 57

Thyroid homomes Catecholamines (epinepherine, norepinepherine, dopamine)

Question 58

What essential amminoacid is needed for the sysnthesis of amine hormones

Answer 58

Tyrosine - they are all derivatives of tyrosine

Question 59

Examples of hormones that are protein bound in the circulation What are the benefits of being protein bound?

Answer 59

Protein bound - thyroid hormones - steroid hormones - insulin-like growth factors Benefits; 1) creates a pool of hormones which are not currently active but ready for recruitment 2) stabilises free hormone levels

Question 60

what is long loop, short loop and ultra-short loop feedback

Answer 60

Long loop -> hormone feeds all the way back to the beginning of the hypothalamic-pituitary axis Short loop -> hormone feeds back to an intermediate step - e.g anterior pituitary -> hypothalamus Ultra-short -> hormone inhibits its self (e.g. GHRH inhibits GHRH)

Question 61

what are ways the body can downregulate a response to a hormone?

Answer 61

- negative feedback loops -> hormone concentration feedback to the synthetising pathway downregulation it - dose-dependent receptor response -> magnitude of the response is dependent on the concentration of the hormone - downregulation -> hormone decreases the number or affinity of its receptors in response to a target tissue

Question 62

what are the two activities that G proteins can have and what is the designated for each

Answer 62

Inhibitory (Gi) or stimulatory (Gs)

Question 63

which hormones use tyrosine kineases as a mechanism of action?

Answer 63

Insulin like growth factors (IGF1) Insulin Growth hormone Prolactin

Question 64

Which homones use guanylate cyclase mechanism?

Answer 64

Atrial nutrietic peptide Nitric oxide

Question 65

Which homones use IP3 pathways?

Answer 65

GnRH TRH GHRH Angiotensin II ADH (V1) Oxytocin alpha 1 receptors (most releasing hormones)

Question 66

which hormones use cAMP as an activation mechanims

Answer 66

ACTH LH FSH TSH ADH (V2) HCG MSH CRH Calcitonin PTH Glucagon ß1 and ß2 receptors (most stimulating hormones )

Question 67

what are examples of hormones catalytic receptors?

Answer 67

Guanyl-cyclase (through cGMP) Serine/theorine kinases (CaMK and MAPKs) tyrosine kinases (JAK and STAT)

Question 68

How do peptide and amine hormones activate secondary messages ? how does this differ from steroid? How does this effect the time it takes them to activate

Answer 68

Peptide amine -> fucntion via cAMP, phospholipase C or tyrosine kinases (minutes to act) Steoroid homrones diffuse through the nuclear membrane and bind to nuclear receptors that initiate DNA transcription and protein production (this is why they are slow acting (>hours)

Question 69

what is the difference from the long and short portal hypophyseal system

Answer 69

These are both portal systems ; Long; superior hypophyseal artery delivers blood to the hypothalamus -> forms the primary capillary plexus in the hypothalamus - > the long hypophyseal portal vessels take blood from the hypothalamus with hormones and delivery it to the pituitary Short - > parallel to the long, but this found at the level of the infundibulum where it delivers blood to the anterior pituitary

Question 70

What are the 2 important physiological implications of the portal blood supply to the anterior lobe of the pituitary ?

Answer 70

1) hypothalamic hormones can be delivered to the anterior pituitary directly and in high concentration 2) the hypothalamic hormones do not appear in the systemic circulation so they do not have effect while in the portal system

Question 71

Where is growth hormone synthesised and by what cell type?

Answer 71

Somatotroph cells in the anterior pituitary

Question 72

What are other names for growth hormone?

Answer 72

Somatropin or somatotropic hormone

Question 73

why are growth hormone and prolactin in the same hormone family?

Answer 73

because they are made by the same gene and structurally similar (GH is a 191aa straight chain with 2 disulfide bridges) and prolacting 198aa straight chain with 3 disulphide bridges. These have 98% homology

Question 74

what messanger does the pituitary need for the production of growth hormone?

Answer 74

Growth hormone releasing hormone (GHRH)

Question 75

what receptor and secondary messaging system is used by growth hormone?

Answer 75

GHRH from the hypothalamus binds GHRH-receptor on the somatotrophs of the anterior pituitary -> Gs activation -> alpha+GTP -> phospholipase C AND Protein kinase A-> IP3 AND cAMP

Question 76

What hypothalamic molecule binds to somatotrophs, preventing GHRH from binding its receptor and resulting in somatotrophin release? How does it do this?

Answer 76

SomatotATITN - binds to its own receptro coupled with Gi protein which inhibits cAMP. Remember somatoTROPHIN IS Grouwth Hormone (GH). It also inhibits Ca channels which are modulated by IP3

Question 77

what are the 3 feedback loops for GH, and state if they are short, ultrashort or long

Answer 77

1) GHRH inhibits its own secretion from the hypothalamus via ultrashort feedback 2) somatoMENDINGS, which are byproducts of GH action on target cells downregulate the anterior pituitary and hypothalamus (Long and short) 3) GH and somatoMENDIN stimulate secretion of somatoSTATIN from the hypothalamus. Short .

Question 78

How does GH have a diabetogenic effect?

Answer 78

GH causes insulin resistance resulting in hyperglycaemia, increased gluconeogenesis in the liver and decrease glucose uptake by target cells. Lipolysis is also increased. Blood insulin levels will be high

Question 79

How does GH promote growth?

Answer 79

In virtually all organs it increases uptake of aminoacids and stimulates the synthesis of DNA, RNA and protein. This increases lean body mass and organ size

Question 80

where is prolactin synthesised ?

Answer 80

By lactotrophs which make up 15% of the anterior pituitary

Question 81

What increases prolactin production, and what decreases it? what do these effect in the prolactin pathway?

Answer 81

Dopamine inhibits the prolactin gene in lactotrophs while thyrotropin releasing hormone increases prolactin gene transcription. Both dopamine and TRH are secreted by the hypothalamus.

Question 82

what is meant by tonic inhibition of prolactin ?

Answer 82

In non-pregnant people, prolactin secretion is tonically inhibited by dopamine (prolactin inhibiting factor PIF) from the hypothalamus. In other words, the inhibitory effect of dopamine dominates, and overides the stimulatory effect of TRH,

Question 83

what are the 3 main sources of dopamine which inhibit prolactin gene upregulation in lactortrophs? list the major one first

Answer 83

1) dopamine is produced by dopaminergic neurons in the HYPOTHALAMUS which secrete dopamine into the hypothalamic-hypophyseal portal system which then binds to receptors on lactotrophs in the anterior pituitary 2) dopamine released from non-lactotroph cells of the ANTERIOR PITUITARY (paracrine action) 3) Dopamine is released from dopaminergic neurons of the POSTERIOR pituitary

Question 84

What are stimulatory factors for prolactin release?

Answer 84

pregnancy (oestrogen) brest-feeding sleep stress TRH dopamaine antagonists (dopamine major inhibitor)

Question 85

what are inhibitors of prolactin release?

Answer 85

Dopamine Bromocriptine (dopamine agonists) Somatostatin Prolactin (negative feedback )

Question 86

what are the effects of prolactin?

Answer 86

Lactogenesis -> prolactin stimulates milk production by inducing the synthesis of milk components inc lactose, casein, and lipids Breast development -> in puberty prolactin + oestrogen + progesterone stimulate branching of the mammary ducts, and during pregnancy prolactin +progesterone stimulate growth and development of mammary alveoli Inhibition of ovulation -> prolactin inhibits the synthesis and release of gonadrotropin-releasing hormone (GnRH). This inhibits ovulation .

Question 87

what is a phantom pregnancy;

Answer 87

prolactin can stimulate lactogenesis in the abscence of pregnancy Lactogenesis -> prolactin stimulates milk production by inducing the synthesis of milk components inc lactose, casein, and lipids

Question 88

Does prolactin have any clinical implication in male fertility?

Answer 88

Little. In cases of a prolactinoma (non cancerous pituitary tumour) can result in high prolactin levels which will inhibit spermatogenesis

Question 89

When should bromocriptine be used and why?

Answer 89

When you want to inhit excess prolactone productions effects. This can only be used in hypothalamic destruction or prolactinoma as bromocriptine only inhibits prolactone secretion by the anterior pituitary

Question 89

What conditions can cause failiure to produce prolactin and which ones cause excessive lprolacting production?

Answer 89

Prolactin deficiency; caused by ether destruction of the entire pituitary or selective lactotrophe destruction -> failure to lactate PRolactin excess; caused by; - destruction of the hypothalamus - interruption of the hypothalamic hypophyseal tract - prolactinomas - loss of tonic inhibition of dopamine Major symptoms are galactorea and infertility

Question 90

what is prepropressophilin?

Answer 90

peptide precursor for antidiuretic hormone (preprohormone). it is composed of a signal peptide + ADH + neurophysin II + glycoprotein

Question 91

what is prepro-oxyphysin?

Answer 91

it is the precursor to oxytocin(preprohormone). It is composed of a signal peptide + oxytocin + neurphisin I

Question 92

what are the precursor molecules for ADH and oxytocin ?

Answer 92

ADH; Prepropressophilin Oxytocin; prepro-oxyphilin

Question 93

How is prepropressin converted to ADH ?

Answer 93

Prepropressophilin in the golgi is converted to pro-pressophillin via removal of the signal peptide (prohormone). This is then packaged into a secretory vesicles which travels down the axon of the neuron through the hypothalamic hypophyseal tract to the posterior pituitary. In the posterior pituitary neurophysin-II is cleaved leaving vasopressin

Question 94

How is pre-prooxyphysin converted to oxytocin ?

Answer 94

pre-prooxyphysin in the golgi is converted to pre via removal of the signal peptide (prohormone). This is then packaged into a secretory vesicles which travels down the axon of the neuron through the hypothalamic hypophyseal tract to the posterior pituitary. In the posterior pituitary neurophysin-I is cleaved leaving oxytocin

Question 95

how is ADH and oxytocin secreted into the circulation?

Answer 95

ADH and ocytocin + their neuorophins are contained within vesicles at the synapse. When an action potential reaches the synapse, Ca enters the neuron and the vesicles fuse with the synapse secreting their contents. The hormones cross the sypatic space and porus wall of the blood vessels to enter the circulation

Question 96

What are the two most potent drivers of ADH secretion, and what pathways are used to upregulate this hormones release? what are the other 7 drivers ?

Answer 96

1) increased plasma osmolarity -> detected by osmoreceptors in the hypothalamus -> action potentials -> secretion of ADH at the nerve terminal. Decreased osmolarity downregulates nerve firing 2) hypovolemia -> detected by baroreceptors in the aortic arch, carotid artery and left atrium -> vagus nerve conveys signal to the hypothalamus -> action potentilas -> release of ADH at the synapse The other drivers are; - angiotensin II - Pain - Nausea - Hypoglycaemia - Nicotine - Opiats - Antineoplastic drugs

Question 97

once released into the blood stream, what are the roles of ADH?

Answer 97

1) increased H2O permeability of the late distal tubule and collecting duct. ADH -> V2 -> Gs -> PKA (via adenylate cyclase) -> cAMP -> upregulates AQP2 gene -> increased aquaporin 2 deposition in luminal membrane -> reuptake of H20 = correction of hypovolemia and hyperosmolarity + concentration of urine 2) contacting of vascular smooth muscle. ADH->V1->Qq->phospholipase C-> IP3 -> increased Ca entry -> smooth muscle contraction

Question 98

In nephrogenic diabetes insipidus, where may there be a defect preventing ADH from having an effect?

Answer 98

mutation may be in the V2 receptor, adenylate cyclase, or Gs protein

Question 99

What is nephrogenic diabetes insipidus, and why are thiazide diuretics used to treat nephrogenic diabetes insipidus?

Answer 99

Nephrogenic diabetes insipidus is the lack of response of the principal cells to respond to ADH (mutation in V2, Gs or Adenylate cyclase). Thiazides help by; 1) inhibit Na reabsorption in the early distal tubule -> prevents urine dilution at this site 2) Thiazides decrease GFR -> less water excreted, less urine dilation and increased osmolarity 3) increase Na secretion cause secondary ECF volume contraction. in response to volume contraction, proximal reabsorbtion of solutes in water is increased ## Footnote Thiazide diuretics are given to people with nephrogenic diabetes insipidus (NDI) to paradoxically reduce urine output. While thiazides are diuretics that typically increase urination, in NDI, they induce a slight volume depletion, leading to decreased glomerular filtration rate (GFR) and increased proximal tubule reabsorption of sodium and water. This ultimately reduces the amount of water delivered to the distal nephron, where water is normally reabsorbed under the influence of vasopressin (ADH), which is not effective in ND

Question 100

you have a serum [Na] of 110mEq/L, osmolarity of 225mOsm/L and urine osmolarity of 650mOsm/L? What is a key differential, what diagnostics should be performed and how can this be treated?

Answer 100

SIADH - Chest imaging and if mass found biopsy (ddx inc oat cell carcinoma of the lung) - Treat if clinical -> NaCl hypertonic infusion to raise serum osmolarity (want to increase ECF volume and increasing osmolarity will reduce H2O loss - Na needed to retain water). long term treatment with demeclocycline or water restriction. remove lung mass if possible

Question 101

What is the main structural difference between T3 and T4?

Answer 101

one single atom of iodine

Question 102

where are thyroid hormones synthesised

Answer 102

in the follicular epithelial cell of the thyroid

Question 103

What is an essential element for thyroid hormone formation? Are thyroid hormones synthesised at the time they are needed or are they stored? What is the most active thyroid hormone and which one is more abundant ?

Answer 103

1) large volumes of iodine are needed and this must come from the diet 2) synthesis of thyroid hormones is partially intracellular and extracellular , with the complete hormone stored extracellulalrly in the follicular lumen until the thyroid is ready to secrete 3) T4, the more inactive form, is the major secretory unit, and require conversion to T3 post secretion

Question 104

what are the steps involved in thyroid hormone synthesis ?

Answer 104

1) thyroglobulin (TG) is synthesised from tyrosine by the golgi of the follicular epithelial cell -> TG is incorporated into vesicles and excreted into the lumen of the thyroid gland 2) Na-I cotransport, or I-trap; I- is actively transported from blood -> follicular epithelial cells (against chemical and electrical gradient - pump activity is regulated by I- levels) 3) oxidation of I- to I2; thyroid peroxidase catalyses oxidation and the next two steps of organification of I2 into TG and the coupling reactions ) 4) Organification of I2; at the apical membrane I2 combines with tyrosine moieties on TG, catlysed by thyroid peroxidase to form monoiodotyrosine (MIT) and Diiodotyroside (DIT). MIT and DIT remain attached to TG until secretion stimulus 5) coupling reaction; While attached to TG, two coupling reactions occur to DIT and MIT. 1) two molecules of DIT combine to form T4. 2) one DIT and one MIT combine to form T3. A portion of DIT and MIT do not couple and are left over 6) endocytosis of thyroglobulin; When thyroid gland is stimulated, iodinated-TG (with its attached T3, T4, MIT and DIT) is endocytosed into the follicular epithelial cells. Pseudopods are pinched off the apical membrane, engulf a portion of colloid and absorb it into the cell. Once inside TG is transported in the direction of the basal membrane by microtubules 7)hydrolysis of T4 and T3 from TG by lysosomal enzymes; TG droplets fuse with lysosomes. Lysosomal proteases hydrolysed peptide bonds to release T4, T3, MIT and DIT from TG. T4 and T3 are transported across basal membrane into the capillaries. MIT and DIT are recycled into the synthesis of new TG 8) deiodination of MIT and DIT; thyroid deiodinase removes I- from DIT and MIT. This is recycled.

Question 105

why is T4 secreted at 10x the concentration of T3?

Answer 105

becuase the coupling of DIT+DIT (produces T4) is significantly faster that DIT+MIT (produces T3)

Question 106

what is the wolff-chaikoff effect?

Answer 106

this is where high levels of I- inhibit organification (this is where I2 combines with tyrosine of TG to form DIT and MIT) ` How it works: Iodine organification: The thyroid gland uses iodine to produce thyroid hormones (T3 and T4). Excess iodine inhibits the process of iodine organification, where iodine is incorporated into thyroid hormones. Inhibition of thyroperoxidase (TPO): The mechanism involves the formation of iodopeptides that temporarily inhibit the activity of TPO, an enzyme crucial for thyroid hormone synthesis. Downregulation of Na+/I- symporter (NIS): The Wolff-Chaikoff effect may also involve downregulation of NIS, a protein responsible for transporting iodine into thyroid cells.

Question 107

What effect does the chemotherapeutic agent PTU (polyurcil) have on thyroid function? What thyroid disease may this be treated for?

Answer 107

inhibits thyroid peroxidase blocking thyroid hormone synthesis. PTU is an effective treatment of hyperthyroidism

Question 108

How is T3 and T4 transported in the circulation?

Answer 108

Most is bound to thyroxine binding globulin (TBG) . A small amount of T4 will not not be bound to TG but is transported by albumin and pre-albumin. A smaller amount of T4 is still not bound at all and is free (fT4)

Question 109

why is it important to distinguish total and free t4 on blood tests?

Answer 109

Total T4 is Free+TBG bound and is not metabolically active, while free T4 is metabolically active

Question 110

Why is it beneficial to have both free T4 and TG bound T4?

Answer 110

Free T4 is metabolically active, while the TBG bound is not. The TBG bound acts as a T4 reservoir in the circulation

Question 111

Give an example of when low total T4 may result in negative feedback inhibition of T4 synthesis?`

Answer 111

In advanced liver disease, Thyroxin binding globulin (TBG) decreases. This results in a transient increase in free T4. As a consequence, the increased fT4 negatively feedback inhibiting the formation of new thyroid hormone

Question 112

What abnormalites may you see on a thyroid panel in a pregnant person

Answer 112

normal free T4 but increased total T4. This is physiologically euthyroid. this is because estrogen inhibits hepatic breakdown of TBG and thus increased TBG levels. The increased TBG will bind more free T4. This is detected as dected as decreased T4 and more is produced filling the fT4 gap. T3 is also increased as the thyroid is trying to replace the fT4.

Question 113

what is a T3 resin uptake test?

Answer 113

measures binding of radioactive t3 to synthetic resin. The idea is that radioactive T3 preferentially binds TBG and that which is not will bind to resin. This can give an idea if TBG is decreased (hepatic failure) or when endogenous T3 is increased (endogenous hormone occupies the TGH) or when T3 is decreased in cases such as pregnancy

Question 114

Most thyroid hormone which is secreted is the less active T4. How does the body convert this to the more active T3?

Answer 114

Target tissues (e.g. liver, kidney) use an enzyme called 5'-ionidase to convert T4 to T3 by removing one atom of I2 from the OUTER ring of T4

Question 115

What is the small difference in conversion of T4 which can result in ether T3 or rT3 being produced? Why is this important?

Answer 115

The 5' ionidase produces T3 by removing one atom of I2 from the OUTER ring of T4. Conversely, 5'ionidase, produces rT3 by removing one atom of I2 from the INNER ring of T4. Some rT3 is always produced, but this difference is what lets the cell determine how much active hormone is produced by the target tissue

Question 116

during starvation (or fasting), what functional changes do we see in brain and other tissue 5' iodinase function?

Answer 116

in non brain tissue, 5' iodinase is inhibited, thus lowering O2 requirements and basal metabolic rate. However, in the brain, 5'-iodinase is not inhibited (there is a slightly different structure), protecting brain T3 levels

Question 117

what is the main hormone that stimualtes thyroid hormone synthesis? What pathological condition can imitate this pathway?

Answer 117

TSH Thyroid stimulating immunoglobulins increased thyroglobulin binding protein (e.g. pregnancy or autoimmune)

Question 118

What factors inhibit thyroid hormone synthesis?

Answer 118

Iodine deficiency Deodinase deficiency excessive I- intake (Wolff chaikoff effect) perchlorate thiocynate (inhibits Na-I cotransporter) PRopylthiouracil (inhibits peroxidase enzyme) Decreased TBG levs (e.g. liver failiure/disease)

Question 119

what effect does PRopylthiouracil have on the thyroid?

Answer 119

inhibits peroxidase enzyme which converts thyroglobulin to TG+I2 and then TG+MIT+DIT and then TG +MIT+DIT+T3+T4

Question 120

where is TRH secreted from?

Answer 120

paraventricular nucleous of the hypothalamus

Question 121

where does TRH act on? what does it do?

Answer 121

Thyrotrophs of the anterior pituitary to upregulate TRH to stimulate transcription of TSH gene and secretion of TSH. TRH also regulates prolactin release

Question 122

What is the role of TSH ? What controls the release TSH function?

Answer 122

secreted in response to TRH and has trophic effects (i.e. regulates thyroid growth). 1) TRH from the hypothalamus stimulates TSH 2) Thyroid hormones inhibit TSH by downregulation TRH receptor on thyrotrophes (free T3 regulates this - anterior lobe has thyroid deidinase

Question 123

what actions does TSH have on the thyroid gland?

Answer 123

TSH -> TSH receptor -> Gs -> alpa-GTP -> PKA ->cAMP resulting in 2 actions; 1) upregulates every pathway in thyroid hormone synthesis (I- uptake, oxidation, lrganification of I2 into MIT&DIT, coupling of MIT&DIT to form T3/T4, proteolysis of TG and release of T4,T3. 2) TSH trophic effect -> hypertrophy of the gland after sustained exposure.

Question 124

what are thyroid immunoglobulins and why are these important?

Answer 124

Part of the IgG plasma proteins. They bind to TSH receptors producing the same response as TSH -> hyperthyroidism + hypertrophy of the gland = Graves disease

Question 125

if you have sings of hyperthyroidism, and run a thyroid profile, what changes would you see in a case of hyperthyroidism secondary to thyroid immunoglobulins? Explain

Answer 125

HIGH T3, fT4 and tT4, but LOW TSH You have hyperthyroid levels of thyroid hormones as the immunoglobulins are bound to TSH receptors, stimulating production and hypertrophy. But the anterior pituitary is detecting the high T3 and T4 and trying to compensate by supressing production TSH

Question 126

whith what other homene do thyroid hormones act synergistically with to increase bone growth

Answer 126

GH

Question 127

Once thyroid hormone reaches a target tissue, what is the first step that has to be undertaken for the hormone to have effect?

Answer 127

T4 conversion to T3 by 5' ionidase, which removes an atom of I- from the outer ring of T4

Question 128

how much T3 and rT3 is produced in the tissue ? What would affect the ratio of T3 to rT3?

Answer 128

under NORMAL circumstances, T3 45%, rT3 55%. The ratio would be affected by things like pregnancy, fasting, shunts, stress, hepatic and renal failiure etc

Question 129

How does T3 affect protein production ?

Answer 129

T3 binds nuclear receptors on TRE's (thyroid receptive elements) increasing DNA translation and protein synthesis. There are T3 receptors within the ribosomes to increase protein production

Question 130

what effect does increased T3 levels have on cardiomyocytes at a molecular level?

Answer 130

- increased Na:K ATPase - increased ß-1 receptor concentration - increased Ca-ATPase concentration -increases cardiomyocyte hypertrophy by increasing the number of Contractile units

Question 131

how do thyroid hormones affect liver funciton?

Answer 131

- increase carbohydrate, fat and protein metabolism

Question 132

how do thyroid hormones affect basal metabolic rate?

Answer 132

- increase O2 consumtyion by increasing the synthesis of Na:K ATPases = increase in temperature Na:K ATPase is one of the receptors responsible for the largest use of O2 (need a lot of ATP)

Question 133

What tissues are immune to thyroid homones increase in O2 consumption?

Answer 133

Brain, gonads and spleen

Question 134

How do thyroid hormonws affect energy metabolism? What about nutrient absorbtion? What can thyroid hormones potentiate the effects of ?

Answer 134

increase protein, fat and carb metabolism - increase glucose absorption by the GIT - potentiate the effects of other hormones (catecholamines, glucagon, GH etc) - increase gluconeogenesis, lipolysis and proteolysis (net effect is catabolic though)

Question 135

why is infarction relatively uncommon in veterinary patients with hyperthyroidism

Answer 135

The increased thyroid hormone increases HR, ionotropy, NA:K-ATPase activity and Ca-ATPase activity resulting in increased O2 use. However, hyperthyroidism also increases ventilation and O2 delivery to the tissue

Question 136

what effects does hyporthyroidism have on the CNS?

Answer 136

Oftem age dependent impacts. - Perinatal; thyroid hormone essential for CNS development with hypothyroidism resulting in mental retardation. - Adults; listlessness, slowed movement, irritability, somnolence, impaired memory and decreased mental capacity

Question 137

what are causes of hyperthyroidism?

Answer 137

- Thyroid adenoma or adenomatous hyperplasia is the most common cause of feline hyperthyroidism (70% of cases) - Thyroid carcinoma, the primary cause of hyperthyroidism in dogs (rare in cats <3% of cases) - Autoimmune (thyroid stimulating immunoglobulins - Graves) -Other thyroid neoplasia - excessive TRH or TSH secretion (e.g. hypothalamic disorders) -

Question 138

what are differentials for decreased TSH in hyperthyroidism?

Answer 138

If non euthyroid, they are; - Neoplasia of thyroid gland (adenoma cat, carcinoma dog) - endogenous administration (overdosing)

Question 139

what are differentials for hyperthyroidism with increased TSH or TRH ?

Answer 139

- disorders of the anterior pituitary or hypothalamus

Question 140

How to treat hyperthyroidism? Pros and cons of each

Answer 140

Gold standard I131 - can be given as first line - can be given to IRIS 1 without other intervention - beneficial for those with cardiovascular disease once euthyroid state is achieved medically - 95% will be cured but supplementation Thyroidectomy - can be curative - specialised skillset - invasive - risk of damaging parathyroid gland Methimazole - control the symptoms - not a cure - start low and titrate up to the dose needed to maintain T4 levels between 1.0 and 2.5 mcg/dL. Dosing of 1.25–2.5 mg every 24 hr for the first week of treatment, increasing to 2.5–5 mg every 12–24 hr, will help minimize side effects Hyperthyroid diets with low iodine can help with medical management

Question 141

If an owner elects to treat with hyperthyroidism with methimazole, what is the recommended treatment plan and schedule? When do blood samples have to be taken?

Answer 141

- Start low and titrate up to the dose needed to maintain T4 levels between 1.0 and 2.5 mcg/dL. Dosing of 1.25–2.5 mg every 24 hr for the first week of treatment, increasing to 2.5–5 mg every 12–24 hr, will help minimize side effects - T4 monitoring should occur every 2–4 wk until the goal levels are reached. Complete blood count, chemistry profiles, and urinalysis will provide information on potential bone marrow dyscrasias, development or progression of azo- temia, resolution of any liver enzyme changes, and any other issues that may have been concealed by the hyper- thyroid state. * Blood samples for T4 measurement may be taken at any time during the day after methimazole administration. - once control is achieved, minimum database should be performed at least every 6 mo and more frequently if there are significant comorbidities

Question 142

what are side effects of methimazole? when do they occur?

Answer 142

vomiting, bone marrow dyscrasias, and skin excoriations can occur up to several months after initiating therapy.

Question 143

Once a dose of methimazole which is controlling the hyperthyroidism symptoms has been reached, is there need to change this?

Answer 143

Methimazole doses will need to be adjusted over time because the drug does not affect the growth of the adenomatous hyperplasia.

Question 144

is. propylthiouracil used in cats with hyperthyroidism?

Answer 144

Not anymore, been replaced by carbimazole and then methimazole which have less side effects

Question 145

Most common causes of hypothyroidism/

Answer 145

- autoimmune destruction (thyroiditis - antibodies ether block production of thyroid hormones or destroy the gland) - prior surgical removal/I131 - hypothalamic or pituitary failure - I- deficiency - (rare) tissue resistance due to downregulation of thyroid receptors

Question 146

How do you diagnose hypothyroidism

Answer 146

Have to have low fT4, tT4. - IF TSH is low, then there is an issue with the hypothalamus, pituitary or hypothalamic-pituitary axis - IF TSH is high, then there is a problem with the thyroid (e.g. thyroiditis)

Question 147

symptoms of hypothyroidism?

Answer 147

- decrease metabolic rate - weight gain without increased caloric intake - decreased heat production - cold intollerance - decreased HR - slow movements - slowed mentation - lethargy - Somnolence - myxadema

Question 148

what is goiter?

Answer 148

this is when hypothyroidism is caused by a defect in the thyroid gland by high circulating TSH.

Question 149

when do you treat for hypothyroidism ?

Answer 149

have to demonstrate a T4 and elevated TSH. Cats with naturally occurring hypoT4 are more likely to be azotemic (not dogs). Cats should be treated if clinical with multiple laboratory signs showing hypo T4 If the cat has concurrent disease, that should be treated first and then thyroid function re-evaluated. If hypothyroid <3-4months and not symptomatic monitor T4 for rebound. if >4 months and T4 is low, TSH elevated supplement with levothyroxine If the cat is asymptomatic with no concurrent disease then monitor labs every 6 months, watch for clinical signs and azotemia. If goiter is present consider TSH testing. If the cat is older than 2 and symptomatic then recheck T4 in 2-4 weeks, if still low, check TSH, and treat if hypo. If T4 is normal, then the cat is not hypothyroid

Question 150

what is euthyroid sick syndrome?

Answer 150

Euthyroid sick syndrome can decrease circulating thyroid hormone concentrations, with preferential impact on TT4. In severe illness, fT4 is also impacted. TSH may be subnormal or within the reference range. Ideally, further thyroid testing should be delayed until clinical illness has resolved and the dog is clinically well

Question 151

K9 breed predisposition for hypothyroidism>

Answer 151

begles, golden retrievers, Doberman pinschers, Great Danes)

Question 152

if you have signs of hypothyroidism, or the patient is normal with high T4, what next step should be taken?

Answer 152

fT4 and TSH. Although uncommon, circulating autoantibodies against thyroxine (T4) can cross-react with the TT4 assay, caus- ing an artificially high reported result. A free T4 by equilibrium dialysis (fT4ed) or quantification of circu- lating autoantibodies may be warranted

Question 153

DOGS WITH CLASSICAL SIGNS OF HYPOTHYROIDISM AND A LOW TT4 - treatment approach?

Answer 153

Submit additional thyroid testing to document a subnormal fT4 and/or an elevated TSH concentration to confirm diagnosis Initiate treatment with twice-daily levothyroxine supplementation Monitor therapy based on clinical improvement and serial TT4 test- ing. Assess a TT4 level 4–6 hr post morning pill 4 wk after starting medication or after dose adjustments until control is achieved, then every 6–12 mo as indicated.

Question 154

why is it challenging to determine if the hypothyroidism is true in dogs?

Answer 154

Approximately 20–40% of dogs with hypothyroidism have a low TT4 and low fT4 but a normal TSH concentration.However, this scenario could also indicate nonthyroidal illness, so additionaltesting such as assessing for the presence of antithyroid autoantibo- dies or a TSH response test can be run to help confirm diagnosis,

Question 155

What are the 3 zones of the adrenal cortex and what do they secrete?

Answer 155

Glomerulosa =mineralocorticoids - ie aldostererone Fasciculata = corticosteroids - ie cortisol Reticularis = androgens

Question 156

glucorticoid have a rhythmic secretion, when are they most prevalent and least?

Answer 156

circardian rhythm - peak in AM, low in PM

Question 157

whar are the actions of glucocorticoids?

Answer 157

1) gluconeogenesis -> increased protein catabolism, increased lipolysis 2) anti-inflammatory -> increase liportin, decrease phospholipase 2, inhibit IL-2 production, decrease T cell proliferation, inhibit histamine (mast cells) and serotonin (platelet release) 3) suppress immune system; inhibit IL2 and T cells 4) Maintain vascular responsiveness to catecholamines -> increase alpha-1 receptors

Question 158

what is the most important mineralocorticoid and what is its role?

Answer 158

Aldosterone. Increases blood volume by retaining Na and therefore water. Increase K loss as Na is exchanged for K in the collecting duct. Acid is also excreted by the kidney by aldosterone. Aldosterone also increases water absorption in the colon

Question 159

There are two types of adrenocortical insufficiency. Which are these and what are defining characteristics ?

Answer 159

Primary; Addisons. - Autoimmune destruction of adrenal cortex; Decreases cortisol + aldosterone and ACTH levesl as a result are increased. Lack of cortisol leads to hypoglycaemia and a decrease in ECF, leading to hypotension (in addition to loss of vascular tone). They are also hyperkalaemic due to the lack of aldosterone and have low Na and water retention. Additionally, due to the lack of aldosterone which does not pump out H+ and becuase they are hypoglycaemic leading to acidic ketone production they have a metabolic acidosis Secondary; ACTH deficiency - Same as primary but with NORMAL ALDOSTERONE levels

Question 160

What are diseases of adrenal excess?

Answer 160

- adrenocortical excess = Cushings; increased cortisol and aldosterone -> hyperglycaemia, increased protein catabolism, central obesity, hypertension (too many alpha1), poor wound healing, - hyperaldosteronism = Conns syndrome. Aldosterone secreting tumour = hypokalemia, hypertension (increased volume), metabolic alkylosis (more H+ excretion) and decreased Renin - 21ß-hydroxylase deficiency; decreased cortisol and aldosterone but increased androgens - 17alpha-hydroxylase deficiency = decreased androgens, decreased glucocorticoids and increased minearolocrticoids

Question 161

what is the cellular organisation of the exocrine pancreas?

Answer 161

Alpha, ß, gamma cells, Delta and pp -> form islets of langherhans

Question 162

What is the role of pancreatic alpha, beta and gamma cells? are these cell types independent or not?

Answer 162

alpha; secrete glucagon Beta; secrete insulin Gamma; secrete somatostatin and gastrin Alpha and beta are linked by gap junctions

Question 163

what is the role of glucagon? What does this cause when released ?

Answer 163

Prevents hypoglycaemia, by upregulating glucose production. Increases AA catabolism, and releases CCK and modulates the autonomic nervous system to help digerstion Actions; 1) Liver and adipose tissue (via cAMP) - increase gluconeogenesis, and glycogenolysis - Lipolysis - increased Urea production -> AA groups left over from gluconeogenesis form urea

Question 164

What is the structure of insulin?

Answer 164

made of an alpha and beta chain linked by 2 disulfide bridges. Pro-insulin - single chain peptide wchihc contains a C peptide. The C peptide is removed to form insulin

Question 165

what is the role of insulin? How is insulin secreted i?

Answer 165

Allows glucose to enter cells with GLUT4 insulin dependent receptors (skeletal and adipose tissue) Glucose binds Glut2 receptors on ß cells -> enters cell (insulin indipendent receptir)-> glucose used to make ATP-> increased ATP induces K channels to close-> cause depolarisation of the cell-> leads to Ca channels to open -> insulin packed vesicles induced to fuse with membranel -> insulin secreted (2alpha and 2ß subunits)

Question 166

once insulin is secreted, how does it interact with target cells and what does it cause?

Answer 166

insulin binds to insulin receptors which are tyrosine kinases. This results in; 1) Increased glucose uptake (increase glucose transporters (GLUT4), increases glycogen formation, decreases gluconeogenesis, increases fructose 2,6 diphosphate 2) decrease fatty acid breakdown and ketoacid production - increases fat deposition, decrease lipolysis, inhibits keto acid production due to decreased acetyl-coa availability 3) decrease blood ammino acid levels -> anabolic protein synthesis 4) decrease K - increased cellular uptake no

Question 167

what gastrointestinal hormone inhibits insulin ?

Answer 167

somatostatin

Question 168

What proportion of Ca is protein bound?

Answer 168

40% of total calcium. 60% is ultrafiltatable and complexed to anions or free ionized

Question 169

what are the main sources of Ca for the body?

Answer 169

GIT absorbtion Bone reabsorbtion

Question 170

where is Ca exreted ?

Answer 170

kidneys

Question 171

how does the parathyroid respond to Ca levels?

Answer 171

Decreased [Ca] is detected by Ca Ca-sensing receptor on the chief cells of paratyroid, which produces PTH Decreased Ca, decreased receptor binding, increased PTH

Question 172

How do Mg levels affect PTH

Answer 172

Decreased Mg increases PTH. However, severe hypomagnesemia inhibits PTH, which can lead to hypoparathyroidism

Question 173

what are the actions of PTH?

Answer 173

1) bone reabsorbtion of Ca and phosphate- P renally excreted hence Ca can increase as there is less P to bind it 2) PTH inhibits renal phosphate reabsorbtion in proximal tubule -> phosphaturia 3) Increased Ca reabsorbtion in the distal tubule 4) Increased intestinal Ca absorbition via 1, 25-dihydroxycholecalciferol

Question 174

why do young animals have high P?

Answer 174

They have increased bone remodelling, which results in PTH increasing the release of Ca and phosphorous. Ca release is not significantly appreciated on blood test

Question 175

What is the relationship between P and Ca

Answer 175

Calcium and phosphorus have an inverse relationship in the body; when levels of one increase, the levels of the other typically decrease. as blood calcium levels rise, phosphate levels fall. This is because phosphate binds to calcium reducing the available free calcium within the bloodstream

Question 176

What are pathological conditions which affect PTH levels?

Answer 176

1) primary hperparathyroidism -> parathyroid adenoma; Increased Ca, decreased P, phosphaturia, calcinuria, increased urinary cAMP, increased bone reabsorbtion 2) hypercalcaemia of malignancy-> PTH related peptide (PTH-rp) - > same side effects as primary 3) secondary hyperparathyroidism -> thyroid surgery or congenital; hypocalcemia, tetany, hyperphosphatemia, decreased urinary phosphate secretion 4) chronic renal failure -> decreased GFR, decreased 1, 25 dihydrocholecalciferol production= hyperphopshatemia, decreased free [Ca] which can result in secondary hyperparathyroidism (increased PTH and bone reabsorbtion)

Question 177

what effects does vitamin D administration have on calcium levels?

Answer 177

Vit-D is active form of 1, 25 dihydrocholecalciferole -> increases serum [Ca]m serum PTH, and decrease serum [P]

Question 178

Describe the pathway towards vitamin D production from the source and what functions vitamin D performed? How is this pathway regulated?

Answer 178

Sources of Vitamin D such as UV rays and diet deliver vitamin D in their precursor forms, D2 and D3. These precursors then bind to the Vitamin D-binding protein (DBP) at the site of synthesis and form the DBP-D protein complex. Vitamin D is then carried in the DBP-D complex through the blood plasma to the liver. Precursors D2 and D3 are hydroxylated into inactive 25-hydroxvitamin D [25(OH)D] by 25-hydroxylase, coded by the cytochrome P2R1 (CYP2R1) gene. 25(OH)D is taken up into the kidney from the blood and activated via 1-α-hydroxylation by the CYP27B gene to the 1,25-dihydroxyvitamin D (1,25(OH)2D) activated state. An increase in parathyroid hormone (PTH), reductions in phosphorous and calcium upregulates CYP27B gene activity, while an increase in fibroblast growth factor (FGF-23) downregulates CYP27B gene activity.

Question 179

what are the actions of vitamin D

Answer 179

1) increase serum Ca and phosphate 2) increased intestinal Ca absorption via calbindin (D-28K) 3) increase intestinal phosphate absorption 4) increase renal re-absorbtion of [Ca] and [phosphate] 5) increase bone resorbtion -> provides [Ca] and [phosphate] to make new bone

Question 180

How do you treat hypercalcaemia? How does the drug work

Answer 180

calcitonin. Calcitonin lowers blood calcium levels by inhibiting the breakdown of bone (osteoclast activity) and increasing the excretion of calcium in the urine

Question 181

What are the main structural differences between the adrenal cortex and medulla?

Answer 181

Medulla is an extension of the CNS -> epinephrine and norepinephrine Cortex; endocrine - Grlomerulosa -> Mineralocorticoids (ADH) - Fasciulata -> corticosteroids (cortisol) - Reticularis -> androgens

Question 182

what all cortical hormones derived from and what is the rate limiting step in their synthesis?

Answer 182

All are steroid compounds derived from cholesterole. The adrenal cortex has receptors for LDL. The rate-limiting step is the cleavage of the cholesterol side chain by the Cholesterol Side-Chain Cleavage Enzyme to form pregnenolone, which is the initial step in forming cortisol, aldosterone, and estriol. This step is under control of PKA ->cAMP which is what allows enzyme activation to occur

Question 183

Which is more potent: prednisone, methyprednisone, or dexamethasone?

Answer 183

prednisone > methyprednisone > dexamethasone

Question 184

how is cholesterole trnasported in the body ?

Answer 184

bound to cholesterole binding protein or transcortin

Question 185

which hormones have mineralocorticoid activity ?

Answer 185

90% of the activity is aldosterone. Glucocorticoids have mild mineralocorticoid activity too (deoxycorticosterone 3%). Cortisol has active but it is concerted by 11-ß-hydroxysteroid dehydrogenase to cortisone which doesn't mind minerarolocorticoid receptors well

Question 186

what are the sites of action of aldosterone?

Answer 186

Kidney Colon Sweat and salivary glands

Question 187

where does aldosterone act and what does it do?

Answer 187

Increases the expression of Na and K channels on the luminal wall. Increase Na absorption increases water intake into the principal cell. On the blood side, there is an increase in production of Na:K ATPase which secretes 3 Na into the blood (drawing water with it), importing 2K into the cell. This is why there is an increase in K channels on the luminal side, as the increased intracellular K is then pumped out into the urine. This is why hyperaldosteronemia results in mild hypernatremia (diluted out by water in ECF)), hypokalemia Note; also see hypomagnesemia (cofactor) and urinary pH decrease and metabolic alkylosis)

Question 188

which are the Na and K channel types which are upregulated on the tubular aspect of principal cells in response to aldosterone?

Answer 188

Na - eNak K - romK

Question 189

if the RAAS upregulates aldosterone, or if there is hyperaldosteronism, why may serum Na be normal ?

Answer 189

because this is diluted out by the increased water in the ECF. Mild hypernatremia are usually only seen with pathological hyperaldosteronism

Question 190

what is the role of Mg in aldosterone function ?

Answer 190

Mg2+ acts as a cofactor for the Na+/K+ ATPase pump, which is essential for maintaining the electrochemical gradients of Na+ and K+ across cell membrane

Question 191

what is aldosterone escape?

Answer 191

refers to two distinct phenomena: (1) the kidneys' ability to increase sodium and water excretion despite elevated aldosterone levels (2) the failure of ACE inhibitors to reliably suppress aldosterone release in certain conditions

Question 192

Describe how aldosterone escape affects the kidneys ability to increase Na and Water excretion?

Answer 192

In conditions like primary aldosteronism, where there's excessive aldosterone, the kidneys initially retain sodium and water, but this effect is short-lived. 1) Renal Adaptation: The kidneys adapt to the excess aldosterone by increasing sodium excretion, preventing the development of edema (swelling) that might otherwise be expected. 2) Pressure Natriuresis: Increased renal perfusion pressure and volume expansion lead to increased sodium delivery to the distal nephron, overriding the aldosterone's sodium-retaining effect. 3) Natriuretic Peptides: Volume expansion also increases levels of natriuretic peptides, inhibiting sodium reabsorption in the collecting duct.

Question 193

why does increased aldosterone levels cause metabolic alkylosis and increased urine acidity?

Answer 193

H ions are excreted in the intercalated disks in exchange for Na

Question 194

why would hypoaldosterolemia or excessive aldosterone blockade cause diarrhoea?

Answer 194

By blocking aldosterone we decrease Na, K and Cl absorption in the colon which decreases H2O reabsorbtion

Question 195

How long does it take from aldosterone secretion to this having an effect, and why ?

Answer 195

45 min Two pathways; Major pathway Increased Na and decreased blood volume detected by the kidneys -> upregulate RAAS -> AngII -> increase aldosterone Minor pathway acth pathway - less important increased osmolarity detected by osmoreceptors in the hypothalamus-> CRH release which inteacts with corticotrophs -> release ACTH -> interacts with zona glomerulosa -> deoxycorticosterone is made and a precursor to aldosterone -> this is modified into aldosterone in the fasciculata Both pathways; aldosterone into blood -> aldosterone filters into the tubules by the kidneys where it travels to principal cells via the tubules -> enters the cytoplasm -> upregulate DNA transcription of genes for Na-KATPase and Na and K ion channels

Question 196

How do increased glucocorticoid concentrations affect carb metabolism ? What does this result in physically

Answer 196

increases it- increased glucocorticoids result in; - increased gluconeogenesis -> increased glycogen - Increases enzymes needed to convert AA in liver into glucose - mobilised AA from muscle - decreases cell glucose utilisation All of this increases fat deposition and muscle loss.

Question 197

what is the mechanism of action of glucocorticoids that results in decreased glucose utilisation?

Answer 197

not fully know. Thought to be due to depressed NADH oxidation to form NAD+. NADH must be oxidised during glycolysis

Question 198

what is the difference in insulin sensitivity between pancreatic, pituitary and adrenal-dependent diabeters

Answer 198

Pancreatic; strongly insulin sensitive Adrenal; moderately insulin sensitive Pituitary; weakly insulin sensitive

Question 199

What are the 3 endocrine forms of diabetes, and how do they differ in the way they respond to insulin?`

Answer 199

Pancreatic; strongly insulin sensitive Adrenal; moderately insulin sensitive Pituitary; weakly insulin sensitive

Question 200

why does muscular weakness occur in hyperadronocorticoism?

Answer 200

there is increased AA mobilisation from the muscle, and decreased protein synthesis with increased protein catabolism (which forms glycogen and fat) weakening mucles

Question 201

What shift in protein metabolism occurs between different cell populations in a Cushing's patient? What clinical exam features may this change in cause

Answer 201

Decreased extrahepatic protein metabolism (decreased transport of aminoacids into these cells), increased mobilisation of AA from muscle cells, and increased protein metabolism in the liver, which increases gluconeogenesis in the cells. One reason why you may get hepatomegaly and muscle loss

Question 202

why do you see obesity in cushings?

Answer 202

1) increased glucose metabolism rsulting in glycogen and fat formation 2) polyphagia increases caloric intake 3) decreased metabolic energy demand 4) mobilisation of protein from muscle to form glycogen or fat if the glycogen stores are full

Question 203

why does fat deposition occur during stress?

Answer 203

Excess cortisol mobilises AAs and FAs to form glucose for energy. However, if the energy is not needed the FA and the AA are concerted to fat. Also, cortisol decreases glucose utilisation by most cell populations resulting in gluconeogenesis and lipogenesis.

Question 204

What are cortisols' anti-inflammatory effects?

Answer 204

- stabilise lisosome walls preventing leakage of enzymes - Inhibit IL1 which reduces fever - Inhibit T cell production - decreases capillary leakiness - decreases phagocytic activity of WBS This is what allows cortisol to have protective effects during stress

Question 205

what adrenal zones does ACTH affect?

Answer 205

Fasciculata and reticularis. The glomerolosa is not heavily affected (mostly affected by AngII - AKA RAAS)

Question 206

what part of the hypothalamic-pituitary- adreanal axis is affected by stress?

Answer 206

stress increases CRH which is secreted by the hypothalamus and induces the pituitary to secrete ACTH ->thus cortisol

Question 207

what are the secondary messengers ACTH induces when binding to receptors on the adrenal cortex

Answer 207

ACTH+receptor -> Gs ->apha-GTP->PKA (adenylate cyclease) -> cAMP ->activates proteins

Question 208

why does cortisol have a protective effect during stress?

Answer 208

- stabilise lisosome walls preventing leakage of enzymes - inhibit IL1, which reduces fever - Inhibit T cell production - decreases capillary leakiness - decreases phagocytic activity of WBS

Question 209

what cells secrete pancreatic polypeptide?

Answer 209

PP cells

Question 210

what hormone inhibits both the secretion of insulin and glucagon? What are the effects of insulin on glucagon?

Answer 210

Somatostatin inhibits both. Insulin inhibits glucagon

Question 211

what is somatostatin? Where is it Produced ?

Answer 211

Somatostatin is a cyclic peptide well known for its strong regulatory effects throughout the body. Also known as growth hormone inhibiting hormone, it is produced in many locations, including the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS).

Question 212

What is the half-life of insulin and glucagon?

Answer 212

5-10min

Question 213

where is insulin and glucagon metabolised

Answer 213

First pass in the liver where 50% is metabolised, rest in the kidneys

Question 214

what are pancreatic acini and what is their role?

Answer 214

Acinar cells are arranged in clusters called acini. Each acinus is composed of Acinar cells, cuboidal epithelial cells that synthesize and store digestive enzymes, and intercalated ducts that collect enzymes from the acinar cells. Acinar cells produce and secrete digestive enzymes, including: - Proteases (e.g., trypsin, chymotrypsin) - Lipases (e.g., pancreatic lipase) - Amylase (breaks down carbohydrates) -Nucleases (e.g., DNase, RNase

Question 215

what effect does insulin have on protein metabolism?

Answer 215

- stimulates uptake of AA to form proteins by the liver (and other cells). - inhibits breakdown of existing proteins

Question 216

how does insulin interact with cellular receptors? Define pathway

Answer 216

Interacts with tyrosine kinases. Insulin binds external alpha receptors -> changes conformation of the inner ßreceptor-> these become autophosphorylated which activates a protein kinase on the receptor -> protein kinase phosphorilates IRS (insulin response substrate) -> increases Glut4 and increases cell permeability to K, phosphate and AA

Question 217

what is the largest cell population of the medulla and what are these analogous to? what are they innervated by ?

Answer 217

chromaffin cells -> analogous ti sympathetic postganglionic neurons Innervated by pre-ganglionic cholinergic neurons

Question 218

what do chromaffin cells secrete?

Answer 218

catecholamines - epinepherine and norepinepherine

Question 219

explain how chromaffin cells secrete catecholamines?

Answer 219

Preganglionic nerves secrete acetylcholine -> stimulates chromaffin cells -> secrete catecholamines

Question 220

what are the steps in catecholamine synthesis?

Answer 220

L-tyrosine -> L-DOPA -> Dopamine -> norepinepherine -> epinepherine Tyrosine hydroxilase which converts L-tyrosine to L-dopa

Question 221

what is the rate limiting step in the formation of catecholamines

Answer 221

L-tyrosine conversion to L-DOPA by tyrosine hydroxilase

Question 222

what enzyme converts dopamine to norepinepherine

Answer 222

Dopamine-beta-hydroxilase

Question 223

what enzyme converts norepinepherine to epinepherine

Answer 223

PNMT

Question 224

what is the ratio of epi:norepi ?

Answer 224

Species dependent but epinepherine is always more (e.g. dog 70:30)

Question 225

why is the blood flow through the adrenal gland important in catecholamine production ?

Answer 225

Blood flow from the capsular artery dives through the cortex first and then into the medulla where it drains out of the medullary vein. This is important as cortisol regulates catecholamine production, so blood goes through the cortex fasciculata, picks up the cortisol and then takes this into the medulla where it can help upregulate catecholamine production

Question 226

what do alpha 1 and alpha 2 receptors do?

Answer 226

Apha 1; vasocostriction, increase glycogenolysis and gluconeogenesis, incrase ciliary muscle contraction (pupil dilation) Alpha 2; vasocostriction, decrease norepinepherien release, decrease release of insulin and glucagone, increase platelet aggregation

Question 227

what do ß1 andß2 receptors do?

Answer 227

ß1; increase cardiac contractility and rate, increases renin secretion, increase nerve conduction velocity ß2 vasodilation in skeletal muscles, bronchodilation, increase glycodenolysis and gluconeofenesis, increase insulin and glucagon

Question 228

at low concentration what beta or alpha receptors are affected by epinephrine ? What baout high?

Answer 228

Low->ß1 High->ß2

Question 229

what is a phaechromocytoma?

Answer 229

neuroendocrine tumour of chromphin cells which secrete catecholamines

Question 230

why do phaechromocytomas have a high variability in side effects

Answer 230

phaechromocytomas catecholamine secretion is highly variabe. Sometimes there is continuous release of catecholamines, other times it is pulsatile, other times a stimulus occurs which causes a large release of catecholamines and it depends if it is mostly norepinepherine or epinepherine

Question 231

are phaeo usually epinepherine or norepinepherine secreting?

Answer 231

Despite most of the catecholamine being secreted by the normal cells being epinepherine, phaeos are usually norepinepherine. However, it is possible for them to be epinepherine and in very rare cases they produce only dopamine. Rarely non secretory. Not so much evidence in vet. Suspect primarily norepi in dogs

Question 232

Are phaeos unilateral or bilateral? and do they occur in isolation?

Answer 232

90% unilateral, 10% bilateral. Can occur with other neoplasias of the adrenal or other adrenal conditions.

Question 233

What determines the amount of catecholamine release in pheo ?

Answer 233

variable but in humans there is a correlation on tumour size and increased secretion - these are highly vascular neoplasias so it is easy for the tissue to remain perfused and secrete more.

Question 234

What is the growth rate of phaeos?

Answer 234

unpredictable and 50% are locally invasive

Question 235

what are symptoms dependt on in phaeos?

Answer 235

Size of mass (bigger - more secretion 50% are localy invasive 13-25% are metastatic (lymph node, liver, lung, kidney, spleen, bone , heart) Is secretion constant vs pulsative is it primary Norepi or epi secreting.

Question 236

Signalment for phaeo?

Answer 236

Dog; Older, with no breed or sex predilection Cat; RARE (case reports).

Question 237

what are the most common signs with phaeo;

Answer 237

Highly variable, can be continuous symptoms or episodic Excess catecholamines; Panting, tachypnea, lethary, anorexia, pale mm, acute blindness, tachycardia/arrythmia, pacing, anxiety, disorientation Tumour; abdominla enlargement, ascities, abdominal pain, hemoabdomen, collapse, hind limb edema, thrombi Metastatic Dz; Depends on organ affected

Question 238

what diagnostic changes do you see with phao; list CBC, CHEM and Urinalysis

Answer 238

highly variable - CBC; stess leukogram, anaemia, high or low PLT most common - Chem; elevated liver enzymes are the most common (unknown why - possibly due to hypertension and inflammatory cytokine), hypercholesterolemia (catecholamines can induce lipolisis), 20% will be mild-moderate hyperglycaemia (sometimes severe - rare DKA). Hypoalbuminimea. Urine; proteinuria (suspect secondary to hypertension). Hyposthenuria and isosthenuria seen in ~50% of cases

Question 239

Why may phaeos cause hyperglycaemia ? Also, why do some phaes not cause hyperglycaemia?`

Answer 239

Depends on whether they are epinepherine or norepinepherine secreting and how much they secrete. Overall it is down to what adrenergic receptors are stimulated. alpha 1; increase glucogenolysis and gluconeogenesis Alpha2; decreases insulin and glucagon release, but this is counteracted by ß2 stimulation causing glycogenolysis and gluconeogenesis, plus these receptors increasing insulin and glucagon

Question 240

are all phaeos hypertensive?

Answer 240

No, depends on secretory pattern. 50% of dogs with phae in one study had normal BP

Question 241

Diagnostics for phaeo ?

Answer 241

- Advanced imaging- helps for met check and cardiopulmonary changes - ultrasound - find mass Biopsy - can bleed and cause massive catecholamine release so can be risky cytology - can help identify cortical vs malignancy but not helpful for maligancy Urine Metanepherine testing (metabolite of epinepherine) Urine normetanepherine (diagnostic of choice)

Question 242

What is COMT enzyme in phaes why is this important?

Answer 242

It breaks down norepinepherine into normetanepherine and epinepherine into metanepherine

Question 243

Why do we test for metanepherine and not epinepherine?

Answer 243

metanepherine is more stable in the blood, while epinepherine has a short half life and secretion is more episodic. If you find a lot of the metabolite breakdown for epinepherine (ie metanepherine) then you can diagnose if epinepherine secretion is increased over time

Question 244

why is urine noremetanepherine the diagnostic of choice over urine metanepherine?

Answer 244

Norepinenepherine is likely the most commonly secreted catecholamine in phaes (based off humans) and its metabolic breakdown product is noremetanepherine

Question 245

Gold standard treatment for phaeo? What can be given pre- gold standard treatment to improve outcomes

Answer 245

- adrenalectomy is treatment of choice. Prior treatment with phenoyxebenzamine has been shown to improve outcomes

Question 246

What is phenoxibenzamine?

Answer 246

binds alpha-1 and alpha-2 adrenegrgic receptors (more affinity for alpha-1) blocking them and it is used in the supression of hypertension of phaeo symptoms.

Question 247

what beta receptors does phenoxybenzamine affect?

Answer 247

none

Question 248

where does triloastane work and what is this?

Answer 248

Trilostane (vetoryl) is a synthetic steroid analogue that competitively inhibits the enzyme 3-β-hydroxysteroid dehydrogenase within the adrenal cortex. Inhibition of this enzyme reduces synthesis of cortisol and, to a lesser extent, aldosterone and adrenal androgens

Question 249

what is a rate limiting enzyme for aldosterone proction, only found in the glomerulosa?

Answer 249

Aldosterone synthase, otheriwse known as CYP11B2

Question 250

what is gene family which produces aldosterone synthase?

Answer 250

CYP11B2

Question 251

what are the stimuli for aldosterone secretion ? How?

Answer 251

- hyperkalaemia; high K stimulates aldosterone by depolarizing the membranes of the zona glomerulosa cells - RAAS activation; Ang II acts on adrenal cortex to release aldosterone

Question 252

what is CYP11B2

Answer 252

Aldosterone synthase

Question 253

what is the role of aldosterone?

Answer 253

regulates blood pressure (vasocostriction and fluid retention) and regulaiton electrolyte (increase Na and Cl retention, K loss, Mg loss), acid base status (H+ lost - exchanged for Na) and intravascular fluid volume.

Question 254

where does aldosterone act?

Answer 254

principal cells of the distal collecting tubules mainly. Also in the distal convoluted tubule

Question 255

In primary hyperaldosteronism, what is the negative feedback loop that tries to lower aldosterone?

Answer 255

Renin is reduced in the atempt to stop RAAS

Question 256

In seconary hyperaldosteronism, what happens to renin?

Answer 256

It is increased, as there is some other factor (heart disease, CKD, hypovolemia etc) which causes renin activation, thus raas activation and increased aldosterone production

Question 257

what are the most common cause of primary aldosteronism?

Answer 257

Most commonly adrenocortical neoplasait, usually unilateral adenoma or carcinoma. Adrenocortical hyperplasia may also happen

Question 258

are tumours that are producing aldosterone also affecting cortisol or androgens?

Answer 258

Not well known. However, there are reoports, esp in cats, where alterations in progesterone secretion also affect cortisol levels as this part of the pathway is shared between the corticosteroids and mineralocorticoids (not androgens though)

Question 259

Most common signalment for hyperaldosteronism?

Answer 259

Olders cats -no breed or sex predisposition. Very rare in dogs and mostly documented in case reoports

Question 260

Common clinical findings in patients with hyperaldosteronism?

Answer 260

Hypolalamia - Weakness-> hypokalaemic polymyopathy (persistent and progressive and usually seen at K<3mb/dl) - cervical ventroflexion - Plantigrade stance at time - ataxia / weakness - rarely limb rigidity/dysphagia/collapse Hypertension; - blidness/eye colour change -> do fundic exam -azotemia +/- Pu/Pd Ie all signs of CKD

Question 261

when should you test aldosterone levels?

Answer 261

In hypertensive hypokalaemic patients

Question 262

what is the main differential for hyperaldosteronism

Answer 262

CKD - they also are azotemic, hypertensiove, often olf with Pu/Pd and hypokalaemic

Question 263

what concurrent disease may you see with hyperaldosteronism?

Answer 263

diabetes melitius, ckd hypokalaemia can cause nephrogenic diabetes insipidus via downregulation of acquaporin 2 channel or mineralocorticoid induced resistance to AVP Aldosterone:renin -> high aldosterone low renin (uncommon test) Aldosterone:creatinine ratio -> wide refernace range and not sensitive (uncommon test)

Question 264

what diagnsotics should you perform for hyperaldosteronism

Answer 264

minimum database + T4 and BP Mostly diagnosed on US. CT used for planing.

Question 265

If you have a patient with hyperaldosteronism what 3 medications do you give to treat the condition and side effects ? What is the gold standard tx though?

Answer 265

Big 3 medications; - spironolactone - Bp measurement (usually amlodipine - remeber renin is reduced so ACEi is not so useful - K supplementation Surgical removal of the adrenal tumour

Question 266

Why is spironolactone given to cats with hyperaldosteronism?

Answer 266

It is an aldosterone receptor blocker, so it causes K retention and increased secretion of Na, Cl, P. Acts on the distal renal tubules luminal membrane

Question 267

Why is amlodipine prefered over ACEi for the control of BP in hyperaldosteronism?

Answer 267

1) Renin is downregulated via negative feedback from increased aldoseterone levels. Thus there is little Ang I-> Ang II conversion so ACEi will be innefective at controlling BP 2) often these patients are azotemic and have an AKI from the hypertension

Question 268

how does amolodipine affect blood pressure?

Answer 268

Dihydropiridine L-type Ca channel blocker in cardiac and vascular smooth muscle. The L-type though are more commonly found in afferent arterials and the vasculature in general. Thus is has a greater affect in dilating peripheral vessels

Question 269

which drugs used can cause this

Answer 269

Amlodipine and cyclsporine cause gingival hyperplasia

Question 270

what are the 5 cell types of the islets of langerhans? Which ones are the acini?

Answer 270

1) alpha 2) beta 3) delta 4) gamma 5) epsilon Tha acini are none of those. Those are exocrine pancreatic glandular cells while the islet cells are the endocrine pancreatic cells

Question 271

what are the 3 roles of glucagon in response to low BG ?

Answer 271

1) Insulin antagonism 2) glycogenolysis -> break down glycogen into glucose 3) Gluconeogenesis -> make glucose from AA and FA

Question 272

why are ketones produced when glucagon is excreted?

Answer 272

Fatty acids are oxidised to ketones as an energy sorce.

Question 273

what are the 3 main ketones found in the body?

Answer 273

Acetone - breath ketones Acetoacetate - urinary ketones D-ß-hydroxybutyrate - blood ketone

Question 274

what supresses glucagon secretion?

Answer 274

1) insulin 2) Amylin 3) glucagon like peptide 1 (GLP1)

Question 275

what are tumours of alpha cells and what are the sings?

Answer 275

Glucagonoma This is a rare type of cancer; Clinical sings; - Superfical necrolytic dermatitis - Hyperglycaemia - Small intestinal diarrhoea

Question 276

what is a differential for this?

Answer 276

This is superficial necrolytic dermatitis which is a symptom seen in glucagonomas

Question 277

what is the structure of insulin during formation by ß-cells?

Answer 277

Preproinsulin (signal sequence + proinsulin) -> proinsulin (A&B segments bound by disulfide bonds + C-peptide) -> Insulin (A&B only)

Question 278

What physiological factors induce the synthesis and secretion of insulin

Answer 278

- increased [glucose] - other nutrients (Fa's and AA's) - incretins - ACh - xylotol

Question 279

in what section of the cell is preproinsulin modified to insulin

Answer 279

Like other hormones; Preproinsulin looses signal peptide in the endoplasmic reticulum leaving proinsulin Proinsulin looses the c-peptide in the Golgi. Insulin is packed into vescicles waiting for release

Question 280

what is the carrier protein for insulin and why is this improtant?

Answer 280

it does not have one. That is why it has a short half life of 3-10 min

Question 281

where is insulin degraded and how what is the half life?

Answer 281

Live and T1/2 is 3-10min

Question 282

what are the main types of glucose transporters, where are they found, and what are special features of each?

Answer 282

Glut1; brain, RBC, fetal tissue-> insulin indipendent so glucose passively diffuses into the cell (except satiety center which is insulin dependent) Glut2; ß-cells, liver, renal tubules, interstinal epithelium. These are insulin independent (glut 2 are the ones whcih depolarise the memrbase and allow insulin release from ß cells) Glut 3; found in neurons and sperm and is also insulin indipendent Glut4; skeletal muscle and adipose tissue -> INSULIN DEPENDENT

Question 283

most of the brain has insulin indipendent glucose transporters. Which are these ? and what is the secotion of brain that has insulin dependnt glucose transportters?

Answer 283

The brain has GLUT1 while the CNS has GLUT3 insulin indipendent transporters. The one exception is the satiety center which has GLUT4 insulin dependent transporters

Question 284

why are diabetics polyphagic?

Answer 284

The satiety center needs insulin to allow glucose into the cell, thus with the lack of insulin or resistance, the brain cannot detect that there is glucose and drives the patient to eat

Question 285

what inhibits glut4

Answer 285

cortisol and catecholamines

Question 286

How is insulin released from ß-cells

Answer 286

Glucose binds to GLUT2 allowing glucose to enter-> increased ATP -> increased [ATP] causes K channels to close -> depolarises the cell causing Ca voltage gated channels to open -> increased [Ca] causes the insulin storage granules to fuse with the cell membrane releasing insulin

Question 287

how much insulin is primed for relase and how much is in reserve?

Answer 287

1% primed for release 99% in reserve

Question 288

what are sulfonourea drugs? What do they do and what is an example?

Answer 288

oral drugs for diabetics which bind to Kir subutin of the K ATP channel. This will cause closure of this channel inducing the cell to depolarise and release insulin. An example is Glipizide

Question 289

what is diazoxide?

Answer 289

It is a drug that binds to the Kir subunit of the K ATP sensitive channel on ß islets causing desensitization of the channel to ATP making it less likely to close with increased intracellular glucose concentration, and therefore, depolarize the cell. This reduces insulin release

Question 290

what does insulin stimulate in the body?

Answer 290

1) Binds GLUT4 allowing glucose into skeletal musle and adipose tissue 2) Stimulates glycogenesis 3) stimulates lipogenesis 4) stimulates protein synthesis from amino acids in the blood stream (not by extracting them from muscle cells) 5) promotes cell K uptake IT essential induces the formation and storage of all enegy sources

Question 291

What does insulin inhibit in the body?

Answer 291

1) gluconeogenesis 2) glycogenolysis 3) hormone sensitive lipase 4) protein degradation (proteolisis) 5) ketogenesis Essentially inhibits all energy storage form breakdown and alternative energy pathwyas

Question 292

what are insulinomas? predispositions and clinical findings?

Answer 292

tumours of ß cells that secrete insulin resulting in episodic hypoglycaemia Most common in large breed dogs and pomeraneans. Insulin concentrations are high, BG often low (which is the opposite of what it shoudl be) , ketones can be high. Clinical signs are often chronic (1-3 months) and include seizures, collapse, weakness, muscle twitchin and ataxia

Question 293

is you have a high insulin level and low BG what is a leading differential and why>

Answer 293

Insulinoma. Normally, low BG will have LOW insulin and HIGH glucagon, as insulin release is due to high glucose and promotes storage of energy sources. Insulinomas are insulin secreting tumours, so insulin is high and they force all of the glucose into the cell making BG low

Question 294

How do you diagnose an insulinoma?

Answer 294

Bloodwork -> Low BG and HIGH insulin (key) CT - most sensitive (90%)

Question 295

what is the prefered imaging modality for insulinomas and why?

Answer 295

CT - most sensitive (90%) Aus - not very sensitive (30-75%)

Question 296

How do you differentiate an insulinoma from normal pancreatic tissue on a CT?

Answer 296

Insulinomas hyperattenuate on the arterial phase, while pancreatic tissue has normal attenuation

Question 297

recommended treatment for insuloma? Other available treatments

Answer 297

surgery recomended Other; - Steroids - Octreotide (somatostatin analogue) - diazoxide (inhibit insulin release by Katp dependnt channel inhibiton) - Stroptozoxin (cytotoxic to ß cells) - palladia

Question 298

Is insulinoma malignant?

Answer 298

yes - 50% have metastasis based on a 2021 study

Question 299

median survival with medical management for insulinoma? What about with surgery ?

Answer 299

8 months for medical 20 months for surgery (OVERALL survival -most had regional mets, 15-20% had distant mets) Unknown median with mets - Hz ratio 1.7 so more likely to die sooner but had better survival compared to medical alone. Based on a 2021 study of 116 dogs with insulinoma.

Question 300

What species similarities are there in the amino acid sequence for insulin

Answer 300

Cats most similar to cow (one aa difference to cow but 3 to dogs and 4 to human) Dog/human most similar to pig (one aa difference)

Question 301

what other hormon is secreted by ß cells with insulin and what does this do

Answer 301

they co-secrete amylin Amylin decreases glucagon secretion, delays gastric emptying and suppresses appetite.

Question 302

What toxicity can amylin cause and in what species?

Answer 302

In cats and primates, amylin can aggregate into amylin fibrils which are toxic to ß-cells

Question 303

what do Delta cells secrete? What does this do? What other site secretes it?

Answer 303

Somatostatin, which inhibits other islet hormomes, decreases GI and gallbladder motility, decreases absorbiton and secretion in the GIT It is also secreted by the GIT

Question 304

what is the overall job of somatostation?

Answer 304

to shut down everything. Gallbladder secretion, GIT motility and islet secretions

Question 305

what are somatostatinomas? How common? What do they cause ?

Answer 305

Extremely rare tumours of the delta cells of the pancreas which secrete somatostatin. Somatostatin SHUTS it DOWN - hyperglycaemia (decreased insulin secretion) - Cholelithiasis (decreased bile and GB emptying) - Small intestinal diarrhoea (decreased pancreatic enzyme and bicarb secretion

Question 306

what role do delta cells have in foetal development and what tumour can occur in these cells becuase of this role? What are the clinical consequences of this tumour?

Answer 306

They produce both somatostatin AND Gastrin during foetal develoment. You can get gastrinomas in the pancrease which results in severe gastric acid hypersecretion -> Zollinger-Ellison Syndrome

Question 307

what is Zollinger Ellison Syndrome?

Answer 307

Severe gastric acid hypersecretion caused by a gastrinoma in the pancreatic delta cells

Question 308

what are ocretodide and pasireotide? What are they used to treat?

Answer 308

these are somatostatin analogues - Acromegaly -> inhibits GH - Insulinoma -> inhibits insulin release - Gastrinoma -> inhibits gastrin release

Question 309

What are 3 diseases where we would use somatostatin analogues? what are two somatostatin analogue drugs

Answer 309

- Acromegaly -> inhibits GH - Insulinoma -> inhibits insulin release - Gastrinoma -> inhibits gastrin release Two analogues are OcretoTIDE and pasireoTIDE (the blocks the tide from coming in)

Question 310

what do epsilon cells secrete and when? What does this do?

Answer 310

Secretes Ghrelin in response to an empty stomach -> increases appetite (orexigenic), body weight, gastric motility and gastric secretion It also supresses insulin release and decreases fat mobilisation

Question 311

what are the major sources of Ghrelin synthesis in the body?

Answer 311

Stomach is the major source Epsilon cells of the pancreas are a minor source

Question 312

what inhibits ghrelin?

Answer 312

fatty meal or gastric dilation

Question 313

what is orexigenic mean

Answer 313

stimulates hunger

Question 314

what are PP cells of the pancreas? what do these do?

Answer 314

AKA F-cells Secrete pancreatic polypeptide in response to protein means and vagal stimulation. This does the following; major - inhibits gallbladder contraction - inhibits pancreatic enzyme and fluidsecretion minor' - stimulates glucocorticoid secretion - modulates gastric acid secretion and GI motility - Reduces appetite and food intake

Question 315

what is another name for PP cells of the pancreas?

Answer 315

F cells

Question 316

what is the role of progesterone in insulin function and what common disease can this cause?

Answer 316

Progesterone stimulates growth hormone release and GH is an insulin secretion inhibitor During pregnancy (diestrus), progesterone spikes, this causes growth hormone to spike and can lead to gestational diabetes (in DOGS not humans- that is different) Progesterone primarily inhibits insulin release by blocking calcium entry into beta cells of the pancreas, ## Footnote Growth hormone (GH) can cause insulin resistance by increasing the availability of free fatty acids (FFAs) and promoting the use of these fatty acids for energy, which reduces the body's ability to utilize glucose. GH also stimulates the liver to produce more glucose, further contributing to insulin resistance. Additional GH is involved in uncoupling Kinases involved in insulin signalind

Question 317

How does cortisol cause diabetes (ie how can cushings cause diabetes)?

Answer 317

It inhibits GLUT4 translocation to the cell membrane resulting in insulin resistance. Additionally it promotes glycogenolysis which increases BG

Question 318

how can catecholamines cause diabetes

Answer 318

1) inhibit insulin release 2) cause glucogenolysis 3) cause gluconeogenesis 4) cause lipolysis All of which increase BG ## Footnote insulin resistance caused by stimualtion of α-adrenergic receptor on ß cells and reducing Ca entry and insulin release. Also indirectly via cortisol release

Question 319

What are incretin hormones?

Answer 319

These increase insulin secretion and sensitivity. These are Glucose-dependent Insulinotropoc Peptide (GIP) and Glucagone-like Peptide 1 (GLP1)

Question 320

what do incretin hormones do and what are examples of these?

Answer 320

Examples are; Glucose-dependent Insulinotropic Peptide (GIP) and Glucagon-like Peptide 1 (GLP1) These; - Increase glucose dependent insulin secretion - increase insulin biosynthesis - decrease glucagon decretion (glucagon inhibits insulin) - increases receptor sensitivity to glucose - inhibit apoptosis and stimulate proliferation of ß-cells

Question 321

where are GIP and GLP-1 secreted?

Answer 321

secreted in the endocrine cells of the small intestine

Question 322

what is type 1 diabetes and is it reversible?

Answer 322

Type 1 is the charachterised by ß-cell destruction and results in an absolute insulin deficiency. IT is not reversible as the cells have been destroyed

Question 323

causes of type I in people

Answer 323

- 98% are autoimmune - infiltration of ß islets by lymphocytes and there are antibodies against islet cell antigens or insulin

Question 324

In autoimmune type I diabetes, what are examples of antigens towards which antibodies are created?

Answer 324

- GADA (glutamate decarboxylase) - IAA (insulin) - IA-2 (islet antigen) - ZnT8 (zinc transporter 8)

Question 325

Dogs tend to develope which form of diabters?

Answer 325

Type I - not much evidence for autoimmunue. There are vacuolated cells, suggesting ß-destruction, but there is not usually evidnece of lymphocytic infiltration Occasionally pancreatitis and pancreatic neoplasia can cause ßislet apoptosis

Question 326

If you are not overweight, and have insulin resistance, why may you not have diabetes.

Answer 326

have to have 2 things for type II diabetes ; - peripheral insulin resistance - some degree of ß-cell destruction If you are normal, with a healthy pancreas and have some degree of insulin resistnace, you will end up with a hypersecretion of insulin as the pancreas is trying to let that glucose into your skeletal muscle and adipose tissue. This is normal and how you overcome diabetes But the type II cannot compensate so they must have some loss of ßcells

Question 327

why do horses never become diabetic

Answer 327

They develope insulin resistance, however, they do not loose ß-cells so they are able to hyper-secrete insulin to overcome the resistance.

Question 328

what is type II strongly associated with

Answer 328

Obesity Fat inhibits insulin signaling and causes peripheral insulin resistance.

Question 329

which form of diabetes is reversible? And what stage must it be addressed to allow for reversal?

Answer 329

Type II insulin resistant (type I has ß cell destruction so it cannot be reversed). It has to be treated early on in develoment before ß-cells are lost. If you do not treat it early you get glucotoxicity whereby the chronic hyperglycaemia causes ß-cell apoptosis

Question 330

what are the components of glucotoxicity?

Answer 330

Chronic hyperglycaemia causes; - impares insulin secretion - downregulates insulin receptors - impairs glucose transport Additonally you get the formation of advanced glycation end products (AGE) which cuase glucose autoxidation, formation of glucosamine and increased oxidative phosphorilation which reads to the production of Reactive Oxigen Species (ROS)

Question 331

what do you see on histo of the ß islets in cats?

Answer 331

islet amyloidosis

Question 332

how is insulin sensitivity quantifiably associated with weight in cats?

Answer 332

For every 1Kg of weight gain, there is a 30% reduction in insulin sensitivity

Question 333

what does islet amyloidosis look like in dogs?

Answer 333

Dogs do not get islet amyloidosis - only cats with type II diabetes

Question 334

what form of diabtes causes islet amyloidosis and in what species?

Answer 334

type II - only in cats and primates

Question 335

if you have islet amyloidisis in an old cat histo of ßcells, what type of diabetes would it have?

Answer 335

maybe type II - but old cats can develop this in the abscence of diabetes

Question 336

is obesity a risk factor for diabetes in dogs? what pecularities are there with diabetes and weight in dogs

Answer 336

Obesity is an increased risk factor you will see insulin resistnace but most can appropriatelly compensate for this by hypersecreting insulin.

Question 337

how common is hypersomatotropism in diabetic cats?

Answer 337

1 in 4 (25%)

Question 338

What is hypersomatotrophisms and how is it associated with diabetes ?

Answer 338

pituitaty adenoma which secretes growth hormone. Growth hormone causes insulin resistance and the release of Insulin-like Growth Factor 1 (IGF-1)

Question 339

why do acromegalic cats have large faces?

Answer 339

Acromegaly is secretion of growth hormone from a pituitary adenoma. GH increases the release of insulin-like Groth Factor 1 which causes overgrowth of bones, resulting in protrusion of the mandible and broadenign of the face

Question 340

are hypersomatotrophism or acromegaly the same thing?

Answer 340

Hypersomatrophism is the increase release of growth hormone, however, it can occur in the abscence of clinical signs. Acromegaly is hypersomatrophisms once we start seeing the sings of face broadening and mandible protrusion

Question 341

What does excessive IGF-1 cuase?

Answer 341

Bone growth and broadening of the face and mandible protrusion organomegally (hepati, pancreatic etc) hypertrophic cardiomyopathy

Question 342

If you have a diabetic cat, what test can you run to rule out hypersomatotrophism?

Answer 342

IGF-1. If this is normal then they are just diabetic, if high, hypersomatotorphic with the diabtes possibly being secondary to the hypersomatotrophism

Question 343

when is the best time to check a cat for hypersomatotrophism? why?

Answer 343

at the time of the diagnosis of diabetes. Once you start treating them IGF-1 can drift up and you can end up in a grey some where it overlaps with the diagnosis of acromegaly

Question 344

If IGF-1 is high, which is the next step?

Answer 344

CT as this has a sensitivity of 94%

Question 345

why can hypersomatotrophysim complicate the treatment for diabetes?

Answer 345

These cats may beed 10-20x the normal insulin dose due to resistance. This can be challenging to administer and expensive

Question 346

what are the treatment options for hypersomatotrophism? If the cat is diabetic, what changes do you expect?

Answer 346

- Surgery (gold) - Radiation 50-85% of Diabetes cases should go into remission bit it can take weeks to months.

Question 347

what percentage of cats treated for hypersomatorophysm will go into remission? what is the timeline

Answer 347

50-85% of Diabetes cases should go into remission bit it can take weeks to months.

Question 348

what changes do you expect in IGF-1 when hypersomatotrophism is successfully treated?

Answer 348

It often does not change - we do not know why

Question 349

IF a cat which is successfully treated for hypersomatotrophysism, but its diabetes does not resolve, what changes in insulin requirements do you expect?

Answer 349

Pre treatment HST cats may need 10-20x the insulin dose. This dose requirement should improve post treatment

Question 350

what changes do you expect in fructosamine levels post successful treatment of a hypersomatotrophic cat whose diabetes has not gone into remission?

Answer 350

The frutosamine levels usually improve

Question 351

when treating hypersomatotrophism what should you warn owners about in regards to the diabetes management?

Answer 351

50-85% will go into remission, however, even those that do not, their diabetes should become more manageable through insulin dose reductions

Question 352

what is pasireotide?

Answer 352

IT is a long acting somatostatin analogue which is give SQ once monthly in catrs with hypersomatotrophysm and diabetes. This causes IGF-1 reduction and reduced insulin requirement. In the trial 3/8 cats went into remssion. Diarrhoea was a common side effect. It is prohibitively expensive (16,000$ per month)

Question 353

what is cabergoline?

Answer 353

it is a dopamine agonist with a high affinity for dopamine receptor 2 which is in the pituitary of cats with hypersomatotrophysim and diabetes. 35% of cats achieved remission in 6 months. Given Po q48h and is affordable Most cats had small pituitary tumours though (3-4mm RI 3m), but many with bigger ones did not responde

Question 354

what is dostinex

Answer 354

carbergoline -> dopamine receptor 2 agonist for the treatment of hypersomatotrophism and diabetes

Question 355

what percentage of dogs with hyper-A have diabetes?

Answer 355

14% But many dogs treated with trilostane will have mildly elevated BG and giving them insulin reduces the risk of them going into diabetes

Question 356

why are dogs with hyperadrenocorticocism more likely to develop diabetes?

Answer 356

Cotisol increases insulin resistance, and increased gluconeogenesis increasing BG which will result in increased insulin release and increased risk of glucotoxicity

Question 357

what are key considerations when considering potency and duration of action of insulin?

Answer 357

more potent the shorter the duration of action

Question 358

what is the potency and duration of action of the following; - glargine -prozinc (PZI) - Vetinsulin - Regular - neutral protamine hagedorn (NPH)

Answer 358

- glargine -> long acting, low potency -prozinc (PZI) -> medium acting and medium potency - Vetinsulin -> medium acting and medium potency - Regular -> potent, short acting - NPH -> intermediate portency and time of duration (dogs - very short in cats)

Question 359

what is humilin? onset and duration of action?

Answer 359

regular insulin -IV, onset immediate, duration 1-4h, hence best given as a CRI - IM, onset 45min, duration 3-8h - SQ not given, unpredictable potency and duration Higher potency = lower dose needed

Question 360

Appart from regular insulin, which are appropriate for DKA treatment?

Answer 360

- Lispro; dog and cat - Glargine; cats - Aspart; dogs

Question 361

what is the DKA glargine protocol

Answer 361

- protocol involves a combo of SQ and IM (initial is SQ, then 4h later start IM and give q4h IM and ontop SQ every 12h

Question 362

what type of insulin of vetinsulin? What are key charachteristics of note when administering this?

Answer 362

Porcine lente insulin - intermiediate acting U40 (not U100). mixed in supernate so has to be shaken and has biphasic peak in dogs due to the supernate Start 0.25U/Kg q12h dogs

Question 363

How do NPH and vetsulin compare in dogs? If not responding to one do you switch to the other?

Answer 363

Similar Both reach glycaemic control in 60-70% of patinets. Nadir for NPH is 2-4h while vetinsulin is 4-6h. Can try, should not make a difference.

Question 364

how does accuracy compare between vet pen and syringe?

Answer 364

pens slightly underdose, although syringe commonly overdose, especially at high doses Pens are more precise at low dose (esp <1U) but higher dose the precision drops with these too and can become comparable to syringe

Question 365

Protamine sinc insulin (PZI, proZinc) is used in what species and what characteristics need to be considered for administration?

Answer 365

It is for cats, and one of the top choices. Unpredictable in dogs. Start at 1IU/Cat q12h. ROLL to MIX

Question 366

Glargine (lantus) is used in what species and what characteristics need to be considered for administration?

Answer 366

Long acting u100 recombinant insulin. soluble at acidic pH and precipitates at a neutral pH (upon SQ injection) which allows for slow absorbtion. Has a long duration and a peakless effect Start at 1U/cat q12h No mixing needed Top choice for cats. Highly variable in dogs (high risk for subclinical hypoglycaremia)

Question 367

what changes are there in glargine compared to human insulin?

Answer 367

3 changes; - Change of A21 asparagine -> glycine - 2 extra arginines at B31 and B32 Insulines are named for their changes Gl ->glycine ARG -> arginine =GL-ARGine

Question 368

what is a risk of using glargine in dogs?

Answer 368

can cause sub-clinical hypoglycaemia at recomended dose

Question 369

what is Toujeo? How do you start this or transition this?

Answer 369

It is a U300 glargine for dogs- longer duration of action and less day to day variability. But it is less potent New diabetics; start at 0.5U/Kg q24h Transition from other; use current q12h insulin dose x1.33 to determine q24h dose

Question 370

what is detemir?

Answer 370

Human recobinant u100 lysine. Forms a hexamere at the injection site and ireversibly binds to albumin prolonging duration of action. Good for cats. Also an option for dogs if NPH and Vetinsulin does not work (or Torjeo). Can also cause subclinical hypoglycaemia in dogs 0.1U/kg for dogs so can be hard for small dogs

Question 371

what is degludec

Answer 371

U100 and U200 insulin, also forms a hexamere, but very expensive so not used often

Question 372

what are ultra-long acting insulins and what are their charachteristics in dogs and cats

Answer 372

These are recombinant fusion proteins of synthetic insulin and canine or feline FC. FC the fragment crystallizable region of immunoglobulins which allows for the extended half life allowing them to be once weekly injections.

Question 373

what is bexagliflozin?

Answer 373

this is Bexacat, a tablet oral feline insulin. It is a SGLT2 inhibitor. should not be used in cats that are already on insulin. There is a large list of contraindications

Question 374

What are SGLT2 inhibitors?

Answer 374

(Bexacat -ie Bexagliflozin) these inhibit the SGL2 channel in the proximal tubule. The SGL2 channel is the one which re-absorbs glucose and these help prevent glucotoxicity

Question 375

you have glucosuria while on a SGL2 inhibitor. What actions should you take?

Answer 375

Determine if they are type I or II diabetic? If they are type I they should not be on SGL2. Next, check BG. If normal do not worry. SGL2 inhibitors prevent glucose reabdorbtion in the proximal tubule (more lost in urine) to help prevent glucotoxicity

Question 376

why should you not use bexagloflozin in type I diabetics or those which have had DKA

Answer 376

Because it will increase glucose loss in the urine. The cells cannot take in the glucose as there is no insulin, but they actually need the glucose. Ketotic patients are producing ketones because they do not have enough glucose, and if we give Bexacat to them, we will decrease the amount of glucose available for them to uptake when they do get given insulin

Question 377

waht are GLP-1 inhibitors

Answer 377

Incretins --> these increase insulin secretion and may reduce glycemic variability in cats

Question 378

What is sulfonylurea (glipizide)

Answer 378

increase insulin secretion by closing the K-ATP channels allowing the ß cells to depolarise more promptly. However, these can cause disease progression (increase insulin exposure > desensitization) and amylosis in cats. Also risk for cholestasis, vomiting and hypoglucaemia

Question 379

What is metformin?

Answer 379

Biguanides - inhibit glucose release/gluconeogesis and increase insulin secretion. They also reduce cholesterole, triglyceride and glucose concentration in dogs with hyper-A

Question 380

what is arcarbose

Answer 380

drug that reduces glucose abdorbtion

Question 381

why may vanadium and chromium be given in a diabetic patient

Answer 381

Increase insulin sensitivity

Question 382

what are the priorities for diabetic dog nutritional management?

Answer 382

priority is to feed a balance diet 2x daily paired with insulin. The formulated diets have a lot of fiber and complex carbs and they can lead to weight loss which is good in the overweight but not those which are thin - should be avoided in these patients

Question 383

what are the priorities for diabetic cat nutritional management? what macronutrient breakdown do you want the food to have?

Answer 383

weight loss and low carbohydrate diet is critical. Low carb diets are associated with remission and longer survival. Carb 12% (most normal are 40%) Protein 40% Fat 48%

Question 384

what is the key target for glycaemic control

Answer 384

prioritise clinical sign resolution over the curve, especially if you only have one day of data. If the patient feels good and the curve has a massive BG drop, then you will need to address this even if the patient feels well. If the curve looks great but the patient is clinical then keen treating until the clinical sings are gone.

Question 385

what methods are there to determine the glucose curve?

Answer 385

In hospital day curve Free style libre - great in stable

Question 386

if you have a free style libre reading which is suggesting hyperglycaemia, how do you respond to this?

Answer 386

If the patient is asymptomatic then you do not need to address this. Could be just the innacuracy of the device, but they are also feeling well so we do not change

Question 387

what is the most common complication of a libre in a cat?

Answer 387

cats knock them off or the sensor fails 40-80% of the time

Question 388

how long do you aim to leave the freestyle on for?

Answer 388

hopefully 2 weeks

Question 389

when comparing free style to pinna or other blood sumples, what are the benefits and cons of a freestyle?

Answer 389

Freestyle is more likely to catch nadirs and hypoglycaemic events as the in hosptial curves will miss these if they are outside of the hospitalised periods.

Question 390

At which Bg do you start reducing insulin dose on a glucose curve if the patient is non clinical

Answer 390

50mmol/l Can tollerate 50-60 if it is occasional and short lived

Question 391

when is glucose the higher in dogs? why?

Answer 391

insulin is under circadian control - dogs tend to run a little higher overnight (1-6am on average)

Question 392

what is fructosamine? When should this be used?

Answer 392

product of irreversible glycosylation of plasma proteins. Reflects mean BG of the preceding 1-2 weeks. Individual trends are more improtant than lab reference range and only has moderate correlation with control . Useful in cats to confirm diabetes and rule out stress hyperglycaemia Being replaced by freestyle, but good in those where owner doesnt want to pursue libre / patient not tolleration / not much sq space so sensor doesn't work well. Used in those which you see infrequently, owners think they are doing ok or do not. If it comes back similar to prior, great, if singificantly higher then you have to curve

Question 393

what factors can influence fructosamine?

Answer 393

- False results with low or high serum proteins (e.g. PLE/PLN etc) - hyperthyroidism lowers fructosamine (increases protein turnover) - positively correlated with body weight so massive changes can change results - male cats run slightly higher than female

Question 394

you have a high frusctosamine level in a cat, what does this tell you if it is a newly diagnosed and when it is a recheck>

Answer 394

Newly diagnosed -> can confirm diabetes and rule out the change being stress hyperglycaemia Recheck - have to compare to prior. IF same, patient non clinical, then diabetes is controlled. If higher, diabetes is apparently controlled, you need to curve (owner maybe nonobservant or dumb). If clinical and high, doesnt matter what the fructosamine says, you need to treat to resolve clinical sings.

Question 395

what is glycated haemoglobin A1C test? what does it detect?

Answer 395

Similar to fructosamine test. Reflects average glucose over previous 2-3 months. Glucose irreversibly binds to the amino-terminal group of haemoglobin HbA1c, thus can help detect chronic hyperglycaemia

Question 396

what is the chance of a cat goning into diabetic remission and wht is the relapse rate and over what time frame?

Answer 396

25-50% go into remission 30% relapse over 9 months

Question 397

what are positive predictors of diabetic remission?

Answer 397

- New diabetics (shorter duration) - recent corticosteroid therapy (maybe partially iatrogenic - big thing) - Older age - Lower insulin dose - lower mean glucose contration during treatment - ie doing well

Question 398

what are negative predictors of diabetic remission?

Answer 398

- hypercholesterolemia - diabetic neuropathy

Question 399

how do IGF-1 levels and DKA predict likelyhood of remission

Answer 399

They do not predict anything

Question 400

complications of diabetes?

Answer 400

Dogs; - cateracts; 50% by 6m and 75% by 12m -can reduce with good glycaemic control Dog and cat - bacteruria; often subclinical - proteinuria; no known clinical consequences

Question 401

how does diabetes cause caterachts and why don't we see chateracs in most diabetic cats? what is a subpopulation of cats which will form cateracts?

Answer 401

It is rare. Glucose is metabolised to sorbitol by aldose reductase in the lens. This is then converted to fructose. These pull water into the lens causing diabetes Older cats >7yo are defficint in aldose reductase. You will as a reuslt only see caterachts in juvenile diabetes

Question 402

if you find bacteruria in a diabetic animal when should you culture and treat? How long do you treat for?

Answer 402

If non clinical you do not need to culture or treat. If clinical culture, treat as per usual. You do NOT need to give a longer course

Question 403

why is proteinuria common in dogs and cats with diabetes? How do we treat this

Answer 403

membraneous glomerulonephropathy with fusion of the foot processed, glomerular and tubular basement membrane thickening, subendothelial deposits, fibrosis and sclerosis occur. This prevents re-absorption We do not treat unless we think there is a glomerulonephropathy which is not associated with diabetes

Question 404

Prognosis for diabetes?

Answer 404

Good. Highest mortality in the first 6 months while trying to gain control

Question 405

majority of total body calcium is found within the _____________ as ___________

Answer 405

bone as hydroxyapatite crystals

Question 406

What percentage of total body calcium is found in… - Extracellular fluid (ECF) - Intracellular (ICF) - Bone

Answer 406

Approximately 0.1% of calcium is in the extracellular fluid (ECF). 1% is in cellular organelles. 98.9% is stored within bone.

Question 407

Amajority of total body phosphate is found within the _____________ as ___________

Answer 407

bone as hydroxyapatite crystals

Question 408

What percentage of total body phosphate is found in… Extracellular fluid (ECF) Intracellular (ICF) Bone

Answer 408

Extracellular fluid (ECF) - <1% Intracellular (ICF) - 14-15% Bone - 85%

Question 409

What percentage of ECF calcium is found as… - Ionized Ca - Protein-Bound Ca - Complexed Ca

Answer 409

Ionized Ca - 50% Protein-Bound Ca - 40% Complexed Ca - 10%

Question 410

T/F: The terms “hypocalcemia” and “hypercalcemia” are reflective of intracellular calcium concentrations.

Answer 410

FALSE - these terms indicate relative concentrations of extracellular calcium.

Question 411

hat changes in skeletal muscle and neuronal hyperexcitability can we expect with HYPOcalcemia? HYPERcalcemia? Why?

Answer 411

Hypocalcemia - INCREASED excitability producing clinical signs of facial pruritus (humans report tingling and numbness), tetany (twitching, tremoring), and seizures. Hypercalcemia - DECREASED excitability producing clinical signs of PU/PD, weakness, hyporeflexia, depression, and constipation. When calcium concentrations fall below normal, the neuronal permeability to Na ions increases. This allows the central nervous system and peripheral nerves to become easily excitable and fire an action potential.

Question 412

why do you see uncontrolled tremmoring and/or facial priritis in hypocalcaemia?

Answer 412

When calcium concentrations fall below normal, the neuronal permeability to Na ions increases. This allows the central nervous system and peripheral nerves to become easily excitable and fire an action potential.

Question 413

What changes would you expect to see in ionized calcium Ca+2 concentration in acidemia? Alkalemia?

Answer 413

Albumin has a set number of binding sites for positively charged cations (H+ and Ca+2). Therefore, if you have excessive H+, more of the sites will be taken up by H+. Therefore, acidemia causes shifting of the protein-bound to ionized-form. In acidemia, you will have an INCREASED ionized calcium. In alkalemia, you will have a DECREASED ionized calcium because you have a deficit of H+ in the blood and more of those binding sites will be available for calcium to bind.

Question 414

Calcium and phosphorus are both absorbed from the __________ and excreted in the __________.

Answer 414

gut and urine

Question 415

What percentage of calcium and phosphorus are absorbed from the gut?

Answer 415

Phosphorus is actually absorbed well - nearly 100% of dietary phosphorus is absorbed by the gut. Calcium is absorbed poorly through the gut. Only 35% is absorbed, rest lost in the faces

Question 416

how is calcium absorbed in the gut? how effictive is this pathway?

Answer 416

Calcium is absorbed poorly through the gut. Vitamin D promotes calcium absorption via formation of calbindin by the intestinal brush epithelium. Even with calbindin binding calcium and enhancing facilitated diffusion, only 35% of dietary calcium is actually absorbed. The rest is excreted in the feces!

Question 417

how much of the injested Ca is secreted by the kidneys in the urine and what component (Ica, protein bound or compexed Ca)?

Answer 417

10% of ingested Ca is excreted by the kidney, but only 1% of all calcium is lost Plasma-protein bound calcium cannot be filtered through the glomerulus. The remainder of anion-bound and free, ionized forms are filtered into the tubular lumen.

Question 418

where is Ca reabsorbed by in the kidney ?

Answer 418

90% proximal tubule and loops of henle 10% late distal tubule and collecting ducts

Question 419

what hormone mediates renal re-absorbtion of Ca and in which segments of the kidney?

Answer 419

PTH 90% proximal tubule and loops of henle 10% late distal tubule and collecting ducts

Question 420

How is phosphate secreted and re-absorbed ?

Answer 420

secreted by overlflow. If hypophosphatemia ensue then all P is reabsorbed

Question 421

Calcium homeostasis is achieved through the actions of three hormones:

Answer 421

Parathyroid hormone Vitamin D Calcitonin

Question 422

PTH is stimulated by _____________ in extracellular calcium.

Answer 422

Stimulated by decreases in extracellular calcium (hypocalcemia).

Question 423

where does PTH act upon to increase Ca concentration in hypocalcaemia?

Answer 423

Bone (increase release of calcium salts from resevoid) Gut (increase absorbtion) Kidney (increased re-absorbtion_

Question 424

How many parathyroid glands are there

Answer 424

4

Question 425

how is hypocalcaemia detected and what occurs when this is?

Answer 425

Hypocalcemia is detected by the calcium sensing receptors (CaSR) within the parathyroid glands. Chief cells within the parathyroid glands will produce parathyroid hormone (PTH) in response to hypocalcemia.

Question 426

PTH has direct and indirect effect. Define these

Answer 426

Rapid Phase - Osteolysis (DIRECT) - PTH binds to receptors on OSTEOBLASTS and OSTEOCYTES. -These cells are connected cell-to-cell by long, filmy processes.(osteocytic membrane system). - When PTH binds the receptors, it causes activation of osteocytic membrane pumps that shuttle soluble calcium ions from the bone fluid (intracellular fluid of the osteocytic membrane system) → extracellular fluid. - This causes a rise in extracellular calcium within minutes to an hour! Slow Phase - Osteolysis (INDIRECT) - PTH binds to receptors on osteoblasts that release two molecules (Receptor Activator for Nuclear Factor kB Ligand - RANK L) and (Macrophage Colony-Stimulating Factor - MCS F) that bind to preosteoclastic cells and aid in their maturation / differentiation process. - The mature osteoclasts then develop a ruffled border and release enzymes and acids that promote bone resorption.

Question 427

during maintance phase (normocalcaemia) how does the body prevent excessive bone re-absorbtion? How does PTH prevent this?

Answer 427

In normal “maintenance” phase of calcium homeostasis, osteoblasts send a signal to osteoclasts to decrease osteolytic activity. The name of this signaling molecule is Osteoprotegerin (OPG). It will bind to RANK L and prevent maturation / differentiation of osteoclasts. PTH prevents the secretion of OPG!

Question 428

PTH will __________ the rate of tubular reabsorption of calcium, and __________ tubular excretion of phosphate.

Answer 428

INCREASE and INCREASE

Question 429

what are the 2 forms of vitD in food? where are these synthesisded from and which is more bioavailable

Answer 429

D2 and D3 which are Vit-D pro-hormones. D2 (synthesized from ergocalciferol) - found in plant sources (ergot it a plant) D3 (synthesized from cholecalciferol) - found in animal sources (fish oil, egg yolk, butter, liver, etc.) D3 is generally more bioavailable compared to D2

Question 430

Both Vitamin D2 and D3 are prohormones. In which organ are they first activated? By which enzyme class? What is the product? what about the second organ, enxyme and what product

Answer 430

First Vitamin D2 / D3 are hydroxylated at C25 in the liver by the cytochrome P450 family of enzymes. The result is 25-hydroxyvitamin-D (25 (OH) D) Second 25(OH) D is hydroxylated into the hormonally active 1,25(OH)2 D (calcitriol, 1,25 dihydroxyvitamin D) within the proximal tubule of the kidney. The enzyme responsible for this enzymatic reaction is 1-alpha-hydroxylase.

Question 431

What are mediators of 1-alpha hydroxylase activity? For example, what increases and decreases its activity?

Answer 431

- PTH - INCREASES activity - FGF-23 - DECREASES activity - 1,25 (OH)2 D3 - DECREASES activity (negative feedback loop)

Question 432

Vitamin D Receptor (VDR) is present in most cells of the body. 1,25 (OH)2 D3 is a _________ hormone and therefore, the receptor is located __________ the cell.

Answer 432

Vitamin D Receptor (VDR) is present in most cells of the body. 1,25 (OH)2 D3 is a steroid hormone and therefore, the receptor is located within the cell (primarily the nuclei)!

Question 433

Vitamin D receptors have two specific binding sites. What are these for?

Answer 433

Vitamine D is a steroid hormone, so it crosses into the nucleous where it binds the vitamin D receptor, while the second then binds DNA allowing fro gene transcription

Question 434

where is calcitonin produced an what is the role of this?

Answer 434

Secreted by the thyroid gland, specifically the parafollicular (C-cells) in the interstitium between follicles. Its overall effect is to respond to high levels of extracellular calcium, and decrease extracellular calcium.

Question 435

which hormone antagonizes PTH

Answer 435

calcitonin as this decreases extracellular calcium

Question 436

what is calcitriol?

Answer 436

tablet version of 1,25-dihydroxycholecalciferol

Question 437

what are examples of CONGENITAL vitamin D disorders? How are these inherited and how common? Test available?

Answer 437

Very rare - case reports only Due to enzymatic or receptor deficiency Autosomal recessive inheritance Not related to diet Can be classified in three main types: 1) Vitamin D Dependent Rickets Type 1B-> affects CYP2R1 which results in a lack of 1-alpha-hydroxylkase (convers D3 ->25 (OH)D 2) Vitamin D Dependent Rickets Type 1A -> CYP2B1 defect which convers 25 (OH)D to 1,25 (OH)2D in the kidney 3) Vitamin D Resistant Rickets Type 2A ->Affects vitamin D receptor in the GIT and bones making this Vit-D resistant rickets Genetic test available for pomeranian dogs

Question 438

with vitamin D dependent rickets 1A, what abnormal biochem findins do you see?

Answer 438

Hypocalcemia Hyperphosphatemia PTH ↑ 25 (OH) D Normal (deficiency blocks next enzyne 1,25 (OH)2 D ↓

Question 439

with vitamin D dependent rickets 1B, what abnormal biochem findins do you see?

Answer 439

Hypocalcemia Hyperphosphatemia PTH ↑ 25 (OH) D ↓ 1,25 (OH)2 D ↓

Question 440

with vitamin D dependent rickets 2A, what abnormal biochem findins do you see?

Answer 440

Hypocalcemia Hyperphosphatemia PTH ↑ 25 (OH) D ↑ 1,25 (OH)2 D ↑

Question 441

Prognosis and treatment for the Vitamine D dependent congenital rickets diseases

Answer 441

1B = lifelong calcitriol, regular checks of iCa. Good prognosis 1A = lifelong calcitriol, regular checks of iCa. Good prognosis 2A = poor prognosis (very rare). can try to treat with calcium supplementation and calcitriol but rarely respond.

Question 442

examples of aquired VitD disorders?

Answer 442

- poorly supplemented diet (home cooked diets) - has been reported in dogs and cats with PLE, EPI, and acute pancreatitis.

Question 443

what are clinical signs of aquired vitamin D deficiency ?

Answer 443

Clinical signs include osteomalacia (in adults) and rickets (in puppies and kittens), pain when long bones are palpated, lameness, and stiff gait.

Question 444

where are Ca sensing receptors found ? what type of receptor are they?

Answer 444

G-protein, found in the parathyroid gland, kidneys, cartilage, and bone. CaSR maintains Ca within normal range.

Question 445

in hypoparathyroidism what changes do you seen on Ca and P blood work and what changes are there in absorbition and secretion in the kidney, GIT and bone

Answer 445

↓ PTH → INCREASE calcium and DECREASE phosphate. ↓ resorption Ca from bone → ↓ Ca and phosphorus ↓ absorption Ca and phos from intestines ↓ resorption Ca and ↑ excretion phosphorus through renal tubules PNS and CNS hyperexcitable

Question 446

what do we give for the actue and chronic treatemtn of hypoparathyroidism?

Answer 446

Acute Calcium gluconate IV (give slow and monitor EKG - bradycardia, PVCs, of QT) shortening Chronic - Calcitriol - initial dose for 2-4 days, then decrease - Ergocalciferol - initial dose until Ca 8-9.5 mg/dL, then decrease (usually can be to EOD). - PO calcium (Ca carbonate; others Ca gluconate and Ca lactate) Usually taper and stop within 1 week of starting calcitriol

Question 447

in hyperparathyroidism what changes do you seen on Ca and P blood work and what changes are there in absorbition and secretion in the kidney, GIT and bone

Answer 447

Inappropriate ↑ PTH → INCREASED calcium and DECREASED phosphate. ↑ osteoclastic activity in bones → ↑ Ca and phosphorus - ↑ osteoblastic activity → secretion of ALP - Risk of fractures due to weakened bones ↑ absorption Ca and phos from intestines ↑ resorption Ca and ↓ excretion phosphorus through renal tubules PNS and CNS depression

Question 448

what are the causes of primary and secondary hyperparathyroidism?

Answer 448

Primary Hyperparathyroidism Usually 1 gland, but can be more About 87% solitary adenoma, 8% hyperplasia, 5% carcinoma Secondary Hyperparathyroidism Usually hyperplasia of more than 1 gland CKD or chronic dietary Ca deficiency

Question 449

what clinical signs result due to hyperparathyroidism in dogs and cats?

Answer 449

PU/PD (Ca antagonizes effects of ADH in collecting ducts → HyperCa inhibits tubular uptake of Na and Cl → inhibits concentrating ability) GI - inappetence, vomiting, constipation (secondary to Ca-induced smooth muscle hypoexcitability and dysmotility) Urolith formation Renal failure?

Question 450

what are therapies, MOA and adverse effects for hyperparathyroid management of hypercalcaemia?

Answer 450

Question 451

what are clinical sings of hypoparathyroidism in dogs and cats ?

Answer 451

Dogs: tetany or hyperexcitability Seizures, muscle tremors, muscle fasciculations (some have “jaw champing”, stiff gait, panting, facial rubbing, biting at paws (seen as results of with muscle cramping and pain) Episodic with exercise/excitement Cats: Same as dogs, though more often inappetence and lethargic; lenticular cataracts and/or prolapsed third eyelid

Question 453

what is the site of action and effect of the following medications? Thyroxine MEthimazole Calcitriol Calcitonin Levothyroxine Somatotropin Carbegoline

Answer 453

Trilostane - 17-alpha hydroxylase -> prevents synthesis cortisol, aldosterone and mineralocorticoids Methimazole - thyroid peroxidase inhibitor - formation of T3 and T4. Also blocks coupling of DiT and MIT (use same enzyme) Calcitriol - Vit D analogue which works with calcitonine and PTH to oncrease calcium release/reabsorbtion/reduce secretion Calcitonin - decreases osteoclast function, and reduces tubular absorbtion of Ca, P Na, Mg, K and Cl Levothyroxine - synthetic T4 - increases thyroid metabolism and is used in hypothyroidism Somatotropin - growth hormone - given as a replacement in jhyposometotrophism Carbergoline - ergot alakloid derived Dopamine D2 receptor agonist - reduces prolactin levels and used to treat hyperlactenima, pyometra (estrogen is inhibited by dopamine). Also used to reduce growht hormone in cats

Question 454

How does growth hormone affect fat metabolism ?

Answer 454

Preferentially results in the release of FA so that protein doesn’t need to be used for energy generation: 1) GH causes a release of FA from fat 2)enhances conversion of FA to acetyl-coa -> energy formation

Question 455

What binds to Cortisol as a transport protein ?

Answer 455

Cortisol binding globulin or transcortin

Question 457

Why does BG increase with GH?

Answer 457

GH reduces carb utilization for energy promoting glycogen formation. Less glucose enters the cell as less is used, more insulin is then secreted. Excessive insulin release can result in insulin resistance

Question 458

Why do bones get thicker with increased GH?

Answer 458

They promote osteoblasts to form new bone. This helps bone growth when young, but once growth plates are closed it causes the deposition of new bone over old bone. This is how acromegaly results in

Question 459

What is the role of GH in bone thickening

Answer 459

They promote osteoblasts to form new bone. This helps bone growth when young, but once growth plates are closed it causes the deposition of new bone over old bone. This is how acromegaly results

Question 460

What is the active name of methimazole

Answer 460

Propylthiouracil

Question 462

What enzymes in glucose metabolism are affected by an increase in insulin ? And decrease

Answer 462

- phosphorylases in the liver -> principle enzymes that split glycogen into glucose - increase liver glucokinase which phosphorilates glucose in hepatocytes -increase receptor uptake of glucose - promotes enzymes which increase glycogen synthesis Decrease Glucose phosphatase -> was inactivated by insulin is now upregulated-> this allows free glucose to be transported back into the blood -lack of insulin upregulates glucose phosphorylase which splits glycogen into glucose phosphate

Question 464

What are the effects of insulin on fat metabolism? What about lack of insulin

Answer 464

1) inhibits hormone sensitive lipase -> decrease rate of lipolysis and release of FA into the circulation 2) glucose (once glycogen stores are full) first split into pyruvate (glycolic path) -> converted to Acetyl-coa 3) insulin activates lipoprotein lipase in the adipose tissue -> split triglycerides into FA Insulin inhibits the action of hormone sensitive lipase - this normally breaks down fat stored in cells, thus FA release from fat is inhibited Lack of insulin Hormone sensitive lipase becomes strongly activated resulting in fat breakdown releasing FA for energy use (excess use of fat results in ketosis and acidosis)

Question 465

Effect of insulin on protein metabolism

Answer 465

Anabolic (hence lack of causes waisting in DM) Promotes protein storage post meal. Promotes formation and prevents protein degradation Insulin lack causes protein depletion and increases plasma aa.

Question 466

What controls insulin secretion

Answer 466

2 factors 1) PRIMARY - feedback of blood glucose on beta cell release 2) other - amino acids -> strong stimator of insulin release (needed for aa uptake) - GI hormones -> gastrin, secretin, cholecystokinin and gastric inhibitory peptide (anticipate increase bg and therefor insulin need) - other hormones -> cortisol and GH increase insulin secretion because they antagonize insulin effect on glucose uptake -> increase Bg