Rilllema Flashcards
1
Q
What are the the different types of cellular regulation of hormones?
A
- Intracrine: active principals act IN the same cell which they are produced; Example: Follicles of female reproductive system
- Autocrine: active principals act ON the same cells from which they were secreted ; Example: Growth factors
- Paracrine: active principals act on ADJACENT cells from which they are secreted
- Neurocrine: active principals are released from axons and function on dendrites ; Example: at NMJ
- Endocrine: hormones produced in certain cells and function at distant targets
2
Q
What are the different sources of hormones?
A
- Head: pineal gland, pituitary gland, hypothalamus
- Neck: thyroid gland, parathyroid gland
- Abdomen: pancreas, adrenal gland, gut, gonads
- Skin: secretes vitamin D3 (using sunlight)
- Heart: secretes ANF (anthypertensive hormone that causes vasodilation)
- Fat Cells: secrete leptin (inhibits appetite)
3
Q
What are the hormones that are secreted from the anterior pituitary (know all of the different names for them and their general function )
A
- Prolactin (PRL, LTH- lactotropic hormone, MTH- mammotropic hormone): Lactotroph Cells (~15%); Stimulates lactation
- Growth Hormone (GH, STH- somatoropichormone): Somatotroph Cells (~40-45%); Stimulates growth processes; Regulates plasma level of glucose, free FAs and amino acids
- Thyrotropin (TSH-thyroid stimulating hormone): Thyrotroph Cells; Stimulates thyroid gland to grow and produce thyroid hormone
- Corticotropin (ACTH, adrenocorticotropic hormone): Corticotroph Cells; Stimulates adrenal cortex and growth of adrenal gland
- Follicle Stimulating Hormone (FSH): Gonadotroph Cells; Stimulates follicle growth in the ovary; Stimulates spermatogenesis in the testis
- Luteinizing Hormone (LH, ICSH- interstitial cell stimulating hormone): Gonadotroph Cells; Stimulates ovulation; Stimulates steroid hormone production in ovary and testis
4
Q
What are the hormones secreted from the intermediate lobe of the pituitary?
A
Melanocyte Stimulating Hormone (MSH):
Disperses melanin granules in the skin
Virtually non-functional in humans (MSH is not produced in humans normally)
5
Q
What are the hormones secreted from the posterior pituitary? what is their roles?
A
Hormones synthesized in the paraventricular and supraoptic nuclei of the hypothalamus
- Oxytocin: stimulates milk letdown and partuition
- Antidiuretic Hormone (ADH, Vasopressin): stimulates water reabsorption in nephrons
6
Q
What are the hormones released from the hypothalamus?
A
hormones secreted here regulate the anterior pituitary; carried to anterior pituitary form the capillary bed at the median eminence via long portal vessels
- Growth Hormone Releasing Hormone (GRH)
- Growth Hormone Inhibiting Hormone (GIH, Somatostatin, SRIF)
- Prolactin Inhibitory Hormone (PIH, dopamine)
- Corticotropin Releasing Hormone (CRH): increases ACTH secretion
- Thyrotropin Releasing Hormone (TRH): increases TSH secretions
- Gonadotropin Releasing Hormone (GnRH): regulates LH and FSH secretion
7
Q
What hormones are secreted from pineal gland?
A
Melatonin: regulates reproductive cycles in lower species; may be related to jet lag in humands
8
Q
What hormones are secreted from the Thyroid Gland?
A
- Thyroid Hormones:
A). Thyroxine (T4): precursor for T3, produced in amounts 10x higher than T3 (inactive prohormone)
B). Triiodothyronine (T3): active hormone, increases many metabolic processes - Calcitonin (CT): lowers plasma Ca++ concentration; released from C cells/parafollicular cells
9
Q
What hormones is secreted from the parathyroid gland?
A
PTH: raises plasma [Ca2+]
10
Q
What hormone is secreted from the skin?
A
Vitamin D: functions with PTH to raise plasma [Ca2+]
11
Q
What is the endocrine function of the pancreas ? (what is secreted)
A
- Insulin: β cells = Lowers plasma glucose, amino acids and free FAs; Mitogenic (stimulates growth)
- Glucagon: α cells = Raises plasma glucose and free FAs
- Somatostatin: Δ cells
12
Q
What hormones are secreted by the adrenal glands?
A
- Cortex:
A). Glucocorticoids (Cortisol): stimulates gluconeogenesis and lipolysis; zona fasciculate
B). Mineralcorticoids (Aldosterone): increases Na+ reabsorption and K+ secretion; zona glomerulosa
C). Sex Steroids (Androgens): only source of androgens in females; zona reticularis
- Medulla = Catecholamines (Epi and NE): fight or flight response (**made from tyrosine)
13
Q
What hormones are synthesized/secreted in the ovaries, testes, and placenta?
A
- Ovaries = Estrogen, Progesterone, Inhibin
- Testis = Testosterone, Inhibin
- Placenta =
Placental Lactogen (HPL): binds to GH and PRL receptors and carries out similar functions
Chorionic Gonadotropin (hCG): maintains early pregnancy (detected by pregnancy test)
Estrogen
Progesterone
14
Q
What hormones are stimulated by the liver, heart, fat cells, and stomach?
A
liver = IGF-1 (bone growth) Heart = ANP/ANF/ANH (vasodilation/anti-hypertensive/increased water/na release) Fat = leptin (inhibits appetite) Stomach = Ghrelin (stimulates appetite)
15
Q
What are the tyrosine derived hormones?
A
- Catecholamines (dopamine, epi, NE)
TYR = L-DOPA = Dopamine = NE = epi - Thyroid hormones (T4/T3) synthesized on Thyroglobulin
16
Q
What are the lipid homones?
A
- Steroids = progesterone, aldosterone, cortisol, testosterone, estrogen;
all derived from cholesterol (glucose - aceteate - cholesterol - progesterone)
vary by different number of carbons (21, 19, 18), saturation, and oxidation - Vitamin D = derived from cholesterol (UV light in skin) - to cholecalciferol (vit D) stored in liver - active vit D from kidney
- Eicosanoids = prostaglandings, leukotrienes, thromboxanes
Function as circulating hormones in some circumstances
All derived from arachadonic acid (20:4)
A). Prostaglandins: vascular actions, inflammation
B). Thromboxanes: blood clotting and other vascular actions
C). Leukotrienes: mediate allergic and inflammatory reactions
17
Q
What are the peptide hormones?
A
1. Hypothalamic Releasing Hormones: TRH: 3 AA (smallest) GnRH: 10 AA GIH: 14 AA CRH: 41 AA GRH: 45 AA Note: dopamine is not a peptide hormone
- Anterior Pituitary Hormones:
A). Similar Peptides:
GH: 191 AA, 2 disulfide bonds, MW: 22,000
PRL: 198 AA, 3 disulfide bonds, MW: 23,000
HPL: 191 AA, 2 disulfide bonds, MW: 22,000 (not from anterior pituitary)
B). ACTH: 39 AA, MW: 4300
Derived from POMC (Proopiomelanocortin- 239 AA, MW: 30,000)
39 AA located in the center of the POMC molecule
POMC can also be cleaved to release MSH, beta endorphins
C). Pituitary Glycoprotein Hormones (FSH, LH, TSH)
2 peptide chains plus 10% carbohydrate (MW: 30,000; some of the largest hormones)
α chain is interchangeable between all 3 (97-98 AA)
β chain provides specificity
hCG is also a glycoprotein produced by the placenta (similar structure)
D). Posterior Pituitary Hormones: ADH, oxytocin (both 9 AA)
E). Calcitonin: 32 AA
F). Pancreas Hormones:
Insulin: 2 peptide chains (α- 23 AA and β-30 AA), connected by disulfide bridges
Glucagon: 29 AA (MW: 3500)
G). GI Hormones:
Gastrin: 17 AA
CCK: 23 AA
Secretin: 27AA
H). Growth Factors:
IGF-1 (Somatomedin, EGF, FGF, NGF): MW 3000-9000
I). Parathyroid Gland: PTH (84 AA)
J). Heart: ANF (28 AA)
K). Fat cells: Leptin (MW 16,000)
18
Q
In general, what are the three basic ways a hormone functins?
A
- Alter transport processes (ie. insulin stimulates glucose transport in skeletal muscle cells and adipocytes)
- Alter genetic activity (ie. estrogen stimulates mRNA for progesterone receptor in endometrial cells; “estrogen priming”- cannot get progesterone effects unless the cells have been previously exposed to estrogen)
3, Alter enzyme activity (ie. epinephrine stimulates activation of adenylate cyclase, which increases cAMP, activating PKA and phosphorylase)
19
Q
What are the types of Hormone Response?
A
- Direct (ie. insulin stimulates glucose transport)
- Permissive (ie. cortisol allows epinephrine to stimulate glycogenolysis)
- Synergistic (ie. PRL + insulin + cortisol needed to stimulate milk formation)
20
Q
How do Intracellular receptors work? what hormones work this way?
A
= steroids, vitamin D, T3
Hormone enters cell where it binds receptor and then enters nucleus to alter transcription
Intracellular receptors have binding sites for hormone and for genetic material (where it is going to bind to alter mRNA transcription)
21
Q
Generally, what are the different types of extracellular receptors? what types of molecules bind to them?
A
= peptides and catecholamines
- Channel Receptors: Example: Ca++ or Na++; Ca++ activates NOS in NO pathway
- Tyrosine Kinase Receptors: Example: Insulin
When insulin binds, cytoplasmic portion of receptor in a tyrosine kinase enzyme - Cytokine Receptors: Example: PRL, GH, leptin, ghrelin, EPO
Tyrosine kinase activity is on Janus Kinase proteins that are associated with the cytoplasmic portion of the receptor (but not part of the receptor itself) - G Protein Associated Receptors (Serpentine Receptors):
•Gs: activates adenylate cyclase
•Gi: inhibits adenylate cyclase
•Gq: stimulates phospholipase C - Guanylate Cyclase Receptor: Example: ANH
•Binding of hormone activates guanylate cyclase, GTP → cGMP → stimulates G kinase - Serine Kinase
- Phosphatase
22
Q
How do calcium ions mediate an extracellular receptor response?
A
Ca++ much lower inside the cell than outside or in ER (Ca++ pumped out of cell and into ER)
Intracellular Ca++ is increased either by:
•Increasing membrane permeability to Ca++ (enters from outside)
•Increasing release from ER (triggered by IP3)
Once Ca++ is inside cell, binds calmodulin, and activates Ca++ -calmodulin protein kinase enzyme
23
Q
How does Nitric oxide mediate an extracellular response?
A
Nitric Oxide: causes vasodilation
Inactive nitric oxide synthase (NOS) is activated by Ca++-calmodulin ; NO is formed from arginine using this NOS enzyme ; NO activates guanylate cyclase (GTP → cGMP → activate G kinase → physiological response
•Physiological responses include penile erection
cGMP broken down to 5’GMP by cGMP phosphodiesterase enzyme
•This enzyme inhibited by Viagra, Cialis
24
Q
How does the pKA/cAMP pathway work? How does it relate to cholera and pertussis?
A
- Activation of Adenylate Cyclase by Gs:
•Hormone binds receptor, Gs activated (GDP exchanged for GTP on α subunit; βγ lost)
•Gsα + GTP activates AC, increasing cAMP and PKA, which phosphorylates proteins
•Cholera toxin activates Gs in GI tract by ADP ribsoylation, causing diarrhea
2.Inhibition of Adenylate Cyclase by Gi:
•Hormone binds receptor, Gi activated (GDP exchanged for GTP on α subunit; βγ lost)
•Giα + GTP inhibit AC, decreasing cAMP
•Pertussis toxin inhibits Gi in respiratory tract by ADP ribosylation
25
How does the Phosphatidyl Inositol cycle work?
1. Hormone binds receptor, Gq activated (GDP exchanged for GTP on α subunit; βγ lost)
2. Gqα + GTP activate phospholipase C in the membrane, which cleaves membrane lipid PIP2 into DAG and IP3
•DAG activates PKC, which phosphorylates proteins
•IP3 causes ER Ca++ release, which also activates PKC and Ca++-calmodulin kinase, both of which phsophorylate proteins
26
How do tyrosine kinases work? what hormones use this mechanism?
= Insulin, IGF-1 use this mechanism
1. 2 hormones bind 2 receptors and they dimerize, causing activation of tyrosine kinase function of cytoplasmic receptor
2. Autophosphorylation of receptor itself, and then phosphorylation of various intracellular proteins that carry out function of hormone (ie. PP185, IRS)
27
How does the cytokine system work? (janus kinase)
Essentially the same as TK mechanism
1. 2 hormones bind 2 receptors (except GH and PRL; 1 hormone binds 2 receptors) and they dimerize, however the receptor has no enzymatic activity
2. Janus Kinase proteins associated with the receptor each have 2 TK, and they become active after hormone binding and dimerization
•Once active, phosphorylate intracellular proteins to carry out affects
MAP Kinase pathway associated with this system (mitogenic processes; see Biochem notes)
28
What are the different types of Hormone Assays and how do they work? Explain the experimentation you can use to figure out the amount of a hormones present/active
1. Bioassays: increase hormone concentration, increase response (can use this to measure hormone levels)
2. RIA and EIA:
- Radioimmunoassays (RIA)
- Immunofluorescent Assays (EIA): used now, but both work the same way
Need a tagged (radiolabeled) ligand and a dissociable binder (Abs, receptors etc.)
Create a standard curve by adding a known amount of radiolabelled hormone and Ab (equal amounts) and increasing amounts of unlabelled hormone (will equilibrate, and each time a different amount of radiolabelled hormone will be bound to Ab)
Once standard curve is made, can place a serum sample in a tube with known amounts of labellled hormone and Ab, and based on the H*-Ab%, can calculate serum hormone levels
29
How do hormone receptor act? what are some of their typical characteristics? What does hormone response depend on?
* *Bind Very Tightly:
- Behave like antibodies (have very strong binding affinities and very low dissociation constants)
- Hormone response depends on:
1. Number of receptors
2. Number of hormone molecules
3. Affinity of hormone for receptor
Characteristics of Receptors:
- Saturable
- Specific
- High affinity (Kd= 10-8 – 10-12)
- Reversibility
- Biological actions parallel binding
-Scatchard plot yields a straight line
o[Bound Hormone] vs. [Bound Hormone]/[Free Hormone]
Straight line with a negative slope because as you increase the amount that is bound, it makes it harder to bind more hormone (increase concentration of free hormone and therefore decrease the B/F ratio)
30
Biassay vs. receptor binding curve
1. Bioassays look at biological effect of a hormone
2. Receptor binding curves: increase hormone concentration increases the number of receptors bound
When you compare these 2 curves, it is clear that maximum biological effect occurs when only a fraction of the receptors are bound (10-20%); therefore, bioassay curve shifted to the left
Spare Receptors: receptors that do not need to be activated in order to get a maximum response
31
What is upregulation? down-regulation? Negative cooperativity?
- Up-regulation: increase the number of receptors on target tissue
- Down-regulation: decrease the number of receptors on target tissue
- Negative cooperativity: affinity for a hormone decreases as hormone concentration increases
32
In what gender is the pituitary larger?
female
33
Describe the anatomy/embryology of the pituitary gland
1. Adenohypophysis (Anterior Pituitary): derived from upward growth of roof of mouth (Rathke’s pouch)
= Pars distalis (anterior pituitary), Pars tuberalis, Pars intermedia
2. Neurohypophysis (Posterior Pituitary): derived from downward growth of hypothalamus
= Pars nervosa (posterior pituitary), Infundibular stalk, median eminence
34
Describe the blood supply in the pituitary gland
1. Anterior Pituitary: arterial supply to capillary bed in median eminence, then long portal vessels to another capillary bed in the anterior pituitary (blood exits via venous system)
2. Posterior Pituitary: arterial supply and capillary network that picks up post. pituitary hormones and carries them out into blood stream (venous system)
* Short portal vessels: carry some posterior pituitary hormones to the anterior pituitary; can have some effect on anterior pituitary hormones
35
What types of cells are found in the anterior pituitary? (and percentages/what hormones they include)
1. Acidophils: lactotrophs and somatotrophs (35%)
2. Basophils: thyrotrophs, gonadotrophs and corticotrophs* (15%)
3. Chromophobes: corticotrophs* (50%)
36
What types of cells are found in the posterior pituitary? (what hormones they include)
1. Pituicytes: support cells
2. Terminal axons from hypthalamo-hypophyseal tract:
•Contain Herring bodies (store hormones and neurophysins)
•Oxytocin and vasopressin synthesized in PV and SO nuclei and travel down axons
37
Where are (specifically) are the hypothalamic releasing hormones produced?
1. Paraventricular Nucleus: = TRH (3 AA), CRH (41 AA)
2. Arcuate Nucleus: = GnRH (10 AA), PIH/Dopamine, GRH (44 AA)
3. Anterior Hypothalamus: = GIH/Somatostatin (14 AA)
38
What is the source of prolactin and placental lactogen?
1. PRL from mammotroph cells of anterior pituitary
2. Placental lactogen (HPL) from syncytiotrophoblast of placenta has the same biological potency as PRL ; HGH has 10% biological potency as PRL
39
Describe the chemistry make up of PRL/HPL
- 198 AA with 3 disulfide bridges
| - HPL is 191 AA with 2 disulfide bridges
40
Describe the synthesis and storage of PRL/HPL
- HPL and PRL both synthesized by normal protein synthesis mechanism
- PRL is packaged into granules and stored in vesicles in mammotrophs (released upon removal of dopamine stimulation)
- Little is known about storage/secretion of HPL
41
What are normal plasma levels of prolactin? what/when do they increase?
1. Males: 6-8 ng/mL
2. Females: 8-14 ng/mL (higher than males because of higher estrogen levels)
Linear increase in PRL in pregnancy to 250 ng/mL (due to increased estrogen levels); with suckling PRL increases to 300 ng/mL
Fetus also has very high PRL levels in utero
42
What is the mechanism of secretion of PRL?
exocytosis of PRL containing vesicles
43
What regulates the secretion of PRL? HPL?
1. Primarily regulated by PIH/dopamine
TRH and VIP can also stimulate PRL secretion (but dopamine still dominant)
2. Stimuli that Regulate PRL Release:
•Estrogen (decreases lactotroph sensitivity to dopamine, increases number of lactotrophs)
•Stress (reduces dopamine)
•Suckling (reduces dopamine)
•Copulation (increase in PRL occurs with orgasm)
•Diurnal Variation (nocturnal surge occurs in males and females during REM sleep; ~2 hours after going to sleep)
•PRL increases during feeding periods
HPL = increased in 3rd trimester of pregnancy to ~300 ng/mL
44
What is the function of PRL in males and females?
1. Males:
- Acts synergistically with LH to stimulate testosterone production in Leydig cells
- Stimulates prostate growth
- Not necessary in males (will be normal without PRL)
2. Females:
- Both leuteotropic (maintains follicles) and leuteolytic (degrades follicles) functions in rodents; function in human females on menstrual cycle unclear
- Chronically elevated PRL levels (above 20 ng/mL) results in infertility and cessation of menstrual cycle
- Treat with a dopamine agonist
- May function as birth control in lactating women)
- Regulates lactation
45
Describe the structure of the mammary gland alveolus
- Alveoli are functional units of mammary gland
- Alveolar cells (1 layer of active cells) secrete milk into lumen of alveolus
- Myoepithelial cells respond to oxytocin and cause expulsion of milk into the ductal system
46
What are the components of milk?
lactose, free FAs (most are SCFAs), casein (protein) and α-lactalbumin (protein)
47
What are the hormones necessary for lactation?
requires PRL, cortisol, insulin and T3
| **PRL is regulatory because the other 3 are always present (unless defect in one of the others)
48
what is the overall structure/divisions of the mammary gland? How does milk flow out the mammary gland?
-200 alveoli/lobule; 26 lobules/lobe; 15-20 lobes/mammary gland
Milk Flow:
Alveolus → Intercalary Duct → Interlobular Duct → Interlobar Duct → Lactiferous Duct
Exits nipple via lactiferous pore
49
Describe the different phases of mammary gland development and what occurs at each phase
Ectodermal origin
1. At Birth: Atrophic Ducts
- 15-20 rudimentary lactiferous ducts (same in both sexes)
- 80% of neonates produce Witch’s Milk (watery secretion) caused by exposure to high levels of estrogen and progesterone which cross the placenta during pregnancy
2. At Puberty: Duct Growth
- Gland stimulated by estrogens and small amounts of progesterone
- Ductal system partially develops and gland becomes engorged with fat (85% of gland fat cells)
3. Pregnancy: Lobulo-Alveolar Growth
- Estrogen stimulates ductal development
- Progesterone stimulates lobulo-alveolar development (addition of alveoli at the end of ducts)
- Other hormones are also required
Estrogen, glucocorticoids and GH all needed for ductal development
Estrogen, progesterone, GH (from HPL), PRL and glucocorticoids all needed for lobulo-alveolar growth
50
What hormones are need for ductal growth of the mammary gland? for lobulo-alveolar growth?
Estrogen, glucocorticoids and GH all needed for ductal development
Estrogen, progesterone, GH (from HPL), PRL and glucocorticoids all needed for lobulo-alveolar growth
51
How is lactation initiated? What are the hormonal changes that are required to occur to initiate lactation?
**During pregnancy, the glands do not lactate because estrogen and progesterone inhibit milk product formation
Hormonal Changes Requires to Initiate Lactation:
•Decrease estrogen (loss of placenta)
•Decrease progesterone (loss of placenta)
•Increase PRL (suckling)
•Increase cortisol:
➢Increase ACTH (suckling)
➢Free cortisol increased by decrease in transcortin (which binds cortisol in the blood); transcortin produced in liver due to stimulation by estrogen
52
What are the hormones necessary for maintenance of lactation?
PRL, cortisol, insulin, T3 (thyroid hormones) + maybe others!
53
What is milk let-down stimulated by?
Oxytocin
54
Describe the physiology of lactation
1. Suckling stimulates mechanoreceptors in nipple, stimulates PRL secretion
• Stimulates neurons in PV nucleus to increase oxytocin release
• Increases CRH, ACTH and cortisol release
2. Oxytocin stimulates myoepithelial cells causing milk letdown
3.PRL and cortisol stimulate further manufacturing of milk products for future meals
• Suckling also causes decrease in dopamine release from median eminence (allows for PRL secretion)
55
What are some pathologies associated with mammary development?
1. Gynecomastia: abnormal growth of mammary gland in males
2. Galactorrhea: spontaneous flow of milk from breasts not associated with pregnancy or breast feeding
3. Infertility
4. Breast Cancer: most commonly in ductal cells of mammary gland
56
Describe the chemistry of the thyroid hormones and their general activity
1. Thyroxine (T4): = Prohormone of T3 (remove I with deiodinase enzyme; not very specific so you can get T3 or reverse T3); Thyroid gland releases 10x more T4 than T3
2. 3,5,3’ Trioodothryronine (T3): biologically active hormone (50% of T4)
3. 3,3’5’ Trioodothryronine (reverse T3): not made by the thyroid gland and not biologically active (50% of T4)
57
What are the net reactions associated with thyroid hormone synthesis?
2 Tyrosines + 1 ½ I2 → T3 + Alanine
| 2 Tyrosines + 2 I2 → T4 + Alanine
58
Describe the transporters associated with the thyroid follicular cell and their role in thyroid hormone synthesis
From Bloodstream:
1. Na-I Symporter: pumps I- into follicular cell
- Very powerful (can pump against gradient of 250:1); Driving force from Na,K-ATPase (secondary active; requires ATP); Present in many other places in the body: intestine, mammary gland, salivary glands, Cori plexus (no I- in the CSF), ciliary body (no I- in aqueous humor)
Once iodide is in the cell, converted to iodine (I2) using thyroperoxidase enzyme
Tyrosine enters follicular cell as well
To enter Colloid:
1. Pendrin Iodide Transporter: pumps iodide into colloid; Also in mammary gland; Pendrin Syndrome: leads to hypothyroid, deafness
59
What are the two steps needed for thyroid hormone synthesis?
1. iodination:
Tyrosine → Mono-iodotyrosine (MIT) or Diiodotyrosine (DIT) using thryoperoxidase enzyme
2. Conjugation:
2 DITs can combine → T4 + Alanine (require coupling enzymes at apical surface)
1 DIT + 1 MIT combine → T3 + Alanine (require coupling enzymes at apical surface)
***Note: to be active T3 (and not reverse T3) MIT must be the molecule that loses the alanine
60
How is thyroid hormone actually synthesized?
1. Thyroglobulin (TGB): glycoprotein with 2 peptide chains (~115 tyrosine residues)
Peptide chains synthesized in ER, glycosylation occurs in Golgi
Iodination and conjugation occur in TGB at the apical border of the cell (thyroperoxidase)
Thyroid hormones are stored within TGB in colloid (~2 month supply)
2.Conjugation:
Requires the use of coupling enzymes, which cleave pieces of MIT and DIT from A and B chains and move them to other DIT residues to form T3 and T4
Cleaving and moving a DIT to an MIT gives you reverse T3, which is not active
Alanine is left at the cleavage sites after removal of the ring structure (maintains integrity of chains)
61
What makes up the colloid in the thyroid?
6 MIT : 5 DIT : 0.3 T3 : 3 T4
| 20% of 115 tyrosine residues get iodinated
62
How are thyroid hormones secreted? How much of each hormone is secreted/active?
Endocytosis of colloid into follicular cells and condensation of endocytosed vesicles with lysosomes
Proteolytic cleavage of TGB to AA, MIT, DIT, T3 and T4
- T3 and T4 released into bloodstream
- MIT and DIT are deiodinated, and I- and AA are recycled into new TGB
Amount Secreted: 10x more T4 secreted than T3
Fate of T4: 35% converted to T3, 45% converted to reverse T3, 20% destroyed
Source of Plasma T3: 80% from T4 conversion, 20% from thyroid
63
How are the thyroid hormones transported into the plasma?
T3 and T4 bound to plasma proteins (99.9%)
1. Thryoxine Binding Globulin (TBG):
Binds T4 strongly; binds T3 1/3 as strongly
Binds 45-60% of plasma T4; 75% of plasma T3
2. Prealbumin: binds 15-35% T4, does not bind T3
3. Albumin: binds 15% T4 and 25% T3
4. Free T3 and T4: only fraction available to target cells
0. 5% plasma T4 is free (3 ng/100mL)
0. 5% of plasma T3 is free (1.5 ng/100mL)
64
How long are thyroid hormones active for?
Have very long half lives (6 days for T4, 1-3days for T3)
65
What are the general and specific functions of thyroid hormones?
**Only T3 is biologically active
Binds to receptor in the nucleus and alters transcription (in concert with retinoic acid receptor, forms a heterodimer)
Functions on all body cells, increasing hundreds of metabolic processes and is long acting (days)
Specific Functions of T3:
1. Normal Growth Processes: going above or below normal levels impairs growth; T3 Deficiency: dwarfism (cretinism); open epiphyses; T3 Excess: stunted growth; closed epiphysis
```
2. Required for normal function of nervous system:
T3 Deficiency (Children): cretinism resulting in mental retardation (T3 required in first 3 months of life or retardation is permanent); T3 Deficiency (Adults): listless, sleepy, weak, general decreased nervous system function, decreased catecholamine function; T3 Excess: hyperexcitable nervous system (increases beta adrenergic receptors on cells)
```
3. Increases basal metabolic rate:
= Increased O2 used in oxidative metabolism
= Increased turnover of lipids and carbohydrates:
= Increased rate of glycogenesis and glycogenolysis:
4. Stimulates both formation and breakdown, but no net change in glycogen stores
= Increased rate of gluconeogenesis
5. Net decrease in protein (broken down to make glucose)
6. Increased rates of lipogenesis and lipolysis; Stimulates both formation and breakdown, with net decrease in fat stores
7. Increased rate of cholesterol synthesis and degradation; Stimulates both formation and breakdown, with net decrease in plasma cholesterol; Cholesterol levels used in clinics to assess thyroid status
➢ Hyperthyroid- low cholesterol
➢ Hypothyroid- high cholesterol
8. Required for normal protein metabolism:
Excess T3 results in protein loss (increased gluconeogenesis); T3 deficiency results in myxedema (accumulation of mucopolysaccharide in the skin resulting in swelling and edema not due to fluid)
9. Required for heat production: needed to survive cold climates
10. Required for various other processes:
Lactation , Digestion, Kidney function, CV function, Reproduction (infertility can result from excess or deficiency of T3)
66
Describe the regulation of T3 Secretion
Thyroid functions at 50% capacity without TSH input (but this is not enough to prevent hypothyroidism)
Feedback inhibition occurs at anterior pituitary (inhibits TSH release; major pathway) and at the hypothalamus
Neural inputs causing TRH release from hypothalamus: cold, stress, exercise
Wolff-Chaikoffe Effect: give oral slug of iodide→ release of T3 and T4 inhibited for 2-4 days (used in clinics)
67
What are some of the pathological conditions associated with thyroid hormone?
1. Goiter: enlarged thyroid gland
- Can be associated with normal secretion of thyroid hormone
- Can be caused by dietary iodide deficiency
2. Hyperthyroidism:
Symptoms: Irritability, Increased basal metabolic rate, Fatigue, Weight loss, Increased body temperature, Exopthalmos, Positive chronotropism (increased heart rate), Increased activity, Loss of hair
Causes:
Graves Disease: autoimmune disease in which TSI (thyroid stimulating immunoglobulin; Ab to TSH receptor) is produced; TSI stimulates the TSH receptor on the thyroid gland
Tumor of thyroid gland
Tumor of pituitary gland (increased TSH)
3. Hypothyroidism:
Symptoms: Sluggishness, Mental retardation, Reduced growth rate, Thick and dry skin, Sensitive to cold, Increased sleep, Frog-like voice
Causes:
Poor development of thyroid, Thyroid insensitive to TSH (no goiter), Thyroid with goiter but reduced production of thyroid hormones (metabolic defect in hormone production)
Hashimoto’s Disease: Abs formed against TGB result in breakdown of thyroid tissue
68
What does elevated glucose levels cause? depressed?
1. Elevated Glucose:
For extended periods of time causes osmotic problems, cell dehydration and hyperosmolarity
Polyuria (kidney Tm for glucose= 250mg%)
Polydipsia
Polyphagia
2. Depressed Glucose:
For an extended period of time causes demise of certain cells (neural, RBCs, renal medulla cells)
These cells need glucose to survive because they cannot use free FAs for energy
40-60mg%: semiconscious state
Below 40mg%: coma
69
How is the GI involved in metabolism?
Takes up the following into the blood stream:
1. Glucose
2. Free FAs = Taken up as chylomicra, which are made in the gut and deposited into the lymph; Enter the blood stream at the level of the thoracic duct
3. AA
70
How is the liver involved in metabolism?
1. Stores 1/3 of the body’s glycogen (100g);
Storage of glycogen stimulated by insulin (stimulates glycogen synthase enzyme)
Note: although insulin is not required to bring glucose into the liver, by activating glycogen synthase it converts free glucose to glycogen, creating a glucose gradient that draws excess blood glucose into the hepatocytes
2. Primary site of gluconeogenesis
3. Primary stimulation is cortisol (breaks down protein in the periphery to provide AA for gluconeogenesis)
4. Primary site of free FA synthesis (lipogenesis) in humans ; ~50% of glucose undergoes conversion to free FAs released into circulation (VLDL)
Insulin activates this process in 2 ways:
a) . Stimulates the PP shunt (to give NADPH, required for synthesis)
b) . Stimulates enzymes required to convert Acetyl CoA to free FAs (ie. fatty acid synthetase
71
How is adipose tissue involved in metabolism?
1. Primary site of lipid (TAG) storage:
TAG synthesized from:
a). Glycerol phosphate (derived from glucose undergoing glycolysis)
➢ Insulin stimulates GLUT4 expression on adipocyte, causing glucose to enter
➢ The availability of glucose is the rate limiting step in lipogenesis
b). Free FAs derived from:
➢ TAG in chylomicrons (ingested fats)
➢ TAG in VLDLs (from free FAs synthesized in the liver)
➢ Lipoprotein lipase in vessel wall cleaves both (stimulated by insulin)
2. Lipolysis:
TAG → free FAs and glycerol, using hormone sensitive lipase enzyme
Free FAs bind to albumin and enter cell to be used as nutrients
HSL inhibited by insulin
HSL stimulated by epinephrine and glucagon (Gs/cAMP/PKA pathway)
**Note: HSL NOT stimulated by cortisol or GH (these stimulated lipolysis by some other long-term mechanism that is unclear)
72
How is the muscle involved in metabolism?
= 50% of body mass
1. Stores 2/3 of body glycogen (200g):
Insulin stimulates uptake of glucose from the blood, converted into glycogen (glycogen synthase also stimulated by insulin)
```
2. Oxygen requirements:
At rest- uses 30% of O2
More than 50% of this O2 is used to break down/oxidize free FAs (FFAs are the preferred substrate for ATP generation)
Light work- uses 70% of O2
Heavy work- uses 80-90% of O2
```
3. Production of ATP:
Free FAS are preferred substrate for ATP production
Glucose also used to produce ATP
Neutral amino acids can also be used to produce ATP (very small amount via the alanine cycle)
Muscles use more than 50% of ingested neutral AA to produce ATP
Alanine Cycle: generates a small % of substrate used for producing ATP in muscle
Muscle:
Glucose (from liver) → Pyruvate amidated to Alanine (using ALT), which goes to liver
**Breakdown of glucose to pyruvate generates ATP
Liver:
Alanine → Pyruvate (used for to make glucose for muscle) and urea
73
What are the different storage pools of "energy" in the body?
- Glycogen: 8-14 hours supply
- Fat: 40 day supply
- Protein: 16% is expendable
74
What happens in excess nutrient states?
1. Excess Glucose:
Most shuttled into glycogen in muscle and liver
Incorporated into α-glycerol phosphate (free FA synthesis) in adipocytes and liver
Metabolized via glycolysis and used to generate ATP
Metabolized via PP shunt
2. Excess free FAs:
Processed into chylomicrons and transported to fat cells to be stored as TAG
Used to produce ATP (preferred substrate)
3. Excess AA:
Incorporated into proteins
75
What is the effect of insulin in the body? when is it stimulated?
in excess nutrient stages:
1. Stimulates glycogenesis:
Stimulates glucose transport into muscle (increase available glucose)
Stimulates glycogen synthase
Inhibits glycogen phosphorylase
2. Stimulates glycolysis:
Activates several enzymes
3. Stimulates lipogenesis:
Stimulates glucose transport into fat cells (increases glycerol phosphate)
Stimulates LPL (increases FFA uptake from chylomicra and VLDL)
Inhibits TAG lipase (HSL) in fat cells
Stimulates PP shunt (increase NADPH production in liver)
Stimulates FFA formation in liver cells
Activates FFA synthetase and acetyl CoA carboxylase
4. Stimulates protein metabolism:
Stimulates AA transport into cells
Stimulates protein synthesis
76
What are the major consequences of an energy deficient state?
1. Lipolysis:
TG → FFA + glycerol; FFA binds albumin in circulation and is used as nutrients
Metabolized in muscles for ATP
FFA → Acetyl CoA (inhibits PDH) → Citrate (inhibits PFK via Randle Mechanism)
Randle Mechanism: lipolysis causes a build-up of acetyl CoA, which impairs glucose breakdown in muscle, saving glucose for tissues that need it (eventually leads to insulin R)
2. Glycogenolysis:
Liver glycogen → circulating glucose
Muscle glycogen → metabolized for ATP
Can also donate lactate from breakdown of muscle glucose by glycolysis to liver for the production of more glucose
```
3. Gluconeogenesis (Liver):
Using AA (85%), glycerol, pyruvate and lacatate
```
77
What are the hormonal controls of metabolism?
1. Epinephrine (Short Term):
Stimulates glycogenolysis in liver and muscle; Increase cAMP (inhibits glycogen synthase)
Stimulates lipolysis in fat cells; Elevates cAMP to stimulate TG lipase (HSL)
Stimulates gluconeogenesis (liver)
Inhibits insulin secretion
2. Glucagon (Short Term):
Stimulates glycogenolysis in liver only (via cAMP mechanism); No glucagon receptors in muscle cells
Stimulates lipolysis in fat cells (via cAMP mechanism)
Stimulates gluconeogenesis in liver (via cAMP mechanism)
3. Growth Hormone (Sustained Effects):
Stimulates lipolysis
Decreases glucose utilization by muscle cells by increase FFA available (Randle mechanism)
Decrease insulin-sensitivity of cells (probably via Randle mechanism)
Stimulates synthesis (not activation) of gluconeogenic enzymes in liver; Does NOT stimulate glucogenogenesis itself
Readies the liver for stimulation by epinephrine and glucagon
4. Cortisol (Sustained Effects):
Stimulates gluconeogenesis (both synthesis and activation of enzymes)
Provides AA for gluconeogenesis ; Inhibits protein synthesis in most cells (does not inhibit in liver cells)
Stimulates lipolysis and redistribution of fat stores
Permissive for:
GH, glucagon and epinephrine to stimulate lipolysis
Epi and glucagon to stimulate glycogenolysis and gluconeogenesis
Causes insulin resistance (probably via Randle mechanism)
Essential for survival during starvation state
78
Generally, what happens in diabetes?
Starvation state responses:
1. Increased gluconeogenesis
Increased amount of AA converted to glucose
Increased urea production
2. Increased urea and glucose in the urine (causing osmotic diuresis)
Loss of body fluids, salts and buffers
All result in circulatory shock and failure
3. Increased lipolysis:
Increases FFA in liver → Keto Acids → Ketoacidosis → Diabetic Coma
