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-Enuociinology- the communication anu contiol
system within a living oiganism by biomolecules that
oveilaps all bouy systems

-The bouy balances inteinal anu exteinal changes to
the bouy to maintain homeostasis

Piimaiy Enuociine 0igans
-Bypothalamus, Pituitaiy, Paiathyioius, Auienals,
uonaus, Pineal, Thyioiu, anu Pancieas
Seconuaiy Enuociine 0igans
-Beait, Kiuney, Auipose, Thymus, anu uI tiact
Tiansitoiy Enuociine 0igans
-Coipus luteum anu placents


-hemociine = enuociine

Types of cell-to-cell communication






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-Nembiane-bounu ieceptois aie highly vaiiable anu
hoimone specific
-Biomolecules binuing to membiane-bounu ieceptois
*#(*%0)$+- iegulate tiansciiption thiough seconu
messengei signaling pathways

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-Steioius, thyioiu hoimone, anu some vitamins fieely
uiffuse acioss the cell membiane
-Thyioiu hoimones aie "shuttleu" acioss the cell
membiane by chapeione pioteins
!Caiiiei-meuiateu tianspoit
-9*%0)$+- iegulate gene tiansciiption

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)&#)0#$%/$*&# /#( $;0 %0)06$&% (0#7*$- /$ $;0 7*$0
&< /)$*&#
-Localling-acting biomolecules uo not iepiesent the
systemic concentiation since they binu iapiuly with
ieceptois upiegulateu at site of ielease causing less
to escape into systemic ciiculation
-Systemic concentiations of hoimones iepiesent
level of hoimone acting on tissues uistiibuteu
thiough entiie bouy.

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-Localizeu 'Buist'- locally-acting hoimones aie
ieleaseu iapiuly in iesponse to local stimuli like a
hemoiihage
-Pulsatile Release- many hoimones aie continuously
secieteu in iegulai, iepeateu shoit buists (each
buist=pulsatile ielease) fiom a baseline
concentiation

-Ciicauian ihythm- hoimones secieteu in a 24 houi
pattein with uaily high anu low
-Episouic Release- secieteu in iesponse to a systemic
stimulus

*This is an episouic ielease, anu also it is biphasic!
-Sleep cycles can affect the ciicauian ihythm of
hoimone secietion. Sleep uepiivation affects
hoimone secietion in ciicauian ihythm.
Supiachiasmatic nuclei, pineal glanu, anu ciicauian
genes iegulate ciicauian ihythm.

-Coitisol is highest in the moining when we wake up
anu uecieases thioughout the uay

-Nelatonin is highest at night

-uB is highest at night! impoitant foi chiluien
! Bigh in stienuous exeicise
-Without sleep ! uecieaseu coitisol, piolactin, anu
uB & incieaseu TSB causing incieaseu thyioiu
activity








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-Boimones can seciete in moie than one type of
pattein ! All have pulsatile mannei except thyioiu
since it has to be constant foi metabolism
-Bypothalamic-Pituitaiy-Auienal axis
-ACTB- ciicauian in pulsatile mannei
-Coitisol- ciicauian in pulsatile mannei
With acute stiess:
-ACTB anu Coitisol ! episouic
to stimulate auienal glanus
With chionic stiess
-ACTB levels inciease leauing to
incieaseu Coitisol

Amount of hoimone available is uepenuent on
amount 6%&(8)0( by the enuociine glanu, amount
that is ?<%00@ to binu to ieceptois foi cellulai
iesponse, amount that is 4&8#( to seium pioteins,
amount of time the hoimone is active in ciiculation
anu able to cause an effect (;/+<A+*<0), anu the amount
(0,%/(0( into weakei metabolites that may oi may
not be active.

*All peptiues aie "fiee" except IuF-1 & uB
*All pioteins in hypothalamic-pituitaiy axis aie
pioteins (in the biain basically!)
ueneial Functions of Bounu Pioteins
-Bounu hoimones aie piotecteu fiom enzymatic
bieakuown anu ienal excietion
-Binuing pioteins buffei the concentiation of fiee
hoimones
-Binuing piotein-hoimone complexes follow
Nichaelis-Nenton kinetics


Boimone-Albumin complex acts as shuttle system
-The complex uissociates easily!is bioavailable
-Boimone is available at cellulai ieceptois taiget
-Complex is a ueliveiy system to taiget tissues


Boimone-specific binuing globulins binu hoimones
with high affinity to cieate a ieseive
-Anuiogens anu Estiogen
! Sex hoimone binuing globulin (SBBu)
-Coiticoius anu Piogesteione
! Coiticoiu binuing globulin (CBu)
-Thyioiu hoimones
! Thyioiu binuing globulin (TBu)

-The livei metabolizes hoimone-Boimone-binuing
globulin complexes anu a majoiity of them aie
conjugateu with ,+8)8%&#*(0 oi 78+</$0.


*ulobulin-binuing inciease leaus to less availability!
The site, iate, anu amount of hoimone uegiauation
ueteimine the iesponse
-Enuothelial cells uo the majoiity at site of
uegiauation
-Begiauation happens in bloou vessels in the
livei, kiuney, lung, anu taiget tissues
piimaiily. BC*D0% /#( E*(#0- /%0 3/*#F
-Local uegiauation uecieases systemic
effects
-Local piouuction, local action, anu local
uegiauation aie impoitant foi a piopei
localizeu effect.

-Nost hoimones uegiaueu by livei oi kiuney
-Bioactive peptiues may be inteinalizeu anu uegiaueu
locally
-2/G&%*$- &< 30$/4&+*$07 ! 4*+0 &% )&#G8,/$0( /#(
0H)%0$0( 4- I*(#0- *# $;0 8%*#0

2J5= metabolic cleaiance iate = total iate of
iemoval of a hoimone
:/+<A+*<0= the time foi a compounu to lose V of its
functional activity

2 Extiemes:
1-Bigh NCR anu Shoit Balf-life- biomolecule is
stoieu, oi the bouy is constantly piouucing the
hoimone
2-Low NCR anu Long Balf-life- biomolecule is ieauily
available anu the bouy neeus to stoie oi piouuce less

K0#0%/+ 58+07 &< ;/+<A+*<0 &< 4*&3&+0)8+07
1-C&)/++-A/)$*#, 4*&3&+0)8+07 ;/D0 7;&%$ ;/+<A+*<0
(80 $& %/6*( 4*#(*#, /#( 30$/4&+*73 &< +&)/++-A
6%&(8)0( (0,%/(*#, 0#L-307
2-=3/++ 606$*(07 /%0 +&)/+ /#( ;/D0 7;&%$07$ ;/+<A
+*D07 $-6*)/++-
S-Bypothalamic hoimones have shoit half-lives
4-:-(%&6;*+*) 4*&3&+0)8+07 ;/D0 7;&%$0% ;/+<A+*<0
7*#)0 ;-(%&6;&4*) 4*&3&+0)8+07 $-6*)/++- 4*#( $&
70%83 6%&$0*#7M N;*); 0H$0#(7 ;/+<A+*<0
S-Piohoimones anu metabolites typically have longei
half-lives than active biomoleculehoimone



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Plasma concentiation of hoimones
-Nost hoimones levels aie low
-Boimone-binuing plasma pioteins uo not contiibute
to biological effect, since the complex neeus to
uissociate befoie enteiing tissue
-Fiee hoimone, not total concentiation ueteimines
the biological effect

Plasma level uepenus on:
-Rate of hoimone secietion
AO3&8#$ &< 4&8#( ;&%3&#0PP
-Rate of metabolizeuexcieteu hoimone
*Beficiency in binuing uoes not affect hoimone
activity, since only fiee hoimone has biological effect

-Piotein binuing piotects hoimone fiom enzyme
uegiauation
-Total, fiee, anu bounu hoimone can be measuieu
-Binuing piotein can be measuieu too
-Piotein binuing is impoitant foi thyioiu anu steioiu

Test foi measuiing hoimone levels iequiie high
!"#!$%$&$%' anu high !(")$*$)$%' ! O#$*4&(*07
! Q*#( ;&%3&#0 /#( *,#&%0 &$;0%7

5/(*&*338#&/77/- B3/*#+- <&% ;&%3&#07F
-Auu patient seium to antibouy anu iauiolabeleu
hoimone complex
-Rauiolabeleu hoimone is uisplaceu by hoimone in
patient's seium
-Boimones aie sepaiateu fiom complexes
-Neasuie iauioactive (fiee) hoimones= measuiement

=/#(N*); O77/- /#( 'C"=O B3/*#+- <&% 6%&$0*#7F
-Immobilize an antibouy to test tube oi beaus in test
tube
-Auu patient's bloou, then wash. The patient's piotein
shoulu binu to stationaiy antibouy
-Auu the iauiolabeleu antibouy to test tube. The
seconu antibouy must binu to BIFFERENT iegion of
piotein.
-Neasuie the iauioactivity oi enzyme activity
*ELISA= enzyme-linkeu immunosoibent assay

-Testosteione anu Coitisol aie synthesizeu fiom
cholesteiol mainly in specializeu enuociine glanus
-What kinus of ieactions have to take place in
these enuociine glanus to conveit cholesteiol into
coitisol oi testosteione. Reau auienal biochem

-Steioiu hoimones, thyioiu hoimones, ietinoic aciu,
calcitiiol, anu uietaiy lipius binu to intiacellulai
ieceptois to become tiansciiption factois

-Thyioiu hoimones: Inciease metabolic iates anu
have uevelopmental effects
-Thyioxine (T4)
-Tiiiouothyionine (TS)

Paiaciine agents: Piostaglanuins
-Piecuisoi is Aiachiuonic aciu
-Cyclooxygenase auus a cyclic iing anu auus oxiuases
to foim piostaglanuins (PuE2, PuF2)

Catecholamines
-Act as hoimones anu neuiotiansmitteis
-Epinephiine ! auienal meuulla piouuces
-Bopamine ! biain piouuces

Catecholamine synthesis:



Catecholamine inactivation:

-Taken back up into neive teiminal in high-affinity
Na+ cotianspoit, then enzyme activation occuis.
Two enzymes complete iest anu can act in sequence
1-Nonoamine oxiuase (NA0) uoes oxiuative
ueamination in the neive teiminal
2-Catechol-0-methyltiansfeiase (C0NT) methylates






Peptiue anu Piotein Boimones
-Synthesis: secietoiy pathway
-Ribosomal synthesis, post-tianslation,
vesiculai stoiage, anu exocytosis

.*$8*$/%- ;&%3&#07 /%0 606$*(07 /#( 6%&$0*#7
1-Posteiioi pituitaiy glanu (neuiohypophysis)
-Posteiioi pituitaiy glanu's neuial tissue axons aie
connecteu to neuional cell bouies in the
hypothalamus
Small Peptiues piouuceu by hypothalamus:
-0xytocin- uteiine contiaction at biith anu
milk ejection
-Antiuiuietic hoimone (ABB, vasopiessin)-
antiuiuiesis as a tonic effect (v2 ieceptois),
anu vasoconstiiction (v1 ieceptois) at
highei concentiations uuiing hypovolemia

Synthesis of vasopiessin anu 0xytocin
-Site of synthesis: neuiosecietoiy neuions in the
hypothalamus.
-Piohoimone piocessing: both hoimones aie pait of
piecuisoi that is cleaveu by specific pioteases

2-Anteiioi pituitaiy glanu (auenohypophysis)
(glanuulai tissue)
Small Peptiues:
-Auienocoiticotiopic hoimone (ACTB)
ulycopioteins:
-Thyioiu stimulating hoimone (TSB)
-uonauotiopins: Luteinizing hoimone (LB),
Follicle-stimulating hoimone (FSB)
Pioteins:
-uiowth hoimone: uiowth, metabolic effects
-Piolactin: Lactation
Synthesis of ACTB anu NSB (Nelanocyte stimulating)
-Synthesizeu fiom pio-opiomelanocoitin (P0NC)

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Pancieatic Boimones- contiolleu by nutiients mainly
-K+8)/,&#- ieleaseu by alpha-cells uuiing fasting anu
acts on livei to stimulate glucose piouuction when
sugai is low (gluconeogenesis, glycogenolysis)
-"#78+*#- ieleaseu by beta-cells aftei a meal in
iesponse to elevateu bloou glucose anu amino acius.
Stimulates pathways that consume glucose anu othei
amino acius (glycogenesis)
-=&3/$&7$/$*#- ieleaseu by uelta-cells anu have
unknown effects. Naybe have paiaciine effects on
glucagon anu insulin secietion. (inhibition)

*Insulin synthesis

-(Pie)pioinsulin is synthesizeu at the iough ER
-Signal sequence is iemoveu uuiing iibosomal
synthesis
-Teitiaiy stiuctuie foims spontaneously
-Bisulfiue bonus foim in ER
-Enuopeptiuase (piohoimone conveitase) cuts out
C-Peptiue
-'R8*3&+/% /3&8#$7 &< *#78+*# /#( JA606$*(0 /%0
%0+0/70(
-C-peptiue has no known hoimonal effects

*Clinically! Test foi C-peptiue in patients so they uo
not have to get off insulin meuication to get ieal
measuiement of self-piouuction of insulin





*Neisenbeig talkeu about Renin-Angiotensin System
-veiy stiaightfoiwaiu. Review Renal block if anything
-ACE inhibitois aie useu foi antihypeitensive uiugs,
but iemembei that bieakuown of biauykinin is
inhibiteu ! vasouilation



































































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Piostaglanuins
-Not hoimones ! foimeu fiom lipius in all tissues &
act as shoit-liveu paiaciine anu autociine
messengeis


Substiates foi Piostaglanuin Synthesis (2u C FAs)
-O%/);*(&#*) /)*( (most impoitant since abunuant)
!0mega-6 Fatty aciu
-Eicosatiienoiu aciu ! 0mega-6 Fatty aciu
-Eicosapentaenoic acius ! 0mega-S Fatty aciu

.;&76;&+*6/70 O> libeiates aiachiuonic aciu fiom
membiane lipius

Cyclooxygenase ieaction piouuces PuB2


*Remembei that piostaglanuins have 2u caibons,
caiboxyl gioup, anu a iing
*Subsciipt inuicates the numbei of uouble bonus
outsiue the iing anu Capital lettei inuicates the type
of piostaglanuin
P.K"> S .%&7$/)-)+*#
J-)+&&H-,0#/70 &))8%7 *# > *7&<&%37
C0X-1! most tissues, piesent all the time
C0X-2 ! Inuucible, mainly in leucocytes anu some
othei tissues ! inflammation meuiatoi

S foims of PuE:
1-Eicosatiienoic aciu ! PuE1
>AO%/);*(&#*) /)*( ! .K'>
S-Eicosapentaenoic aciu ! PuES

.%&7$/,+/#(*# /)$*&#7T "36&%$/#$ &#07 $& I#&N
1-Platelet aggiegation (TXA2)
2-vasouilation (PuE2, PuI2)! iaise cANP level
S-0teiine contiaction (PuE2, PuF2alpha)
! Similai to oxytocin, but oxytocin ieceptois
aie only piesent at enu of gestation foi laboi.
Piostaglanuin ieceptois aie always piesent anu can
facilitate aboition oi help with uteiine bleeuing
4-Inflammation (PuE2, TXA2)! vasouilation + WBC
iesponse to meuiate pain at neive enuings anu
swelling
S-Fevei (PuE2)!acts in pieoptic aiea foi
theimoiegulation
6-Reuuceu gastiic aciu secietion, enhanceu mucus
foimation (PuE2) ! Remembei that NSAIB use can
uamage gastiic mucosa
*PuE! Think Bilation, PuF! Think Constiiction
.%&7$/,+/#(*#7 4*#( U KA6%&$0*# %0)06$&%7

-Piostacylin is a thiomboxane antagonist that
uecieases Ca2+
-In clotting, platelet is in uamageu epithelium wo
piostacyclin ! Thiomboxane is bettei at incieasing
Ca2+ in the platelet

Effects of piostaglanuins as uiugs
1-Rapiu metabolism of natuial piostaglanuins anu
some synthetic analogs aie metabolically moie stable
2-Nultiple effects on many oigan systems, so injecteu
piostaglanuin = systemic effects

Lipoxygenase pathway
-Seveial lipoxygenases make biologically active
polyunsatuiateu fatty acius ! 3&7$ *36&%$/#$ *7
VA+*6&H-,0#/70
-Piouuces 2u-caibon acius without a iing stiuctuie
-Leucotiienes aie faiily stable & long living
***Leucotiienes contiact bionchial smooth muscle
anu contiibute to asthma ! coiielate with
pieunisone tieatment foi asthma!!!


Eicosanoius: Phaimacology
-Antiinflammatoiy steioius (glucocoiticoius) inhibit
the phospholipase A2 ! foimation of piostaglanuins
anu leucotiienes (affect immune system) is ieuuceu
-NSAIBs- inhibit C0X 12both anu foimation of
piostaglanuins, but N0T leucotiienes
-Reuuce inflammation, pain, fevei, platelet
aggiegation, anu thiombus foimation
*Cause gastiitis anu peptic ulcei anu aie
contiainuicateu in asthma ! Pus aie goou,
leukotiienes aie bau in asthma

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"36/)$ &# W8$)&307

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A90<*#0 / X#0/% 3*77Y
AC*7$ $;0 Z&8% :/4*$7 &< :*,;+- '<<0)$*D0 .;-7*)*/#7
A"(0#$*<- $;0 <&++&N*#, *# / )+*#*)/+ D*,#0$$0
A'+*)*$*#, $;0 6/$*0#$@7 60%760)$*D0
A903&#7$%/$*#, 036/$;-

Neai Niss
-In meuicine, a neai miss is any event when an eiioi
coulu have iesulteu in haim oi ueath, but uiun't uue
to a coiiection to the eiioi oi the eiioi not causing
haim

Nalpiactice= eiioi anu the bau outcome that iesults
in injuiy, uamage, oi loss (impiopei oi negligent
tieatment)

S Coie Components of RCC
1-Ninuful Piactice: 50R8*%07 [ :/4*$7
1-Attentive obseivation
2-Ciitical cuiiosity anu couiage to see
thiough own weaknesses
S-A fiesh eyeminu
4-Piesence! unuistiacteu compassionate
attention to the peison anu the task at hanu
2-Foimation
1-Chaiactei ! "thieau you follow."
2-Babits-
*4 Babits of highly Effective Physicians play a iole in
the foimation of a physician, but they essentially aie
the coie component of communication skills
A[ :/4*$7 &< :*,;+- '<<0)$*D0 .;-7*)*/#7

S-Relationships
"The thieau" helps pievent buinout
-Compassion anu empathy aie two fiist qualities to
uiminish when a physician suffeis buinout
S-Communication skills

:/4*$ 1T "#D07$ *# $;0 40,*##*#,
-2 simple, not easy, skills
1-Elicit all of the patient's conceins in the beginning
of visit
2-Bon't inteiiupt

:/4*$ >T '+*)*$ $;0 ./$*0#$@7 .0%760)$*D0
-Basis of physician-patient collaboiation
-Ask the patient's iueas
-Iuentify the patient's goals foi the visit
-Exploie the impact on the patient

:/4*$ \T 903&#7$%/$0 '36/$;-
-Empathy is the act of coiiectly acknowleuging the
emotional state of anothei without expeiiencing that
state oneself
-Selfiiuge mentioneu that we cannot let empathy tuin
into sympathy. We shoulu nevei have to take caie of
ouiselves while taking caie of a patient, anu the
patient shoulu ceitainly nevei have to caie foi us as
uoctois in a meuical settingvisit.
-Empathy useu to be lookeu uown upon in the last
geneiation! "iemain uetacheu anu have neutial
empathy foi accuiate uiagnosis- Aiing anu Blumgait"
-Eviuence says otheiwise about empathy anu it helps
iesult in moie thoiough uiagnoses, patient
auheience, patient satisfaction anu tiust, anu
impioveu patient physiology anu uisease outcomes

Who uo you finu most uifficult to ueal with. Suivey
Patients that aiecannot
-Bostile oi angiy
-Not following instiuctions
-Too uemanuing oi neeuy
-Besciibe hishei symptoms
-Asking too many questions

Suggestions of cultivating empathy in leaineis
1-Tell stoiies in gioups
2-Stait awaieness gioups
S-Begin eaily in tiaining
4-Faculty uevelopment anu moueling
S-Liteiatuie anu aits
6-Piactice the skills neeueu anu involveu anu KN0W
B0W T0 BIFFERENTIATE ENPATBY ANB
SYNPATBY


















































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:*7$&+&,- ./,0 1

907)%*40 $;0 +&)/$*&# /#( 034%-&#*) &%*,*#7 &<
6*$8*$/%- ,+/#( B;-6&6;-7*7F
-Pituitaiy glanu is locateu in Sella Tuicica of Sphenoiu
bone in the cianium
-Attacheu to hypothalamus by infunuibulum
2 lobes
1-Auenohypophysis is ueiiveu fiom oial ectoueim
! Foimeu by Rathke's pouch
2-Neuiohypophysis is ueiiveu fiom neuial ectoueim
!Extension of hypothalamus (uiencephalon)
^/30 $;0 (*D*7*&#7 &< $;0 6*$8*$/%- ,+/#(
1-Aueno
-Pais uistalis (anteiioi pituitaiy)
-Pais tubeialis
-Pais inteimeuia
2-Neuio
-Pais neivosa (posteiioi pituitaiy)
-Infunuibulai stem
-Neuian eminence


^/30 $;0 )0++ $-607 *# 0/); 6*$8*$/%- (*D*7*&# /#(
*#(*)/$0 /#- );/%/)$0%*7$*) 7$/*#*#, 6%&60%$*07M
*338#&)-$&);03*7$%-M /#( '_2_ 6*)$8%07
PP=$/*#*#, %0<0%7 $& ,%/#8+07 #&$ )-$&6+/73
Pais Bistalis (Anteiioi Pituitaiy)
1-Chiomophils
ZCO` .*K! Z=:M C:M OJ`:M `=:M .%&+/)$"#M K:
-Aciuophils anu Secietions
1) Somatotiophs! uB (somatotiopin)
2) Nammotiophs ! Piolactin
-Basophils anu Secietions
PQAZCO`! Q/7&6;*+7!Z=:M C:M OJ`:M `=:
1) Thyiotiophs ! TSB
2) Coiticotiophs ! ACTB, LPB, NSB,
enuoiphins anu enkephalins
(All piouuceu thiough post-tianslational
mous of P0NC)
S) uonauotiophs ! FSB anu LB
2-Chiomophobes ! no cytoplasmic staining
S-Folliculostellate cells- have long piocesses anu
pioviue a netwoik of inteicommunication anu
suppoit to paienchyma
Immunohistochemistiy
-Piecise iuentification of enuociine cells in the
auenohypophysis by using specific antibouies to
show hoimone content

Pais Tubeialis
-Q/7&6;*+*) cells contain secietoiy gianules of Z=:
anu C: ! No secietion though!
Pais Inteimeuia
-Ruuimentaiy in humans
-Contains colloiu-filleu follicles (Rathke's cysts) lineu
by small 4/7&6;*+*) cuboiual shapeu cells that can
piouuce .W2J. Pais uistalis secietes P0NC
piimaiily.

C*7$ $;0 6*$8*$/%- ;&%3&#07M *#(*)/$*#, <&% 0/);
$;0 (*D*7*&# /#( )0++ $-60 &< &%*,*#M /#( $;0 $/%,0$
&< $;0 ;&%3&#0

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)&#$%&++*#, 6*$8*$/%- ,+/#( <8#)$*&#
1-TRB ! TSB ! T4 + TS
2- CRB ! ACTB ! ulucocoiticoius
S-unRB ! FSB ! Estiogen (ovaiy)
FSB ! Seitoli cells (testis)
LB ! matuiation, ovulation, anu coipus
luteum foimation
LB ! Leyuig cells of testis (testosteione)
4-uRB(SRB) ! uB ! Somatoceuin C (IuF1)
S- Somatostatin ! uecieases uB
6- Bopamine ! uecieases piolactin


907)%*40 $;0 4+&&( 7866+- $& $;0 6*$8*$/%- ,+/#(
/#( *$7 %&+0 *# 6*$8*$/%- <8#)$*&#


Stimulation of anteiioi pituitaiy glanu:
1-Bypothalamus secietes ieleasing hoimones into
piimaiy capillaiy plexus at meuian eminence
2-Inteinal caiotiu aiteiy ! supeiioi hypophyseal
aiteiy ! piimaiy capillaiy plexus ! hypophyseal
poital veins ! seconuaiy capillaiy plexus of pais
uistalis (fenestiateu capillaiies)
-Boimones go fiom seconuaiy capillaiy plexus to
influence cells of pais uistalis
-Pais uistalis secietes into anteiioi hypophyseal
veins
-Bloou fiom pituitaiy uiains into caveinous sinus

'H6+/*# $;0 %&+0 &< $;0 #0,/$*D0 <00(4/)I *#
6*$8*$/%- ,+/#( <8#)$*&#

See negative feeuback pathway foi uB in Physiology
notes
Negative Feeuback Pathway foi hypothalamus anu
thyioiu glanu
-TS anu T4 iegulate hypothalamus anu pituitaiy
glanu in long-loop feeuback






Neuiosecietoiy
Neuions foi
Pais uistalis
Bypothalamo-
Bypophyseal tiact fiom
paiaventiiculai
Anu supiaoptic nuclei
.*$8*$/%- K+/#( ] :-6&$;/+/387
:*7$&+&,- ./,0 >

9*7$*#,8*7; 40$N00# $;0 #08%&;-6&6;-7*7 /#(
$;0 /(0#&;-6&6;-7*7 /#( *(0#$*<- $;0*%
784(*D*7*&#7M 7*#87&*(7M /#( )0++ $-607 *# /
3*)%&,%/6; &< $;0 6*$8*$/%- ,+/#(

Pais Neivosa (Posteiioi pituitaiy)
-No secietoiy cells
-Bas ."`a"Jb`'= anu many unmyelinateu axons of
neuiosecietoiy neuions that come fiom
hypothalamus anu teiminate neai capillaiies
-Pituicytes aie glial cells with the piotein glial
fibiillaiy aciuic piotein anu show chaiacteiistics of
astiocytes. They suiiounu axons of the
neuiosecietoiy cells anu contact the basal lamina of
the fenestiateu capillaiies
-:0%%*#, 4&(*07 contain hoimones (0T & ABB)
maue by the hypothalamus anu theii caiiiei piotein-
neuiophysin. Beiiing bouies aie useu foi stoiage in
the pais neivosa anu aie containeu in uilations of the
unmyelinateu axons
-Bypothalamus secietes into the hypothalamo-
hypophysial tiact to get hoimones to pais neivosa
-Paiaventiiculai nucleus ! piimaiily 0T
-Supiaoptic nucleus ! piimaiily ABB





Immunohistochemistiy Sliue

Cells of Pais uistalis































.;-7*&+&,- &< $;0
:-6&$;/+/3*)A.*$8*$/%- OH*7 ./,0 1


-C*40%*#= ieleasing hoimone (i.e.- TRB)
-=$/$*#= inhibiting hoimone (i.e.-uopamine)
-`%&6*) ;&%3&#07- act on anothei enuociine glanu
-^&#A$%&6*) ;&%3&#07A uiiectly act on taiget cell

*Bopamine is not a peptiue ! Catecholamine!
*ACTB is iesult of post-tianslational piocessing of
P0NC ! Also piouuces melanocyte stimulating
hoimones (alpha, beta, gamma). So, CRB stimulates
the piouuction of P0NC anu ielease of P0NC ueiiveu
peptiues
Chaiacteiistics of Bypothalamic Boimones
1. Secieteu in pulses
2. Binu to membiane bounu ieceptois as 1
st

messengeis
S. Stimulate ielease of stoieu anteiioi pituitaiy
hoimone
4. Stimulate synthesis of anteiioi pituitaiy hoimone
S. Nay iegulate post-tianslational piocessing of
anteiioi pituitaiy hoimones
6. Nay iegulate own ieceptois
7. Inuuce ;-60%6+/7*/ anu ;-60%$%&6;- of taiget
cells. K%&N$; S ;-60%6+/7*/ /#(c&% ;-60%$%&6;-
Z00(4/)I C&&67


a+$%/7;&%$ +&&6- hypothalamic ieleasing factoi is
secieteu anu feeus back on itself to iegulate its own
piouuction ! Can be positive oi negative
-Najoiity of ultiashoit loop feeuback loops
aie seen in abnoimalheighteneu
physiological states
I.E! Fight oi Flight, CRB has positive effect
on ultiashoit feeuback loop to hypothalamus
-0ltiashoit loops tenu to be shoit liveu oi
pathological anu uoes not exist in CBR0NIC
states

=;&%$ C&&6- Pituitaiy hoimones iegulate the ielease
of the hypothalamic-ieleasing hoimone
! Pieuominantly negative iegulatois
*EXCEPTI0N
-Piolactin is the exception since it is unuei tonic
inhibitoiy contiol of uopamine
-Piolactin anu Bopamine have inveise ielationship


:-6&6%&+/)$*#03*/
! a78/++- 70)&#(/%- $& 6*$8*$/%-
-"Piolactin Beficiency"
-Sexual Bysfunction in Nen anu Women
NEN'S Symptoms:
-Loss of libiuo
-Infeitility uue to ieuuceu speim count anu
ieuuceu testosteione


W0NEN'S Symptoms:
-Belayeu pubeity
-Nenstiual uisoiuei
-Infeitility
-Subfeitility
-Alactogenesis oi inauequate lactation
:-60%6%&+/)$*#03*/ B50(8)0( 9&6/3*#0dddF
-Above 2ungml
-Suppiesses the ielease of unRB
-Low to low-noimal levels of FSB anu LB
NEN'S Symptoms:
-Loss of libiuo
-Eiectile uysfunction
-visual pioblems
-Beauache
W0NEN'S Symptoms:
-0ligomenoiihea
-Amenoiihea
-Infeitility

C&#, +&&6- Boimone ieleaseu fiom enuociine glanu
iegulates the ielease of hypothalamic ieleasing
factois anuoi pituitaiy hoimones
-Nost of the time is a negative loop
-9*%0)$! acts on pituitaiy glanu
-"#(*%0)$! acts on hypothalamus
*Inuiiect Long loop feeuback iequiies the molecules
to cioss the BBB, so it is sepaiateu into inuiiect anu
uiiect ! Biiect-Inuiiect feeuback has the hoimone
ciossing the BBB (i.e.-steioiusFAs), anu Inuiiect-
Inuiiect feeuback has the hoimone acting as a 1
st

messengei, oi thiough caiiiei-meuiateu
tianspoit(thyioxin), oi etc.

0nueistanuing Abnoimal Secietion!Clinically

.;-7*&+&,- &< $;0
:-6&$;/+/3*)A.*$8*$/%- OH*7 ./,0 >

Long .&7*$*D0 Feeuback loops = EXCEPTI0N
*0sually NEuATIvE
1-Nenstiual cycle
-FSB & LB stimulate Estiauiol piouuction by
uominant follicle in ovaiy, which stimulates
unRB to cause LB suige ! 0vulation
-0vulation will not occui without long loop
2-0xytocin ieflex aics
-0xytocin binus to oxytocin ieceptois
-Nyometiium uteius! Z0%,87&#
%0<+0H
-Nyoepithelial cells lining the
mammaiy alveoli ! =8)I+*#, %0<+0H
-0xytocin action stimulates the ielease of
moie oxytocin fiom the posteiioi pituitaiy
uuiing 6/%$8%*$*&# /#( 4%0/7$<00(*#,


Posteiioi Pituitaiy is consiueieu extension of
hypothalamus
-Posteiioi hoimones
-0xytocin (0T)
-vasopiessin (ABB)

-W` anu O9: aie synthesizeu in the hypothalamus
anu tianspoiteu via the hypothalamo-hypophyseal
tiact to be 7$&%0( anu 70)%0$0( fiom the posteiioi
pituitaiy

+,$-.,$/':
-Supiaoptic nucleus (S0N)! ABB
-Paiaventiiculai nucleus (PvN) ! 0T
*Both secieteu by magnocellulai neuions
*Stoieu in :0%%*#, 4&(*07 that aie uistiibuteu along
axons
0T anu ABB tiansmission & secietion:
-S0N anu PvN piouuce 0T anu ABB anu they aie
tianspoiteu in specific-caiiiei pioteins, calleu
neuiophysins, along axons to neive teiminals at
posteiioi pituitaiy lobe
-S0N anu PvN senu neive impulses to cause Ca2+
uepenuent exocytosis of 0T anu ABB fiom the
posteiioi pituitaiy

0T anu ABB aie veiy similai anu have uiffeient
amino aciu compositions at #S anu #8.
-Aig at 8 of ABB is impoitant foi antiuiuiesis
-Leucine at 8 of 0T uoes N0T iemove ALL of the
antiuiuietic capabilities ! at high levels of 0T
! Antiuiuiesis!!!

*Phaimacological coiielation ! Besmopiessin



2034%/#0A4&8#( WH-$&)*# 50)06$&% BW`5F
-u piotein coupleu ieceptoi! IPSBAu
-=3&&$; 387)+0 )&#$%/)$*&# BI0- );/%/)$0%*7$*)F
!Q%0/7$ &% 8$0%*#0 )&#$%/)$*&#
-Phospholipase C (PLC)
-Stimulates Ca2+ mobilization

e/7&6%077*# 50)06$&%7! KA6%&$0*# )&86+0(
v1 Receptoi
A=3&&$; 387)+0 )&#$%/)$*&# BI0- );/%/)$0%*7$*)F
!eO=WJW^=`5"J`"W^
-Phospholipase C (PLC)
-Stimulates Ca2+ mobilization
-IPSBAu signaling


v2 Receptoi
Af/$0% Q/+/#)0 BI0- );/%/)$0%*7$*)F
-Stimulates auenylate cyclase
-Stimulates cANP



9*/40$07 "#7*6*(87
! Excess piouuction of uiine
1) Cential
-Inability of the bouy to piouuce oi ielease
ABB
-Tumois, tiauma, suigeiy, etc.
2) Nephiogenic
-Inability of the kiuneys to iesponu to ABB
-Renal uisease, ABB-uniesponsiveness,
Biugs like lithium, etc.

Synuiome of Inappiopiiate ABB Secietion (="O9:)
-Excess ABB !Excess Watei Retention
-Excess ieleaseu by posteiioi pituitaiy oi fiom
anothei souice like a small cell caicinoma
-Restiict watei intake foi immeuiate tieatment





Stimulates
Piolactin, too, to
ieplenish milk
0teius to ueliveiy anu to
vasoconsiict vessels
.;-7*&+&,- &< K%&N$; :&%3&#0 ./,0 1

uiowth Boimone (uB)
-Regulates uiowth ! 0bvious
-Woiks with insulin-like giowth factois
(IuFs) to maintain anu stimulate giowth

K: =0)%0$*&#

=5"ZSK:":S=&3/$&7$/$*#
-uB iegulates uBRB anu SRIF in shoit-loop feeuback
& uB iegulates anteiioi pituitaiy in autociine
mannei as an ultiashoit feeuback loop
-uB stimulates ielease of IuFs fiom livei & IuFs can
iegulate uBRB anu SRIF

uB is secieteu in noimal ciicauian ihythm (pulsatile
mannei) anu in iesponse to stienuous
exeicisefasting (episouic)
-Pulsatile secietion pattein
-Incieaseu in ueep sleep!!!! ! impoitant foi
chiluien!!!!
-uB opposes insulin in acute effects on +*D0%M
387)+0M /#( /(*6&70 $*7780
-uB piouucing tumois ! insulin iesistance,
glucose intoleiance, anu may be uiabetic
-Su% bounu to uB-binuing piotein (uBBP)
-uB piomotes the mobilization of fuel stoies to
inciease plasma glucose foi tissues in neeu
-uB peaks in pubeity
-uB anu IuF1 inciease togethei in pubeity, anu both
iegulate anu maintain bouy mass in auulthoou as well
as fulfill )&360#7/$&%- ,%&N$; B*_0_A $/I0 &#0
I*(#0- &8$ /#( $;0 &$;0% ,%&N7 $& 3/$); <&%30%
3/77 &< 4&$; I*(#0-7F
P50,8+/$07 ;-6&$;/+/387 70)%0$*&# &< K:5:


Receptoi-associateu tyiosine kinases stimulate the
}AK anu STATNAPK pathways thiough
phosphoiylation
-uB binus with uB ieceptoi on hepatocytes
to stimulate secietion of IFus
P.%0(&3*#/#$+- 4*#(7 $& +*D0%M /(*6&70M ] 387)+0
Nembiane-bounu uB ieceptoi can be
metallopioteolytically cleaveu to foim uBBP
-uB ieceptoi has intiacellulai anu
extiacellulai uomains
-Seium levels of uBBP ieflect ielative uB
ieceptoi uensity ! uoes not coiielate
to uB seium level!!!
-uBBP = soluble uB ieceptoi
-Auipose tissue is piimaiy souice of uBBP
-uBBP extenus uB half-life, maikeuly
-Binus 4u-Su% ciiculating uB
-uB anu IuF aie unique, since they have BPs
*Piotein hoimones typically uo not have binuing
piotein

uB actions
-Incieases lipolysis in auipose tissue
-Reuuces ulucose uptake in muscle
-Incieases hepatic gluconeogenesis
-uI tiact hoimone! uhielin is ieleaseu piioi to meal
anu incieases uB ielease
*uB anu IuFs anu Insulin utilize glucose

IuFs meuiate the effects of uB
-IuF1 anu IuF2 aie ieleaseu fiom livei to
iegulate maintenance anu giowth of tissue
thioughout bouy
IuF1:
-IuF1=Somatomeuin C
-Regulates fetal uevelopment of pancieas
anu majoi oigans
-IuF1-null knockout is lethal foi majoiity of
mice
IuF2:
-IuF2=Somatomeuin A
-Pieuominant ciiculating IuF in auults
-IuF2 levels ueviate in uiseases
-IuF2-null knockout mice ieach matuiity
-IuF2-null knockout mice aie giowth
impaiieu but giowth iate is noimal




IuFBPs aie uynamic: tianspoit IuF anu have
enuociine & paiaciine functions, unique since
pioteins uon't tenu to have BP's anu uoes not neeu to
uissociate to have a function.

Enuociine functions of IuFBPs
"KZQ.A\! majoi caiiiei in ciiculation
IuFBP-S! stimulates enuociine function
"KZQ.A[! inhibits IuF & seium concentiation is low
"KZQ.Ag! 0nly bonus IuF2 & inhibits IuF2 action

Paiaciine functions of IuFBPs ! K%&N$; Z/)$&%7!
IuFBP-1 ! amniotic fluiu
IuFBP-2 anu -6 ! CSF
IuFBP-S ! Folliculai fluiu (fluiu suiiounuing ovum)
IuFBP-4! tissue specific anu iegulates IuF
IuFBP-S ! bone matiix

\ 50)06$&%7 4*#( "KZ7

Type 1 IuF Receptoi:
-Beteiotetiamei
-Binus IuF1 & IuF2 with high affinity
-Stiuctuially iuentical to insulin ieceptoi
-Piesent in all tissues except livei
-ACTIvE seconu messengei signaling
-Receptoi signaling:
-Intiinsic tyiosine kinase ieceptoi
-Nultiple pathways

Type 2 IuF Receptoi:
-Binus IuF2 with high affinity
-Binus IuF1 with low affinity
-Nostly INACTIvE anu Acts as cleaiance ieceptoi foi
IuF2

Insulin Receptoi:
-Binus IuF1 with N0CB lowei affinity than insulin
-IuF1 must be at veiy high level to binu to insulin
ieceptois

IuF-Insulin Receptoi Bybiiu
-Cell effects unknown
-Potential factoi oi souice in ieceptoi-
meuiateu insulin iesistance
-Bon't ieally binu anything (insulin oi IuF)


.;-7*&+&,- &< K%&N$; :&%3&#0 ./,0 >

uB-IuF axis iegulation
-uB piimaiily uoes shoit-loop feeuback
-IuFs exeit long-loop feeuback
-uBRB exeits ultiashoit loop feeuback

K:@7 $*7780A760)*<*) 0<<0)$7
=$*38+/$*&# "#;*4*$*&#
O(*6&70 -Lipolysis -ulucose uptake
C*D0%
-Piotein synthesis
-uluconeogenesis
-ulycogenolysis
-IuFs
-ulycogenesis
287)+0
-Piotein synthesis
-Amino aciu uptake
-ulycogenolysis
AK+8)&70
86$/I0
AW66&7*$0
<%&3 "KZ

*IuF typically opposes uB's metabolic effects
"KZ7 $*7780A760)*<*) 0<<0)$7
=*38+/$*&# "#;*4*$*&#
J;&#(%&)-$07
-}ust know that
it causes bone
giowth, so a lot
of synthesis anu
giowth as well
as hypeiplasia
anu
hypeitiophy

C*D0%
Not a lot of IuF
ieceptois but
uoes inhibit:
-uluconeogenesis
-ulycogenolysis
287)+0
-Piotein
synthesis
-Amino aciu
uptake
-K+8)&70
86$/I0
AW66&7*$0
<%&3 K:







0nueistanu the ielationship between IuF anu uB
-uB causes IuF secietion
-uB happens fiist to inciease plasma glucose
then IuF utilizes the glucose to iegulate
maintenance anu giowth.
-Although they oppose in glucose uptake of
muscle, IuF1 anu uB inciease piotein
synthesis in muscle
-Piomote hypeiplasia anu hypeitiophy

P5030340% $;0%0 /%0 1 K:Q. /#( g "KZQ.7

Clinical Coiielates
-uigantism
-Pituitaiy gigantism ! pie-closuie of
epiphyses
-Exaggeiateu lineai giowth that is mainly
in chiluien
-Aciomegaly
-Excessive secietion of uB uuiing auulthoou
-Enlaigement of facial stiuctuies, hanus, anu
feet
-Soft tissue swelling of oigans
-Beepeneu, slow voice fiom vocal coiu
swelling
-Pituitaiy Bwaifism
-Pie-closuie of epiphyses
-Nainly in chiluien










-Panhypopituitaiism ! occuiiing in auulthoou
-Bypothyioiuism
-Bepiesseu piouuction of glucocoiticoius in
auienal glanu
-Chionic hypoglycemia
-Fat inciease
-Piotein uecieases
-Nuscle weakness
-Eaily exhaustion
*Pictuie that of a lethaigic peison (fiom lack of
thyioiu hoimones) who is gaining weight (because of
lack of fat mobilization by uB, auienocoiticotiopic,
auienocoitical, anu thyioiu hoimones) anu has
impaiieu sexual functions.



































.*#0/+ K+/#( :*7$&+&,-

907)%*40 $;0 7$%8)$8%0M <8#)$*&#M /#( +&)/$*&# &<
$;0 6*#0/+ ,+/#(
907)%*40 $;0 034%-&#*) &%*,*# &< $;0 6*#0/+ ,+/#(
The pineal glanu uevelops fiom the ioof of the
uiencephalon anu is consiueieu a uoisal uiveiticulum
-06*6;-7*7 )0%04%*_
The pineal iecess communicates with the S
iu

ventiicle


^/30 $;0 ;&%3&#0B7F 6%&(8)0( 4- $;0
6*#0/+&)-$07



-Light stimulates the ielease of noiepinephiine,
which in tuin incieases seiotonin.
-Light uecieases N-acetyltiansfeiase (SAN), which
conveits seiotonin to an inteimeuiate in the
synthesis of melatonin
-At night, S-hyuioxy inuol 0-methyltiansfeiase
incieases (only founu in pineal glanu) anu conveits
seiotonin to melatonin.

20+/$&#*#
-O#$* ,&#/(&$%&6*) 0<<0)$ *# 3/33/+7
-Nelatonin uecieases gonaual steioiu levels by
inhibiting unRB in neuiosecietoiy neuions
! Can cause seasonal sexual activity
-Also, melatonin can stimulate uB ielease by
inhibiting somatostatin ielease


J+*#*)/+ J&%%0+/$07
Seasonal affecteu uisoiuei (SAB):
-Bepiession that is coiiecteu by biight light

}et lag:
-Nelatonin can be useu to help counteiact symptoms
of uiowsiness anu uisoiientation
!Pineal glanu aujust to suuuen changes in
uay length

Pineal glanu tumoi:
-.%0)&)*&87 6840%$- (eaily onset) if tumoi
uestioys pinealocytes &% pubeity can be
uelayeu if tumoi is maue of pinealocytes






"(0#$*<- 6*#0/+&)-$07M /7$%&,+*/+ )0++7M /#( 4%/*#
7/#( B)&%6&%/ /%0#/)0/F *# / 3*)%&,%/6; &< $;0
6*#0/+ ,+/#(

Pineal glanu is composeu of two cell types
1-Pinealocytes
-0iganizeu into coius anu clusteis
-Seciete melatonin that is conveiteu fiom seiotonin
(tiyptophan is the piecuisoi)
-Nelatonin is highest at night
-Light uecieases melatonin synthesis
-Responsive to uiuinal (uaily) light anu uaik peiious
-Pinealocytes have one oi two long cytoplasmic
piocesses with bulbous expansions that teiminate
neai fenestiateu capillaiies
P5*44&#7 /%0 (0#70 $848+/% 7$%8)$8%07 $;/$
</)*+*$/$0 0H&)-$&7*7 /#( 0#(&)-$&7*7 &< D07*)+07
/#( J/>h );/##0+ 6&7*$*&#*#, *# %076&#70 $&
,%/(0( 6&$0#$*/+7_ Z/7$ /#( 787$/*#0(
#08%&$%/#73*77*&#d

2- Neuioglial Cells
-Act like inteistitial cells

-The pineal glanu has 4%/*# 7/#(, also iefeiieu to as
)&%6&%/ /%0#/)0/
AJ&#$/*# J/.W[ /#( J/JW\ 6%0)*6*$/#$7
-Appeai in chiluhoou anu inciease with age
Aa70( /7 / %/(*&+&,*)/+ 3*(+*#0 3/%I0%

`;-%&*( K+/#( :*7$&+&,-

907)%*40 $;0 7$%8)$8%0M <8#)$*&#M /#( +&)/$*&# &<
$;0 $;-%&*( ,+/#(

P.$ 3/- ;/D0 / 6-%/3*(/+ +&40
-The thyioiu glanu is composeu of thyioiu follicles
anu paiafolliculai (C cells) cells

Thyioiu Follicle Cells
-Folliculai cells cieate a lumen calleu a follicle that is
full of colloiu (gelatinous mateiial)
! Stoies hoimones
-Follicles aie lineu by simple epithelium
-Cuboiual ! Noimal
-Squamous ! Inactive
-Columnai ! Stimulateu

Paiafolliculai cells (C cells because they aie cleai)
-Beiiveu fiom Neuial ciest cells that migiateu to
ultimobiachial bouy in the 4
th
phaiyngeal pouch, then
to the thyioiu glanu (supeiioi paiathyioiu is 4
th

pouch ueiivative)
-Seciete calcitonin that acts on osteoclasts
-Inhibits bone ieabsoiption
-Incieases Ca2+ ietention by bones
-Becieases Ca2+ anu P04- bloou levels
-Incieaseu Ca2+ level in seium causes
incieaseu calcitonin anu uecieaseu PTB

907)%*40 $;0 034%-&#*) &%*,*# &< $;0 $;-%&*(
,+/#(
-Foims at the foiamen cecum on the ueveloping
tongue of cephalic uI tiact. (Enuoueim)
-Bescenus in the miuline as a bilobeu uiveiticulum
anu is connecteu to thyioglossal uuct uuiing
migiation
-Thyioglossal uuct can peisist as a cyst oi a sinus that
communicates with the suiface of neck.
!Nainly founu close to miuline
^/30 $;0 ;&%3&#07 6%&(8)0( 4- $;0 $;-%&*( /#(
6/%/<&++*)8+/% )0++i Z&% 0/); ;&%3&#0M *(0#$*<- $;0
)0++ $-60 %076&#7*4+0 <&% *$7 70)%0$*&# /#(
%0,8+/$*#, </)$&%7

Thyioiu Follicles Seciete:
-Tiiiouothyionine (TS)
-Tetiaiouothyionine (T4)
C Cells Seciete:
-Calcitonin

Regulation:
Level of iouine ! hinueis synthesis
! Bypothyioiuism
! Thyioiu hypeitiophy fiom TSB inciease
in negative feeuback loop. TSB binuing to
TSB ieceptois can solely cause thyioiu
hypeitiophy
! Calleu Iouine ueficiency uoitei oi Enuemic
uoitei

Bisoiueis:
-Cietinism- hyposecietion of thyioiu hoimones
uuiing fetal life oi infancy
! Bwaifism since T4 anu uB woik
syneigistically in bone foimation
! Nental ietaiuation

-uiaves Bisease- thyioiu hypeifunction fiom
immunological uysfunction. Autoantibouies binu to
TSB ieceptois causing elevateu thyioxine levels
! Exophthalmos (bulging eye)
! Enlaigeu thyioiu glanu

`%/)0 $;0 7$067 *# $;0 7-#$;07*7M 7$&%/,0M /#(
70)%0$*&# &< ;&%3&#07 4- $;0 $;-%&*(@7 <&++*)8+/%
)0++7
O<$0% `=: 4*#(7 $& `=: %0)06$&% &# 4/7/+ 7*(0T
1-Thyioglobulin (TuB) is synthesizeu in thyioiu
folliculai cell's RER anu golgi system with tyiosine
2-Iouiue is tianspoiteu into folliculai cell by a Na+I-
ATPase-uepenuent sympoitei. Iouiue is oxiuizeu to
iouine by 60%&H*(/70 in the apical membiane anu
shuttleu out via 60#(%*#
S-Iouination anu coupling of NIT anu BIT foim TS
anu T4 in the colloiu. BIT +NIT= TS, BIT+BIT= T4
BIT= Bi-iouotyiosine, NIT=Nono-iouotyiosine
4- TSB stimulates secietion
S-Iouine-conjugateu TuB is pinocytoseu via ieceptoi
meuiation. 2 uiffeient intiacellulai pathways to
basilai membiane siue
1-Lysosomal pathway- TuB is uegiaueu into
amino acius, caibs, fiee NIT, fiee BIT, TS,
anu T4 anu ieleaseu into cytosol. NIT anu
BIT aie ieuseu while TS anu T4 aie
exocystoseu on basilai siue into capillaiies
(majoi pathway)
2- Tiansepithelial pathway- conjugateu TuB
is tianspoiteu uiiectly to basilai siue aftei
binuing to 30,/+*#, which is a
tiansmembiane piotein.
!high TSB causes megalin to binu to laige
amounts of TuB causing TS anu T4 ieuuction

"(0#$*<- $;0 <&++*)+07M <&++*)8+/% )0++7M 4/7030#$
3034%/#0M )&++&*(M )/6*++/%*07M /#( 6/%/<&++*)8+/%
)0++7 *# / 3*)%&,%/6; &< $;0 $;-%&*( ,+/#(


`;-%&*( Q*&);03*7$%-

=-#$;07*7 &< `;-%&*( ;&%3&#07
-TS anu T4 aie synthesizeu fiom piotein-bounu
tyiosine anu iouine
-2 BITs = T4 & BIT + NIT = TS
BIT= Bi-iouotyiosine
NIT=Nono-iouotyiosine
*Thyioglobulin is stoieu in the thyioiu glanu in the
colloiu anu has a supply sufficient foi S months
! Boes not stoie TS oi T4!!!!


`%/#76&%$ &< $;-%&*( ;&%3&#07
Thyioiu hoimones aie bounu non-covalently to
plasma pioteins
-Thyioxine-binuing globulin (TBu)
! Najoiity
-Tiansthyietin! Binus vitamin A too
-Albumin

Steioiu hoimones aie piotein-bounu too
-Tianscoitin! ulucocoiticoius
-Sex hoimone binuing globulin! estiogen
anu anuiogen
*Biological activity of hoimone is piopoitional to
level of unbounu hoimone, N0T total hoimone
TBu ueficiency ! no clinical signs

`/%,0$ $*7780 30$/4&+*73 &< `\ /#( `[
-Thyioiu piouuces moie T4 than TS, but TS is moie
biologically active. Nost TS piouuceu by othei tissues
-TS is moie potent than T4 since TS has highei
affinity foi ieceptois
-T4 is bounu moie tightly in bloou than TS
-Nost of thyioxine is piotein bounu in bloou
-T4 is activateu at taiget tissue to TS oi inactivateu to
ieveise TS

-T4 is conveiteu to TS oi ieveise TS (iTS) in taiget
tissues anu uepenus on the iouinase in taiget tissue

Thyioiu action on taiget tissue:
1-Bissociates fiom binuing piotein
2-Caiiiei biings hoimone into cell
S-Receptoi is zinc-fingei piotein that usually
suppiesses tiansciiption without hoimone but
enhances it when hoimone is piesent
4-Conveision occuis in cell!TS
S-TS will binu to nucleai ieceptoi
-Bighei affinity than T4!

.*$8*$/%-A$;-%&*( <00(4/)I B+&#,A+&&6F


O)$*&#7 /#( <8#)$*&#7 &< $;-%&*( ;&%3&#07
-Nain effect is incieaseu metabolic iate
! incieaseu ATPase activity

- Appetite
A =&(*83A6&$/77*83 O`./70
A J/+)*83 O`./70
- Piotein synthesis anu uegiauation
- Lipogenesis anu lipolysis
- Plasma fiee fatty acius
- Futile cycling in caibohyuiate metabolism
- 0ncoupling pioteins ! Beat geneiation




0thei Effects:
- Biain matuiation
- Stimulation of bone giowth (syneigistically wuB)
- Beait iate
- N0 piouuction! Peiipheial vasculai iesistance
- Nental aleitness
- Sensitization to many -auieneigic effects.
-Beait, kiuneys, anu auipose tissue

TS iegulation
-TS is iegulateu mostly with ieveise TS in the taiget
tissues
-TS is uecieaseu anu TS:T4 iatios uecieases in
piolongeu fasting
-Colu exposuie incieases TSB secietion in infants
only anu incieases TS foimation in muscle anu
auipose tissue in all ages

"36&%$/#)0 &< (*0$/%- *&(*#0
-Na+I- ATPase-uepenuent sympoitei can be
inhibiteu by thiocyanate that is in cabbage anu othei
inoiganic anions

Bypothyioiuism
Seveie hypothyioiuism = Nyxeuema in auults
-Reuuceu metabolic iate
-Subcutaneous euema
*Nainly causeu by autoimmune thyioiuitis (thyioiu
glanu is the piimaiy souice of hypothyioiuism in
most cases too). Can be causeu by iouine ueficiency,
thyioiu suigeiy, exposuie to iauioactive iouine

















.;-7*&+&,- &< `;-%&*( K+/#( ./,0 1

TSB stimulates:
-Iouiue pump
-Iouination of tyiosine substiate in TuB
-Pioteolysis of TuB
-Bypeitiophy of thyioiu cells
-Piouuction of TS anu T4

T4 is conveiteu to TS by S uiffeient types of tissue-
specific ueiouinases (T4 is a piohoimone foi TS)

Type 1 Beiouinase
AC*D0% /#( E*(#0-
-Piimaiily iesponsible foi T4 to TS conveision
A.8$7 *$ 4/)I *#$& 7-7$03*) )*%)8+/$*&# /7 `\

Type 2 Beiouinase
AQ%/*#M 6*$8*$/%-M 4%&N# /(*6&70 $*7780
-Conveits T4 to TS intiacellulaily
Aa70( N*$;*# $*77807

Type S Beiouinase
AQ%/*#M 7I*#M 6+/)0#$/ B6+/)0#$/ +*3*$7 ;&%3&#0 *#
6%0,#/#)-F
-Najoi sites of inactivation
A"#$%/)0++8+/% )&#D0%7*&# &< `[ $& 50D0%70 `\

Reveise TS = inactive TS


TBu bounu ! unavailable
Tiansthyietin ! available & ieseivoii
Albumin ! easily uissociates & bioavailable

*Nost thyioxine is bounu

TBu Beficiency
-Patients exhibit euthyioiu conuitions ! noimal
thyioiu function
-Can be acquiieu in patients tieateu foi
hypeithyioiuism
-Levels of fiee thyioiu hoimone initially iise causing
a ueciease in TSB levels
-Repiesents subclinical hypeithyioiuism at
1
st

-Fiee thyioiu hoimone levels stabilize in feeuback
loop
-In the enu, moie hoimones aie bounu to
tiansthyietin anu albumin

*hoimone bounu to albumin is consiueieu
bioavailable
1-Nost molecules binu with weak affinity to albumin
2-Bioavailable amount = # fiee + # bounu to albumin
*Binuing globulins allow quick anu efficient
iegulation
Boimone-specific globulins as enuociine buffeis
-Inciease ! less hoimone bounu to albumin
! less bioavailability
-Beciease ! moie hoimone bounu to albumin
! moie bioavailability



Noimal thyioiu function:
-Log-lineai ielationship between seium TSB anu fiee
T4
-Small change in fiee T4 causes laige inveise change
in TSB

Bieiaichy of Assessing Thyioiu function
1-TSB concentiation ! most common maikei
2- Total T4 concentiation
S-Total TS concentiation
4-Fiee T4 (oi TS) concentiation
-Thyioiu hoimones aie "shuttleu" acioss the cell
membiane by chapeione pioteins
!Caiiiei-meuiateu tianspoit
-9*%0)$+- iegulate gene tiansciiption
-Nembiane ieceptoi that shuttles T4 may have othei
affects ! Ca2+ ATPase, auenylate cyclase, uL0Ts, anu
Type 2 ueiouinase
*T4 conveiteu to TS intiacellulaily anu TS actually
has a nucleai ieceptoi as majoi isofoim unlike othei
steioius

Thyioiu Boimone: ueneial Effects
Piimaiy Effects ! Basal NETAB0LISN
-0xygen consumption
-Piotein metabolism
-Caibohyuiate metabolism
-Lipiu metabolism
-vitamin metabolism

Thyioiu hoimones aie also peimissive hoimones
-Peimissive hoimones- augment the action of othei
hoimones
-A 2
nu
hoimone can act on a cell to inciease
the iesponsiveness to the 1
st
hoimone
-Peimissive hoimone allows piimaiy
hoimone to maintain homeostasis
-Abnoimal peimissive hoimone causes
abnoimal piimaiy hoimone function
*Thyioiu hoimones inciease # of auieneigic
ieceptois in caiuiomyocytes foi catecholamines
*ulucocoiticoius enhance uB effects in hypoglycemic
states oi insulin on skeletal muscle in hypeiglycemics
states in myocytes foi iegulation of glucose
metabolism


*Noimal levels of thyioiu hoimone piomote bone
giowth in uevelopment anu help Ca2+ homeostasis
thiough incieasing PTB ieceptois
.;-7*&+&,- &< `;-%&*( K+/#( ./,0 >

Thyioiu iegulation of caiuiac output anu vasculai
iesistance:
Biiect Effects! iegulate BR anu Caiuiac 0utput
-Incieases Caiuiac muscle uue to !
-Regulates caiuiac myosin heavy chain gene
tiansciiption (causes alpha > beta heavy
chain)
-Incieaseu Na+K+ ATPase
-Stimulates Beta-auieneigic signaling anu
iesponsiveness
-Incieaseu iatio of stimulatoiy coupling u-
piotein to inhibitoiy coupling u-pioteins
-Incieases caiuiac output ! 02 to tissues incieaseu
-Positive chionotiopic (speeu)
-Positive ionotiopic (foice)
-Becieaseu TPR

Inuiiect Effects
-Incieaseu heat piouuction
-Inciease tissue C02
-Beciease TPR
-Regulates saicoplasmic ieticulum Ca2+-ATPase
activity ! iate of uiastolic ielaxation is iegulateu
-Systolic incieaseu (stioke volume uepenuent) anu
uiastolic uecieaseu (TPR uepenuent) to wiuen pulse
piessuie
-Becieaseu uiastolic BP & uecieaseu
auieneigic stimulation! Bloou volume
incieaseu fiom activating ienin-angiotensin
-aluosteione system
! iegulates heait iate anu caiuiac output
*TS tieatment can help post caiuiac suigeiy patients

-Thyioiu hoimones have uiiect effects on white anu
biown auipose tissue
!Stimulates $;0%3&,0#07*7 in biown auipose tissue
-Stimulates auipose uiffeientiation
-Regulates lipolysis anu lipogenesis
-Incieases Beta-auieneigic ieceptoi
iesponsiveness
-Regulates leptin piouuctionielease
TS functions in nutshell (Fiist Aiu):
4 B's
1-Biain matuiation
2-Bone giowth
S-Beta-auieneigic effects
4-Incieaseu BNR


-Biown auipose tissue has S-monoiouothyionin
ueiouinase foi T4 to TS conveision
-Coiu cutting, neonatal cooling, catecholamine
stimulation, anu T4 to TS augmentation causes
theimogenesis in neonates
-T4 anu NE iegulate concentiation of heat


BAT is eneigy uissipating, WAT is eneigy stoiing

*BAT is piimaiily aiounu kiuneys, auienal glanus,
anu bloou vessels of the meuiastinum anu neck.

Thyioiu hoimone anu liveihepatic function:
-Stimulates malic enzyme, u6P BB, anu FA synthase
to iegulate lipogenesislipolysis
-Stimulatesiegulates many enzymes iequiieu foi
cholesteiol metabolism
-Regulates piolifeiationapoptosis of hepatocytes


Thyioiu anu bone giowth, osteoclasts, anu
chonuiocytes

BAS PERNISSIvE FEAT0RE IN AB0LTS ANB B0NE


-Thyioiu hoimones aie ciitical foi neuial
uevelopment but mechanisms aie unknown
-Ceiebial coitex, visual anu auuitoiy coitices,
hippocampus, anu ceiebellum

Summaiy of Physiological effects of thyioxine


Abnoimal Enuociine glanu function anu hoimone
levels have uiffeient classifications
.%*3/%- ! Abnoimal function of glanu anu glanu
uoes not iesponu coiiectly to tiopic hoimone
=84)+*#*)/+ ! Piimaiy hoimone level is noimal but
pituitaiy hoimone is abnoimal. Bifficult to uiagnose
=0)&#(/%- ! Abnoimal levels of tiopic hoimone anu
enuociine glanu hoimones. Pioblem is not fiom
enuociine glanu, but uue to insufficient tiopic
hoimone secietion by pituitaiy

Bypothyioiuism
.%*3/%-! high TSB anu low T4
=84)+*#*)/+ ! high TSB anu noimal T4
=0)&#(/%- ! low T4 anu noimal TSB since pituitaiy
is not iesponuing to low T4
*Noie common in women

.;-7*&+&,- &< `;-%&*( K+/#( ./,0 \

.%*3/%- :-6&$;-%&*(*73

:/7;*3&$&@7 `;-%&*(*$*7
-Autoimmune uisease when autoantibouies
attack thyioglobulin (TuB) anu peioxiuase.
These aie anti-TP0 antibouies causing
thyioiu tissue uestiuction

Bypeithyioiuism
Piimaiy ! low TSB anu incieaseu T4 anuoi TS
-TSB below u.uS inuicates hypeithyioiuism
*Nust evaluate TSB too!
Subclinical ! low TSB anu noimal TS anu T4

*Again, moie common in women than men

uiaves uisease
-Nost common cause of hypeithyioiuism
-Anti-TSB autoantibouies binu to TSB ieceptois
-Stimulates thyioiu hoimones
-Common symptoms
-Exophthalmos (bulging eyes)
-uoitei
-Beat intoleiance
-Incieaseu appetite
-Restlessness iiiitability
-Weight loss
-Incieaseu heait iate

*Raie but Non-activating anti-TSB autoantibouies can
be piouuceu causing.BYP0thyioiuism




ueneially:

Bypeithyioiuism
-INCREASEB metabolism
-Iiiitability
-Symptoms associateu with too much eneigy

Bypothyioiuism
-BECREASEB metabolism
-Fatigue
-Symptoms associateu with low eneigy





Wolff-Chaikoff Effect- tiansient ueciease in TST4
levels uue to excess ingestion of iouiue, which inhibits
iouiue pump activity




































































2*)%&#8$%*0#$7 1 "#$%& ./,0 1

=&(*83! Nost impoitant extiacellulaily

Causes of hyponatiemia
-Kiuney failuie anu uefect in auienal coitex
-vomiting anu uiaiihea

Causes of hypeinatiemia
-Bypeiactivity of auienal coitex when watei loss
exceeus Na+ loss (uehyuiation)
-Symptoms: high bloou piessuie, fluiu ietention, anu
swelling

.&$/77*83! Nost impoitant intiacellulaily
-Essential intiacellulaily foi enzyme-meuiateu
ieactions (pyiuvate kinase, glycogen synthesis,
piotein synthesis, & etc.)
-Impoitant extiacellulaily foi caiuiac muscle

Bypokalemia anu Bypeikalemia aie mainly causeu by
ienal function

J;+&%*(0
-Naintains electiolyte balance anu osmotic piessuie

Bypochloiemia! metabolic alkalosis

Bypeichloiemia! metabolic aciuosis, uehyuiation,
uecieaseu ienal bloou flow, meuications, ammonium
chloiiue, anu hypeipaiathyioiuism

Na+, K+, anu Cl-
-Naintenance of fluiu volumes anu osmotic piessuie
-Foimation of buffeis
-Neive impulse tiansmission
-Nuscle contiaction
-Cl- activates amylase enzyme
-Cl- is impoitant foi foimation of gastiic BCl

J&660%A 0H*7$7 *# h1 &% h> 7$/$0
-Component of metalloenzymes
-Nainly bounu to ceiuloplasmin seium, but also
albumin oi histiuine complex
*Key Function-Cytochiome oxiuase in e- tianspoit
chain



Coppei ueficiency's uistinguisheu symptoms:
-Low ceiuloplasmin levels
-Niciocytic hypochiomic anemia fiom uecieaseu
feiioxiuase activity
-Bepigmentation

Coppei toxicity's ANBIu000S symptoms:
-uastiic pain
-Nausea
-vomiting
-Biaiihea
-Coma
-0liguiia
-Bepatic neciosis
-vasculai collapse
-BEATB

Wilson's uisease oi Bepatolenticulai Begeneiation
-Autosomal iecessive uisease with Cu2+ATPase
-Bistinguisheu symptoms:
-Fatal uisease
-Kaysei-Fleischei iings in both eyes
-Lenticulai nuclei (uementia, movement
uisoiuei)
-Low ceiuloplasmin in seium (feiioxiuase)
-Bigh coppei level in bloou anu uiine
Cu2+ Beficiency: hypochiomic miciocytic anemia
Tieatment: coppei chelatoi, B-penicillamine

Nenkes Synuiome oi Kinky-haii uisease
-X-linkeu iecessive, uefective Cu2+ATPase
tianspoitei
-Coppei is not available foi noimal functions anu
accumulates in the intestine, spleen, muscle, anu
kiuney
-Symptoms iesemble coppei toxicity anu ueficiency
Clinical Piesentation
-uiowth ietaiuation noticeu in infancy
-Connective tissue uisoiuei
-Bypopigmentation in skin anu haii! coaise, giey, &
kinky
-Nental ueficiency & Seizuies
-Failuie to thiive
-BEATB BY S YEARS
Can tieat with coppei-histiuine complex, but ueath is
inevitable



Kaysei-Fleishei iings

Bypopigmentation of haii in Nenkes


j*#) Bj#>hF! &#+- 0H*7$7 *# h> 7$/$0
-Functions in Zn-uepenuent enzymes, noimal giowth,
uevelopment, anu iepiouuction
-Absoiption enhanceu by Bis anu Cys

Zinc Beficiency

O)%&(0%3/$*$*7 0#$0%&6/$;*)/ is an autosomal
iecessive uisease uue to a paitial uisoiuei of
intestinal zinc uptake. Signs usually appeai within the
fiist months of life, with a chaiacteiistic cutaneous
iash that is symmetiical, locateu aiounu the bouy
oiifices, behinu the eais, anu on hanus, feet, anu heau.
Bisoiueis of the mucous membianes incluue
gingivitis, stomatitis anu glossitis.
`%0/$30#$ consists in zinc sulfate auministiation, foi
which the uoses aie iegulaily incieaseu thioughout
the giowth peiiou, as well as uuiing piegnancy anu
nuising. Long-teim piognosis is goou but tieatment
must nevei be uiscontinueu.

-`&H*)*$-: No shoit teim toxic effects up to 2uu mgu,
but long teim effects aie unknown. veiy high uoses of
Zn2+ leau to fevei, vomiting, uiaiihea, immune
suppiession, Fe loss fiom livei, Cu2+
2*)%&#8$%*0#$7 1 "#$%& ./,0 >

Acioueimatitis enteiopathica


2/#,/#070 B2#F ! ^W` `'=`'9
-Acts as a cofactoi oi an activatoi foi seveial enzymes
-Toxicity= psychosis anu paikinsonism

2&+-4(0#83 B2&F
-Legumes, meat, anu whole giain
-Cofactoi in metabolism of C, N, anu S
-Can catalyze the tiansfei of single elections anu of
elections paiis in ieactions with H/#$;*#0 &H*(/70
anu aluehyue oxiuase

No Beficiency
-Low appetite
-Slow giowth
-Reuuceu feitility
-Bigh moitality of infant anu mothei
-Nental uistuibances, coma, & ueath

No Toxicity
-Biaiihea
-Anemia
-Slow giowth
-Failuie of ieu cell matuiation
-uout
-Pievents Cu2+ utilization

=0+0#*83 B=0F
-Antioxiuant
-Pait of ,+8$/$;*&#0 60%&H*(/70 in piotection of Bb,
polyunsatuiateu fatty acius, anu cell membianes fiom
oxiuation
-Complements vitamin E







Z+8&%*(0
-Isomoiphous ieplacement of 0B- in hyuioxyapatite
in bone anu teeth
-F- causes incieaseu haiuness anu iesistance acius

F- Beficiency
-Toothy uecay
-0steopoiosis

F- Toxicity
-Fluoiosis with chalky anu biownish stains on
enamel
-Pitting as enamel foimation is inhibiteu
-Acute toxicity ! inhibits enolase (glycolysis)

F- in Phaimacology
-Tooth paste
-Biinking watei fluoiiuation
-uiey stoppei phlebotomy tubes to stop metabolism
in bloou samples

`%/)0 0+030#$7T
-Chiomium- cofactoi foi insulin. Potentiates the
action of enuogenous anu exogenous insulin. Acts as
the metal poition of glucose toleiance factoi (uTF).
uTF affects metabolism with insulin, glucose,
cholesteiol, anu tiiacylglyceiiues

-Cobalt- In cobalamine (vitamin B12)



































































./%/$;-%&*( K+/#(

-Paiathyioiu is locateu on the posteiioi suiface of
thyioiu glanu
-4 Lobes total
-2 supeiioi fiom 4
th
phaiyngeal pouch
-2 infeiioi fiom S
iu
phaiyngeal pouch

-2 Cell types in paiathyioiu glanu
1-Piincipal (chief) cells
-Seciete PTB
AQ/7&6;*+*)
A.&+-,&#/+!Z%*0( 0,, /660/%/#)0
-Seciete PTB in iesponse to low Ca2+
A\ `/%,0$7 &< .`:
1-0steoclasts via osteoblast to
inciease Ca2+ in bloou fiom bone
iesoiption
2-Kiuneys to inciease Ca2+
ieabsoiption anu causes foimation
of calcitiiol (fiom vitamin B
ueiivative)
S-Piomotes intestinal absoiption of
Ca2+ via vitamin B (calcitiiol)
! Peimissive effect
2-0xyphil cells
-0nknown function
-Abunuant mitochonuiia! Aciuophilic
-Pyknotic nuclei! Conuensateu nuclei
























































2*)%&#8$%*0#$ /#( 2*#0%/+ :&30&7$/7*7
J&34*#0( .;-7*&+&,- /#( Q*&);03*7$%-
./,0 1

J/+)*83T
T0TAL B0BY content of Ca2+= 1uuu giams
-9S% in bone in foim of hyuioxyapatite
Calcium ion is in soft tissues like the following:
-12 ciiculating Ca2+ is fiee, iest is piotein bounu oi
complexeu with P04-, BC0S-, anu Citiate
-Impoitant foi bone anu most bio piocesses
-Waim milk anu honey -> natuial tianquilizeu, but
milk has tiyptophan! seiotonin ! melatonin

2/,#07*83T
*Smolanoff mentioneu nuts as a piimaiy souice
seveial times
-Ng2+ is in muscle, neive, heait (SA), liganu-ieceptoi
binuing, anu homeostasis foi bloou piessuie, bloou
sugai, eneigy metabolism, anu piotein synthesis
-Chloiophyll has Ng2+ (Baik leafy gieens)
-Absoibeu by small intestine anu excieteu by kiuney
in tight iegulation

*Ng2+ anu Ca2+ homeostastis! 2 mechanisms
1-Ca2+ is uepenuent on Ng2+. Incieaseu intiacellulai
Ng2+(foims with B20) ! inhibition of Ca2+
tianspoit into cell anu fiom saicoplasmic ieticulum
!Ng2+ ueficiency = incieaseu Ca2+ intiacellulaily
2-Ng2+ is neeueu foi ielease of PTB. So calcium
supplementation may not help if PTB is not in effect
to help absoib Ca2+ fiom the gut
*Patients on pioton pump inhibitois aie susceptible
to Ng2+ ueficiency as well as patients that vomit anu
have uiaiihea. Lose little Ng2+ in sweat.

.;&76;/$0T
P04- is in soft tissues
-Eneigy, phospholipius, metabolism, & pB
Beficiency= fatigue anu loss of appetite
-Fiee P04- (most) = ionizeu anu uiffusible
-Piotein bounu=non-uiffusable
-w extiacellulai cations- non-ionizeu&uiffusable

-Remembei Ca2+ anu Phosphoius absoibeu togethei
-Aciuity incieases solubility, alkalinity opposes



Nilk-alkali synuiome: Tieatment of peptic ulcei
uisease
Ca2+ + BC0S- = hypeicalcemia anu alkalemia
*Basically causes seconuaiy hypeipaiathyioiuism
-Can cause uiabetes insipiuus
-Tieat with noimal saline to iestoie volume
-Follow with loop uiuietic to iiu Ca2+
*Be mentioneu 0TC bicaibonate anu
calcium(antacius) like in tums can cause
hypeicalcemia

e*$/3*# 9T
-Souices mentioneu: Fish, ieinueei, & shitake
mushiooms
-Cou livei is iich in vitamin B but has vitamin A, so
too much can cause vitamin A toxicity

*vitamin B anu effects on Ca2+ & P04- homeostasis:
-Stimulates absoiption of Ca2+ anu phosphoius in gut
-Regulates ieabsoiption of Ca2+ anu Phosphoius in
kiuney
-Regulates mobilization of Ca2+ anu phosphoius.
Kiuney anu bone can change to iesponu to pathology
that ueviateu fiom homeostasis
*Piegnant anu lactating women neeu vit B!

907)%*40 e*$/3*# 9 30$/4&+*73


***vitamin B2 veisus vitamin BS

Also, one main point mentioneu by Smolanoff is that
B2 can be piematuiely alpha-hyuioxylateu at 24
position uue to allylic hyuiogen anu in that foim has
lowei affinity to B binuing piotein foi tianspoit to
livei anu kiuneys! gets uegiaueu anu cleaieu fastei
-Still can binu to vBR

Activateu vitamin B (1,2S-uihyuioxyvitamin B) binus
to vitamin B ieceptois that aie piactically
eveiywheie in the bouy. Nost of these tissues have
been shown to have 1-alpha hyuioxylase as well

BS Functions (Not all, just main)
-Immune function ! incieases antimiciobe activity
anu uecieaseu autoimmunity
-Reuuces, ienal issues, insulin iesistance, vasculai
stiffness, bloou piessuie, anu inflammation fiom
ieuucing cytokine levels
-0p-iegulates J/$;0+*)*(*# (LL-S7), which is a bioau-
spectium antimiciobial anu pieventative foi
influenza




Kiuney (main) oi Paiaciine cells
BJ/+)*(*&+F
BJ/+)*$%*&+F
9>S'%,&)/+)*<0%&+
9\SJ;&+0)/+)*<0%&+
'H)077 )/# 40 *#/)$*D/$0( /#( 6%&(8)07 J/+)*$%&*) /)*(
a70( (*/,#&7$*)/++- $& /))077
e*$/3*# 9 /)$*D*$-



2*)%&#8$%*0#$ /#( 2*#0%/+ :&30&7$/7*7
J&34*#0( .;-7*&+&,- /#( Q*&);03*7$%-
./,0 >

-Net bone ueposition until Su
-Net bone uepletion afteiwaius
-Becieases testosteione anu estiogen ueciease bone
uensity (testosteione becomes estiogen
intiacellulaily)
4 Piimaiy hoimones that iegulate mineial
homeostasis
1-Paiathyioiu hoimone (PTB)
2-Calcitonin (CT)
S-Fibioblast giowth hoimone 2S (FuF2S)
4-vitamin B (vitB)

*PTBiP-ielateu to PTB anu acts like it. Not pait of
enuociine Ca2+ homeostasis anu is sometimes pait of
cancei anu the associateu Ca2+ uysiegulation that
accompanies cancei

1-PTB
-Releaseu fiom chief cells of paiathyioiu
-Binus to u-piotein coupleu ieceptoi! cANP
-Seium Ca2+ is piimaiy feeuback iegulatoi
! Inveise ielationship foi PTB anu Ca2+
-Paiathyioiu has Ca2+-sensing ieceptoi (CaSR)
-Regulateu by vitamin B (FuF2S ieuuces
vit B) *********
-Betects the changes of seium Ca2+

PTB's Effects on Bone:
-Bigh |PTBj! bone NATRIX iesoiption incieaseu
-Low anu inteimittent |PTBj ! incieaseu bone
foimation anu consistent bone iemoueling occuis to
mobilize Ca2+ into bloou fiom the extiacellulai fluiu
of the bone, N0T the matiix

PTB's Effects on Kiuney:
-Becieases Ca2+ excietion
-Incieases phosphoius excietion
-Stimulates calcitiiol piouuction (vit B Activation)

PTB's Effect in bloou
-Inciease Ca2+
-Becieases phosphoius (uue to kiuney excietion)


PTB's Effects on uI tiact
-Incieases Ca2+ anu phosphoius absoiption
***This is a peimissive effect uue to
incieaseu calcitiiol piouuction in kiuney
-PTB ieceptois aie pieuominantly on bone anu
kiuney to have tight iegulation of Ca2+ concentiation

*PTBiP
-Binus to PTB ieceptoi
-Piouuces giowth anu piolifeiation anu can have
some of PTB's effects
-Typically moie paiaciine anu less systemic
Piouuceu by some malignant tumois
-Squamous cell
-Bieast anu piostate cancei
-Exeits systemic effects anu stimulates osteoclast
activity foi iesoiption ! hypeicalceimia!!

2-Calcitonin
-Synthesizeu anu secieteu by paiafolliculai cells in
thyioiu
-Stimulateu by gastiin anu elevateu Ca2+ to help
ietain uietaiy Ca2+
-Thyioiu has CaSRs too anu theie is a uiiect-
piopoitional ielationship between Ca2+ anu
Calcitonin (CT)
-Bas u-piotein coupleu ieceptois! cANP
-Piomotes bone mineializationueposition
-Incieases ienal excietion of phosphoius uue to
inhibition of phosphoius ieabsoiption

S-FuF2S
-Piotein piouuceu by osteoclasts anu osteoblasts
PA:*,; .W[A h :*,; e*$ 9 ! ZKZ>\ 86%0,8+/$*&#
-Inhibits ienal ieabsoiption of phosphate
-Inuiiectly incieases net excietion

Phosphate homeostasis

a#(0%7$/#( $;0 %&+0 &< e*$/3*# 9 &# )/+)*83 /#(
6;&76;/$0 ;&30&7$/7*7
-vitamin B is tianspoiteu bounu to seium pioteins
-B binuing piotein oi albumin
-BBP is not satuiateu, veiy little fiee
calciuiolcalcitiiol
-vitamin B ieceptoi ! cytosolic steioiu ieceptoi
-Intiacellulai
-REu0LATES uENE TRANSCRIPTI0N
-Regulate theimogenesis thiough inhibition
of conveision of white fat to biown fat

vitamin B anu Nineial homeostasis:
In the gut: (fulfills peimissive effect of PTB)
-Incieases Ca2+ & Phosphoius uptake
-Incieases membiane fluiuity of intestinal epithelia
-Incieases intiacellulai tianspoit of Ca2+ fiom apical
miciovilli
-Stimulates tiansciiption anu tianslation of
)/+4*#(*#, which is piimaiy Ca2+ binuing piotein in
cytosol

In the kiuney:
-vBRs aie on epithelial cells! vit B iegulates itself
-Peimissive effect on kiuney ieabsoiption anu
excietion

vitamin B anu Bone
-vBRs aie on osteoblasts
-0steoblasts stimulate RANKL piouuction, which
binus to RANK osteoclast piecuisoi leauing to
osteoclast ieciuitment
-Incieases the iate of iesoiption uuiing
hypocalcemia, Theiefoie PTB anu Calcitiiol aie
elevateu togethei
kll3,

\ll 3,

gll 3,

'H$%/)0++8+/% .W[A )&307
Z%&3 7&<$ $*7780 7$&%/,0M
(*0$M &% 4&#0 %03&(0+*#,

2*)%&#8$%*0#$ /#( 2*#0%/+ :&30&7$/7*7
J&34*#0( .;-7*&+&,- /#( Q*&);03*7$%-
./,0 \

Calcium Bomeostasis


*Kiuneys aie physiologically bettei at ieabsoibing
Ca2+ than phosphate

*0nueistanu that in acute iesponses to hypocalcemia,
PTB mobilizes Ca2+ fiom EXTRACELL0LAR fluiu of
B0NE to inciease seium Ca2+ anu also stimulates
kiuney ieabsoiption of Ca2+ anu conveision of
calciuiol to calcitiiol in the kiuney
*Kiuney will not conveit calciuiol to calcitiiol foi no
ieason.
*Calciuiol is measuieu foi vitamin B ueficiency

Piolongeu Bypocalcemia Response:
-Piolongeu high PTB foi bone iesoiption anu vitamin
B foi gut absoiption to supply Ca2+
-Kiuney must exciete phosphate to avoiu
hypeiphosphatemia!!

907)%*40 $;0 (*70/707 /#( (*7&%(0%7 /77&)*/$0(
N*$; /4#&%3/+ 6+/73/ )&#)0#$%/$*&#7 &< 0/);
4*&3&+0)8+0

0steopoiosis
-Beciease in bone uensity ovei time
-Beciease in estiogen foi women
-Beciease in testosteione foi men (testosteione
become estiogen so essentially the same)
!Bietaiy vitamin B anu Ca2+ supplementation

Piimaiy hypeipaiathyioiuism: Chionic
hypeicalcemia
Symptoms:
-Stones, thiones, bones, abuominal gioans, anu
psychiatiic moans
-Stones- kiuney stones, nephiocalcinosis, anu
uiabetes insipiuus (fiom polyuiia)
-Thiones- Polyuiia
-Bones-bone uisease -Fibiouysplasia ossifican
piogiessiva, osteopoiosis, osteomalacia, anu aithiitis
-Abuominal gioans- peptic ulceis, pacieatitis,
constipation, inuigestion, nausea anu vomiting
-Psychiatiic moans- lethaigy, fatigue, uepiession,
memoiy loss, psychosis, ataxia, ueliiium, anu coma

Seveie Bypeicalcemia: Fibiouysplasia ossificans
piogiessiva ! RARE!
-Nuscle anu connective tissue aie giauually ossifieu
-Extia-skeletal bone seveiely constiains movement
-Injuiy to soft tissue causes ossification in affecteu
aiea
-Affecteu chiluien boin with big toes

Chionic kiuney uisease: Bypeiphosphatemia
!Seconuaiy Bypeipaiathyioiuism happens too!!
-FuF2S is incieaseu to stimulate phosphate excietion
as mentioneu above
-BIuB FuF2S ieuuces vitamin B. Paiathyioiu
becomes iesistant to negative iegulation of FuF2S
-Bo not confuse with how FuF2S is
upiegulateu with incieaseu vitamin B anu
phosphoius ! this concept is just pait of
FuF's positive feeuback loop
-Elevateu PTB messes with homeostasis in kiuney
uisease anu the net mobilization of phosphate causes
hypeiphosphatemia
-Incieaseu PTB accompanies paiathyioiu hypeiplasia
anu enlaigement as well as iesistance to iegulation
-FuF2S is supposeu to suppiess PTB secietion, but
theie is uown-iegulation of Klotho-FuFR1c complex
foi ieception of calcitiiol, FuF2S, Ca2+ (CaSR), vBR,
anu PTB

Botcheu Thyioiuectomy anu Bypocalcemia
-Acciuental iemoval of paiathyioiu glanus
! Bypopaiathyioiuism
-Caiuiac aiihythmias
-Bepiession
-Convulsions
-Skeletal muscles
-Spasms
-Nuscle ciamps
-Chvostek's sign! flick facial neive anu facial
twitches occui
-Tiousseau's sign! caipal spasms uue to BP
cuff
-Painful anu fiagile bones

vitamin B ueficiency
-Bypocalcemia
Causes:
-Insufficient uiet of vit B
-Inauequate exposuie to sunlight (Keatoi mentioneu
sunscieen anu clothing aie to blame too)
-Renal anu livei uisease
-Pseuuovitamin B ueficiency
-"vitamin B-uepenuent iickets Type-1"
-uenetic uefect
-Cannot conveit calciuiol to caltiiol
-Type-2 vitamin B uepenuent iickets is uue to vBR
uefect
Ballmaik pioblems in vitamin B ueficiency is
unueimineializeu bone
! Rickets in chiluien
!0steomalacia in auults



vitBS toxicity is veiy haiu to accomplish
>4u,uuu I0suay
-Boes not piouuce hypeicalcemia
'H$%/)0++8+/% J/>h 4/7*)/++-
&#+- )&307 <%&3 (*0$ /#(
7$&%0( J/>h *# 4&#

1lll 3,

gVl 3, 8#/47&%40(
1Vl 3, 0H)%0$0(

>ll 3,


TBYR0IB BISEASE
EPIBENI0L0uY

Thyioiu uiseases aie:
- veiy common
- mostly autoimmune
- most common in women

uiaves uisease: 0veistimulation of
thyioiu glanu by an Igu antibouy
- Pievalence: 1% to 2% in women
u.1% to u.2% in men
- Natuial couise: vaiiable, 1S uevelop
hypothyioiuism aftei 2u yeais of
conseivative tieatment.

Bashimoto uisease: Autoimmune
thyioiuitis, leaus to uestiuction of
thyioiu glanu
- Pievalence: 2% to S% in women
u.4% to 1% in men
- Natuial couise: Recuiient attacks with
hypo- oi hypeithyioiuism, eventually
lasting hypothyioiuism.


u0ITER
Enlaigement of the thyioiu glanu is calleu goitei.
Nost foims aie causeu by oveistimulation of the
thyioiu glanu thiough the TSB system:
- Iouine ueficiency iaises the TSB level.
- In uiaveu uisease, an abnoimal antibouy stimulates
the TSB ieceptoi.

TBYR0T0XIC0SIS
SIuNS & SYNPT0NS

Netabolic:
Netabolic iate
Appetite (most patients)
Ion pumps (Na+-K+, Ca2+)
Piotein synthesis & uegiauation
Lipogenesis & lipolysis
Plasma fiee fatty acius
Futile cycling in caibohyuiate metabolism
0ncoupling pioteins
LBL cholesteiol
Neuiological:
- Restlessness
- Neivousness
- Sleeplessness
- Fatigue
Caiuiovasculai:
N0 piouuction
Peiipheial vasculai iesistance
Beait iate
Sensitivity to -agonists
Atiial fibiillation (2-2u%)
0culai:
Exophthalmus (some patients)
Repiouuctive:
Nenstiual suppiession
Female feitility
Piegnancy:
Risk of complications
Newboin has signs of thyiotoxicosis

BIFFERENTIAL BIAuN0SIS

Nost cases of thyiotoxicosis aie causeu by uiaves
uisease.

0thei possibilities:
1. Thyioiu auenoma
2. Pituitaiy auenoma
S. Post-paitum hypei- (oi hypo-)thyioiuism

Biagnostic pioceuuies:
1. Physical uiagnosis: Thyioiu enlaigement
2. Total anu fiee TS anu T4
S. TSB
4. Neasuiement of thyioiu-stimulating
antibouy
S. Rauioiouine scan


RISK FACT0RS F0R uRAvES BISEASE

1. uenetics: uiaves uisease is a multifactoiial
tiait that is moie common in close ielatives of a
patient.
2. uenuei: Risk is 7-1u times highei foi females
than males. uiaves uisease is iaie befoie pubeity but
continues unabateu aftei menopause.
S. Piegnancy: Impiovement uuiing piegnancy,
exaceibation a few weeks aftei biith.
4. viial infections: 0nceitain.

TREATNENT 0F
TBYR0T0XIC0SIS

1. Antithyioiu uiugs: Thiocaibamiues
inhibit thyiopeioxiuase.
- Piopylthiouiacil
- Nethimazole
- Caibimazole
2. Wolff-Chaikoff effect: Excess iouiue
inhibits hoimone ielease acutely, also
inhibition of thyiopeioxiuase.
S. -blockeis: Foi caiuiac symptoms.
4. Suigeiy: Effective, but iisks of iemoving
paiathyioius anu uamaging iecuiient
laiyngeal neive.
S. Rauioiouine: Accumulates in thyioiu glanu,
uestioys the glanu.
6. Any uietaiy inteiventions.





























./#)%0/7

1_907)%*40 $;0 034%-&#*) &%*,*# &< $;0 *7+0$7 &<
+/#,0%;/#7 /#( 0H&)%*#0 /)*#*_
-Pancieas is ueiiveu fiom 2 buus oiiginating fiom the
enuoueimal lining of the uuouenum
-vential buu- close to bile uuct anu foims the
uncinate piocess anu infeiioi pait of heau
-Boisal buu- in uoisal mesenteiy anu foims
iest of the pancieas
-2/*# 6/#)%0/$*) (8)$ is foimeu by entiie vential
pancieatic uuct anu uistal uuct of uoisal poition
-Pioximal poition of uoisal buu can become
/))077&%- 6/#)%0/$*) (8)$ if it peisists
-2 buus iotate anu fuse in C-shapeu pait of uuouenum

J+*#*)/+ J&%%0+/$0T
-Annulai pancieas- left pait of vential buu iotates
noimally, anu iight pait iotates in opposite uiiection
to constiict uuouenum anu cause obstiuction

>_907)%*40 $;0 7$%8)$8%0 /#( <8#)$*&# &< $;0
0H&)%*#0 6&%$*&# &< $;0 6/#)%0/7.
-Exociine poition is a compounu $848+&/)*#/%
70%&87 ,+/#(
ASecietes bicaibonate anu uigestive enzymes
-Pancieatic uuct (of Wiisung) extenus the entiie
glanu anu empties into hepatopancieatic ampulla (of
vatei) aftei common bile uuct joins
-Accessoiy pancieatic uuct (of Santoiini) may oi may
not be piesent
-Loose C.T. foims a capsule with septa that sepaiate
the glanu into lobules

-Each acinai cell is pyiamiual shapeu anu has a iounu
nucleus suiiounueu by 4/7&6;*+*) )-$&6+/73
-Acinai cell apex is full of secietoiy gianules that
have enzymes
-Receptois aie locateu on the basal siue of acinai cell
membianes foi binuing of CCK anu acetylcholine
-Buct system begins with centei of acinus at cells
calleu centioacinai cells, which aie squamous to low
cuboiual anu an extension of the inteicalateu uuct.
-Both centioacinai anu inteicalateu cells have
ieceptois foi secietin anu Ach foi stimulation of
bicaibonate secietion to buffei aciu chyme in
uuouenum coming fiom stomach
-Bucts join to make intialobulai uucts, then
inteilobulai uucts, anu then uump into the main
pancieatic uuct


-Acinai cells ielease amylase, lipase, iibonuclease,
BNAse, anu pioenzymes w tiypsin inhibitoi to
pievent piematuie activation of tiypsin, which can
cause pancieatic uamage
-CCK anu Ach stimulate ielease fiom acinai cells
\_907)%*40 $;0 7$%8)$8%0M <8#)$*&#M /#( +&)/$*&# &<
$;0 *7+0$7 &< +/#,0%;/#7 *# $;0 6/#)%0/7_

-Composeu of Islets of Langeihans that aie
suiiounueu by ieticulai fibeis anu a netwoik of
fenestiateu capillaiies
-Cannot uistinguish cell types on tiauition B&E stain
-Call types appeai on Nalloiy-Azan stain aftei Zenkol-
foimal fixation
AV J0++ $-607
1-OB/+6;/FAglucagon secieting, locateu
peiipheially anu some centially
2-QBQ0$/FA insulin secieting, locateu
centially
S-9B90+$/FA somatostatin secieting
(inhibitoiy on A anu B), scatteieu thioughout
Islets. Nainly paiaciine effects on A anu B
cells. Bas enuociine effects on ielaxing
smooth muscle in uI tiact to ieuuce motility

4-91 )0++7- Seconu type of uelta cell that
secietes vasoactive intestinal peptiue (vIP)
to inuuce glycogenolysis, hypeiglycemia, anu
iegulate smooth muscle motility in the gut.
S-Z )0++ $-60- hoimone inhibits exociine
pancieas. It stimulates gastiin ielease fiom
chief cells while inhibiting BCl secietion fiom
paiietal cells
98/+ 4+&&( 7866+-

[_"(0#$*<- $;0 *7+0$7 &< C/#,0%;/#7 *# 3*)%&,%/6;7


O3-+&*(&7*7 &))8%7 *# "7+0$7 *# $-60 > (*/40$07
!=&+84+0 6%&$0*# 40)&30 *#7&+84+0
!O3-+&*( *7 3/(0 &< /3-+*# <*40%7 *# 40$/ )0++7
!O660/%7 0&7*#&6;*+*) *# $;0 *7+0$

.;-7*&+&,- &< '#(&)%*#0 ./#)%0/7
./,0 1

-Insulin follows the classical piohoimone pathway
-Pioinsulin is not secieteu fiom pancieas, insulin is
secieteu
-Piepioinsulin cleaveu in ER
-Pioinsulin cleaveu in uolgi
-Natuie insulin anu C-peptiue stoie in laige vesicles
-Bisulfiue bonus link insulin chains
-C-peptiue is cleaveu fiom piohoimone anu has a
long half-life that is useful foi uiagnostic puiposes

ulucose's tiiggei of insulin ielease is a 7-step piocess:
1-ulucose enteis Beta cell via KCa`A> tianspoitei
2-ulycolysis tiiggeis iise in ATP
S-K+ATP channels close
4-Beta cell uepolaiizes
S-Ca2+ channels open
6-Ca2+ influx leaus to intiacellulai Ca2+ ielease
(fiom smooth ER.)
7-Intiacellulai Ca2+ inciease tiiggeis insulin
mobilization anu ielease

-ulucose is the piimaiy factoi contiolling insulin
ielease
-Seconuaiy types of stimuli foi insulin ielease
consists of Ach, ulanin, ulucagon-like Peptiue 1
(uLP-1), anu epinephiine

-Insulin ieceptoi is composeu of 2 alpha subunits in
extiacellulai uomain anu 2 beta subunits in
intiacellulai uomain. Alpha-beta uimeiization occuis
when insulin binus ! ieceptoi is in same family as
IuF-1 ieceptoi
-TYRK phosphoiylation in insulin binuing to insulin
ieceptoi activates uL0T4 tianspoitei foi glucose
uptake in muscle anu auipose
-Insulin ieceptoi is an intiinsic TYRK phos ieceptoi
Insulin iesponse to a meal
-Baseline secietion is pulsatile anu follows ciicauian
ihythm
-Response to a meal causes a Biphasic iesponse
1-Initial inciease
2-Tiansient iise
-Note that this is tiiggeieu as an Episouic ielease uue
to the meal that was ingesteu



uL0T tianspoiteis facilitate glucose tianspoit acioss
cell membianes ! 4 Class 1 uL0Ts

uL0T1! Biain anu RBCs
uL0T2!INS0LIN INBEPENBENT, BIBIRECTI0NAL,
beta islet cells, livei, kiuney, anu small intestine
uL0TS! Biain, neuions, anu placenta
uL0T4!INS0LIN BEPENBENT, Beait, skeletal
muscle, anu auipose
-Biain too
-Neuiates postpianuial glucose uptake

Insulin's Stimulatoiy anu Inhibitoiy effects
-Stimulates glucose foimation anu stoiage


-Inhibits bieakuown of glucose stoies anu glycogen
-Insulin is consiueieu catabolic
-Inhibits gluconeogenesis by incieasing f2,6-
bisphosphate ! incieases p=PFK in glycolysis


ulucagon
-ulucagon is stoieu in uense gianules in alpha-cells of
islets in pancieas
-Secieteu in Ca2+ uepenuent pathways like insulin

-Bypoglycemia stimulates glucagon ielease
-Low levels
-Suuuen uiops of glucose, too
-Bypeiglycemia inhibits glucagon ielease

-Insulin iegulates glucagon ielease to an extent
-Key: glucose, fatty acius, anu ketone bouies aie
piimaiy iegulatois of glucagon ielease
0theis that can stimulate:
-Epinephiine
-uastiin
-CCK
-vIP
-uIP
0theis that can inhibit:
-Insulin
-Somatostatin
-Beta-auieneigic ieceptoi pathway

*Bypeithyioiuism anu Bypeicoitisolemia inciease
ulucagon secietion

ulucagon ieceptoi
-0n livei anu auipose tissue


Somatostatin (SRIFuBIB)
-Shoit half-life
-Low concentiation systemically, exeits paiaciine
effects
-2 foimulations- 14 anu 28, uo same thing
-Abunuant in BYP0TBALAN0S, biainstem, spinal
coiu, neives in heait, thyioiu, skin, anu eye
-Inhibits uB ielease fiom hypothalamus by
oveiiiuing uBRB
-Inhibits ielease of insulin anu glucagon fiom
pancieas
-Inhibits cell cycle giowth
-Inhibits angiogenesis
-Inhibits giowth factoi secietion, stimulates
apoptosis
-S ieceptoi subtypes

.;-7*&+&,- &< '#(&)%*#0 ./#)%0/7
./,0 >
Incietins
-uut-biain peptiues that iegulate pancieas function
-Piouuceu in small intestine
-ulucose-uepenuent insulinotiopic polypeptiue (uIP)
-Piouuceu by K-cells
-ulucagon-like peptiue (uLP-1)
-Piouuceu by L-cells
****Incietin Effect
-Insulin secietion inciease substantially when
hoimones aie ieleaseu by the uI tiact anu uuiing
hypeiglycemia
-Compaie Iv glucose veisus oial glucose
-*Be stiesseu this uuiing lectuie

Pioglucagon is cleaveu uiffeiently uepenuing on
wheie it is
-Pancieas!glucagon
-uutBiain!uLP-1 & 2, uRPP, ulicentin, inteivening
peptiue 1 & 2, anu 0xyntomouulin

uLP-1 stimulates insulin ielease uiiectly anu inhibits
glucagon ielease inuiiectly by stimulating uLP
ieceptois (u-piotein) in beta cells

uIP is ueiiveu fiom PiouIP, N0T pioglucagon
-vIP-Secietin-glucagon family
-uIP stimulates ielease of insulin like uLP-1
anu uiiectly stimulates glucagon secietion
-uIP ieceptois aie on alpha anu beta cells

-uIP anu uLP-1 aie uegiaueu by BPPIv

ulucose Bomeostasis

*Incietin plasma concentiation occuis slightly befoie
the iise of insulin, postpianuial





ulucose Balance has a constant anu continuous
metabolic shift
-Absoiptive state: Su-6u min aftei a meal
-Insulin piomotes anabolism
-Fuel is absoibeu into cells
-Post-absoiptive state: 2 hi aftei meal
-ulucagon piomotes catabolism
-Fuel is utilizeu

Bungei
-Bungei causes the stomach to seciete uhielin that
stimulates Aicuate neuions of the hypothalamus

-Neuiopeptiue Y stimulates appetite anu eating
-uB is ieleaseu befoie a meal
-uB has uiveigent activity
-Involveu in maintenance anu giowth
piimaiily at night
-Involveu with metabolism (glycogenolysis
anu lipolysis) like in hungei, which is its
antiinsulin effect. uB secieteu befoie
glucagon in fasting
*uB ieleaseu in stienuous activity too
Staivation anu fasting aie uiffeient since fasting is a
choice
-Fasting incieases uB ! incieaseu glucagon to
mobilize glucose stoies fiom livei (gluconeogenesis &
glycogenolysis) anu auipose (lipolysis)

-Bigh glucose anu insulin inhibit NPY, uBRB, anu uB
secietion by stimulating hypothalamic SRIF

Relationship between uB, glucose, anu insulin
-uB levels slowly iise aftei insulin has causes uptake
of glucose anu uecieaseu in concentiation itself
-uB anu IuFs stimulate uiffeient anu vaiious giowth
factois~12 houis aftei a meal

Leptin is pait of satiety. It inhibits NPY, uB like
glucose anu insulin aftei a meal. SRIF is also
stimulateu





Acute staivation
-Similai to fasting except moie glycogenolysis in
muscle, which is still little foi fuel since muscle aie
gieeuy anu keep it to itself
-A lot of mobilization of tiiglyceiiues leauing to the
use of fatty acius foi eneigy
-Befineu as fiist S uays aftei the 24 hi peiiou
postpianuial

Chionic Staivation
-Chionic staivation staits about S to 7 uays anu at
that point uBRB will stait to ueciease uue to
ultiashoit feeuback anu uB ueclines then
-uL0C0SE LEvELS ARE C0NTIN0INu T0 BECLINE
-Livei oxiuizes fiee Fas
-Ketone bouy piouuction
-Nuscle anu biain can use ketone bouies
-Chapeione-meuiate autophagy occuis in tissues
othei than biain anu muscle
-Piolongeu staivation will eventually ueplete
glycogen stoies in livei anu then the livei hepatocytes
will unueigo autophagy too

.;-7*&+&,- &< '#(&)%*#0 ./#)%0/7
./,0 \

-Bypoglycemia can kill you quickly while
hypeiglycemia can take time

Ameiican Biabetes Association uuiuelines


-Biabetic patients have insulin iesistance causing a
high concentiation of seium glucose
Bypoglycemia Symptoms




Type 2 Biabetes Complications







Biagnostic Testing

C-Peptiue foi beta cell function
-Longei half-life than insulin anu cannot skew iesults
in a patient alieauy taking supplementaiy insulin

Bemoglobin A1C
-ulycateu hemoglobin
-RBCs live foi 9u uays, so a iepiesentation of glucose
levels can be seen foi S months!
Noimal<S.7%
Pie-uiabetes S.7-6.S%
Biabetes >6.S%



































uo 0vei Nutiition Lectuie By Lambeit


















































































































































J/%4&;-(%/$0 20$/4&+*73 ./,0 1



K+-)&+-7*7 50D*0NT

















`JO J-)+0 50D*0NT


K+8)&#0&,0#07*7T


-S enzymes 4-6/77 iiieveisible glycolytic ieaction
-Reaction is unique to livei since it has
ulucose-6-phosphatase
-Impoitant foi glucose ueliveiy to biain, testes, RBC's,
anu kiuney meuulla
-S staiting points
1-Lactic aciu
2-Amino acius- entei TCA(anapleiotic) oi
pyiuvate
S-ulyceiol
*Nuscle has eveiything except glucose-6-
phosphatase ! it is gieeuy anyways anu keeps all the
glucose foi its own ATP piouuction via glycolysis

Wheie uoes Lactate anu Alanine come fiom.

*Alanine cycle feeus ammonia into uiea cycle in livei
*Note the laige amount of ATP useu to make glucose

1
7$
Q-6/77
.'. J/%4&H-I*#/70T
Activateu by
-ulucagon
-Coitisol
Inhibiteu by
-Insulin

.-%8D/$0 J/%4&H-+/70T
Activateu by
-Acetyl CoA allosteiically- since ATP has to be
available
Inhibiteu by
-ABP allosteiically since ATP has to be available!

*Note that in pyiuvate kinase ieaction of glycolysis,
all of the 1
st
bypass iegulatois have iecipiocal action












J/%4&;-(%/$0 20$/4&+*73 ./,0 >

>
#(
Q-6/77
Z%8)$&70 1Mg 4*76;&76;/$/70T
Activateu by
-ulucagon
-Epinephiine anu Noiepinephiine
-ATP allosteiically
-Citiate allosteiically
Inhibiteu by
-Insulin
-Fiuctose 2,6 bisphosphate- since that woulu mean
PFK-1 is allosteiically activateu, anu glycolysis is
going the othei way

*Note that in PFK-1 ieaction of glycolysis, all of the
2
nu
bypass iegulatois have iecipiocal action
-(ulucagonInsulin au EpiNoiepi)

\
%(
Q-6/77
K+8)&70 gA6;&76;/$/70T
Activateu by:
-ulucagon
Inhibiteu by:
-Insulin
-ulucose- allosteiically
-Chloiogenic- allosteiically, since it inhibits
tianslocase


Q/7*) :&%3&#/+ J&#$%&+ &< Q+&&( K+8)&70


*uluconeogenesis with the livei anu auipose tissue
-FFAs piouuceu by auipose tissue lipolysis by
hoimone sensitive lipase aie oxiuizeu in livei foi
piouuction of acetyl-CoA anu eneigy, theiefoie
piomoting pyiuvate caiboxylase activity of 1
st

bypass.
-Auipose tissue feeus glyceiol into gluconeogenesis
-Remembei that glyceiol is feu into tiiglyceiiue
synthesis as a glycolytic inteimeuiate
! Explains how glucose becomes fat!!!

uiogan's uiagiam ! Nake new one if time


O(*6&I*#07
Leptin
-Piouuceu mainly by white auipose tissue anu level of
ciiculating leptin is piopoitional to amount of
auipose tissue in the bouy
-Infoims biain of eneigy stoies in bouy
Auiponectin
-Stimulates fatty aciu oxiuation anu glucose uptake in
skeletal muscle to suppiess glucose output fiom livei

Tumoi neciosis factoi (TNF-a)
-Releaseu by maciophages neai auipose tissue
-Inuuces muscle anu hepatic cell insulin iesistance

Balancing of FA ciiculation anu oxiuation
-Low glucose ! glucagon ! inciease in hoimone
sensitive lipase
-Auipokine (leptin anu auiponectin) aie enuociine
iegulatois of appetite
-BIuB leptin = L0W appetite
-N0 leptin = BIuB appetite! tenuency of obesity
-Leptin insensitivity is associateu with
eating uisoiueis anu metabolic synuiome

Fiuctose anu ualactose
-Both aie metabolizeu in livei
-Fiuctose- bounu to glucose in suciose
-Boney anu fiuits
-BIuB FR0CT0SE C0RN SYR0P
-ualactose- bounu to glucose in lactose
-ulycolipiu
-ulycopioteins
-Nilk sugai

Fiuctose anu ualactose Netabolism

Pioblem with Bigh Bietaiy Fiuctose
1-F-1-P can accumulate uue to slow action of
Aluolase-B! low eneigy fiom phosphate tiapping
2-Fiuctose bypasses PFK-1 contiol in glycolysis
!Lactate anu tiiglyceiiues accumulate
!uAP feeus into glycolysis anu tiiglyceiiue
synthesis!!!!! (ulyceiol!!!!!)
K0#0$*) 9*7&%(0% N*$; Z%8)$&70 20$/4&+*73
1. Fiuctokinase uefect! Essential Fiuctosuiia
!Benign
2.Aluolase B uefect ! Beieuitaiy Fiuctose
Intoleiance (BFI)
-Incieaseu F-1-P changes glucose levels
-Pooi feeuing, failuie to thiive, hepatic anu
ienal insufficiency, anu ueath
-Asymptomatic in uiet excluuing fiuctose anu
suciose
-Symptoms iesemble fiuctose 1,6-
bisphosphatase uefect






`%*&I*#/70
J/%4&;-(%/$0 20$/4&+*73 ./,0 1

K0#0$*) 9*7&%(0% N*$; K/+/)$&70 20$/4&+*73
Classical ualactosemia! Autosomal Recessive
-Beficiency in galactose1-phosphate uiiuyl-
tiansfeiase (ual-1-P 0BPu tiansfeiase)
-No conveision to glucose
-AST & ALT incieaseu in newboins
-Nental ueficiency anu ciiihosis of livei
-Cataiacts fiom galactitol accumulation in
lens
-Tx: Reuuce uietaiy galactose
*A New Retaiueu Livei with Cataiacts

2*#&% ./$;N/-7-Pioviue metabolites foi
biosynthetic puiposes
1-... (oxiuative anu non-oxiuative bianches)
-Piouuces C02, NABPB, anu iibose

Non-0xiuative
-Links iibulose S-phosphate (enu piouuct of
oxiuative bianch) to glycolysis anu gluconeogenesis
in ieveisible ieactions
-}ust know that Tiansaluolase anu Tiansketolase aie
the most impoitant enzymes
*ulucose-6-phosphate BB inhibiteu by high
NABPBNABP+ iatio
*Piocess impoitant in mitotic cells anu ieuuctive
tissues! 5QJ7M +*D0%M /(*6&70M 3/33/%-M ]
/(%0#/+ )&%$0H

J0++8+/% ^00(7 &< ^O9.:! ... WH*(/$*D0 Q%/#);d
-Foi iibonucleotiue ieuuctase in ieuuction of ueoxy-
nucleosiue tiiphosphate (ueoxy-NTPs)
-FA anu steioiu biosynthesis
-Livei! FA synthase & BNu-CoA ieuuctase
-0xiuant contiol in RBCs via glutathione ieuuctase

-0xiuants uamage lipius anu cell membiane
-u6PB ueficiency ! acceleiateu uamage

>A.&+-&+ 6/$;N/-! 2 enzymes to make Fiuctose
-Bigh concentiation of fiuctose in seminal
fluiu ! 703*#/+ D07*)+07 piouuce


\AO3*#& 78,/% 7-#$;07*7- glucolipius, glycopioteins,
uAus ! key foi extiacellulai matiix
[Aa%&#*) /)*( 6/$;N/-7- uAus (Aciuic sugai
biosynthesis) ! key foi extiacellulai matiix


K+-)&,0# 20$/4&+*73
-Polymeiizeu on piotein calleu glycogenin (tiivial
knowleuge)
-alpha 1,4 anu alpha 1,6 (biancheu) connections



K+-)&,0# =$&%/,0 9*7&%(0%7
1Ae&# K*0%I0@7 B1/ /#( 14F
-ER glucose 6-phosphatase oi glucose tianspoit
ueficiency ! Livei
-Fasting hypoglycemia since livei cannot piouuce
glucose anuoi shuttle it out into bloou stieam
Symptoms:
-Lactic acauemia
-Bypeiuiicemia
-Ketosis
Tx: Steauy caibohyuiates fiom uiet

>A2)J/%(+0@7 BeF
-Nuscle phosphoiylase ueficiency
-Nyoglobin anu CK aie in bloou
Symptoms:
-Painful muscle ciamps on exeicise

\A.&360@7 B""F
-Lysosomal aciu alpha-glucosiuase ueficiency
-Affects heait anu muscles
Symptoms
-Beath in infancy fiom heait failuie

C0)$8%0 =833/%-
-All cells uo glycolysis since they have all of the
enzymes
-uluconeogenesis is only in livei
-Nuscle can uo gluconeogenesis but is missing u 6-
phosphatase anu can not foim glucose anu shuttle it
out
-Lactate, amino acius, anu glyceiol aie staiting points
foi gluconeogenesis
-Boimones, insulin anu glucose, thiough
phosphoiylation fiom seconu messengei signaling,
iegulate glucose stoiage
-ulucose is neeueu to piouuce iibose anu NABPB in
biosynthesis
-ulucose is useu foi special sugai synthesis anu helps
with the biosynthesis of extiacellulai matiix! uAus
foi example








BIABETES NELLIT0S 0B}ECTIvES
1. Clinical piesentation
2. Types of uiabetes
S. Nanagement of insulin-uepenuent uiabetes
4. Bietaiy iecommenuations
S. Acute complications
6. Late complications

TYPES 0F BIABETES
Type 1 uiabetes: S% - 1u% of all uiabetics.
- 0nset most common in chiluien anu
teenageis
- Autoimmune uestiuction of -cells
- Anti-islet antibouies piesent (9u%)
- Insulin uepenuence
Type 2 uiabetes: >9u% of all uiabetics.
- 0nset most common in miuule-ageu anu olu
people
- ieuuceu insulin secietion, oi insulin
iesistance, oi both
- Tieateu with uiet, oial antiuiabetics, anuoi
insulin injections

INS0LIN EFFECTS 0N uL0C0SE PATBWAYS

Livei: ulycolysis
ulycogen synthesis
uluconeogenesis
ulycogen bieakuown
Nuscle: ulucose uptake (uL0T4)
ulycogen synthesis
Auipose t.: ulucose uptake (uL0T4)


BYPERuLYCENIA IN BIABETES

- Excessive gluconeogenesis, inhibiteu
glycolysis in the livei
- Reuuceu glucose consumption in muscle anu
auipose tissue because of low uL0T4 tianspoitei
- Thiesholu foi ienal glucose excietion is
about 16u mguL
Question: Why is gluconeogenesis moie impoitant
than glycogen bieakuown foi hypeiglycemia in
uiabetes.

KET0uENESIS
- Ketones aie foimeu fiom acetyl-CoA in the
livei
- Nain souice aie fatty acius fiom auipose
tissue
- Ketogenesis noimally occuis in piolongeu
fasting, but is out of contiol in uiabetes
- Ketones aie impoitant souices of eneigy foi
most tissues uuiing staivation
- Impoitant contiol sites aie lipolysis in
auipose tissue anu cainitine shuttle in livei
- Ketones aie oxiuizeu by most tissues, but not
the livei

KET0ACIB0SIS

Ketoaciuosis is the most impoitant acute
complication in type 1 uiabetes.
- Ketogenesis in the livei exceeus ketone bouy
oxiuation in the tissues
- Rampant hypeiglycemia accompanies
ketosis
- Behyuiation uue to osmotic uiuiesis (glucose
in uiine)
- Can be tiiggeieu by stiess thiough insulin-
antagonistic stiess hoimones: coitisol, epinephiine
- Tieatment: Insulin injections, iv fluius
Biabetic ketoaciuosis is an emeigency that is fatal
without inteivention!

BYP0uLYCENIA
Bow can hypoglycemia be pieventeu.
Bow uo you tieat hypoglycemia.
What is woise: hypoglycemia oi
hypeiglycemia.
Bow aggiessively shoulu uiabetes be tieateu.

LATE C0NPLICATI0NS IN BIABETES
Nost late complications oiiginate in
abnoimalities of small bloou vessels.
- Enuothelial cell uysfunction
- Abnoimal basement membianes
- Incieaseu vasculai peimeability
- Beposition of excess matiix pioteins anu
plasma pioteins
- Naiiowing of the lumen of small bloou
vessels
Nechanisms of these changes aie incompletely
known.







LATE C0NPLICATI0NS: CARBI0vASC0LAR
Biabetes acceleiates atheioscleiosis. Incieaseu
iisks of:
- Acute myocaiuial infaiction
- Stioke
- uangiene
Any suggestions foi pievention anu tieatment.

LATE C0NPLICATI0NS: KIBNEYS
In the 0S, >Su% of patients on hemouialysis have
uiabetes. Nephiopathy staits with glomeiulai
uysfunction, but eventually uamages the tubulai
system.

Bypeifiltiation

Nicioalbuminuiia

Nacioalbuminuiia

0iemia

Any suggestions foi pievention & tieatment.

LATE C0NPLICATI0NS: EYES
Biabetic ietinopathy is the most common cause of
blinuness in people ageu 2S to 7u. It is a
miciovasculai pioblem:
- vasculai peimeability, maculai euema
- Retinal micioaneuiysms & hemoiihages
- vitieous hemoiihages
- Pooi peifusion of bloou vessels
- Neovasculaiization
- Fibiovasculai piolifeiation
- Retinal uetachment
In auuition to ietinopathy, theie is also an
incieaseu iisk of cataiact (lens opacities).
Any suggestions foi pievention anu tieatment.

BIABETIC BIET
Bietaiy iecommenuations foi type 1 uiabetes.
Bow is this uiffeient fiom type 2 uiabetes.
Impoitance of glycemic inuex.
What can iealistically be expecteu fiom uietaiy
tieatment.

INS0LIN TREATNENT
Insulin is iequiieu foi all type 1 uiabetics anu
many type 2 uiabetics.
- Tiauitionally, insulin is injecteu.
- Shoit-, meuium- anu long-acting
piepaiations aie available foi s.c. oi i.m. injection.
- Timing with meals is essential.
- Piogiammable insulin pumps aie becoming
moie common. Basal iate of about 1 0h, with bolus
infusions at meals.
- An amylin analog can be auueu to the insulin.

0RAL ANTIBIABETICS
What patients aie canuiuates foi oial antiuiabetics.
Bow uo oial antiuiabetic uiugs woik.
What aie the auvantages of oial antiuiabetics.
What aie the iisks.

NETF0RNIN
- This is a biguaniue, fiom Fiench lilac.
- Nost effects aie meuiateu by activation of
ANP-activateu piotein kinase.
- Reuuces hepatic gluconeogenesis.
- Stimulates glucose uptake in muscle anu
auipose tissue.
- This is the fiist-line uiug tieatment foi type 2
uiabetes, useu in Fiance since 1979, in 0S since 199S.

ACE INBIBIT0RS
These uiugs (captopiil, elanapiil etc) inhibit
angiotensin conveiting enzyme (ACE). ACE activates
the vasoconstiictoi angiotensin anu inactivates the
vasouilatoi biauykinin.
- Shoit-teim effect mainly thiough biauykinin,
which activates enuothelial N0 synthase
- Long-teim effect thiough angiotensin-
aluosteione
- Fiist-line tieatment foi hypeitension (with
thiaziue uiuietics)
- Reuuces ienal glomeiulai piessuie even
moie than systemic aiteiial piessuie
- 0seu foi pievention of uiabetic nephiopathy








































































































O(%0#/+ K+/#(

-Auienal glanus aie locateu on top of each kiuney

Auienal Bevelopment
-Coitex is ueiiveu fiom inteimeuiate mesoueim
-Neuulla is ueiiveu fiom ectoueim neuial ciest cells
-In uevelopment, coitical cells of fetus suiiounu
ueveloping meuulla anu the peimanent coitex
suiiounus the fetal coitex befoie fetal cells
uisappeais
-ulanus uevelop between uoisal mesenteiy anu
uiogenital iiuges
907)%*40 $;0 4+&&( 7866+- $& $;0 /(%0#/+ ,+/#(7M
/#( *$7 *36&%$/#)0 $& 3/$8%/$*&#
S Aiteiies that supply:
-Infeiioi phienic aiteiy ! Supeiioi supiaienal aiteiy
-Aoita ! Niuule supiaienal aiteiy
-Renal aiteiy ! Infeiioi supiaienal aiteiy

-S aiteiies foim subcapsulai plexus
!Capsulai aiteiies
!Coitical aiteiies ! coitical capillaiies
!Neuullaiy aiteiies! meuullaiy capillaiies
*Neuulla ieceives uual supply
-Neuullaiy capillaiies (not as iich, since last
in plexus)
-Capsulai aiteiy bianches





Coitex: S Concentiic layeis
1) Zona glomeiulosa-
-Columnai oi pyiamiual cells
-Rounu oi aicheu coius
-Inuuceu by ACTB anu Ang II!
mineialcoiticoius
-Nainly aluosteione
2) Zona fasciculate-
-1-2 cell thick stiaight coius that aie
peipenuiculai to the suiface
-Inuuceu by ACTB ! glucocoiticoius
-Nainly coitisol
S) Zona Reticulaiis-
-Anastomosing netwoik
-Lipofuscin gianules
-Pyknotic nuclei (fiieu egg appeaiance)
-Inuuceu by ACTB !Steioiu sex hoimones
Weak anuiogens
-Nainly uehyuioepianuiosteione

-Boimones aie not stoieu in membiane-bounu
gianules
-Synthesize anu seciete only on uemanu
-Biffuse acioss plasma membiane since they aie
steioius
-Togethei, SER anu mitochonuiial enzymes piouuce
auienal hoimones



ulucocoiticoius
-Regulate metabolism via glucose
homeostasis
-Pioviue iesistance to stiess
-Bepiess immune iesponses
-Coitisol exeits negative long-loop feeuback
on anteiioi pituitaiy anu hypothalamus

Auienal Neuulla
-Composeu of Chiomaffin cells in coius oi clumps
-Seciete noiepi anu epi
-Consiueieu postganglionic sympathetic
neuions, but they have no axons oi uenuiites
-Suiiounueu by capillaiies
-Inneivateu by splanchnic neives by Ach
-Noiepi anu epi uiiectly ieleaseu into
piimaiy capillaiy plexus
-Neuulla has membiane-bounu secietoiy
gianules with eithei epi oi noiepi
*Catecholamines synthesizeu in the cytosol aie
tianspoiteu in vesicles via Ng-activateu ATPase in
membiane of vesicle

Secieting uianules
-Epinephiine
-Small gianules
-Less uense than noiepi gianules
-Noiepinephiine
-Laige gianules
-Noie uense thane epi gianules
-Lucent layei

*ulucocoiticoius (coitisol) stimulate PNNT to conveit
noiepinephiine that is in the cytosol into epinephiine
via coitical capillaiies

Clinical Coiielate
-Pheochiomocytoma- iaie tumoi ueiiveu fiom
chiomaffin cells that piouuces excessive
catecholamines


Z/$ /7 /# '#(&)%*#0 W%,/#

'H6+/*# ;&N +06$*# N&%I7 *# $;0 J^= $& 7866%077
/660$*$0 /#( /<<0)$ 0#0%,- 0H60#(*$8%0
-Leptin incieases eneigy expenuituie by activating
sympathetic neuions thiough ventialanteiioi
stimulation

'H6+/*# ;&N 0H)077 /(*6&70 $*7780 )/# )/870
;-60%$0#7*&#M &7$0&/%$;%*$*7M /#( *338#0 7-7$03
(*7&%(0%7
C06$*#
-Piouuceu by auipose tissue
-Leptin ieceptoi abiues by }AKSTAT pathway to
tiansmit signals fiom extiacellulai stimuli
-Leptin ieceptoi = 0b-Rb
-0sually uecieases foou intake & incieases eneigy
expenuituie
via aicuate nucleus-Inuuces anoiexigenic peptiue
alpha-melanocyte stimulating hoimone &
amphetamine-ielateu tiansciipt (CART)
via aicuate nucleus-Repiesses oiexigenic peptiues
NPY anu agousti-ielateu AgRP, which stimulate foou
intake anu ueciease eneigy expenuituie
-Stimulates immune iesponse
-Stimulates pubeity onset, feitility, & iepiouuction
-Stimulateu by estiogen anu suppiesseu by
anuiogens
-Women have moie auipose tissue*
-Incieases sympathetic tone in CvS oigans
! Incieaseu leptin causes hypeitension
thiough kiuney stimulation! Renin
*-Leptin is piouuceu by placenta anu affects the
mothei ! gestational uiabetes anu pieeclampsia
-Incieaseu leptin can cause osteoaithiitis anuoi
iheumatoiu aithiitis uue to leptin's activity in
caitilage catabolism.
! Causes chionuiocyte apoptosis, chionuiocyte
phenotype loss, anu matiix uegiauation
1- Leptin piomotes osteoclast uiffeientiation
thiough SNS stimulation ! inhibits bone
foimation
2- Leptin's upiegulation of CART inhibits
uiffeientiation of osteoclasts

-Bigh leptin associateu with the following:
-Psoiiasis
-Livei fibiosis in hepatitis B
-Asthma seveiity (associateu w obesity)
C*7$ > (*70/707 <&% N;*); ;*,; 70%83 +06$*# +0D0+7
*7 40#0<*)*/+
1) Bementia anu Alzheimei's uisease
2) Epilepsy
a. Suppiesses uL0-inuuceu excitatoiy
postsynaptic event meuiateu by
ANPA ieceptois

'H6+/*# N;/$ </)$&%7 ;/D0 /# *36/)$ &# $;0 70%83
/(*6&#0)$*# +0D0+7
-Leptin, TNF-alpha, & IL-6 uown iegulate auiponectin
-Low auipose causes less active ANPL anu incieaseu
gluconeogenesis
*Bypoauiponectinemia ! insulin iesistance !
metabolic synuiome ! atheioscleiosis
-TZBs inciease auiponectin anu ANPK by uecieasing
gluconeogenesis (PPARgamma activation) anu TNF-
alpha expiession (ueciease auipocyte size)

J&36/%0 /#( )&#$%/7$ $;0 0<<0)$ $;/$ +06$*# /#(
/(*6&#0)$*# ;/D0 &# </$$- /)*( 7-#$;07*7M </$$-
&H*(/$*&#M ,+8)&70 86$/I0M ,+8)&#0&,0#07*7M
*#78+*# %07*7$/#)0M /#( *#<+/33/$*&#
O(*6&#0)$*# C06$*#
Incieases glucose uptake Becieases glucose uptake
Becieases
gluconeogenesis (livei)
Incieases
gluconeogenesis (livei)
Incieases fatty aciu
oxiuation (livei)
.
Becieases fatty aciu
synthesis (livei)
.
Reuuces TNF, IFN, anu
IL-6 (inflammatoiy
cytokines)
Stimulates TNF, IFN, anu
IL-6 to inuuce
inflammation
ueneially suppiesses
immune iesponse
ueneially inuuces
immune iesponse
Inciease ANPK .
'H6+/*# $;0 6%*3/%- 7&8%)0 &< `^ZA/+6;/ /#( "CAg
$;/$ *7 6%&(8)0( <%&3 /(*6&70 $*7780
-Naciophages piouuce TNF-alpha anu IL-6 aftei
phagocytosis of leptin in uying auipose

'H6+/*# ;&N /(*6&70 $*7780 M N*$; 760)*/+
036;/7*7 &# `^ZA/+6;/ /#( "CAgM *7 )/87*#,
*#78+*# %07*7$/#)0
TNF-alpha & INF-6
`^ZA/+6;/-Inuuces insulin iesistance via activating
seithi kinases (PKC, Raf1, & IKK-beta) that act on
the insulin ieceptoi anu IRS-1 by phosphoiylating
enzymes involveu in insulin ieceptoi stimulus
"CAg- uowniegulates IRS-1 anu glucose tianspoitei
gene expiession in auipocytes making them
insensitive to glucose (insulin iesistance anu
hypeiglycemia). IL-6 also upiegulates S0CS-S,
negatively mouulating insulin signaling

`^ZA/+6;/
-Piomotes lipolysis ! elevateu seium FAs
-0piegulates hepatic genes foi FA synthesis
-Bowniegulates hepatic genes foi FA oxiuation
!Bypeitiiglyceiiuemia thiough inuuceu
vLBL synthesis in livei anu inhibition of LPL
secietion in auipose tissue
-Counteis insulin inuuceu uegiauation of ApoB
-0piegulates IL-1 & IL-6

"CAg
-Auipose contiibutes much of ciiculating amount
-Piomotes lipolysis ! elevateu seium FAs
-Inuuces high eneigy expenuituie anu ieuuceu bouy
fat in CNS, 0PP0SITE in peiipheiy


O(%0#/+ K+/#( Q*&);03*7$%-

1_ ./$;N/-7 &< 7$0%&*( ;&%3&#0 7-#$;07*7

Souices of cholesteiol
-LBL & BBL fiom the bloou
-Enuogenous synthesis
-Stoieu cholesteiol esteis
Cholesteiol ! uesmolase enzyme ! Piegnenolone
*Regulating ieaction
! Piegnenolone!Behyuiogenase! Piogesteione
*Cholesteiol is ueliveieu by =$O5 to the mitochonuiia
wheie uesmolase is containeu

2&#&&H-,0#/70 50/)$*&#

Steioius aie hyuioxylateu in a ieaction with a specific
P-4Su enzyme that is containeu in ER anu
mitiochonuiia. This is moie specific anu not as
geneial as liveiuetox P-4Su enzymes
Cytochiome P-4Su is heme-containing subunit of
enzyme

>_ Q*&+&,*)/+ %&+07 &< 7$0%&*( ;&%3&#07
Classes of steioiu hoimones
1-Piogestins- foimeu by coipus luteum uuiing
menstiual cycle anu placenta uuiing piegnancy
! i.e.- piogesteione
2-ulucocoiticoius- stiess hoimonesmetabolic
iegulatois piouuceu by auienal coitex
! i.e.- Coitisol
S-Nineialcoiticoius-Foimeu by auienal coitex &
iegulate Na+ & K+ excietion
! Aluosteione
4-Estiogens- Female iepiouuctive iegulatois
piouuceu by ovaiies anu placenta
! Estiauiol
S-Anuiogens- viiilizing hoimones foimeu by auienal
coitex
! Testosteione
*Testosteione is conveiteu to uihyuiotestosteione in
testis, which is moie potent. Test is also conveiteu to
estiauiol by /%&3/$/70 oi metabolizeu into inactive
piouucts (little conveision to estiauiol in testis)
*Nineialcoiticoius + glucocoiticoius = coiticosteioius
\_ O(%0#/+A6*$8*$/%- <00(4/)I

[_ O4#&%3/+*$*07 &< /(%0#/+ 7$0%&*(&,0#07*7
1-Cushings synuiome- Excess glucocoiticoius. Can be
causeu by an ACTB-secieting pituitaiy tumoi, which
woulu cause Cushings BISEASE. Nost of the time, this
is causeu by excessive auministiation of
glucocoiticoius anu affects women mostly.
(Coitisol ! insulin antagonist)
*Also, in most cases the patient has auienogenital
synuiome anu is on glucocoiticoiu tieatment that
leaus to Cushing's synuiome

2-Licoiice-inuuceu hypeitension- component of
licoiice pievents oxiuation(inactivation) of coitisol to
coitisone by blocking 11beta-hyuioxysteioiu
uehyuiogenase!Coitisol incieases salt ietention

S-Congenital auienal hypeiplasia (auienogenital
synuiome)
-Lack of coiticosteioius leaus to no iegulation of
ACTB ielease ! auienal stimulation
4-S-alpha-ieuuctase ueficiency
-Conveits testosteione to
uihyuiotestosteione
-Ambiguous exteinal genitalia
-viiilization occuis at pubeity, so the patient
is often iaiseu as a giil when the appiopiiate
tests aie not conuucteu
V_ 9*7&%(0%7 &< 70H8/+ (0D0+&630#$ %0+/$0( $&
/4#&%3/+ 7$0%&*( 30$/4&+*73
J&#,0#*$/+ O(%0#/+ :-60%6+/7*/
BO(%0#&,0#*$/+ =-#(%&30F
! 9*<<0%0#$ 0#L-30 (0<*)*0#)*07
-Reuuceu coitisol !Elevateu ACTB
-ALL uisoiueis leau to auienal glanu enlaigement uue
to incieaseu ACTB
**Inteimeuiates of the auienal coitex ieactions can
be caiiieu to auienal meuulla uue to aiiangement of
bloou supply causing oveipiouuction of anuiogens

>1/ :-(%&H-+/70 90<*)*0#)- B6%070#$7 U4*%$;F
-Nineialcoiticoius anu ulucocoiticoius aie ueficient
-Anuiogens aie oveipiouuceu
-viiilization
-Female pseuuoheimapiouitism
-volume uepletion !BYP0tension
-LowNo Aluosteione ! BYPERkalemia
-Incieaseu ienin ! salt ciaving

1m/ :-(%&H-+/70 90<*)*0#)-
-Incieaseu mineialcoiticoius! BYPERtension
-Incieaseu Na+ ieabsoiption !BYP0kalemia
-Nales! uecieaseu BBT !
pseuuoheimapiouitism! female phenotype, no
inteinal iepiouuctive stiuctuies
-Females ! exteinally phenotypic female wnoimal
inteinal sex oigans anu lacks seconuaiy sex
chaiacteiistics

1140$/A;-(%&H-+/70 90<*)*0#)-
-Becieaseu aluosteione
-Incieaseu 11-ueoxycoiticosteione !
mineialcoiticoiu ! BYPERtension
- Incieaseu Na+ ieabsoiption !BYP0kalemia &
Euema
*Remembei that ieceptois iesponu to any
coiticosteioiu when it is in excess in the seium
-viiilization
-Nales ! piecocious pubeity
-Females ! pseuuoheimaphiouitism, viiilization

Weak
anuiogens
&
Testosteione

*Testosteione
can be
conveiteu to
estiauiol by
aiomatase
O(%0#/+ K+/#( .;-7*&+&,- ./,0 1

Catecholamine Synthesis in Auienal Neuulla
-Sympathetic stimulation anu ACTB stimulation
inciease activity of uopamine beta-hyuioxylase to
piouuce noiepinephiine fiom uopamine
-Coitisol stimulation incieases SAN anu P-N-N
activity to piouuce epinephiine fiom noiepinephiine

Catecholamines
-Piimaiy NTs foi paiaciine anu autociine effects
-Secieteu fiom auienal meuulla into systemic
ciiculation
-Begiaueu at sight of action via NA0 anu C0NT
-Cleaieu in livei bile of kiuney uiine
-Alpha auieneigic ieceptois! piefei noiepinephiine
-Beta auieneigic ieceptois ! piefei epinephiine

.%*3/%- /(%0#/+ /#(%&,0#7
1-Anuiosteneuione
2-BBEA
S-Testosteione (veiy small amount)
*Anuio anu BBEA aie weak anuiogens anu binu to
SBBu weakly ! laigely bioavailable
-Auienal anuiogens contiibute to Su% of anuiogens
anu women anu plan a iole in menopause

Besmolase = CYP11A1
-Locateu in innei mitochonuiial membiane
-Conveits cholesteiol to piegnenolone
-StAR = Steioiuogenic Acute Regulatoiy Piotein
-Caiiies cholesteiol acioss outei
mitochonuiial membiane to CYP11A1


*Coitisol is piimaiy active hoimone piouuceu anu
secieteu by auienal! BBEA is secieteu but has weak
biological activity
-Auienal hoimones aie tianspoiteu in the bloou
bounu to coiticosteioiu binuing globulin anu albumin
-Bounu to albumin ! bioavailable
-Coitisol is mainly bounu to CBu, but 2S%
that is fiee oi bounu albumin is consiueieu to be an
excess causing the question of why theie is even CBu
to iegulate it

O+$0%0( J&%$*7&+ 20$/4&+*73
-Bypeiinsulinemia can inciease uiinaiy excietion of
coitisol metabolites
-0bese patients exciete gieatei amounts of coitisol
metabolites
-Bypeithyioiuism incieases cleaiance iate
-B0T incieaseu age iesults in uecieaseu
cleaiance causing a shift in total coitisol, but
a sustaineu level foi noimal function



ACTB & Auienal Steioiuogenesis
-u-piotein ! cANP
-Stimulates ACTB ieceptoi piouuction
-Stimulates StAR piotein piouuction
-Stimulates CYP11A

*ACTB Receptoi piouuction is iegulateu by the
following
-ACTB
-ulucocoiticoius
-Angiotensin II

-Piogesteione, Nineialcoiticoius, anu Anuiogens all
show piomiscuity in binuing to theii ieceptois when
eithei one of the steioius aie high in content of
ciiculation
***Except ESTR0uEN

J&%$*7&+ Z8#)$*&#7!"#78+*# /#$/,&#*7$
-Nainly anti-anabolic anu peimissive
-Conveits piotein to glycogen
-ulycogen!ulucose!Fuel
-Incieases piotein mobilization & uegiauation
-Conveits aminos to glucose piecuisois
-Inhibits piotein synthesis
-Inhibits glucose uptake anu uecieases glucose
utilization uuiing hypoglycemia
-Enhances glucagon ielease

J&%$*7&+@7 .0%3*77*D0 0<<0)$7T
-Amplifies glucagon
!Stimulates muscle glycogenolysis
-Regulates uL0T4 piotein
!Regulates insulin
*Catecholamines anu glucocoiticoius suppiess
immune system ! Think flightfight in stiess foi
catecholamines & pieunisone's effects of immune
system foi glucocoiticoius

Foi Coitisol Function
QQ""K
Qloou piessuie maintenance
Becieases Qone foimation
Anti-"nflammatoiy
Incieases "nsulin iesistance
Incieases Kluconeogenesis, lipolysis, & pioteolysis

Aluosteione
-Regulates kiuney, uI, Sweat glanus, & Salivaiy glanus
via epithelial cells
-Incieases Na+ ieabsoiption in collecting uuct of
kiuney
!Incieases K+ & B+ excietion
-Aluosteione has iapiu non-genomic effects as well as
tiansciiption-uiiect effects (ENaC, Na+K+ ATPase)
! Na+ ieabsoiption incieases ovei time
O#,*&$0#7*#&,0#AO^K"AO^K> =-7$03
ANuI! Becapeptiue, stable, inactive
ANu2! 0ctapeptiue
-Receptois on vasculai smooth muscles
-AT1, AT2, AT4 uPCR ieceptois
-AT1 iegulates ANuII function
-Incieases vasoconstiiction
-Shoit half-life


O(%0#/+ K+/#( .;-7*&+&,- ./,0 >

*Exam tip! You shoulu be able to cleaily iuentify
piepiohoimones, piohoimones, active matuie
hoimones, anu bieakuown metabolites foi vaiious
biomolecules

Fight oi Flight Response Physiology
Acute Effects:
1. Epi anu Noiepi heightens senses
2. Noiepi binus to alpha1 ieceptois
! stimulates gluconeogenesis
S. Epi binus to beta2 ieceptois on pancieatic beta
cells
!Stimulates spuits of insulin ielease
!Pioviues muscles with glucose foi fight oi
flight
Extenueu Effects:
4. CRB staits positive ultiashoit feeuback loop to
piouuce moie CRB
!Now, CRB is iegulating itself
S. Incieaseu ACTB incieases coitisol to keep the
system going

.;0&);%&3&)-$&3/
-Auienal meuulla tumoi
-Incieaseu catecholamines
Symptoms
-Episouic hypeitension
-Seveie heauache
-Excessive sweating
-Palpitation w oi wo tachycaiuia

.%*3/%- O(%0#/+ "#78<<*)*0#)-
! Auuison's Bisease
-Elevateu ACTB, but low auienal output

=0)&#(/%- O(%0#/+ "#78<<*)*0#)-
-Low ACTB anu low auienal output

O((*7&# 9*70/70
Symptoms
-Salt ciaving
-Baikening of skin
-Nausea & vomiting
-Low BP anu uizziness when stanuing uue to
oithostatic hypotension
-Nuscle anu joint pain
-Women may expeiience uecieaseu libiuo anu haii
piouuction

O((*7&#*/# J%*7*7
Emeigent Situation
-Shock
-Seveie uehyuiation
-veiy low BP
-Loss of consciousness
-Na+ anu K+ imbalance
-Common Causes
-Infection
-Tiauma
-Seveie stiess
0thei symptoms that can piesent
-Fevei
-Nausea & vomiting
-Abuominal pain
-Extieme weakness
-Confusion

Biffeient Cases foi Auienal Bypeifunction















Cushing's Synuiome- Bisease if tumoi oi if genetic
uefect causing enuogenous uysfunction
-Nost often causeu by excess glucocoiticoiu
auministiation