Week 1 Flashcards by Stephen Barna

Endocrine cells must ALWAYS be close to ___ capillaries aka they are very well vascularized

Fenstrated

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Hormones have a ___ onset and ____ duration that nervous system control

The cells on which the hormones act, the target cells, contain surface or cytoplasmic receptors for specific hormones. Those that contain surface receptors, respond to ___ hormones, that attach and activate ___

^** Like peptides

Those that contain cytoplasmic receptors respond to ___ hormones that cross the cell membrane and bind to ___ receptors binding to the DNA

** ^ Like steroids

Slower, Longer

Protein, secondary messengers

Lipid soluble, intracellular

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The master gland that controls everything in the endocrine system in the ___, which is located at the floor of the diencephalon and forms part of the wall of the ___ventricle

** It connects the NS to the ES since it is part of the brain (the neural network), but its signals, which are hormones, act on the pituitary gland

Hypothalamus, 3rd

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What two hormones are synthesized in the hypothalamus and stored in the posterior pituitary?

The hypothalamus also oversees the ___, thereby helping to stimulate the adrenal medulla via ___ innervation

** So the hypothalamus can send out its own releasing hormones, its own inhibiting hormones, it can make its own hormones, and it can help regulate other endocrine glands via the SNS

Oxytocin and ADH (vasopressin)

ANS, sympathetic

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The two important clusters of neurons, called hypothalamic nuclei, that we talk about are the Supraoptic and Paraventricular nucleus.

BOTH of them can make ADH and oxytocin, but the Supraoptic nucleus PRIMARILY makes ___ and the Paraventricular nucleus PRIMARILY makes ___

ADH, Oxytocin

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****Come back to slide 13***

Giant table

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The pituitary gland is located in the ___, within the ___ bone of the skull. It is posterior to the optic chiasm and has a sellar diaphragm, which is dura mater that extends over and covers the pituitary within the sella turcica

It is also located next to the optic chiasm, so if the pituitary glad is enlarged, then it can compress the optic chiasm.

^This is important because not only would there be excess hormones produced, but there is also a problem with vision. *** This compression of the optic chiasm causes bitemporal hemianopsia, which is a problem with ___ vision

Sella turcica, sphenoid bone

Optic chiasm (nerves)

peripheral vision

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The anterior pituitary is an outgrowth from the roof of the mouth, aka it comes from ___ Origin. It then forms a small evagination called a __ pouch, which grows cranially and then eventually pinches off (loss of connection) at the base of the pouch to separate it from the oral cavity where it fuses with the posterior pituitary

The posterior pituitary is an outgrowth of the brain (from the hypothalamus), aka it comes from ___ origin and it grows as an evagination from the floor of the diencephalon where it grows caudally as a stalk but it NEVER detaches from the brain

The regressing stalk of Rathke’s pouch can leave residual tissue, which may become a tumor called ___ ** So it is derived from remnants of Rathke’s pouch

Oral ectoderm, Rathke’s

Neuroectoderm

Craniopharyngioma

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The anterior pituitary has 3 regions. Name the 3

1) The largest portion, aka the anterior portion
2) The part the surrounds the infundibular stalk
3) The division between anterior and posterior pituitary

The posterior pituitary has the Pars nervosa and the Infundibular stalk

** Anterior pituitary stains darker

1) Pars distalis
2) Pars tuberalis
3) Pars intermedia

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The pars distalis, the anterior and largest portion of the anterior pituitary is made up of glandular epithelial cells arranged in thick cords, ___ capillaries (sinusoids), and some connective tissue stroma to hold it all together

Its cells are classified into two groups based on staining. ___’s granules in the cells take up the stain and ____s do not take up the stain

** Which type of cells DO NOT produce hormones?

Fenestrated

Chromophils (Divided into acidophils and basophils), Chromophobes

Chromophobes (only chromophils do)

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For the chromophils, the basophils stain ___ in color and Acidophils stain __ in color

Name if the hormone is from a basophil or acidophil chromophil

1) ACTH
2) GH
3) TSH
4) FSH
5) Prolactin
6) LH

Purple/blue, Pink

1) B
2) A
3) B
4) B
5) A
6) B

The Pink hormones, Prolactin and GH are the ones that make up “PiG” in the pneumonic Flat PIG

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FSH is released by ___ cells (basophil) in the anterior pituitary when stimulated by ___. It’s effect is to stimulate ovarian follicle maturation and estrogen production in females, and stimulates spermatogenesis via Sertoli cells that produce sperm in males

It is inhibited by ___ in the females and ___ in the males

LH is released by ___ cells (basophil) in the anterior pituitary when stimulated by ___. It’s effect is to stimulate ovulation, ovarian production of estrogen and progesterone in females; and promotes testosterone synthesis via Leydig cells that produce testosterone in males

It is inhibited by ___ in the females and ___ in the males

Gonadotrophs, GnRH

Estrogen, Inhibin

Gonadotrophs, GnRH

Estrogen and progesterone, testosterone

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If a patient has delayed/absent puberty and no sense of smell, it’s called ___ syndrome and this is due to a defect in the migration of ___ neurons to the arcuate nucleus and olfactory neurons to the olfactory bulb

Kallman, GnRH

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ACTH (Adenocorticotropin) is released by ___ cells (basophil) from the anterior pituitary when stimulated by ___ from the hypothalamus

It then continues to act on the ___ and causes it to release ___ and androgens

^** One example is cortisol

ACTH is inhibited by negative feedback via the ___

Corticotroph, CRH

Adrenal cortex, glucocorticoids

glucocorticoids

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TSH (Thyroid stimulating hormone) is released by ___ cells (basophils) from the anterior pituitary when stimulated by ___ from the hypothalamus

The effect of TSH is to act on the ___ gland to release ___ and ___, which control metabolism.

The effects are inhibited by a negative feedback mechanism of T3 and T4

Thyrotrophs, TRH

Thyroid, T3 and T4

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Prolactin is is released by ___ cells (acidophils) from the anterior pituitary when stimulated by ___ or ___, both from the hypothalamus

The effect of prolactin is to stimulate milk production and promote lactation. It also plays an important role in inhibiting ____, and thus LH and FSH

The release from the anterior pituitary is inhibited by PIH (prolactin-inhibiting hormone) AKA dopamine

Mammotrophs/Lactotrophs

Prolactin-releasing hormone or TRH

GnRH

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GH (Growth Hormone) is is released by ___ cells (acidophils) from the anterior pituitary when stimulated by ___ from the hypothalamus

The effect is to indirectly stimulate overall growth of bone and muscle growth/ soft tissues via going to the ___ and causing insulin like growth factor-1 (IGF-1) to be released

It can be inhibited by somatostatin, or feedback inhibition by GH and IGF-1

Somatotroph, GHRH

Liver

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Somatostatin inhibits the release of ___ or ____

PIH (Prolactin-inhibiting hormone) aka Dopamine inhibits the release of ___ (which stimulates lactation and inhibits FSH, LH, and GnRH)

GH or TSH

Prolactin

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Excessive ADULT production of growth hormone is called ___

Acromegaly

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The Pars intermedia is between the Pars ___ of the anterior pituitary and the Pars ___ of the posterior pituitary

It often has a small cleft, which is the remnant of Rathke’s puch

Distalis, nervosa

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The ___ is what suspends the pituitary gland from the hypothalamus

It contains the Infundibular stalk (part of the posterior pituitary) and the Pars tuberalis (part of the anterior pituitary that surrounds the stalk)

The infundibular stalk is the ___ portion

Infundibulum

Neural

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The Pars nervosa, the main part of the posterior pituitary gland contains ___, which are glial-like cells and they seem to support the axons coming down from the hypothalamus

You also see ___ bodies which are expanded axon terminals filled with stored ADH or oxytocin

Pituicytes

Herring bodies

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____ stimulates water reabsorption in the kidney/ regulates serum osmolarity and a potent vasoconstrictor at high doses

It’s release regulated by osmoreceptors and baroreceptors that are up in the hypothalamus

____ has a role in uterine contraction during labor and milk secretion during lactation

ADH

Oxytocin

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THERE IS NO DIRECT BLOOD SUPPLY TO THE ANTERIOR PITUITARY

For the anterior pituitary, the internal carotid artery gives off a ____ artery, which goes to the median eminence and gives rise to the ___ plexus * It is here that the hypothalamic releasing and inhibitory hormones are collected

This plexus then gets drained by the ____, which deliver blood into the secondary capillary plexus (located in the ___) and there the IH and RHs can act on cells in the anterior pituitary, which allow these cells the secrete THEIR hormones into the secondary capillary plexus, which then gets taken out to the systemic circulation through fenestrated capillaries

Superior hypophyseal A.

Primary capillary plexus

hypophyseal portal veins, Pars distalis

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For the posterior pituitary, the internal carotid artery gives off a ___, which gives rise to a completely isolated ___ capillary plexus, which picks up ADH and oxytocin, stored in the Herring bodies, and sends them into circulation via their own hypophyseal veins

Inferior hypophyseal A., 3rd

The system that supplies blood to the anterior and posterior pituitary is called the ____ circulation

Hypothalamo-hypophyseal Portal circulation

The ___ develops from a posterior out-pocketing of the roof of the diencephalon in midline of the 3rd ventricle Its main functions are to manufacture ___ and ___ and this is done via ___ cells, which are supported by __ cells

Pineal gland Melatonin and serotonin, Pinealocytes, neuroglial

The main characteristic of the Pineal gland is ___ material, also called ___ *** The pineal gland is also a good radiological marker on an MRI

**calcified granular, Brain sand ***

____s MAIN job is to maintain circadian rhythms and this can contribute drowsiness It also has a role in delaying sexual development by inhibiting GnRH and GH secretion and therefore kids who have yet to hit puberty have more melatonin If one were to have a Pineal tumor, therefore affecting the amount of melatonin released, it can lead to precocious puberty since melatonin levels are low and this causes sexual maturity to occur ___ (early or late?)

Melatonin Early

Steroid hormones are hydro___, small, slow and long lasting ^ Steroids are synthesized from cholesterol Peptide hormones are hydro__, rapid, and short lived

Hydrohobic (aka lypophilic) Hydrophilic (water loving)

Steroid hormones are synthesized from ___ ER and peptide hormones from ___ ER

Smooth, rough

Tissues can obtain cholesterol from circulating ___s or from de novo synthesis from ___, or cholesterol esters stored in cytoplasmic lipid droplets *** Remember, 3 Acetyl CoAs make __, which can then be converted to steroids, lipid-soluble vitamins, and other molecules ** *** So remember IPP in the de-novo pathway is essential for deriving anything that is cholesterol based (steroid hormones, vitamin D, etc) ***

LDLs, Acetyl CoA IPP (Isopentenyl pyrophosphate)

In the synthesis of steroid hormones, the rate-limiting step is catalyzed by ___, and this converts cholesterol into ___

Desmolase, Pregnenolone

Pregnenolone must be converted to ____ for the synthesis of other progestrogens (aka enzymes including mineralocorticoids, glucocorticoidsm estrogens, and androgens) and this occurs via what two enzymes? ** So note that these enzymes are UPSTREAM OF ALL of the hormones

Progesterone 17-alpha-hydroxylase and 3-beta-hydroxysteroid dehydrogenase

Where would you expect to find 21-alpha-hydroxylase? What about 11-beta hydroxylase? If there was a defect in this enzyme, would it affect the synthesis of testosterone?

The adrenal cortex, because it is ONLY used in the pathways to convert cholesterol into aldosterone and cortisol, thus, it must be in the adrenal cortex Also specific to the adrenal cortex No

The major mineralocorticoid is ___, the major glucocorticoid is ___, (both found in the adrenal cortex), the major estrogen is ___ and comes from testosterone in the ovaries, and the major androgen is ___, but the one much more specific to males and is made in the testes is ___ In preterm neonates, the process of releasing a burst of ___ is defective and this leads to not enough surfactant being produced to expand air spaces in their lungs, which results in IRDS (Infant respiratory distress syndrome). This can be fixed by supplying glucocorticoids to expected mothers Angiotensin II, from the RAAS, stimulates the release of ___ and ADH to increase Na+ and water resorption

Aldosterone, cortisol, estradiol, testosterone, dihydroterstosterone Glucocorticoids Mineralocorticoids

The expression and activity of desmolase is stimulated by ___ hormones including ___, ___, and ___ ACTH activates the expression of desmolase and causes stimulation and release of __ from the adrenal cortex and some mineralcorticoids if it is acting on adrenal cortex tissue LH increases the activity of desmolase and FSH increases estradiol and estrone synthesis by activating the enzyme ___ when acting on gonadal tissue

Peptide ACTH, LH, and FSH Cortisol (a glucocorticoid) Aromatase

***Since Aldosterone increases water reabsorption in the kidneys via retention of na and H2O, if you have low levels then you lose to much ____, and if you have to much levels you can get ___ syndrome, which is increased blood volume aka hypertension due to to much retention of Na and H2O*** Increased cortisol can lead to ___ syndrome, marked by accumulation of fat

Salt, Conn syndrome Cushing syndrome

***___ has the ability to act as an anti-inflammatory agent by inhibiting both cellular and humoral immune responses. This occurs by creating a protein, called ___ inhibitory protein which inactivates NF-kB and therefore decreased production of cytokines for immune responses***

Cortisol, i-kBa inhibitory protein

*** THIS WILL BE A TEST QUESTION Some tissues have a lot of mineralocorticoid receptors, and this can be a problem because these receptors have equal affinity for both mineralo- and glucocorticoids (like cortisol). **^ AKA aldosterone AND cortisol activate the mineralocorticoid receptors in this tissue The problem is due to the fact that glucocorticoids (cortisol) have 100x higher levels than mineralocorticoids, so if nothing is done then we would get over-stimulation and out-competing of the receptors and increased action of cortisol on the mineralcorticoid receptors, and since we now have excess mineralcorticoid action it causes way to much H2O and Na+ reabsorption and therefore, hypertension. In order to prevent this from occurring, the enzyme ____ converts the excess cortisol to ___, which has a MUCH lower affinity for the mineralocorticoid receptor. Therefore, we don't have excess stimulation of the mineralcorticoid receptors, and we don't get excess water and sodium reabsorption ***Licorice inhibits this enzyme, which results in hypertension*** because you now have excess cortisol activating the mineralcorticoids

11beta-hydroxysteroid dehydrogenase Cortisone

The conversion of testosterone to a more potent testosterone signaling molecule, DHT (dihydrotestosterone), is caused by the enzyme ___ and inhibiting it can treat prostate cancer What drug can act on this enzyme to inhibit it?

5alpha-reductase Finasteride

***The active form of vitamin D is ____ **** And this is derived from vitamins ___ and ___ that we get from our diet or synthesized De-novo from cholesterol that comes from ___ *^ I would probably know the full names

Calcitriol D2 (ergocalciferol) and D3 (cholecalciferol) Sunlight

*****So once again D2 (which comes from out diet) can be converted to D3 in the intestinal cells, and then move to the liver and then kidneys. 7-Dehydrocholesterol, via de-novo synthesis from cholesterol can be converted to D3 via ___ in the skin and this can move from the skin to the liver, and then to the kidney ****** Once D3, which comes from the skin and intestines gets into the liver, it is converted via the enzyme ___ into 25-hydroxycholecalciferol, which then moves into the kidney and is converted to Calcitriol (1,25-dihydroxycholecalcifrol) via the enzyme ___

UV irradiation 25-hydroxylase 1-alpha-hydroxylase

Calcitriols main action leads to an increase in ___ and ___ levels in the blood, due to reabsorption via intestinal cells, kidneys, and bone 1-alpha hydroxylase, which creates calcitriol, is stimulated by ____ and low blood concentrations of phosphate, and inhibited by ___

Ca2+, Phosphate (PO43-) PTH (parathyroid hormone), calcitonin

___ signaling is when a signaling molecule released by a cell distant from the target cell is transported via the bloodstream to the target cell ^EX: Epinephrine ___ signaling is when a signaling molecule is released by one cell type and diffuses to a neighboring target cell of a different cell type ^EX: Testosterone

Endocrine Paracrine

Water soluble molecules are also called hydro___ molecules aka peptides ** Use GPCRs and RTKs on the outside of the cell These hydrophilic molecules are ___ (fast or slow) working and ___ (long or short) lived Lipid soluble are hydro___ molecules aka steroids ** Use cytoplasmic receptors and nuclear receptors These hydrophobic molecules are ___ (fast or slow) working and ___ (long or short) lived

Hydrophilic Fast, short Hydrophobic Slow, long

For the Nuclear Receptors, that are found in the cytoplasm (aka you could technically call them cytoplasmic receptors) of lipophilic hormone signaling, when the hormone binds to the cytoplasmic receptor, it causes __ to dissociate (which was keeping the receptor in the inactive form), and then the complex translocates to the nucleus where it binds to a specific DNA sequence called the ___ in the promoter region of specific genes

HSP 90, HRE (hormone response element)

Remember GPCRs are trimeric G proteins with 3 subunits (alpha,beta,gamma) Inactive G proteins have ___ bound to its alpha subunit and ___ causes GDP to be exchanged for GTP, which makes it active To once again inactivate the GPCR, ____ causes the intrinsic GTPase activity of the G protein to hydrolyze GTP into GDP and phosphate (Pi)

GDP, GEF (guanine nucleotide exchange factor) GAP (GTPase-activating protein)

Once the alpha subunit is activated, the G_ stimulates adenylate cyclase (AC) -> cAMP -> PKA -> Effect target proteins by phosphorylating them (via protein kinase) OR can act inside the nucleus via ___, which binds to CRE and effects gene expression in the nucleus The G_ inhibits AC, and if it's G_ then it stimulates hydrolysis of cGMP A 4th pathway, Gq, works by causing ____ to be cleaved by ____ to yield IP3 and DAG. ___ causes Ca2+ release from the ER/SR and this causes ___ to translocate to the plasma membrane where it is activated by ___

Gs, CREB Gi, Gt PIP2, PLC (phospholipase C), IP3, PKC (protein kinase C), DAG

Name the steps in GPCRs for GsAlpha and GqAlpha What enzyme converts cAMP to AMP and therefore shuts off this system?

Gs alpha = Ligand binds -> Receptor binds G-protein -> Receptor acts as a GEF and causes GTP to bind to G-protein as GDP is lost -> Alpha subunit of G protein is active -> Adenylyl cyclase active -> catalyzation of cAMP -> cAMP activates PKA -> PKA can phosphorylate target proteins to alter their activity or activate CREB to translocate to the nucleus and change gene expression PDE (phosphodiesterase) Gq Alpha = Ligand binds -> Receptor binds G-protein -> Receptor acts as a GEF and causes GTP to bind to G-protein as GDP is lost -> Alpha subunit of G protein is active -> Phospholipase C (PLC) active -> PIP2 cleaved -> IP3 and DAG produced -> IP3 causes Ca2+ release from ER -> Ca2+ causes Protein kinase C (PKC) to translocate to the plasma membrane and is activated by DAG -> Phosphorylation of target proteins to alter the activity

If there is a defect in 21-hydroxylse, there is a ___ production of cortisol, __ production of aldosterone, and possible development of male secondary characteristics due to an ___ flow of intermediates into adrenal ____ (since the other pathways are blocked off, so it all gets pushed into testosterone) If a defect in 17-alpha hydroxylase occurs what steroids are affected? A defect in ___ can cause hypertension due to the accumulation of 11-deoxycorticosterone, which has mineralocorticoid activity and can cause Aldosterone and Cortisol to not by synthesized

Decreased, decreased, increased, androgens Cortisol and sex steroids (but not aldosterone because it can still used 3-beta-hydroxysteroids dehydrogenase to get there) 11-beta-hydroxylase

Name what type of G_ these hormones bind to 1) Epinephrine bound to Beta-adrenergic receptor 2) Epinephrine bound to Alpha-adrenergic receptor 3) Histamine 4) Norepinephrine bound to alpha adrenergic receptor

1) Gs 2) Gi 3) Gs 4) Gi

The second type of receptor used by hydrophilic molecules is RTK (receptor tyrosine kinase) and the ___ hormone (ligand) binds to RTK, which is secreted in response to ___ in order to regulate glucose metabolism

Insulin, glucose

If high glucose levels are sensed, ____ gene is transcribed (into mRNA) in the nucleus and translated (into proteins) in the lumen of the ER, where it is cleaved by a protease to form ___ This is transported into the golgi apparatus, where it is cleaved by protease to form ___ and C peptides. These are present in our ___ cells that connect to the vasculature and can release the insulin when the glucose levels in the blood are detected to be high **The granules that the insulin is stored in are contained in either a "readily releasable pool" or a "reserve pool"

Preproinsulin, proinsulin, insulin Beta

The regulation of insulin synthesis and secretion, like we said is dependent on glucose levels. So what happens is glucose in taken up into B-cells by ___ via diffusion -> Glycolysis via glucokinase -> Enters TCA cycle -> Increased ATP/ADP ratio (since more ATP is made) -> Inhibit ___ channel -> Membrane depolarized -> Influx of ___ and the increased in Ca2+ causes granules with insulin to fuse and be released

GLUT2, K-ATP (a potassium channel), Ca2+

Insulin resistance is the amount of glucose cleared from the blood in response to a dose of insulin This can occur if there is a defect in the __ receptor, OR *** if phosphorylation of ___ occurs instead of the normal tyrosine that should be phosphorylated.** The enzyme that does this is the via ___, and this goes on to inhibit activation and signaling of the IRS (insulin receptor substrate) If you were to have increased insulin resistance, lets say from a reduced activation of PKB in the indirect pathway due to ser/thr kinase inhibiting it, this would lead to decreased ___ in the plasma membrane and therefore decreased glucose uptake into beta cells

Insulin Serine, ser/thr kinase GLU4

Therefore if you have type 1 diabetes or type 2, both have negative effects on insulin, you will end up with ___ blood glucose levels If you have decreased blood glucose, the pancreas will not release insulin, instead it will release ___, which increases blood glucose levels via promoting glycogen breakdown into glucose and inhibiting glycogen synthesis, or ___, which also stimulates the breakdown of glycogen by promoting glucagon secretion If glycogen stores are depleted, what hormone can induce gluconeogensis (glucose synthesis from non-carbohydrate carbon substances like pyruvate, lactate, amino acids, etc)

Increased Glucagon Epinephrine Cortisol

Nuclear receptors, include both those found in the cytoplasm AND those found in the nucleus to begin with These nuclear receptors are divided into 1) Classic steroid nuclear receptors, which contain GR, MR, PR, and AR, ER???? 2) Orphan Receptors (it seems like this can also be called Thyroid Receptors), which include Thyroid hormones (TR), Retionoic acid (RAR), Vitamin D (VDR), xenobiotics, ER??? etc... ^ Our slides say ER (estrogen) is a classic steroid nuclear receptor, but the online thing I read said its a Thyroid Receptor... In conclusion, I'm pretty sure no one knows which class it belongs to

*****

Explain mechanism for RAS dependent and independent signaling for insulin What is the end result of both pathways?

RAS dependent: Insulin binds to RTK -> Dimerization and autphosphorylation -> Insulin receptor substarte 1 (IRS-1) binds to phosphotyrosines -> GRB 2 binds to IRS-1 -> RAS activated -> MAP kinase pathway activated (RAF -> MEK -> ERK ) -> alterations in gene transcription via activation of glucokinase RAS independent: Insulin binds to RTK -> Dimerization and autphosphorylation -> Insulin receptor substarte 1 (IRS-1) binds to phosphotyrosines -> PI3K binds to IRS-1 -> PKB activated -> alterations in protein and enzyme activity via **increased GLUT4** to plasma membrane to cause an increased uptake of glucose. PKB also promotes glycogen synthesis Increased glucose uptake from the blood and promotes glycogen synthesis (which stores the glucose) aka it reduced blood glucose levels

Estrogen receptors are made up of two major types, ER__ and ER___, however BOTH are estrogen dependent transcription factors The ER___ is expressed mostly in the female reproductive tract including the uterus, vagina, and ovaries, along with mammary glands hypothalamus, endothelial cells, and vascular smooth muscle The ER__ is expressed mostly in the prostate and ovaries, along with some in the lungs, brain, bone, and vasculature

Alpha and beta Alpha Beta

Net effect of ER-DNA complex is to recruit co-activators that modify ___ structure, increase ___ activity that loosens up the chromatin, and finally attracts ___ to induce transcription and changes in gene expression An antagonist to this pathway, that can be used to treat breast cancer is ___ by binding to the ER via being hydrolyzed by Cytochrome P450 and being converted to 4-hydroxy-tamoxifen which has a high affinity for ER and therefore inhibits transcription via NcoR and HDAC1 that prevents GTA interaction ** So estrogen is an agonist and tamoxifen is an antagonist

Chromatin, HAT (Histone acetyltransferase), GTAs (General transcription Apparatus), Tamoxifen

**** KNOW THE MAJOR HORMONES OF THE ENDOCRINE GLAND, AND WHAT THEIR SOURCE IS

***

The three general classes of hormones consists of proteins/peptides, amines, and steroids Proteins/peptides are synthesized from __, amines are derivatives of ___, and steroid hormones are derivatives of ___

Amino acids, tyrosine, cholesterol

For the synthesis of proteins/peptides First in the nucleus the gene for the hormone is transcribed into an ___. This mRNA attaches to a ribosome, where it is translated to the first protein product called a ____. The hormone is converted to a ___ in the endoplasmic reticulum (ER) once the signal sequence is cleaved off. Next, the prohormone is transferred to the ___ where it is packaged into vesicles and converted to the final hormone where it is stored in the secretory vesicles until the endocrine cell is stimulated ** Steroid hormones are synthesized from cholesterol, and amine hormones from the amino acid tyrosine (via the biosynthetic pathway for the catecholamines)

mRNA, preprohormone, prohormone, golgi apparatus

The regulation of hormone secretion can occur via __ mechanisms, which have preganglionic sympathetic nerves synapse on an endocrine gland, and when stimulated causes the secretion of the hormone into circulation ___ are another way to regulate hormone secretion and this occurs when a response from the initial hormone feeds back to the endocrine gland

Neural Feedback

Negative feedback is the most common type of hormone secretion regulation ___ loop feedback is when the hormone feeds back ALL THE WAY to the hypothalamic-pituitary axis from the gland ___ loop feedback means the pituitary hormone feeds back on the hypothalamus to inhibit secretion of hypothalamic-releasing hormone ** If they hypothalamic hormone inhibits its own secretion, it can be called ultrashort-loop feedback What type of axis does this consist of?

Long Short Hypothalamic-pituitary axis

The effect of estrogen on the secretion of FSH and LH is the classic example of a ___ feedback loop ** Oxytocin is another example

Positive

Response-driven negative feedback is the idea that to respond, a target tissue must possess specific receptors that recognize the hormone. This can be done by changing the sensitivity of a target tissue by either changing the ___ of receptors, or changing the ___ of the receptors Up regulation is when you increase one of those two, and down regulation is decreasing one of those two ** So pretty much you are changing the overall responsiveness of whatever axis you are affecting

Number, affinity

Name the Guanylyl Cyclase mechanism

ANP or NO bind to receptor on cell surface -> Guanylyl activation -> GTP converted to cGMP -> Activation of cGMP-dependent kinase -> Protein phosphorylation responsible for hormone's actions

There are two types of tyrosine kinases One type has intrinsic tyrosine kinase activity within the receptor molecule such as with insulin and this is called a ___ The other type does NOT have intrinsic tyrosine kinase activity, instead it associates non covalently with proteins that do like those in the JAK-STAT family and these are called ___

RTK (receptor tyrosine kinase) TKAR (Tyrosine kinase associated receptors)

In steroid and thyroid hormone mechanisms, the hormone receptor has an ___ domain, which binds the hormone and the __ domain, which has two zinc fingers, is responsible for binding to the DNA The hormone-receptor complex dimerizes and binds (at the C domain) to ___s where the complex now acts as a TF and can regulate the rate of gene transcription

E, C SREs (steroid-responsive elements)

The connections between the hypothalamus and the Posterior pituitary are ___. ** So in other words the hormones-secreting neuron has its cell bodies in the ___, and its axons in the posterior lobe of the pituitary** ^*secreted by the posterior pituitary are neuropeptides The cell bodies of ADH and Oxytocin-secreting neurons are located in the ___ and __ nuclei within the hypothalamus ** Remember, ADH is mainly made in the supraoptic and oxytocin is mainly made in the paraventricular nuclei

Neural Hypothalamus Supraoptic and paraventricular

Unlike the posterior pituitary which was neural tissue, the anterior pituitary lobe is primarily a collection of ___ and therefore it is important to remember that the anterior pituitary is ****BOTH neural and endocrine**** ***Hypothalamic-releasing hormones and release-inhibiting hormones are synthesized in the cell bodies of the hypothalamic neurons and travel down the axons of these neurons to the median eminence of the hypothalamus. Once these neurons are stimulated, the hormones are secreted into the surrounding tissue and picked up by the nearby capillary plexus when they get delivered to the anterior pituitary. Now, the hypothalamic hormones act on endocrine cells where they stimulate or inhibit the release of anterior pituitary hormones***

Endocrine cells

What are the three main axes?

HPT, HPA, HPG ``` H = hypothalamic P = pituitary T = thyroid, A = adrenal, G = gonadal ```

The hypothalamic-hypophsial portal vessels are important for two main reasons First, they allow hypothalamic hormones to be delivered to the anterior pituitary directly and in ___ concentrations Second, these hypothalamic hormones do not appear in the ___ circulation in high concentrations

High, systemic

A primary endocrine disorder is low or high levels of hormones due to a defect in the peripheral ___ gland Secondary endocrine disorder is low or high levels of hormone due to a defect in the ___ gland Tertiary endocrine disorder is low or high levels of hormone due to a defect in the ___

Endocrine gland Pituitary gland Hypothalamus

Melanocyte-stimulating hormone (MSH) activity comes from the ___ family and if ACTH is increased, like in ___ disease, that is why skin pigmentation is a symptom for this disorder (aka due to the increased MSH levels)

ACTH, Addison

Stress can cause ___ to be released from the hypothalamus, which stimulates ACTH from the anterior pituitary, which stimulates the ____ to make and secrete ___ AKA this is the HP__ axis**

CRH, Adrenal cortex, glucocorticoids HPA

CNS input can cause ___ to be released from the hypothalamus, which stimulates TSH from the anterior pituitary, which stimulates the ____ to make and secrete ___ AKA this is the HP__ axis** Also, what is the primary most active form of the thyroid hormones that can cause negative feedback?

TRH, thyroid gland, thyroid hormones (T3 and T4) HPT T3

***Stress ___ the HPA axis, but ____ the HPT axis***

Activates, inhibits

CNS inputs can cause ___ to be released from the hypothalamus, which stimulates FSH and LH from the anterior pituitary, which stimulates the ____ to stimulate ___genesis and ___genesis AKA this is the HP__ axis** ** The axis is inhibited by puberty/opioids/stress/prolactin

GnRH, gonads Steroidogeneis, Gametogenesis HPG

GHRH acts on the anterior pituitary to stimulate GH (growth hormone) release and ___ acts to ___ HG release GH is secretion in a ___ pattern and in a ___ rhythm and it is secreted throughout life, with a main peak during puberty

Somatostatin, inhibit Pulsatile, circadian

Growth hormone can have either direct effects on target tissue (skeletal muscle, liver, adipose tissue) or indirect effects (mediated by production of somatomedins (IGF-1) in liver) The actions it performs are to increase ___ concentration by causing insulin resistance (because normal insulin lowers blood glucose) ^**A DIRECT EFFECT Increase ___ synthesis and ___ growth by taking up more amino acids, and increase ____ growth aka stimulating synthesis of DNA, RNA, and protein The increase in protein synthesis, organ growth, and linear growth is mediated by ___, which is INDIRECT EFFECT Failure to generate somatomedins would be a ___ endocrine disorder

Blood glucose Protein, organ, linear Somatomedins Primary

GH, which acts on target tissues and produces somatomedins (IGF), feed back on the anterior pituitary to ___ GH release, and feeds back to the hypothalamus to ___ somatostatin release (but remember somatostatin inhibits GH release) ***So excess GH can be inhibited by ___ analogues*** such as Octreotide

Inhibit, stimulate Somatostatin

Prolactin supports the actions of __ and ___ and these play a role in ___ development. Prolactin also induce ___genesis aka milk production, and supression of ___ by inhibiting GnRH secretion

Estrogen and Progesterone, breast development lactogenesis, ovulation

Prolactin deficiency results in the inability to lactate. If we destroy the hypothalamic-hypophysial tract we can loose ___ inhibitory effect, causing prolactin excess, which results in excess milk production and infertility since prolactin inhibits ___ secretion So treatment for excess prolactin can be a ___ receptor agonist, such as Bromocriptine

Domaine, GnRH Dopamine

********** ??????? If there is destruction of the hypothalamus, aka a tertiary endocrine disorder, then the hormones like prolactin will still be present or increased ?????? THIS MAKES NO SENSE TO ME

Ask her this question...

Sheehan syndrome, which causes the pituitary in pregnancy to become enlarged and more vulnerable to infraction causes ___pituitarism Most pituitary tumors are called pituitary adenomas and these effect hormone secretion and are either 1) Functional tumors, which release active hormone secretion, or 2) non-functional adenomas with don't release any active hormone obstruct normal hormone release

Hypo-pituitarism

___ is the major hormone concerned with regulation of body fluid aka stimulates water reabsorption in the kidneys It starts off as preprossophysin in the hypothalamus's cell bodies of neurons and is cleaved by a single peptide and packaged into vesicles and is carried by the ___ aka axons of the neurons to the posterior lobe of the pituitary as ADH and ___ inside the vesicle ** ^ So when ADH is secreted, NPII is also

ADH Hypothalamic-hyophyseal tract NPII (Neurophysins)

An ___ in plasma osmolarity, ___ in blood pressure, or ___ in blood volume causes ADH to be secreted ** ADH secretion is most sensitive to plasma osmolarity changes** ADH act on what two organs, which two receptors, and what functions?

Increase, decrease, decrease Blood vessels, V1 receptors (Vasopressin type 1), vasoconstriction Kidneys, V2 receptors (Vasopressin type 2), increased water reabsorption

When ADH binds to V2 receptors on the basolateral membrane, it activates a G protein -> increased cAMP -> increased PKA -> Change in transcription -> Insertion of ____ channels into the apical membrane of the principle cells lining the late distal tubule or collecting duct allow water to flow into the cell, and then ___ channels are inserted into the basolateral membrane and allow water to be reabsorbed into the blood

Aquaporin-2 Aquaporin-3

A loss of volume (volume contraction) results in ___ ADH secretion and excess volume results in ___ ADH secretion

Increased, decreased

In diabetes insipidus (DI), there is a lack of an effect of ADH on the renal collecting duct... Therefore, patients present with ___ (frequent or non-frequent?) urination and large volumes of ___ (diluted or concentrated?) urine

Frequent, dilute ^** Dilute because no ADH = no H2O reabsorption so your urine is dilute

*** MOST LIKELY A TEST QUESTION ___ DI is due to a lack of ADH in the plasma... This can occur from damage to the pituitary OR destruction of the hypothalamus ^**You can treat this via an ADH analogue like desmopressin ___ DI is when the kidneys can not respond to the ADH even if the plasma ADH is high... This can occur from chronic disorders or drugs ^** Desmopressin will have no effect, since it can't act on the kidneys in the first place!!! Instead, you must use a ___ to inhibit Na+ reabsorption and therefore keeping the urine concentrated instead of dilute

Central Nephrogenic Thiazide diuretic

SIADH = inappropriate ADH secretion from a tumor This can cause excess ADH secretion, which leads to excess H2O retention, and Na+ excretion (Loss)... Therefore you end up with ___natremia (sodium levels), an ____ urine osmolarity and ___ plasma osmolarity You can treat this problem by using a ___ antagonist aka blocking the receptor so no H2O reabsorption can occur or an antibiotic called ____, which decreases the response of the kidney to ADH by interfering with the secondary cascade, specifically AC

Hyponatremia (since you are losing excess Na+) Increased (since you are taking up more water into the blood aka urine has more osmoles AND you are keeping more Na+ in the urine for excretion which also means more osmoles) Decreased (since you are taking up more water and not taking up Na+) V2 receptor antagonist, demeclocycline

Prepro-oxyphysin is the precursor for ___ and in the vesicle before it is released from the posterior pituitary, it contains oxytocin and ___ Also, the target is the __ and deals with the ejection of ___ out of it

Oxytocin, NP I (Not NPII like with ADH) Breast, milk

Name what hormone was decreased to cause the effect when the pituitary failed 1) Diabetes insupidus results 2) Loss of pigmentation 3) Hypothyroidism 4) Infertility 5) Short stature in children, no effect in adults

1) ADH 2) ACTH 3) TSH 4) FSH/LH 5) GH

The thyroid ___ is the structural and functional unit of the thyroid gland It contains a single layer of ____ epithelial cells when active, and when not active the cells are ___ shaped The follicular epithelium surrounds a central lumen, which contains a ____ substance rich in ___ and this is where the hormones are stored ** SO hormones aren't actually stored in the cell

Follicle, columnar, cuboidal Colloid, TGB (Thyroglobulin)

Something made and stored extracellularly, like the hormones of the thyroid gland, are called ___

Exocrine

For the synthesis of the exocrine phase First, TGB is synthesized in the ___ and ___ and then incorporated in secretory vesicles where it is extruded into the follicular lumen Next, ___ binds to the receptors on the follicle cells of the thyroid gland, and this causes ___ ions and amino acids to be taken up into the cell from the blood through a gradient set up via the Na-K+ ATP pump, which drives the ____ cotransport (referred to as an iodide trap) ** You can use ___, such as perchlorate (ClO4-) or thyocyanate to act as a competitive inhibitor of the iodide pump and therefore inhibit the pump. ** Also the activity of the pump is regulated by I- itself, so if I- is high, the pump is ___, but if I- is low, the pump is ___

RER, Golgi TSH, Iodide (I-), Na+-I- cotransport Anions Inhibited, stimulated

For the synthesis of the exocrine phase Next, iodide ions are oxidized to iodine ions at the apical membrane (luminal) by the enzyme ____, and as they are oxidized they are moved into the lumen aka follicle colloid through the channel called ___, which is a transport mechanism using Cl- The iodine is now very reactive and iodinates and gets transferred to the TGB (which is called organification) at its ___ residues to create an active TGB containing MIT and DIT. Next, thyroid peroxidase once again catalyzes the coupling reaction between MIT and DIT to create T3 and T4, and now the TGB with MIT, DIT, T3 and T4 is stored in the lumen inside colloid droplets **Thyroid peroxidase can be inhibited by MMI and propylthiouracil (PTU) by preventing the ability to attach the iodine onto the TGB and this reduces the amount of active TGB ** However, PTU inactivates ALL thyroid peroxidase steps, so the steps of Organification AND the Coupling reaction are also inhibited ******

Thyroid peroxidase Pendrin Tyrosyl

For synthesis of the endocrine phase A colloid droplet with active TGB is taken back up in the follicle cell through ____ when stimulated by ___where it fuses with a lysosome that breaks down TGB into T3, T4, and iodine (MIT and DITs) via a ___, where T3 and T4 diffuse through the membrane into the capillary and are picked up by serum carrier proteins (aka thyroxine-binding proteins TBG --> Don't confuse TBG and TGB) and MIT and DIT are broken down via ___ to recycle the I- T__ is made in less amounts, but is MUCH more potent

Endocytosis, TSH Protease, deiodinase T3

An autoimmune disorder that produces antibodies to the receptors for TSH on the follicular epithelium, and therefore cause hyperthyrodism, is called ___'s disease ^** TSH levels are ___ than normal however, since increased TH production negatively feeds back to inhibit TSH production to try to stop the hyperthyroidism **Goiters (enlargement of the thyroid gland), Bulging of the eyes called ___, and tachycardia are major signs** ^** Remember that picture of the eyes bulging** Also note the reason for goiters are due to the TSI causing trophic growth of the gland Lastly, this is a ___ hyperthyroidism and can be distinguished from secondary hyperthyroidism via TSH-secreting pituitary adenoma aka tumors because if it were a secondary cause, TSH would be high and TH would be high

Graves Lower Exophthalmos Primary

An autoimmune disease where the thyroid gland is destroyed, causing hypothyroidism is called ___ disease It is caused by autoantibodies to ___, causing TGB to not be properly formed TSH levels are ___, because TSH senses that T3 and T4 are decreased so it increases TSH secretion in order to help restore levels, but it has no effect since the gland is destroyed

Hashimoto's ^ This is also Thyroditis** Thyroid peroxidase High

If you have an iodine deficiency, causing the thyroid gland to be hypoactive, the body does not get enough T3 and T4. Since no T3 and T4 is made to exert a negative feedback, TSH synthesis and secretion increases and this causes growth and vascularization of the thyroid gland and this causes a ___ ** But also note that goiters can occur in hyperthyroidism as well if there is excessive stimulation of TSH receptors by an autoantibody like in graves disease, or a tumor that secretes excess TSH ******SO JUST KNOW THAT -> The central principle is that HIGH levels of TSH OR substances that act like TSH (such as thyroid stimulating immunoglobulins) have a trophic effect on the thyroid******

Goiter

Abnormal development or function of the fetal thyroid gland is called ___

Congenital hypothyroidism (**use to be called cretinism**)

Neural crest cells that move into the follicle as it is developing and are not related to the production and development of thyroid hormones are called ____ cells These make a hormone called ___ and these regulate (decrease) the amount of ___ in the blood by inhibiting bone resorption by binding to receptors on osteoclast ** So C cells = Calcitonin = Calci (Ca2+) - Tone in (tone down)

C cells (parafollicular cells) Calcitonin, calcium

The parathyroid glands originate from the interaction of the ___ of the __ and ___ pharyngeal pouch ** The positions of the glands reverse during development so 3 ends up below 4

Endoderm, 3rd and 4th

There are two types of cells for the parathyroid gland 1) __ cells secrete parathyroid hormone 2) ___ cells have an unknown function This is also the ONLY endocrine gland with __ in it

Chief (principle) Oxyphil Fat

There is a ___ sensing receptor associated with G proteins in the plasma membrane of chief cells and when Ca2+ binds, it ___ the secretion of PTH and therefore it's a negative feedback mechanism ** So if serum Ca2+ is low, not enough to bind to CaSR and this stimulates Ca2+ secretion PTH stimulates bone resorption of calcium by stimulating ____ to promote osteoclast activity ^** So there is no direct receptor on osteoclasts for PTH, it must work through osteoblasts

Ca2+ (CaSR) Inhibits Osteoblasts

So calcitonin ____ Ca2+ serum levels and PTH ___ Ca2+ levels Increased Ca2+ levels via PTH works in 3 ways... 1) Like we already said, PTH ___ osteoblasts by stimulating M-CSF and RANKL expression on osteoblasts (ligands needed to bind to the osteoclast receptor to activate it) and this promotes osteoclast activity and therefore increases bone resorption and release of ca2+ and Pi into blood ** ^___ binds to the RANKL receptor so no matter what, osteoclasts can't be activated and no bone resorption can occur and therefore no increase in calcium 2) It also acts on renal tubules to stimulate resorption of Ca2+ and releases calcitriol to work in the intestines 3) Controls the rate of Ca2+ uptake in the GI tract by regulating the production of ___ in the kidneys aka ___

Decreases, Increases, stimulates Osteoprotegerin Vitamin D, calcitriol

Hypoparathyroidism is when there is a deficiency in ___ so blood Ca2+ levels and blood phosphate levels are low, there can be no increase since no PTH is active and this causes spontaneous depolarization of neurons and results in ___, the classic sign of Hypoparathyroidism Hyperparathyroidism is when there is to much PTH, which results in increased calcium (Hypercalcemia) levels in the blood, and this can result in bone loss and weakening since calcium is being taken out of the cell ^^** Hyperparathyroidism can result in ____ in adults, or ___ in children, which is weakening of the bones due the overreactive resorption of calcium from the bone. If there is an absence of ____, then calcium is not reabsorbed properly and this can result in ____calcemia... Rickets and osteomalacia can also occur from this?

PTH, tetany Osteomalacia, Rickets Vitamin D, hypocalcemia

Two iodides (2I-) are oxidized to 2 iodines (I2) by thyroid peroxidase Then I2 combines with the tyrosine moieties of TGB, which is catalyzed by ___, to form ___ or ___, which remain attached to TGB until hormones are needed to be secreted *******To form T4 (thyroxine), ___ and ___ combine and to form T3, ___ and ___ combine. Now TGB has T3, and T4 and these are all stored in the follicular lumen as colloid until it is needed to be secreted********** The T___ reaction is faster, so more is produced... However since T___ is the most potent, T4 can be converted back to T3 in the periphery by the action of ___ aka this is called DEIODINATION **^ Diodinase type 1 is found in the periphery and type 2 is in the brain

Thyroid peroxidase MIT (Monoiodotyrosine) or DIT (diiodotyrosine) DIT and DIT DIT and MIT T4, T3, deiodinase

If you were to have a deiodinase defect, you would have ___ levels of I- aka dietary I- deficiency Also when there is a iodine deficiency, formation of ___ is favored

Decreased (since the enzyme causes T4 to lose one I-, and it gets recycled back into the follicles... So if you cant make T4 -> T3, you don't recycle I- and it becomes decreased) T3

Name if T4 to T3 conversion is increased or decreases? 1) Hepatic and renal failure 2) Obesity 3) Aging 4) Hypothyroid 5) Cold exposure 6) Beta-blockers 7) Hyperthyroid 8) Fasting 9) Pregnancy

1) Decrease 2) Increase 3) Decrease 4) Decrease 5) Increase 6) Decrease 7) Increase 8) Decrease 9) Decrease

___ and ___ can treat hyperthyroidism that is linked to a high production of TSH and therefore increased I- is brought into the cell by inhibiting the Na-I pump ___ inhibits thyroid peroxidase High levels of I- inhibit ____ and synthesis of thyroid hormones and this is called the ___ effect

Percholrate and thiocynate (anions) PTU Organification, Wolff-Chaikoff

If you administer radioactive iodine, for patients with hypothyroidism, your Iodine uptake is very ____ and for patients with hyperthyroidism, your uptake is very ___ If a patient has Graves disease, then their iodine uptake is ___ than normal, HOWEVER, their iodine uptake will be lower than a patient with other causes of hyperthyroidism **^ This is because in graves disease, you have autoantibodies that increase the production of T3 and T4 by binding to the thyroid. However, TSH levels are still lower because the high levels of circulating iodine still have feedback inhibitory effects and can decrease TSH secretion (unlike other hyperthyroid problems where negative feedback does not work)

Low, high Higher, lower

In hepatic failure, less proteins are made so TBG (the carrying protein for thyroid hormones) decreases, which means more unbound THs exist, which negatively feedback to ___ synthesis and secretion of thyroid hormone In Pregnancy, TBGs are inhibited from being broken down, so more TBGs exist, more bound THs aka less active THs, so synthesis and secretion ___ ^ Patient is euthyroid aka their levels of free, physiologically active thyroid hormones are normal

decrease Increase

For the resin uptake test, it measures the binding of radioactive T3 to a synthetic resin (some molecule thing that binds T3) You take the patients blood, and add radioactive T3 to it. The T3 will first occupy the unbound sites of TBGs and then once those sites have been occupied, the leftover T3s will bind to resin. So if you were to have ___ TBG levels, or ____ endogenous T3 levels, your resin uptake would be high If you were to have ___ TBG levels, or ___ endogenous T3 levels, your resin uptake would be low

Low (since low TBG means lots of free leftover T3 in circulation, which all bind to resin), high (since most spots on TBG are already taken by endogenous T3, there is lots of leftover T3) High, low

Name if it's high or low in these conditions 1) Hyperthyroidism: T4 and T3 resin 2) Hypothyroidism: T4 and T3 resin 3) High TBG: T4 and T3 resin 4) Low TBG: T4 and T3 resin 5) Hepatic failure: TBG and T3 resin and T4 6) Pregnancy: TBG and T3 resin and T4

1) T4 = high T3 resin = high 2) T4 = low T3 resin = low 3) T4 = High T3 resin = low 4) T4 = Low T3 resin = High 5) TBG = low T3 resin = high T4 = low 6) TBG = High T3 resin = low T4 = High ^** Since decreased amount of free T3 and T4, it causes feedback to increase T3 and T4 synthesis and secretion

Remember that type 2 deiodinase is found in the brain and 1 is in the periphery, so when T3 and T4 go into the brain to directly effect the anterior pituitary, T3 can act through a direct effect, but T4 must be converted into T3 to have an effect, and this occurs via ____ type ___

Deiodinase type 2

TSH acts via an ___ mechanism It acts to increase the synthesis and secretion of thyroid glands AND has a ___ effect on the gland

Adenylyl cyclase (G protein activate AC -> Increase cAMP etc...) Trophic

Many new proteins are synthesized under the direction of thyroid hormones. In most tissues, ___ is always induced which leads to an ___ in oxygen consumption, ____ BMR, and ____ heat production ^** AKA increased metabolic rate Therefore, ___thyroidism leads to a high BMR and ___thyroidism leads to a low BMR ** Thyroid hormones also increase glucose absorption and potentiates the effects of other hormones on gluconeogensis, lipolysis, proteolysis, and bile acid synthesis

Na-K ATPase Increased, increased, increased Hyperthyroidism, hypothyroidism

Patients with hypothyroidism have ___ blood cholesterol and can suffer from Vitamin __ deficiency leading to blindness and yellowing of the skin Increased ___ and ___ to generate free glucose and increased ___-dependent entry into cell to further metabolize glucose occurs. Lipolysis, proteolysis also occurs and the net effect is ___ (anabolic or catabolic?)

Increased, Vitamin A Gluconeogensis, glycogenolysis, insulin Catabolic

The effect that T3 has on the heart, is what? Also when thyroid hormone levels are high, the myocardium has an increased number of ___ receptors and is more sensitive to stimulation by the ___ nervous system to increase contraction rate and strength and therefore increasing cardiac output

Increase cardiac output B1-adrenergic, sympathetics

Thyroid hormones act synergistically with __ and ___ to promote bone formation and therefore growth

GH and somatomedins

If a patient has an iodine deficiency, they have hypothyroidism and this leads a decreased TH secretion, and an ___ TSH secretion and therefore Goiter

Increased

In a previous question, we were told that lipophilic hormone receptors are either cytoplasmic or nuclear The NRs (nuclear receptors) are 3 major domains 1) Independent of ligand binding and can modify the conformation of the entire receptor 2) Binds to the regulatory sequences on DNA (HREs aka hormone response elements), upstream of the target gene 3) Binds to different molecules that either stimulate (agonist) or inhibit (antagonist) the NRs. So in other words, it regulates ligand-dependent activation of the receptor

1) AF1 (Activation Function 1 Domain) 2) DBD (DNA binding domain) 3) LBD (Ligand binding domain)

Of the total Ca2+ in the body, 40% is ___ and 60% is ___ Of that 60%, 10% is complexed to ___ and the other 50%, which is the ONLY biologically active form, is called ___ 99% of calcium is found in the bones and teeth, 1% in the ICF and 0.5 and 0.1% in plasma and ECF

Protein bound, ultrafilterable anions, Ionized Ca2+

___calcemia produces tingling and numbness (effects on sensory nerves) and spontaneous muscle twitching (effects on motorneurons and the muscle itself) This is because a decreased in serum calcium levels (extracellular), means the activation threshold potential is more negative (since there are less + calcium ions), and this makes the cells more excitable to release APs since the threshold for Na+ channels is reduced Hypercalcemia, aka high extracellular Ca2+ ___ membrane excitability and makes the NS become depressed and slow reflexes result

Hypocalcemia (decreased extracellular Ca2+ aka plasma calcium) Decrease

Changes in plasma protein concentration effect the ____ Ca2+ plasma concentration in the ___ direction **^ Increased [protein] = Increased [Ca2+] Changes in the anion concentration cause changes in the fraction of Ca2+ complexed with ___, and this ends up effecting the active ionized Ca2+ ^For example, increased phosphate (an anion) concentration, ___ the amount of of Ca2+ complexed to anions, which therefore ____ the amount of ionized Ca2+ Changes in acid-base abnormalities alters the ionized calcium concentration by changing the fraction of Ca2+ bound to ___ ^For example, is acidemia, there is more H+ (positively charged), which take up binding spots on albumin for Ca2+ (also positively charged) and therefore causes there to be an increased in ___ ca2+ since less can be bound to albumin. In alkalemia, deficient H+ -> more Ca2+ binds to albumin -> ___ ionized Ca2+ concentrations in plasma ** Last note, just make sure you realized changes in the palsma protein concentration effect the TOTAL Ca2+, and changes in anion concentration or acid base abnormalities effect IONIZED concentration

TOTAL, Same Anions Increases, decreases Albumin, free Decreased

Bone resorption, aka the breaking up of bone, which releases Ca2+ into the exctracellular fluid is stimulated by __ or ___ and inhibited by ___ ^** There is no net gain or loss of Ca2+ during this Also note that the amount of Ca2+ absorbed in the intestines must equal the amount excreted in the urine for a balanced Ca2+ level to be maintained

PTH or Vitamin D, Calcitonin

The extracellular concentration of phosphate (Pi) is regulated by the same hormones that regulate Ca2+ and its extracellular concentration is ___ related to that of Ca2+ **** Although PTH causes Ca2+ and Pi resorption from bone into the blood and Vitamin D causes Ca2+ and Pi to be reabsorbed into the blood as well.... There is a SMALL NET decrease in Pi levels due to the fact that PTH decreases the reabsorption of Pi in the kidney, and this causes more to be excreted in the urine than the amount put into the blood via bones and intestines... So it still ends up being inversely proportional ****

Inversely

What hormone is released in response to low serum Ca2+ levels (ECF)? High concentrations of Ca2+ bind to their receptor in Chief cells, and cause a G_ subunit to become activated. ^**This subunit causes PLC to be activated -> IP3/DAG activated -> IP3 causes increased Ca2+ levels intracellularly, and this increased levels of Ca2+ into the cell __ the secretion of PTH. When extracellular levels are decreased, less Ca2+ to bind, Gq is not activated so pathway does not occur, and PTH is free to be secreted

PTH Gq Inhibit

So chronic hypocalcemia = a decreased Ca2+ plasma concentration and therefore an ___ PTH synthesis and storage, along with hyperplasia Chronic hypercalcemia = increased Ca2+ plasma concentration and therefore a ___ PTH synthesis and storage Just like hypo and hyper-calcemia, hypo and hyper-___ has the exact same effect so low magnesium = increased PTH secretion and high magnesium = decreased PTH secretion ***** HOWEVER, in sever _____, such as an alcoholic and therefore has chronic MG2+ depletion, they have ____ of PTH synthesis

Increased Decreased Magnesium Hypomagnesemia, decreased (inhibition)

It's important to remember that CHIEF CELLS have G__ subunits that get activated when Ca2+ binds to them, however, when PTH acts on the bone and kidneys it works via a G__ subunit In the kidneys, PTH -> Gs -> AC -> cAMP -> Protein Kinase -> Phosphorylation -> Inhibition of ___-___ Cotransporter and this leads to ____ aka decreased Pi reabsorption The cAMP generated in the cells of the proximal tubule is excreted in urine as urinary cAMP *** THIS IS VERY IMPORTANT because the Pi that gets reabsorbed into the blood from bone resorption or intestine reabsorption, is excreted in the urine because if it wasnt, it would have complexed calcium in the ECF and decreased the amount of ionized Ca2+, which is not what we want***

Gq, Gs Na-phosphate (NPT2a), phosphaturia (Increased Pi EXCRETION)

In bone, PTH receptors are located on ___, so when they first bind, they actually have a direct effect on bone FORMATION ^** If you wanted to treat osteoporosis, you could actually administer intermittent synthetic PTH because this would cause bone formation However, over time the osteoblasts release cytokines, which cause stimulation of osteoclasts, and therefore bone resorption (breakdown of bone) so in other words, PTH has an Indirect effect on bone resorption Hyperparathyroidism is a ___ condition, so in this case Ca2+ and Pi levels are increasing in the serum due to bone resportion ___ also acts synergistically with PTH to stimulate osteoclast activity and bone resportion by increased ___ expression on osteoblasts aka **it sensitizes osteoblasts to PTH**

Osteoblasts Chronic Vitamin D, RANKL

If ___ were to interact with the RANKL, found on osteoblasts, it would inhibit the RANKL-RANK interaction between osteoblasts and osteoclasts and therefore inhibit bone resorption PTH causes an ___ in RANKL and ___ in OPG and Vitamin D causes an ___ in RANKL

OPG (osteoprotegerin) Increase, decrease, increase

Vitamin D3, also called ___, is a steroid hormone and like PTH, has actions on the intestine, kidney, and bone to increase Ca2+ and Pi plasma concentrations Remember, it can be converted in our skin from 7-dehydrocholesterol via UV light, or from our diet from D2 to Vitamin D3, which is then converted in our liver via ___ to 25-hydroxycholecalciferol which is the main circulating form but very low activity It is then converted to the active form, 1,25-(OH)2-cholecalciferol aka calcitriol aka Active D3 via ___ in the renal proximal tubule in response to a ___ ca2+ level, ___ Pi level, and ___ PTH level **1-alpha-hydroxylase is regulated tightly at the transcriptional level and it must have cytochrome P-450, Mg2+, O2, and NADPH

Cholecalciferol, 25-hydroxylase 1-alpha hydroxylase, decreased, decreased, increased

As we already said, one action of PTH on the kidney is to cause phosphaturia aka excess excretion of Pi in the urine by inhibiting ____ A second renal action of PTH is on the ____ and causes an ___ is ca2+ reabsorption to complement the increase in serum ca2+ from bone resorption and phosphaturia Vitamin D ___ Ca2+ reabsorption in the kidney and ___ Pi reabsorption in the kidney (Via stimulating NPT2a expression) although it has a much smaller effect on Ca2+ compared to Pi

NPT2a (Na+-phosphate transporter) Distal convoluted tubule, increase Stimulates, stimulates

PTH's effect on the small intestine is ___, and works through ___ by activating the enzyme ___, which creates the active form of D3, and this eventually goes into the nucleus, regulates gene transcription, and creates ___ which can bind the Ca2+ and move it to the basolateral surface, release the Ca2+, and then the Ca2+ moves into the blood

Indirect, vitamin D, 1-alpha-hydroxylase, calbindin

The direct effects of PTH on the parathyroid gland are ___ And the direct effects of Vitamin D on the parathyroid gland are direct ___ of PTH gene expression and direct stimulation of ___ gene expression

None Inhibition, CaSR

***So really this is the important part*** The role of PTH is to maintain the plasma Ca2+ concentration, and when needed its actions are suppose to increase ionized Ca2+ levels towards normal The role of Vitamin D is to promote ____ of new bone and therefore it increases plasma Ca2+ concentrations AND Pi concentrations. ^** 1-alpha-hydroxylase activates Vitamin D3 during levels of ___ plasma ca2+, ____ plasma Pi, and ____ levels of PTH

Mineralization Decreased, decreased, increased

The major stimulus for calcitonin secretion from C cells is an ___ concentration of plasma Ca2+ and its major function is to inhibit ___ to decrease the plasma Ca2+ and Pi (it binds directly) Thyroidectomy, aka ___ calcitonin levels has ___ effect on Ca2+ metabolism and thyroid tumors aka ___ calcitonin levels have ___ effect in Ca2+ metabolism and therefore calcitonin does not participate in the minute-to-minute regulation of plasma Ca2+ concentrations

Increased (opposite of PTH). Osteoclast bone resporption Decreased, no, increased, no

Estradiol-17B ___ intestinal Ca2+ absorption and renal tubular ca2+ reabsorption Estrogen promotes the survival of osteoblasts and apoptosis of osteoclasts and therefore favors bone ___ Adrenal glucocorticoids (cortisol) promote bone ___ and renal ca2+ wasting, along with ___ intestinal ca2+ absorption ^**and therefore patients treated with a glucocorticoid can develop osteoporosis

Stimulates formation Resorption, inhibit

Name if it will increase or decrease 1) Primary hyperparathyroidism: PTH, Ca2+, Pi, Vitamin D 2) Secondary hyperparathyroidism: A) Renal failure B) Vitamin D deficiency PTH, Ca2+, Pi, Vitamin D 3) Hypoparathyroidism PTH, Ca2+. Pi, Vitamin D 4) Pseudohypoparathyroidism type 1a PTH, Ca2+, Pi, Vitamin D 5) Humoral hypercalcemia of malignancy PTH, Ca2+, Pi, Vitamin D 6) Familial hypocalciruic hypercalcemia (FHH) PTH, Serum Ca2+, Urine Ca2+, Pi, Vitamin D

1) Increased, Increased (via increased bone resorption, increased renal Ca2+ reabsorption, and increased intestinal Ca2+ absorption), decreased (via decreased renal phosphate reabsorption and phsophaturia), increased 2) a) Increased, decreased, increased (because they do not properly excrete Pi), decreased (since remember vitamin D is activated in the kidney, so if its failed you don't get vitamin D) b) Increased, decreased, decreased (since vitamin D is needed for Pi reabsorption), decreased 3) Decreased, decreased, increased (since low PTH can't inhibit Pi reabsorption and can't cause any Pi to be excreted, it results in hyperphosphatemia Aka increased blood levels of Pi), decreased 4) Increased, decreased, increased, decreased ^** Same as hypoparathyroidism, except increased PTH instead of decreased PTH 5) Low (since PTH secretion is suppressed by the high levels of Ca2+), increased, decreased, decreased (since you have low PTH) 6) Normal or Increased (since PTH levels are not negatively fed back due to non-sensitive receptors on the parathyroid gland), increased, decreased, normal, normal

Don't be confused, because Primary hyperparathyrodism aka lots of PTH, you would think that should increase Ca2+ into the blood and therefore your amount of Ca2+ excreted would decrease... HOWEVER, what actually happens is so much Ca2+ is reabsorbed that it overwhelms the reabsorption capacity of the nephron so you actually end up with ___calciruia along with hypercalcemia ** Presents with Stones (from hypercalciuria), bones (from increased bone resorption) and groans (from constipation)

Hypercalciruia (excess ca2+ in the urine)

Primary hyperparathyroidism often occurs from parathyroid adenomas (tumors) In secondary hyperparathyroidism, excess PTH is secreted, but it's not due to a defect in the thyroid gland itself, instead it is due to ____calcemia (aka to little calcium) ** So in secondary hyper, PTH is elevated, and Ca2+ is either normal or low, but NEVER high

Hypocalcemia

Abright hereditary osteodystrophy is also called ____ The reason why there is low calcium in the blood (hypocalcemia), and high phosphate in the blood (hyperphosphatemia) is due to a defect from an inherited autosomal dominant disorder that effects ___ for PTH in both bone and kidneys ** So since you have low calcium, your body stimulates the release of PTH from the thyroid, and this works fine until it gets to the target organs (kidney and bone) and then it can't activate these targets to reabsorb ca2+ and excrete Pi.... Which is why your PTH levels are high, but Ca2+ is low and Pi is high **** Patients with this disease present with a short stature, short neck, obesity, subcutaneous calcification, and shortened metacarpals and metatarsals

Pseudohypoparathyroidim type 1a Gs subunit

In humoral hypercalcemia of malignancy, aka some tumor like a lung or breast tumor, can secrete ___, which is structurally homologous to PTH **This can be treated with furosemide to inhibit ca2+ reabsorption and etidronate to inhibit bone resorption

PTH-rp (PTH-related peptide)

In FHH (familial hypocalciuric hypercalcemia), mutations inactivate ___s in parathyroid glands and parallel ca2+ receptors in the ascending limb of the kidney The parallel ca2+ receptors in the kidney sense that the calcium level is low, even though it is high. This leads to PTH secretion, increased reabsorption (decreased ca2+ urine excretion aka hypocalciuria) and increased serum ca2+ ^** Normally, now that you ca2+ levels are high, it would feedback and decrease PTH, but since the receptors on the parathyroid are also messed up, it doesn't inhibit it So in other words, know that FHH = ___calciruia and ___calcemia

CaSRs (Calcium sensing receptors) Hypocalciuria, hypercalcemia

Vitamin D resistance, is when active vitamin D can not be made no matter what, this is due to either the absence of the enzyme ___ or chronic renal failure where the kidney is completely destroyed so no Vitamin D can be made there ****Type 1 Pseudovitamin D-deficient rickets is due to decreased ___ and type 2 is due to decreased ___

1-alpha-hydroxylase 1-alpha-hydroxylase, vitamin D receptor

In vitamin D deficiency, PTH levels are ___, Ca2+ levels are ___, Pi levels are ___, Urine Pi and cAMP levels are ___, Vitamin D is ** Chronic renal failure, Pi depletion, Ca2+ depletion, can all lead to Rickets or osteomalacia

Increased, decreased, decreased, increased, decreased

Obesity is the major cause of Type ___ diabetes which leads to Insulin ____ and relative insulin deficiency Obesity induces inflammation due to the fact that excess nutrition causes the death of adipocytes, and then pro-inflammatory responses are generated

2, resistance

Remember, M__ macrophages are associated with anti-inflammatory effects and M__- are associated with adaptive immunity and therefore elicit an immune response Therefore, lean people have more ___ macrophages and also a ___ number of T regulatory cells Obese people have adipocyte necrosis and increased number of ___ macrophages (mixed M1-M2 phenotypes) and a ___ in T regulatory cells, which therefore leads to an increased in a proinflammatory response such as increase B cells, Cd4+ TH1 cells, and CD8+ T cells

M2, M1 M2, greater M1, reduction

Anti-inflammatory cytokines, specifically IL-__, IL-___, and IL-___ exist in lean cells, but when cells become obese, this cytokine no longer exists since it no longer has NFk-B in the promoter region

IL-10, IL-4, IL-13

Type 1 diabetes is characterized by insulin ____ due to destruction of pancreatic __ cells and therefore it can be thought of as a ___ cell-mediated autoimmune disorder (Islet cell autoantibodies - ICA) These patients are prone to keto___ The onset of T1D is associated with infiltration of the ___ by mononuclear cells and ___ T cells which is why there is an increased expression of MHC1 and the infiltrate is termed Insulitis ** Type 1 DB is due to genetics AND environmental backgrounds

Deficiency, beta, T-cell Ketoacidosis Islets of Langerhans, CD8+

The reason why breast milk is so important is because if you don't breast feed and instead provide cow milk, there is less ___ in the milk and this leads to a decreased tolerance to insulin

Insulin

Your diet and microbiome composition is important in T1D Those who eat plenty of proteins and animal fats and a high fiber diet, leading to a healthy epithelium have increased levels of ___ bacteria which keep mucine synthesis and tight junctions maintained Those who have a high carb diet and a T1D-associated leaky gut have high ___ bacteria instead and this leads to mucine degradation, altered permeability, and then T1D can result

Prevotella, Bacteroides

___ disease also changes permeability of the epithelium (aka wheat gluten is a diabetogen?) so celiacs disease AND bacteroides can work through the same mechanism An immune modulator and suppressant, ___, is another environmental factor linked to T1D

Celiac Vitamin D

Remember, type 1 diabetes is a TH__ type of immune response and also associated with ___ self tolerance that when disrupted, causes a decrease in ___ cells and therefore T1D T regulatory cells are important for production if Il-10 and TGF-betta, both immunnosuppressive cytokines, reducing the ability of APCs to stimulate T cells (via CTLA-4), and consumption of IL-2 Remember, Th0 cells need ___ to become T-regulatory cells

Th1, peripheral, T-regulator TGF-betta

For the role of infection in T1D ___ and ___ from streptomyces are cytotoxic for B cells Bacteria can also act as ___ for the immune response to food antigens Finally, ___ can act against beta cells via cytotoxicity or autoimmunity via molecular mimicry ^ Viruses which have been implicated in T1D include Mumps and Rubella

Streptozocin and bafilomycin A1 Adjuvants Viruses

The HLA region for T1D is found on chromosome ___, and presents insulin antigens for Cd8+ T cells The insulin gene itself is found on chromosome ___ and is the antigen for an autoimmune response The ___ gene is found on chromosome 2 and involved in the regulation of autoimmune responses. It is a ___ homologue expressed on T-cells that binds to the ___ protein (CD80/86) and normally this interaction is needed as a co-stimulation, however CTLA-4 ___ T-cell activation and leads to its apoptosis ^*** Failure of T cells to express the CTLA-4 gene due to a mutation can contribute to aberrant immune responses seen in T1D. If this is the case, you can give a patient ___ treat autoimmune diseases

6 11 CTLA-4, CD28, B7 Suppresses sCTLA-4 (soluble CTLA-4)

HLA alleles in T1D are most often ____, found in 90% of people and ___, which is found most common in children Also, HLA class II molecules with no ___ of the beta chain are often found in those with T1D If you have the HLA __, you have protection agaisnt T1D

DQ2/DQ8, DR3/DR4 ASP57 DR2/DQ6

The insulin gene (IDDM2) can have variable numbers of tandem repeats in the promoter region. There are three classes (which depend on how many repeats there are) and it was found that the susceptible class ___ alleles of the insulin VNTR result in low insulin mRNA synthesis... Since synthesis is decreased, low Ag (insulin) synthesis occurs, which means low Ag presentation in the thymus, and therefore there is a failure of the deletion of self-reactive CD8 T Cells ^ In the thymus insulin-Ags are presented within Class ___ MHCs which causes ___ selection and therefore cell death of self-reactive T cells, this is how central tolerance to insulin is established...****So if you have class 1 alleles, then central tolerance is BROKEN***

1 2, Negative

Transcription expression of insulin in the thymus is controlled by ___ and therefore defects in this result in decreased levels of insulin mRNA, just like with class 1 alleles, and this once again leads to the failure of deleting insulin reactive T cells and causes central tolerance to be BROKEN

AIRE

The presence of __ or more distinct ____ autoantibodies are highly predictive of future T1D (1 = very low, 2 = higher, 3(max) = very high chance) Name the three most common ICAs

2, ICA (Islet cell autoantibodies) GAD65 (Glutamic acid decarboxylase), IA-2 (Insulinoma Antigen-2), IAA (Insulin autoantibodies)

In T1D auto-reactive T cells belong to the Th___ subset, whereas protective T cells are of the Th__ subset Remember, Th0 cells (aka CD4+ T cells aka T helper cells) can differentiate into Th1 cells when APCs with class ___ MHC molecules that secrete IL-___ and now the the Th1 cells are differentiated, they can produce ___ which activates macrophages and ___ Th2 cytokine production

Th1, Th2 2, IL-12 IFN-gamma, inhibits

It is important to realize that in healthy people, there are still self reactive clones of T cells, HOWEVER, T1D does not occur (aka autoimmunity) due to the fact that healthy people have __ -self tolerance maintained by ___ cells ^**In patients with susceptibility to T1D, they have a failure of Treg cells to prevent activation/expansion of auto-reactive T cells **These Treg cells cause suppress APCs directly through cell-cell interactions, of indirectly through cytokines and chemokines like IL-4, Il-10, IL-13, TGFB

Peripheral, T-regulatory

A specific marker of natural T-regulatory cells is ___

Foxp3

In children with Type 1 DM, the most common auto antigen is ___ and in adults, it is ___

Insulin/proinsulin, GAD65

Endocrine and exocrine cells are found during weeks 12-16 Remember, ____ = products secreted into ducts and ___ = products secreted into the blood

Exocrine, endocrine

___ make up the exocrine pancreas, which secrete enzymes that move through the ducts to the small intestine ____ make up the endocrine pancreas that secretes hormones into the blood

Acini Islets of Langerhans

The Islet of Langerhans are composed of anastomosing cords of endocrine cells, which each secrete a single hormone, and a vascular component called the ___ portal system The cells of the islets of Langerhans communicate via ___ junctions This system has an afferent arteriole that gives rise to a capillary network lined by fenestrated endothelial cells, which distribute blood throughout the islet of langerhans. Since venous blood will flow from the middle of the Islet to the rim of the islet, venous blood from one cell type bathes the other cell types. So in other words, venous blood from ___ cells, which are in the middle of the Islet, carries insulin to the alpha and delta cells which are located around the rim. The venules leaving the islets of langerhans then supply blood to the adjacent pancreatic acini and this is what allows local action of endocrine hormones on the exocrine component of the pancreas ** There is also an independent arterial system called the ___ system, which supplies blood directly to only the pancreatic acini (the exocrine cells)

Insuloacinar Gap Beta Acinar vascular

One of the components of the islet of Langerhans, the anastomosing cords of endocrine cells consist of various cells. Name what they secrete or synthesize and their main function 1) Alpha cells 2) Beta cells 3) Delta cells 4) F cells

1) Glucagon, increase blood glucose (via hepatic glycogenolysis) 2) Insulin, decrease blood glucose ^**The actions of glucagon are antagonistic to those of insulin 3) Gastrin and somatostatin, somatostatin inhibits the release of insulin and glucagon in a paracrine manner, and it inhibits HCL secretion 4) Pancreatic polypeptide, inhibits the secretion of somatostatin and inhibits contraction of the gallbladder in order to conserve digestive enzymes and bile between meals

Insulin is a major anabolic hormone and is secreted in response to carbs and proteins The steps of insulin production in Beta cells consists of first, mRNA directs ribosomal synthesis of Preproinsulin, which has its signal peptide cut to yield proinsulin. Proinsulin is shuttled to the RER to, where disulfide bridges form to yield a folded form of insulin. It is then packed in secretory granules transported and processed in the golgi (there is a ___ peptide that connects that A and B chains of the molecule and act as a crystalline core) ^** Preproinsulin = signal peptide, A and B chains of insulin, and C peptide Proinsulin = NO SIGNAL PEPTIDE, A and B chains of insulin, and C peptide Proinsulin is then broken apart by a protease found in the secretary vesicles that its packed into, and then mature insulin, in the presence of ___, yield a dense crystalloid surrounded by C peptides Glucose then enters the B cell through ___ channels and triggers the immediate release of insulin and C peptide This occurs via the closure of the ___ channel, which utilizes ATP derived from glucose metabolism (via the enzyme glucokinase that converts Glucose -> ATP). Then depolarization of the plasma membrane occurs, which allows __ influx following the accumulation of K+ in the cytosol. The ca2+ influx causes exocytosis of the secretory vesicles and release of insulin into the blood

C peptide, Zinc GLUT-2 ATP-dependent K+ channel, Ca2+

___ is used to test beta cell function in patients with T1D, who are receiving insulin injections that way you can see if the injections are working properly ^*(Endogenous insulin secretion) ___ drugs promote the closure of ATP-dependent K+ channels (SUR - Sulfonylurea receptor) and this causes increased insulin secretion and can be used to treat type __ diabetes

C peptide Sufonylurea, T2D

So if you have an increase in glucose, you take the glucose up into B cells and hepatocytes and in response you secrete insulin and C peptide... The insulin then goes on to remove the glucose from the blood and this acts on adipocytes, skeletal muscle, and cardiac muscle The insulin will bind to an __ receptor on adipose cells, activate auto phosphorylation of an adjacent __ subunit, which has tyrosine kinase activity This causes __ to be translocated from the Golgi to the plasma membrane, where it takes up glucose to decrease its concentration in the blood **Insulin also down regulates its own receptor

alpha, beta GLUT-4

Realize that GLUT-2 is insulin ___ and GLUT-4 is insulin ___

Independent, dependent

In patients with increase blood glucose, you would expect insulin levels to rise in order to decrease the blood glucose. However when increased blood glucose levels remain high for an extended period of time, the patient is said to be hyperglycemic and this can be due to 1) Lack of insulin aka Type ___ diabetes 2) Insufficient insulin secretion or relative to glucose levels and resistance of peripheral tissues to insulin aka type __ diabetes ** Both types normally present with hyperglycemia, polyuria, and polydipsia

1 | 2

The ATP-dependent K+ channel contains an Inward-rectifier K+ channel AND a ___ which allows you to produce drugs that bind to this receptor, close the channel, and cause increased release of insulin in order to treat T2D

SUR (Sulfonylurea receptor)

CCK and ACh activate Q__ to increase insulin secretion Somatostatin activates G__ to inhibit secretion Glucagon activates G__ to stimulate secretion

Gq Gi Gs

Like we said, insulin goes on to remove the glucose from the blood and this acts on adipocytes to store glucose as ___, skeletal and muscle to store glucose as ___, and the liver to store glucose as ___

Fat, protein, glycogen

Insulin increases glucose transport into target cells such as muscle and adipose tissue by directing the insertion of ___ into cell membranes (remember this is from a RAS-independent manner) It also promotes the formation of glycogen (the storage form of glucose) via first taking up the glucose and converting it to glucose-6-phosphate via the enzyme ___, and then it can convert this product to Glucose-1-phosphate, which is converted to glycogen via the enzyme ____ Insulin also directs substrates away from the formation of glucose by increasing glycolysis (glucose breakdown) and carbohydrate oxidation. This occurs via the glucose that is taken into the cell and converted to G6P via hexokinase, is then converted to F1, 6P via the enzyme ___ **Protein synthesis is also increased and protein breakdown is decreased

GLUT4 Hexokinase Glycogen synthase Phosphofructokinase

Alright so lets put it this way... Name if there will be an increase or decrease due to insulin SKELETAL MUSCLE 1) Glucose uptake via GLUT4 transporters 2) Glycogen synthesis 3) Glycolysis 4) Protein synthesis 5) Protein breakdown 6) Triglycerides ADIPOCYTES 1) Glucose uptake via GLUT4 transporters 2) Glycolysis 3) Triglycerides 4) Hormone sensitive lipase (HPL) 5) Lipoprotein lipase (LPL) LIVER 1) Glucokinase 2) Glycogen synthesis 3) Glucose release (gluconeogensis) 4) Glycolysis 5) Triglyceride storage and export (VLDLs) 6) Protein synthesis 7) Protein degradation

1) Increase 2) Increase 3) Increase 4) Increase 5) Decreased 6) Increased 1) Increased 2) Increased 3) Increased 4) Decreased 5) Increased 1) Increased 2) Increased 3) Decreased 4) Increased 5) Increased 6) Increased 7) Decreased

In adipose tissue, insulin ____ the mobilization and oxidation of fatty acids (aka it inhibits triglycerides to turn into fatty acids), instead it wants to ___ the storage of fatty acids (which is done so as triglycerides) Along with increasing glucose uptake into the adipocytes, insulin ___ fat deposition/uptake of triglycerides via ____ Insulin ___ lipolysis (breakdown of triglycerides into FFAs) By inhibiting the enzyme ___. It also ___ ketoacid formation in the liver due to the fact that less

Inhibits, stimulate Stimulates, Lipoprotein lipase (LPL) Inhibits, HPL (hormone sensitive lipase) Inhibits

In T1D (insufficient insulin levels) 1) Blood glucose concentration are ___ ^**Due to a) ___ Gluconeogensis, b) ___ uptake of glucose into cells, and c) ___ glucose utilization 2) Blood fatty acid and ketoacid concentrations are ___ ^**Due to a) lipolysis of fat is ___, b) conversion of fatty acids to ketoacids is___, and c) utilization of ketoacids by tissues is ____ 3) Blood amino acid concentration is ___ ^**Due to 1) ___ breakdown of proteins to amino acids

1) Increased a) Increased b) Decreased c) Decreased 2) Increased a) increased b) increased c) decreased 3) Increased a) Increased

Since ketoacids are increased in the blood when insulin levels are low, it presents with keto___ Increased glucose also exceeds the reabsorption capacity of the PCT and this results in no more reabsorption of water since it normally follows glucose, and this leads to osmotic diuresis, polyuria (increased excretion of dilute urine), and thirst ^** The polyuria (loss of large amounts of dilute urine) cause ECF volume contraction and hypotension Lack of insulin also causes a shift of K+ ___ of the cells and results in ___kalemia (since remember insulin normally promotes K+ uptake)

Ketoacidosis (DKA) Out, hyperkalemia

For type 2 diabetes mellitus, there are there main reasons why obesity-induced insulin resistance can occur 1) Decreased ____ uptake of glucose in response to insulin release 2) Decreased ability of insulin to repress ___ glucose production (since remember, insulin is needed to inhibit secretion of glucose out of the liver) 3) Inability of insulin to repress ____ or increase ___ in adipose tissue

1) GLUT4 2) Hepatic 3) HSL (hormone sensitive lipase), LPL (lipoprotein lipase)

Low glucose levels cause secretion of ___ in order to attempt to increase blood glucose levels Also the amino acids __ and ___ stimulate glucagon secretion, along with fasting, CCK, ACh, and B-adrenergic agonists The factors that inhibit glucagon synthesis include insulin, ___, and high F.As/ketoacid concentrations

Glucagon Arginine and alanine Somatostatin

Glucagon used the ___ mechanism Name the effects of glucagon, if it increases or decreases 1) Glycogenolysis 2) Gluconeogensis 3) Lipolysis 4) Ketoacid formation

Adenylyl cyclase (cAMP) 1) Increases (increase blood glucose) 2) Increases (increases blood glucose) 3) Increases (Increases blood fatty acids) 4) Increases (increases blood ketoacids)

GIP ___ insulin secretion (it is glucose dependent) and it ___ glucagon secretion **^ GIP is a member of the family of peptides that glucagon, secretin, and GIP all belong to GIP is an incretin hormone which means it stimulates insulin secretion in response to a meal

Stimulates, inhibits

Week 1 Flashcards

(192 cards)