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Human Physiology > Endocrine system > Flashcards

Endocrine system Flashcards

1
Q

Define the endocrine system

A
  • tissues and cells capable of secreting and responding to hormones
  • communication system
  • the two components communicate via chemical messengers called hormones
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2
Q

Define neural

A
  • functions mediated by electro-chemical conduction along nerves
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3
Q

Define endocrine

A
  • functions are mediated by chemical messengers called “hormones”
  • chemical mediators produced in one part of the body which act on a distant part (“remote control”)
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4
Q

Define hormone. They are:

A
  • a chemical substance, formed in one organ or part of the body and carried in the blood to another organ or part to illicit a response
  • depending on the specificity of their effects, hormones can alter the functional activity of just one organ or of various numbers of them (GnRH -one, vs T3 - several)
    Hormones are:
  • regulators of physiologic events (e.g. increase body temp, metabolism, etc)
  • effective in minute quantities
  • synthesized by cells/ endocrine glands
  • greek hormon, to rouse or set in motion
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5
Q

Define paracrine

A
  • chemical mediators produced in one cell that acts on a neighbouring cells (“neighbourhood watch”)
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6
Q

Define autocrine

A
  • chemical mediator produced in one cell and acts on that same cell (“self control”)
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7
Q

Nervous vs endocrine system:
1. physical form of information transfer
2. speed of information transfer
3. mechanism of gradation
4. mechanism to achieve specificity

A

Nervous:
1. action potentials
2. fractions of seconds
3. frequency
4. “wiring”
Endocrine:
1. chemicals
2. minutes, hours, days (varies)
3. amplitude modulation
4. receptors

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8
Q

What are the different hormone types?

A
  • peptide/ polypeptide
  • steroid
  • amino acid derivatives
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9
Q

Describe peptide/ polypeptide hormones

A
  • string of amino acids
  • small monomers e.g. thyrotropin releasing hormone (TRH); 3 aa
  • large multimeric proteins containing several subunits e.g. thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and insulin (Ins)
  • polypeptide hormones can have upwards of 200 residues
  • larger protein hormones can be very complex in both primary and secondary structure and are often subject to post-translational modifications such as proteolytic processing and glycosylation, necessary to produce functional hormone
  • water soluble; may or may not be associated with carrier/ binding proteins (to cross membrane)
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10
Q

Describe steroid hormones

A
  • derived from cholesterol metabolism, 4 hydrocarbon rings with various side chains
  • lipid soluble (requires serum binding proteins - transporter e.g. CBG-corticoidsteroid binding globulin) help to regulate steroid bioactivity - only free steroid is available to cell
  • examples: testosterone, estrogen, vitamin D
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11
Q

Describe amino acid derivative hormones

A
  • derived from the metabolism of phenylalanine and tyrosine to produce L-dopa, dopamine, norepinephrine and epinephrine, all of which function as neurotransmitters
  • thyroid hormones triiodothyronine (T3) and thyroxine are produced from the biological iodination of tyrosine residues in thyroglobulin, which are then coupled and cleaved from the parent globulin
  • examples: epinephrine, thyroxine (T4)
  • need carrier protein
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12
Q

List some examples of hormones working within the human body

A
  • the gut secretes its own series of hormones to regulate food intake and digestion (CCK, ghrelin, gastrin, secretin, NPY, etc.)
  • the heart secretes ANP, an important factor in regulating vascular tone and volume
  • the kidneys secrete EPO which increases erythrocyte formation
  • the liver secretes angiotensiongen (angiotensin precursor), IGF-I and thrombopoietin (increases platelets)
  • fat produces many “adipokines” e.g. leptin
  • most cells produce locally-acting growth factors and cytokines
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13
Q

Describe the regulation of endocrine secretion

A
  • several schemas for regulation from endocrine gland. most secretion controlled by:
    1. negative feedback
    also have:
    2. positive “feed forward”
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14
Q

Describe negative feedback regulation of endocrine secretion

A

Can occur in a variety of states:
1. between 2 hormones e.g. TSH and T3 - tissue A produces hormone A, goes to act on tissue B, which produces hormone B, which goes back to tissue A to stop production of hormone A
2. between a hormone and a metabolite e.g. PTH and Ca++ - parathyroid tissue produces hormone PTH which acts on bone, and changes Ca++ levels, and calcium sensors in parathyroid gland shut down production of PTH
3. between antagonistic pairs of hormones e.g. insulin, glucose, glucagon - insulin (beta cells of pancreas) acts to lower blood glucose, while glucagon (alpha cells of pancreas) acts to increase blood glucose

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15
Q

Describe feed forward regulation

A
  • one hormone positive feedback on another
  • e.g. increased estrogen has positive feed forward effects on LH + FSH (increased production - release)
  • in comparison progesterone has negative feedback on Lh + FSH
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16
Q

Describe the common characteristics shared by all hormones

A
  1. receptor specificity:
    - only certain cells respond to a given hormone
    - some cells are targets for more than one hormone
    - a cell must have the appropriate receptor to respond to a hormone
  2. a single hormone may elicit different responses in each target tissue
  3. single processes can be altered by multiple hormones (e.g. serum glucose homeostasis)
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17
Q

What are the factors affecting hormone action?

A
  1. hormone production/ release
    - regulation of gene expression by other hormones and cytokines
    - protein translation/ mRNA stability
    - availability of necessary substrates, enzymes and energy (enzyme levels/activity)
    - secretion
    - innervation (unique to neuronal hormones)
    - substrate/ energy availability

effect of hormone production
- more hormone present at a given target cell will lead to the activation of more receptors (at least until receptors are saturated)
- constant exposure to high levels of hormone may eventually lead to down-regulation of the receptor in the target cell(s) - not good thing

variable release rate into blood (so not too many hormones produced at once) -e.g. circadian rhythm
- fine tunes physiological responses
- prevents receptor down regulation
- attenuates negative feedback due to constant exposure
2. Serum carrier proteins e.g. SHBG, CBG, IGFBP3 (transport - important for steroid hormones)
- solubility
- stability
- metabolic clearance
- bioavailability
3. Converting / deactivating enzymes (in plasma and target cells) - may make hormones more or less potent, affect before reach target
- ACE-angiotensin converting enzyme
- ECE- endothelin converting enzyme
- COMT- catecholamine o-methyltransferase
4. Metabolic clearance (if these organs are functioning properly should restrict/decrease time hormone remains active)
- cellular uptake
- liver
- kidney
5. Receptors and signal transduction (
- specificty of hormone action is achieved through receptor expression and available signalling patjways
- signal amplification - 1 hormone-receptor complex activates many second messengers
- compartmentalization of “signalosomes” - creation of distinct cytoplasmic domains

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18
Q

Describe signal amplification

A
  • each hormone/ receptor complex produces multiple second messenger molecules (e.g. cAMP, PKC, Ca++)
  • each second messenger molecule activates different signalling cascades (protein phosphorylation)
  • end result is generation of multiple copies of an mRNA, functional phosphorylated protein
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19
Q

What are the two broad categories of hormone receptors?

A
  1. cell surface (membrane) receptors - for water-soluble ligands and large ligands (e.g. peptides, polypeptides, aa derivatives, ions, cytokines)
  2. intracellular receptors - for lipid soluble ligands (e.g. steroid, thyroid hormones, vit D)
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20
Q

What are the 4 types of cell surface receptors?

A
  1. G-protein-coupled receptors (GPCR) e.g. receptors for LH, GnRH, angiotensin, Ca++
  2. Tyrosine kinase receptors (TKR) e.g. receptors for insulin, FGF, NGF
  3. Tyrosine kinase-associated receptors (TKAR) e.g. receptors for GH, PRL, leptin
  4. Receptor activated ion channels
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21
Q

Describe the lipid-soluble receptors (intracellular)

A
  • e.g. steroids, thyroid hormone, vit D, retinoic acid
  • pass through plasma membrane
  • bind cytosolic steroid receptor (together become transcription factor)
  • translocate into the nucleus, bind DNA promoters (DNA directly)
  • cause changes to DNA transcription/ translation (increase / decrease) -> causes increase or decrease or protein production
  • steroid synthesis all occurs through the derivation of cholesterol and are produced in adrenal gland/ cortex
  • what matters is activity of enzymes (impacts which hormones are concentrated - what adrenal can make)
  • steroid hormones: progesterone, aldosterone, cortisol, oestradiol, DHT, testosterone
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22
Q

Describe steroid secretion

A
  • passive diffusion down the concentration gradient
  • steroids circulate in plasma bound to carrier proteins
    e.g. SHBG (sex hormone binding globulin), CBG (corticosteroid binding globulin)
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23
Q

Describe the mechanism of action of steroid hormones
+ inactivation

A

action
- HSP - heat shock protein, also can help regulate (increase/ decrease transcription/ translation) - regulate activation of cytosolic NR
- bind co-repressors (down-regulate transcription) or co-activators (up-regulate transcription)
inactivation
1. subtle changes in the ring structure of the molecule (oxidation, hydroxylation)
2. conjugation to organic acids (more polar), thereby increasing aqueous solubility -> excreted in urine (may test athletes for steroids in urine) - metabolic clearance

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24
Q

Describe neuroendocrinology

A
  • the hypothalamus is the primary region of integration between the central nervous and endocrine systems
  • input from array of neural, humoral, and endocrine sources are processed, coordinated and then relayed into action- secrete factors which stimulate or inhibit anterior pituitary function
  • together the hypothalamus and pituitary are master regulators of human physiology
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25
Q

Describe the functional anatomy of the neuroendocrinology

A
  • hypothalamus is a structure which surrounds or lines the 3rd ventricle of the brain immediately superior to the pituitary
  • hypothalamus is connect to the pituitary gland by a narrow stalk composed of unmyelinated axons of neurons which project from the paraventricular nucleus to terminate in the posterior pituitary
  • network of blood vessels (or portal system) which transverse between the hypothalamus and anterior pituitary
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26
Q

What are functionally significant structures and nuclei in the hypothalamus?

A
  • preoptic nucleus (PON)
  • paraventricular nucleus (PVN, occasionally PVH)
  • periventricular nucleus (PeVN)
  • arcuate nucleus (AN)
  • supra-optic nucleus (SON)
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27
Q

What are some CNS structures that play a major role in homeostatic regulation and have significant input to the hypothalamus?

A
  • subfornical organ (SFO)
  • organum vasculosum of lateral terminalis (OVLT)
  • medial preoptic area (MeOP)
  • nucleus of tractus solaris (NTS)
  • medial amygdala (MeA)
  • brainstem
    not limited to this list
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28
Q

What are the three categories that hypothalamic neurons can be divided into (based on the type of “output” they use)

A
  1. magnocellular (terminate in posterior pituitary-secrete hormones into capillary bed) - vasopressin and oxytocin
  2. parvicellular (secrete release/ inhibiting hypophyseotrophic factors into portal system) - trophic hormones
  3. hypothalamic projection neuron (synapses with neuronal targets) - e.g. sympathetic preganglionic neuron in spinal cord
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29
Q

Describe parvicellular neurons

A
  • short neurons
  • use hypophyseal portal system to carry hormones
    parvicellular cells: axons (in hypothalamus) -> hormone secretory cells -> bloodstream (in anterior pituitary)
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30
Q

Describe magoncellular neurons

A
  • long neurons
  • they don’t use blood system; direct release in post. pituitary
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31
Q

What are episodic endocrine secretions? types?

A
  • factors and hormones are secreted in bursts or pulses according to rhythms generated in the hypothalamus and/or CNS. types:
    1. Circadian - around 24 hr (once a day)
    2. Diurnal - exactly 24 hr (GHRH, CRH) - almost same as circadian, terms are sometimes used interchangeably
    3. Ultradian - mins or hrs (GnRH, LH)
  • most hormones display more than 1 pattern of secretion
  • important to know in order to treat endocrine disorders with hormonal therapies
  • patterns are diff between male and female
  • cortisol secretion is primarily diurnal with peak secretion upon waking
  • Human GH secretion is both diurnal and ultradian - large peak during the middle of the sleep phase with smaller peaks throughout the day
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32
Q

What is the suprachiasmatic nucleus (SCN) of the hypothalamus?

A
  • the SCN has an intrinsic circadian pattern of secretion and neuronal activity - achieved via coordinated expression of “clock” genes (the cryptochromes, Cry, and period, per, genes
  • utilizes direct input from the retina (non-visual)
  • light “entrains” or resets the pattern to correspond to day/night cycle - quantifies light
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33
Q

What is the pineal gland (the “third eye”)?

A
  • produces melatonin during dark periods from metabolism of serotonin
  • non-visual signals from retina to the SCN are relayed via the spinal cord to the pineal gland
  • in response, melatonin is released and acts on the SCN to “reset” the clock
  • melatonin = decreases body temp, leads to drowsiness, resets SCN
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34
Q

Describe the HP-adrenal axis

A
  • triggers = systemic stress e.g. cold, hypoglycemia, fear (cytokines, oxidative and volume stress)
  • hypothalamus releases CRH (corticotropin releasing hormone)
  • anterior pituitary releases ACTH (adrenocorticotropic hormone) in response - acts on adrenal cortex
  • adrenal cortex produces cortical - function: increase blood glucose, increased glucocorticoid (cortisol) release - glucogenesis, muscle catabolism, etc)
  • cortisol suppresses hypothalamus (CRH), pituitary (ACTH) and immune system (cytokines)
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35
Q

What is Addison’s disease?

A
  • form of hypocortisolism due to adrenal insufficiency
  • leads to high levels of ACTH
  • lack of negative feedback
  • causes: autoimmune disease, adrenal cancers
  • symptoms include: fatigue, decreased appetite, weight loss, increased pigmentation (a-MSH), low blood pressure, salt cravings, hypoglycemia, depression
  • president John F. Kennedy suffered from this disease
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36
Q

Describe the HP-thyroid axis

A
  • triggers = decreased temp,
  • Hypothalamus releases TRH
  • causes anterior pituitary to release TSH
  • acts on thyroid follicles to release T3 and T4 (thyroxine, thriiodothyronine) - leads to increased metabolism and heart rate (increased basometabolic rate)
  • T3 acts to inhibit (negative feedback) release of TRH from hypothalamus
  • T4 acts to inhibit (negative feedback) release of TSH from anterior pituitary
  • also have SRIF (somatostatin - somatropin release inhibiting factor) release from hypothalamus as an inhibitory factor on anterior pituitary release of TSH
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37
Q

What is propopiomelanocortin?

A
  • a 265 aa precursor to many hormones including ACTH
  • arose early in evolution and still functional today
  • excellent example of importance of post-translational processing
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38
Q

Describe the growth axis

A
  • triggers = 5HT and ACh?
  • Hypothalamus releases GHRH (growth hormone-releasing hormone)
  • acts on anterior pituitary to release GH
  • GH acts on many different things, including:
    1. adipose cells which release leptin (decreases apetite, increases energy output, increases puberty, increases GH (growth hormone) release - feed forward, and decreases bone formation) - fat metabolism
    2. bones - leading to growth and repair
    3. liver releases IGF-I (insulin growth factor 1, causing growth - important for overall growth) and goes to inhibit the hypothalamus and anterior pituitary
  • SRIF is also released from hypothalamus to inhibit release of GH from anterior pituitary
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39
Q

What is growth hormone disorder?

A
  • low GH
  • GH treatments can cost 900$/ month
  • Lionel Messi diagnosed - only 4’2
  • GH is a banned performance enhancing drug - but use as a child for corrective height is acceptable
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40
Q

Describe the prolactin axis

A
  • Hypothalamus releases TRH (+ PRF - prolactin releasing factor?)
  • acts on anterior pituitary to release PRL
  • PRL acts on mammary glands (increases secretory cell differentiation, increases milk production)
  • suckling on the glands leads to positive feedback on the hypothalamus and anterior pituitary through estrogen (mechanical stimulation)
  • hypothalamus also releases dopamine which inhibits release of PRL
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41
Q

Describe the HP- gonadal axis

A
  • hypothalamus releases GnRH (hypothalamus is a sensing organ - senses changes in environment)
  • acts on anterior pituitary to release LH and FSH
  • acts on gonads (steroidogenesis, gametogenesis, and maturation)
  • gonads release testosterone, estrogen, progesterone, and inhibin which acts to inhibit the hypothalamus and anterior pituitary (negative feedback)
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42
Q

Describe the transcriptional regulators of anterior pituitary development. What are the different kinds of pituitary failure?

A

coordinated regulation of when hormones are produced by transcription factors
impairment of pituitary transcription factors results in problems with hormone release/ development
pituitary hormones have order of production:
- POMC
- TSH
- GH
- PRL
- LH/ FSH
*don’t memorize
Developmental factor failures:
1. genetic
2. receptor
3. structural
4. transcription factor defect

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43
Q

What is acromegaly?

A

Produces too much growth hormone (GH) - problem in anterior pituitary
- pituitary adenoma e.g.

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44
Q

Describe the vasopressin axis (ADH, AVP)

A
  • brain recognizes increase in the osmolarity (magnocellular hypothalamic neurons)
  • acts on posterior pituitary to release AVP (Arginine vasopressin)
  • acts on nephron for H2O reabsorption and increased Na retention
  • AVP is responsible for pressure-volume regulation
  • Baroreceptors (sense decreased blood volume and blood pressure) activation of renin-angiotensin system
  • causes increased aldosterone secretion which further acts on the nephron to increase same processes (water and sodium retention)
  • brain releases dopamine which inhibits posterior pituitary release of AVP
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45
Q

Describe the oxytocin axis

A
  • good example of neural regulation of hormone secretion
  • brain acts on posterior pituitary to release OXY (oxytocin)
  • acts on the vaginal/ cerival stimulation for uterine contraction - contractions continue to increase during labour, positive feedback to brain + posterior pituitary - stretch
  • also acts on mammary glands (milk ejection) to for milk “let down” - prepares maternal breast for first feed after labour
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46
Q

Describe oxytocin

A
  • love hormone (promotes mating, long-term relationships)
  • parturition-uterine contraction
  • maternal behaviour - care for offspring, grooming (animals without oxytocin do not care for their offspring)
  • central secretion of oxytocin has putative roles in:
    feeding behaviour and satiety, gastric acid secretion, BP, temps and heart rate regulation, stimulation of glucagon secretion, gonadotropin secretion, stress responses, tubule contraction and sperm transfer in testis
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47
Q

Describe the thyroid gland

A
  • found in the neck
  • largest endocrine gland
  • controls how quickly we use energy (regulates basal metabolism)
  • stores iodine
  • produces T3/ T4 and calcitonin
  • not essential for survival, but development and metabolism will be severely compromised with hypo or hyper function
  • bilobed gland of endodermal origin derived from embryonic gut
  • lies over the ventral surface of the trachea just below the cricoid cartilage
  • 15-20 g
  • composed of large colloid containing follicles surrounded by cuboidal (thyroid follicle) cells and parafollicular cells (calcitonin)
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48
Q

Describe the functional anatomy of the thyroglobulin

A
  • massive protein
  • high MW (660 KD)
  • heavily glycosylated
  • 2 subunits
  • ~330 tyrosine residues
  • harbours carrier protein used to produce tri-iodo-thyronine (T3) / thyroxine (T4)
  • produced by thyroid cells
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49
Q

Describe the role of thyroid hormones

A
  1. early growth and development (required for GH secretion and action, essential for early neural development - via induction of NGF - maternal lack of T3/ T4 = growth retardation + cretinism - abnormal brain development) e.g. hypothyroidism = small, neck enlarged (thyroid follicles get bigger) - not a lot of iodine present
  2. increases mitochondrial growth, replication and activity; basal metabolic activity (increased heat production, O2 demand, increased HR and SV)
  3. Stimulates Na+/K+ ATPase activity and B-adrenergic receptors in several tissues including the heart (increased metabolic demand e.g. increased glucose)
  4. increases transcription of energy metabolism enzymes (increases lipolysis, glycolysis and gluconeogenesis leads to increased blood metabolite levels and cellular uptake) - increase availability of glucose
    - T3/ T4 is permissive to GH action and necessary for induction of PRL, GH, surfactant and NGF (nerve growth factor) expression
    - generally increase cellular metabolic activity, amino acid availability and thermogenesis
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50
Q

What is the importance of iodine?

A
  • we require ~ 60 mg iodine/ day
  • major sources are from salt, seafood, dark green vegetables (e.g. kelp)
  • important role in the production of thyroid hormones (T3/ T4) for growth, physical and mental development
51
Q

Describe the actions of thyroid peroxidase (TPO)

A
  • iodination and coupling of tyrosine residues in thyroglobulin (Tg) takes place at the apical microvillus surface of the follicular cell
  • tyrosine becomes diiodotyrosine through iodination (addition of 2 iodines - by iodinase), then 2 of these diiodotyrosines come together to form thyroxine, T4 (by peroxidase)
  • tyrosine becomes monoiodotyrosine through iodination (addition of 1 iodine - by iodinase), then a diiodotyrosine joins to form 3, 5, 3 - triiodothyronine, T3 (by peroxidase) - coupling
    *T3 and T4 are amino acid derivatives
    *iodinated Tg (in lysosomes) is proteolytically processed within the thyroid cells and releases two hormones by intracellular enzymes (T3 + T4)
52
Q

Describe the “iodine trap”

A
  • thyroid has evolved a unique strategy to deal with low environmental availability of iodine
    1. NIS (sodium-iodide symporter) uses Na+ gradient to transport I- into the thyroid cell
    2. “Pendrin” transports I- into lumen for oxidative coupling to thyroglobulin (pendrin is an apical iodide transporter)
53
Q

What is the colloid?

A

reservoir of materials for thyroid hormone production including Tg (thyroglobulin)

54
Q

What does TSH (thyroid-stimulating hormone) do?

A

TSH stimulates multiple activities in thyroid cells
1. increased activity of NIS (stimulates iodide transport)
2. increased Tg production
3. increased TPO activity (peroxidase - responsible for coupling iodinates tyrosines)

55
Q

Describe thyroid hormone transport

A
  1. thyroxine binding globulin (TBG) - 54 kD monomer; high affinity - 75% of circulating T3 + T4
  2. transthyretin (TTR) - 55 kD tetramer; lower affinity than TBG - 20% of circulating T4; 5% of T3
  3. human serum albumin (HSA) - 66.5 kD monomer; low affinity - 5% of circulating T4; 20% of T3
    *TBG and TTR regulate the bioavailability and half-life of T3/T4. Without BPs (binding proteins), thyroid hormones are rapidly cleared from circulation
    * because of aromatic structure - difficult to dissolve in blood - need protein carriers - BPs
56
Q

Describe the serum T3/T4 profile

A
  • % of hormone secreted: T3 = 10% (more active + potent), T4 = 90%
  • % free in plasma: T3 = 1%, T4 = 0.1%
  • relative activity (potency): T3 = 10, T4 = 1
  • half-life (days): T3 =1, T4 = 7 (longer half life)
57
Q

Describe the activity T4

A
  • majority of hormone released is T4 which has a longer half-life in serum
  • T4 is not biologically active and must be converted to T3 within target cells by specific deiodinases (D1 and D2) - essentially T4 is a secreted prehormone
  • T4 may serve as a conservation mechanism for iodide
  • T3 is the active form of thyroid hormones
58
Q

Describe the thyroid hormone - steps to get there

A
  • T3/ T4 action mediated by intracellular receptor
  • thyroid hormone receptor (TR) acts as a transcriptional repressor in a complex with other proteins in the target cell nucleus
  • binds to specific recognition site in a target gene
  • binding of T3 causes the TR to release from the complex thus activating gene transcription
  • T4 must be converted to T3 inside the cell by special deiodinases (D2 converts in the cytoplasm)
  • also exists D3 which may convert T4 to rT3 (reverse T3- inactive), or T3 to T2 (weak thyroid hormone)
59
Q

Mutations or dysfunctions of any component of the thyroid hormone system can lead to thyroid-hormone related pathology including:

A
  • TR activating mutations give rise to hyperthyroid phenotype
  • TR inactivating mutations can lead to end-organ resistance and hypothyroid phenotype
  • TSH receptor mutations can lead to it being permanently “on” or “off”
  • mutations in TBG (thyroid hormone binding globulin) can profoundly affect the presentation and clearance of T4/T3 in serum thus altering the efficacy of the hormone - affects transport (carrier protein)
60
Q

What is goiter?

A
  • causes by excessive TSH secretion (no negative feedback) leading to thyroid cell hypertrophy
  • many geographical areas with low bioavailability of iodine leading to endemic goiter - including N. America
61
Q

What happens with hypothyroidism?

A
  • lack of energy (overall metabolic rate is lower)
  • slow heart rate
  • muscle cramping
  • feeling cold
  • puffy eyes
  • lack of concentration + poor memory
    -> Oprah is a famous person with this disease
62
Q

What is Hashimoto’s disease?

A
  • anti-TPO antibodies -> no availability to iodinate thyroglobulin
  • make antibodies against TPO
  • hypothyroidism
  • with T3/T4 therapy body become phenotypic normal (restore height - taken at young age)
63
Q

What happens with hyperthyroidism?

A
  • feeling hot, increased sweating
  • fast, strong, irregular heartbeat
  • nervousness, trembling hands
  • weight loss
  • Jillian Michaels has disease (workout movies)
  • opposite symptoms of hypothyroidism
64
Q

What is Grave’s disease?

A
  • anti-TSH receptor antibodies - activating (autoimmune - activates TSH receptor without the hormone present)
  • hand tremor
  • insomnia
  • hyperactivity
  • protrusion of the eye
  • mood swings
  • dizziness
  • hyperthyroidism
  • Missy Elliot has the disease
65
Q

What are parathyroid glands?

A
  • 4 small glands that sit in the thyroid gland
  • they help to regulate the calcium metabolism
66
Q

Why is calcium so important?

A
  • signal transduction (secretory vesicle release, transcriptional activation)
  • membrane potential (maintains excitability - neurons and muscle)
  • muscle contraction (necessary for both contraction and relaxation)
  • enzyme co-factor (e.g. troponin-C, calcium-calmodulin)
67
Q

What are the roles of the human skeleton?

A
  • support and protection
  • locomotion
  • hematopoiesis
  • calcium regulation (~99 % stored in bone - calcium phosphate, 50% of skeletal weight
  • the other ~1% is non-skeletal, blood (protein bound, complexed, ionized) but only 0.5% available for activities - very tightly regulated
68
Q

Describe calcium balance

A
  • three organs play a role in calcium balance: intestine, kidney and bone
  • net movement is zero: average ingestion = fecal + urinary output
  • moves between the ECF (extraxcellular fluid) and these organs
69
Q

Describe the role of the intestine with calcium

A
  • brought in through apical side by CaT1
  • transported through gut by CaBP
  • brought down and released through basolateral side
  • the gastrointestinal tracts is the site for calcium absorption
  • calcium is also excreted in the feces (unabsorbed calcium, normal gut secretion of fluids and enzymes)
70
Q

Describe the role of the kidney with calcium

A
  • processes ~ 10 g/day; 98% is reabsorbed
  • active process - saturable and hormone regulated
  • brought in through 2 locations
  • 1 loop of Henle - passive diffusion
  • 2 DCT (distal convoluted tubule)- up-regulated by PTH - parathyroid hormone (increase absorption)
71
Q

Describe the role of bone with calcium

A
  • trabecular bone is metabolically active - provides calcium for the rest of the body - repairs and strengthens the “scaffold”
  • accomplished through process of “bone turnover” or “remodelling”
  • ~15-18% of trabecular bone is remodelling at any given time; scaffold renews itself every 6 years (not perfect process - may lose bone)
  • osteoclasts eat bone and release calcium
  • delicate balance -> mineralization = storage of Ca, bone resorption = increase in plasma Ca
  • with aging -> imbalance – osteoporosis
72
Q

What are chief cells?

A
  • found in parathyroid glands
  • produces PTH
  • Ca2+ sensing receptors (if too high, shut down PTH production)
73
Q

Describe parathyroid hormone (PTH) and receptor (PTHR)

A
  1. PTH
    - peptide hormone; full biological activity in 1-34 fragment
    - parathyroid gland secretes fragments and intact PTH
    - role of C-terminal fragments currently under study
  2. PTHR
    - shared with PTHrP -growth factor (made in the prostate - cancer); also responsible for HHM (hormone- related hypercalcemia) - promiscuous receptor, not just PTH - if have prostate cancer produce a bunch, bind to receptor, leads to high levels of calcium - hypercalcemia
    - highly expressed in bone and kidney
    - G-coupled receptor
74
Q

What does vitamin D3 do?

A

Helps PTH to respond to changes in serum Ca2+
- PTH very tightly regulated, once crosses threshold, production drops rapidly
- vitamin D3 does the same

75
Q

Describe the PTH pathway

A
  • parathyroid releases PTH
  • PTH acts on bone and kidney (decreased bone formation, increased osteoclast activity, increased DCT reabsorption of calcium, activates enzyme important for vitamin D3 production)
  • changes is kidney leads to increased calcium absorption in the GI tract - vit D3 binds in gut to increase calciumreabsorption
76
Q

Describe vitamin D metabolism

A

see last slide - lecture 3

77
Q

Describe overview of glucose homeostasis

A
  • during and after a meal, serum glucose levels rise rapidly (fuel that drives all of human metabolism)
  • is response to rising glucose levels, insulin is secreted which acts on cells to allow the uptake of glucose to drive the cellular machinery (hypoglycemic action = insulin -> decrease plasma glucose)
  • when glucose levels are low, such as between meals, glucagon is secreted which acts to suppress the uptake of glucose by muscle and fat and to mobilize energy stores (hyperglycemic action = glucagon, epinephrine (stress hormones), cortisol, growth hormone -> increase plasma glucose)
78
Q

Refresh cellular respiration

A
  • glucose is the best source for the generation of cellular ATP- the molecule which provides energy for all cellular processes
  • energy is stored in the third phosphate bond of ATP and most activities in the cell are regulated by phosphorylation
  • glucose is broken down in 3 separate, consecutive processes:
    1. glycolysis converts glucose (C6) to pyruvate or lactate (C3) and produces 2 ATP
    2. the TCA cycle (using acetyl co-enzyme A) produces 2 ATP
    3. the electron transport chain (mitochondrial membranes) producres 34 ATP
  • grand total = 38 ATP/ molecule of glucose
79
Q

Describe the different glucose transporters (GLUT 1-5)

A
  • hexose transporters
  • form glucose-selective membrane channels + allow entry into cells
    1. GLUT 1: tissue distribution = brain, erythrocytes, placenta, fetal tissue - low Km (~1 mM) - constant uptake of glucose (found during pregnancy)
    2. GLUT 2: tissue distribution = liver, kidney, intestine, pancreatic B-cell - high Km (15-20 mM) - glucose equilibrium across membrane (digestive tissues - cause of phase 1 insulin secretion)
    3. GLUT 3: tissue distribution = brain - low Km (<1 mM) - preferential uptake in states of hypoglycemia
    4. GLUT 4: tissue distribution = primarily muscle and adipose - med Km (2.5-5 mM) - insulin sensitive (regulated by insulin
    5. GLUT 5: tissue distribution = jejunum - med Km (~ 6mM) - fructose uptake
    *low Km means high affinity
  • normal glucose ~ 5mM
80
Q

Describe the role of the pancreas - exocrine vs endocrine cells

A

has both exocrine (digestive enzymes) and endocrine (glucose-regulating hormones) function. the endocrine cells and hormones are produced within the Islets of Langerhans (endocrine = 4%) - small structures within the larger acinar (exocrine - 96% main composition) structure of the pancreas:
- a-cells produce glucagon (periphery)
- B-cells produce insulin and amyloid- can lead to protein misfolding - don’t want B-cells working too much (central clusters)
- δ-cells produce somatostatin
- D1 cells produce VIP (vasoactive intestinal peptide)
- PP cells produce pancreatic polypeptide

81
Q

Describe insulin biosynthesis

A

insulin is a peptide hormone produced through a series of steps:
1. transcription of insulin gene to produce mRNA
2. translation of the mRNA into preproinsulin
3. enzymatic cleavage (signal peptidase) of the “pre” or “signal” peptide to yield proinsulin
4. enzymatic cleavage (endopeptidase - proenzyme convertase - PC2, PC3/PC1) to remove the “C” peptide
5. packaging of mature insulin into secretory granules - exopeptidase, carboxypeptidase H, cleans up C-termini

82
Q

Describe insulin secretion

A
  • insulin secretion is “biphasic” with 1st peak occuring within 1-5 min of a glucose load (meal). Sharper + higher
  • The 2nd peak occurs 15-20+ min later. shorter + wider
83
Q

Describe phase 1 of insulin secretion

A

Release of stored insulin in pancreatic B cells
1. increased plasma glucose leads to increased glucose uptake by the B-cell via GLUT 2 (constitutively expressed at the cell membrane)
2. increased cytosolic glucose in B cell results in increased cellular respiration - metabolism (generation of ATP)
3. ATP closes ATP-regulated/sensitive K+ channels - resulting build-up of positive charges in the cell causes membrane depolarization
4. the wave of depolarization opens voltage-gated Ca2+ channels and allows influx of Ca2+ ions into the B cell cytoplasm (Ca2+ enter pancreatic beta cells)
5. increased cytosolic Ca2+ is the signal for the release of stored insulin in secretory granules (activates + release vesicles)

84
Q

Describe the 2nd phase of insulin secretion

A

autocrine action of insulin - phase 2 largely dependent on phase 1 - this phase takes longer
1. increased cytosolic Ca2+ (from phase 1) activates CaM kinase (Ca++/ calmodulin-dependent protein kinase)
2. CaM kinase activates transcription of the insulin gene
3. secreted insulin (Ins, from phase 1) binds to B cell insulin receptors (InsR)
4. activated InsRs increase transcription of insulin gene via the PI-3 kinase pathway
5. both mechanisms increase the amount of insulin available for secretion

85
Q

Describe the insulin receptor

A
  • member of the tyrosine kinase family of receptors (TKR) - plasma membrane receptors
  • have canonical structure: IgG-like region, cysteine-rich region, transmembrane domain, kinase domain, protein-interaction domain, C-terminal tail
    All TKRs function in similar manner:
    1. ligand binding induces dimerization of the receptors
    2. the activation (kinase) domain of each receptor phosphorylates the other-autophosphorylation
    3. the activated kinase domains then recruit and phosphorylate the second messenger kinases including Signal Transducers and Activators of transcription (STATs), phosphatidylinositol-3 kinase (PI3-K), phospholipase C (PLC, various isoforms) and membrers of the mitogen-activated protein kinase (MAPK) family
    4. the cell responds with changes in protein turnover, cytoskeletal movements, secretion and gene transcription
  • the insulin receptor mechanism of action includes the recruitment and phosphorylation of a group of receptor-specific proteins known as Insulin Receptor Substrates or IRS proteins (expression varies)
  • insulin receptor (InsR) activation leads to glucose uptake in metabolic organs - GLUT 4 moves to membrane - occurs due to InsR phosphorylating IRS-1, which phosphorylates PI3-kinase
86
Q

What is the signal termination for insulin release>

A
  • receptor dephosphorylation (phosphatases activated by signal cascade)
  • Ca2+ pumps (Ca2+ returned to ER and ECF)
  • phosphodiesterase (inactivates GTP)
  • transcription factor dephosphorylation
87
Q

What are the other functions of the insulin receptor?

A
  • increases growth translation
  • decreased cell cycle arrest- apoptosis, DNA repair
  • decreases apoptosis
  • increases cell cycle, glucose metabolism
  • increased survival, transformation, cytoskeletal rearrangement
88
Q

What are the major roles of insulin in the liver?

A
  • increased glycogenesis (glycogen synthesis - store glucose)
  • increased glucose uptake
  • increased synthesis of fatty acids - store glucose
  • decreased gluconeogenesis
  • decrease glycogenolysis
  • does not have GLUT 4
  • no formation of glucose (decreased)
89
Q

What are the major roles of insulin in muscle?

A
  • increased uptake of glucose and amino acids (GLUT 4)
  • increased glycogenesis
  • increased protein synthesis (anabolic action)
  • decreased gluconeogenesis
  • decreased glycogenolysis
  • no formation of glucose (decreased)- store glucose
90
Q

What are the major roles of insulin in fat?

A
  • increased uptake of glucose and free fatty acids (GLUT 4)
  • increased synthesis of triglycerides and lipogenesis
  • increased transcription and secretion of adipokines, including leptin (leptin suppresses hunger)
  • decreased lipolysis
91
Q

What is the major role of insulin in the brain?

A
  • decreased sensation of hunger
92
Q

Describe the absorptive state (post-meal) of the regulation of glucose homeostasis

A

this is an anabolic state of metabolism (plenty of glucose)
- energy demands are met primarily by absorbed carbohydrate with its conversion to glucose
- in the liver there is net uptake of glucose
- muscle and liver - synthesis of glycogen (glycogenesis), little glycogenolysis
- net protein synthesis
- excess ingested carbohydrate, fat and protein that are not used for energy or structure are stored

93
Q

Describe the post-absoptive (fasting) state of the regulation of glucose homeostasis

A

this is a catabolic state of metabolism
- storage of carbohydrate, fat, and protein all occur at a reduced rate and net catabolism occurs
- the nervous system still requires glucose, this is achieved in two way: 1 hepatic glycogenolysis, 2 hepatic conversion of pyruvate, lactate, glycerol and certain amino acids to glucose (called gluconeogenesis)
- glucose utilization in other tissues is reduced (glucose sparing) and lipolysis (by providing fatty acids) provides most of the energy supply to muscle, etc
* regulated by glucagon and stress response hormones

94
Q

Describe the adipo-insular axis

A
  • parasympathetic stimulation is activatory of insulin release
  • sympathetic stimulation is inhibitory of insulin release
  • studies have shown that leptin and insulin act via a classic negative feedback model
  • insulin causes increased transcription, synthesis and secretion of leptin, which goes back to act on B-cells to decrease the transcription, synthesis and secretion of insulin
95
Q

Describe glucagon

A
  • 29 amino acids
  • pancreatic a-cells
  • GlucR is a GPCR linked to Gsa
  • oppose actions of insulin (1 increase glycogenolysis and gluconeogenesis in liver - glycogen to glucose, 2 increase lipolysis in fat -> increased glycerol and FFA for tissue/ muscle metabolism, 3 increased AA transport -muscle breakdown, for liver gluconeogenesis - AA used by liver to make glucose)
  • stimulated by fall in blood glucose, increased circulating amino acids and increased cholecystokinin (CCK) fro GI tract
  • no direct link to leptin function
  • hypoglycemia sense by central nerves - epinephrine and norepinephrine can cause release of glucagon (CNS control)
96
Q

What happens to glucose overnight?

A
  • due to the surge of circulating cortisol and growth hormone (GH) during the night, the liver increases gluconeogenesis via activation of PEPCK, Glucse-6-phosphate (G6Pase)
  • the surge in these hormones also decreases glucoses uptake in tissues
  • circulating glucose in maintained during the night
97
Q

What are incretins?

A
  • family of peptides produced in the gut, released in response to glucose (meal)
  • act to augment the secretion of insulin from the pancreas (augment insulin response to oral glucose)
  • do this by stimulating the release of Ca++ from the endoplasmic reticulum in pancreas
  • 2 major incretins: 1 GLP-1 (glucose-like peptide 1), 2 GIP (glucose-dependent insulinotropic peptide
  • incretins are rapidly deactivated by serum enzyme, dipeptidyl-peptidase 4 (DPP-4) - actions are very short lived
  • incretins have specific receptors on pancreatic B cells
  • released from K + L cells
  • incretins only respond to gut load (i.e. not to circulating glucose levels
98
Q

What is diabetes mellitus?

A
  • greek diabetes = large volume of urine
  • latin mellitus = a sweet taste
  • “sweet urine disease”
    characterized by:
  • hyperglycemia
  • polyphagia (eating with weight loss)
  • polyuria (high urine volume)
  • glycosuria (glucose in urine)
  • water and electrolyte loss
  • long-term complications: retinopathy (loss of vision), nephropathy (kidney failure), angiopathy (blood clots), and increased susceptibility to infection
  • in severe cases, or left untreated: ketosis (high ketones), acidosis, coma and death
99
Q

Describe Type 1 diabetes mellitus

A

failure to secrete sufficient insulin to regulate glucose utilization
- insulin-dependent
- autoimmune destruction of pancreatic B cells (immune system convinced B-cells are foreign)
- early onset (“juvenille diabetes”)
- ~10% of diabetics
- early symptoms: high glucose, dehydration, low energy

100
Q

Describe type 2 diabetes mellitus

A
  • insulin resistant/ impaired insulin secretion (generally sufficient insulin but receptors impaired)
  • “lifestyle” - overweight, sedentary
  • onset in mid-life 30-40+
  • 90% of diabetics
101
Q

Describe insulin resistance

A

characterized by:
- decreased cellular responses to insulin
- hyperglycemia
- impaired insulin secretion
- insulin present but body and cells no longer capable of responding appropriately to the signal
- common precursor to other metabolic diseases including “metabolic syndrome”, type 2 diabetes and polycystic ovarian syndrome (PCOS)
- often result of obesity (diet, lifestyle, genes)

102
Q

What happens without insulin?

A
  • inability to transport glucose into cells - alternate energy source needed
  • protein (catabolism of protein = gluconeogenesis) -> provide amino acids which are converted to glucose in liver for energy
  • fat (catabolism of fat = lipolysis) -> release triglycerides (TG) and free fatty acids (FFA) from stores -> FA oxidized to acetyl-CoA for use in the TCA cycle
  • can work short term - but long term will lead to complications
  • results in muscle wasting and weight loss (protein breakdown)
  • by-products (fat breakdown) are toxic = ketones -> high ketones = ketoacidosis, marker of diabetics, can lead to death (poison)
103
Q

What is the fate of high serum glucose?

A
  1. increased glucose filtration - increased water excretion -> dehydration
  2. conversion of glucose to sorbitol (the “polyol pathway”) -> damaging to lens, nerves and capillaries (long term issues with retina and sight)
  3. increased glycosylation (i.e. addition of cellulose, a glycan) of proteins (the “glyoxal pathway”). glycation end-products -> protein damage and misfolding
  4. de novo synthesis of diacylglycerol (DAG) leasing to increased protein kinase C (PKC) activation -> nephropathy (DAG in kidney leads to protein kinase C activation, which can cause kidney failure)
104
Q

What are the mechanisms of insulin resistance?

A

Don’t really know - do know some of what contributes:
1. changes in InsR phosphorylation
2. changes in InsR signalling
3. inactivity and obesity (diet and lifestyle) - role of TNF-a, and FFAs
4. impairment of PPARgamma - nuclear receptor
5. contribution of genetics

105
Q

Describe the mechanism of insulin resistance: changes in InsR?

A
  • phosphorylation = activation of receptor
  • changes in phosphorylation = impairing insulin receptor activation
    Alterations in the InsR:
  • adipocytes from obese patients have fewer InsR than those of lean controls -> cannot respond to insulin with same ability
  • InsR in obese patients have inappropriate serine phosphorylation (this is “stop” signal and turns off signalling from the receptor)
  • weaker tyrosine auto-phosphorylation (receptor activation) in obese patients (this is meant to turn “on” signal)
106
Q

Describe the mechanism of insulin resistance: altered InsR signalling

A
  1. IRS proteins
    - IRS-1 KO - mild phenotype, euglycemic (normal glucose)
    - IRS-2 KO (knockout)- hyperglycemic, decreased B-cell mass and functions very much like T2DM (type 2 diabetes mellitus)
  2. decreased phosphorylation of dowstream signalling molecules, PI3 kinase and AKT in T2DM cells
    - decreased insulin signalling (decreased signal amplification and transfer)
  3. decreased translocation of Glut-4 to cell membranes
    - decreased influx of glucose into the cell
    - decreased PI3K activity?
107
Q

Describe the mechanism of insulin resistance: inactivity and obesity

A
  • deposition of central adipose tissue, particularly visceral fat - has altered, or dysfunctional metabolism which ultimately results in insulin resistance
    Ectopic visceral fat is dysfunctional in several ways:
    overloaded fat cells are stressed out - induce ‘ER stress pathway’ leading to:
  • activation of IRE1 (inositol-requiring enzyme 1) activates JNK which inactivates IRS-1 = decreased InsR signalling
  • increased translocation of XBP-1 (x-box binding protein-1) translocates from ER to nucleus; XBP-1 is a non-specific negative transcriptional regulator (decreases all mRNA destined for the ER-including that for InsR = decreased InsR transcription)
    1. the stressed fat cell releases adipokines (e.g. leptin and resistin) and cytokines (TNF-a)
  • TNF-a (transforming growth factor alpha) causes increase in the serine phosphorylation (STOP) of both the InsR and IRS proteins, resulting in insulin resistance in other tissues
    2. less adinopectin is secreted
  • increased gluconeogenesis and triglycerides
    3. insulin resistance of fat cells
  • decreased glucose uptake from plasma
  • increased lipolysis
  • increased levels of glycerol and FFA in circulation
    4. increased FFA (and glycerol) availability
  • switches cellular metabolism away from glucose
108
Q

What are the consequences of increased circulating / serum FFAs (free fatty acids)?

A
  • will be used as the energy source in most cells including liver and muscle
  • are converted to acetyl-CoA for use in the TCA cycle, meaning reduced glucose oxidation
  • both increased FFA availability and system effects of cytokines lead to decreased glucose uptake (particularly in muscle)
  • both muscle and liver will catabolize protein for gluconeogenesis (increased)
  • all contribute to insulin resistance
109
Q

Describe the role of PPARγ (peroxisome proliferator-activated receptor-γ)
- potential therapeutic role of PPARγ?

A
  • PPARγ is a transcription factor that is highly expressed in adipocytes, intestine and macrophages; decreased in IR (insulin resistance)
  • PPAR γ agonists (thiazolidinediones) improve insulin resistance and β-cell function in type 2 diabetics by:
    1. increasing transcription of genes involved in energy metabolism (InsR, IRS, Glut 4 etc.)
    2. in β-cells, PPARγ enhances the insulin response to glucose, stimulates cell expansion/ hyperplasia (growth) and integrity, and reduces the triglyceride content
  • thiazolidinediones is commonly used as a drug
  • may also be helpful in type 1 in those with beta cells remaining
110
Q

Describe association between genes and insulin resistance (IR)

A
  • currently fuzzy area - no direct links
  • mutations in InsR are rare and usually lethal
  • genetic polymorphisms in genes (more common) involved in energy metabolism and its regulation most likely play a role in an individual’s susceptibility to IR and type 2 DM
  • acquired genetic predispositions: inadequate diet, sedentary lifestyle, obesity, and intrauterine insult (“Barker hypothesis”)
111
Q

What is the dutch famine “Honerwinter”? and what does it have to do with diabetes?

A
  • rations were progressively cut from 1,400 kcal/day to 1,000 kcal/day
  • many dutch people perished by malnutrition
  • after famine was over, nutrition was promptly restored
  • however, children exposed in utero showed symptoms of glucose intolerance and cardiovascular disease later in life -> low birth weight children were more at risk for type 2 diabetes later in life (have to be healthy in gestational period, or will catch up to you later in life)
  • Barker hypothesis: in utero insults relate to postnatal disease including infection/ inflammation, hypoxia/smoking, under or over nutrition, poor maternal body composition, and excess glucocorticoids during fetal growth and development may all result in adult disease including type 2 diabetes
112
Q

Describe the functional anatomy of the adrenal gland

A

an adrenal gland sits above each kidney
1. cortex
- 3 “zoness: zona glomerulosa (aldosterone), zone fasciculata (cortisol - glucocorticoids - stress hormones), zona reticularis (sex steroids)
- source of adrenal steroids
- regulated by pituitary ACTH
2. medulla
- composed of “chromaffin” cells (neuroendocrine cells)
- source of catecholamines
- secretion controlled by direct innervation; neuroendocrine

113
Q

Describe adrenal steroidogenesis

A
  • steroid hormones are all derived from cholesterol
  • steroidogenic enzymes are cytochrone p450s e.g. CYP17 (activity of these enzymes decides what hormones are produced in adrenal glands)
  • found in membranes of mitochondria and ER
  • energy comes from electron transport
  • steroid biosynthesis requires several intracellular organelles
  • when ACTH comes and binds to its receptor (G-coupled receptor) in the adrenal gland causes activation of enzyme AC (adenylate cyclase) which upregulates cyclic AMP which activates protein kinases
  • leads to increase in CEH (cholesterol ester hydrolase) - important enzyme which cleaves the cholesterol esters to become cholesterol
  • then free cholesterol enters into mitochondria and steroid factory takes over
  • when ACTH binds its receptor, upregulates production of more receptors
  • ACTH binding also upregulates receptor for LDL (low density lipoprotein) which is a source/ starting material for cholesterol
114
Q

Describe the ACTH receptor

A
  • is a GPCR coupled to cAMP
  • promotes activity of CEH (upregulates receptors)
  • rapidly increases production of StAR (the rate-limiting step in steroidogenesis) - StAR (steroid acute regulatory protein) helps get cholesterol into the mitochondria
  • primarily in zona reticularis and fasiculata
115
Q

Describe cortisol transport and metabolism

A
  • 75% in plasma bound to CBG (corticosteroid binding globulin or transcortin)
  • 15% bound to HSA (human serum albumin)
  • 10% free - available for biological activity
  • primarily metabolized in liver
  • excreted by kidney (urine tests for steroid abuse - sulphated versions)
116
Q

Describe the glucocorticoid receptor

A
  • similar mechanism as thyroid receptor
  • GR (glucocorticoid receptor) binds cortisol
  • cortisol brought to target tissue, goes through membrane (lipid loving)
  • activates heat shock protein (inhibitory?)
  • GR becomes active nuclear/ transcription factor, translocates to the nucleus and turns on/ off glucocorticoid gene
  • then will either bring in co-repressors or co-activators
117
Q

What are cortisol’s actions?

A

Cortisol is a stress hormone:
1. increases serum glucose and amino acids
- increase protein catabolism in muscle -> increased circulating AAs
- increase amino acid uptake in liver -> increased gluconeogenesis and glycogenesis
- decreased peripheral glucose uptake (muscle + adipose tissue)
2. increased catabolism
- increase lipid hydrolysis -> increased circulating fatty acids
- increase bone and connective tissue catabolism -> osteopenia, thinning of skin and supporting structures (bone loss - bad thing)
* cortisol actions oppose those of insulin - make more glucose than glycogen
- cortisol is also anti- inflammatory - suppresses our immune system (can be used with rheumatoid arthritis - but consequence of long-term use may be immune susceptibility)

118
Q

What is Cushing’s disease/ syndrome?

A
  • hypercortilism (too much cortisol)
  • fat deposition face, back, central abdomen (paradox - more of a redistribution of fat)
  • thinning of arms and legs (protein catabolism - less muscle)
  • loose skin with striae
  • osteopenia/ osteoporosis (impairs bone function - bone loss)
  • immune suppression
119
Q

What are the enzymes interconverting “inactive” cortisone (ketone at 11) to “active” cortisol (alcohol at 11)?

A
  • 11B- hydroxy steroid dehydrogenase - 1 (11B-HSD-1) converts to active form
  • 11B-HSD-2 converts to inactive form
  • cells and tissues can modify their responsiveness to cortisol through the expression of certain enzymes
120
Q

Describe the impairment of placental 11B-HSD2 associated with IUGR?

A
  • mother makes 10x more cortisol than fetus
  • don’t want fetus exposed to all this cortisol - cortisol affects growth and development
  • placenta has 11B-HSD2 to inactivate cortisol (at maternal-fetal interface) - turn cortisol into cortisone
  • if the 11B-HSD-2 activity is impaired then cortisol reaches the fetus
  • fetus becomes smaller (IUGR)
  • long term child is susceptible to diabetes etc because of small birth weight
  • IUGR = intrauterine growth restriction
  • black liquorice impairs 11B-HSD2 activity, low oxygen also does this
121
Q

What is aldosterone synthesis increase by?

A

Aldosterone is a big player in pressure-volume regulation in the kidney
1. angiotensin II from RAS (due to drop in blood pressure)
2. high [K+] = low [Na+]
3. availability of precursors (indirect via ACTH stimulation of z. fasciculata to produce corticosterone, which is eventually converted to aldosterone) - more = increased aldosterone

122
Q

What is aldosterone action?

A

Does this through binding to MR
1. increases ENaC transcription
2. increases transcription of genes (structural/ regulatory proteins) which activate current Na2+ transporters
- ENaC = epithelial sodium transporter
* MR is promiscuous - glucocorticoids can also bind (cortisol) with equal affinity - invoke response when we don’t want (sodium retention)
- 11B-HSD2 meant to inactivate cortisol to cortisone in the kidney

123
Q

Describe apparent mineralocorticoid excess syndrome (AME)

A
  • caused by mutations/ deficiencies to 11B-HSD2 (meant to prevent this syndrome - inactivate cortisol to cortisone)
  • increased ‘aldosterone-like’ effects in kidney
  • MR activation without aldosterone
  • leads to hypokalemia, high blood pressure
124
Q

Describe the production of catecholamines in the adrenal medulla and how they work

A
  • primarily epinephrine and norepinephrine
  • responds to acute stress – the “fight or flight” response - can increase heart rate
  • rate of release determined by frequency of AP’s at chromaffin cells
  • neuroendocrine response to release these catecholamines
    1. Norepinephrine - increase heart rate and blood pressure, increase lipid breakdown, and causes peripheral vasoconstriction
    2. Epinephrine - increase heart rate and blood pressure, increase lipid breakdown, cause peripheral vasoconstriction, cause coronary dilation and bronchial dilation, and can cause muscle glycogen to turn to muscle glucose - will also cause smooth muscle contraction
  • catecholamine receptors = adrenergic receptors (several subtypes - a1, a2, B1, B2 and B3)
  • primarily regulate smooth muscle contractility (vascular tone, gastric tone) - e.g. in heart bind

Human Physiology (13 decks)

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