--0

'· ~n vivO, ptoinsulln has a biologic potency that is only about H)% of that of insulin,6

. -- ----- ---- - - - - -

--i!tf It is of clinical significance that insulin and C-peptide are cosecreted in equal amounts.-. ... - _..

~ .. 50% to 60% of the ~nsulin pro­dt?1ced by the pancreas i~ extracted by the liver without ever

reilching the syste~c circulation. In contrast, the liver ~oes l nqt~. extract C-peptide.• T •

. _ Because C-peptide is secreted in J equunola:t concentrations with insulin and is not extracted by the liver, ~-cell insulin secretion rates can be calcul~ted~ - - .

. another advantage of measuring C-peptide is that the standard insulin radioimmunoassay does not- distinguish between endogenous and exogenous insul·in, ·making- ·it ·an-ineffective· measure,·of endogenous 13-cell· function·· in· ·an· ·insulin'" treated· ·diabetic patient

-···~---- ... -----~----------.,.-· -----~-..----_ .. --.----~-. --~-------~-.. -.-----------------------~~---------· --------· ---~- -·-----

...

I

~ t

~

'\

~

~ 1

. ~ /· ...._ ·~- . :.~.;//i ·:~ .

·{f.~~ J . ' ·-"··~ .··.

r\t\fh~n glucose is infused in_travenou~-~y at a cortst~nt rate, ·:·) a brphas1c secretory response 1s observe a- that cons1sts of a J rapi.d, early insulin peak follo\.ved by a second, more slowly 1 risii1g p·eak (Fig. 34.3B ). In contrast to the slo·w rise in plasma ~

"1 glucose concentration follo\ving an oral glucose challenge, l glucose given intravenously promotes a rapid rise i:p. plasma ·1

~ ... glucose concentration (compare Fig. 34.3A and Bf Sensing :1

a rapid rise in plasma glucose concentration, the ~ cells first ~ secrete their stores of presynthesized insulin. Foll0\-\7ing this ~ acute phase, the cells begin to secrete ne-v'lly synthesized insu- ~ lin in the chronic phase, v.rhich lasts as long as the glucose '~

· challenge. In vitro studies of isolated islet cells and the per- -~ fused pancreas ha·ve identified a third phase of insulin secre­tion, commencing 1.5 to 3.0 hours after exposure to glucose and characterized bv a soontaneous decline in secretion to

i .1.

15% to 25% of the amount released during Deak secretion: a " v J.

level maintained for n1ore than 48 hours.----:... .- " ;

1

GLUCAG-oN· /

' ~l_ucagon i~ the other ~ajor panc~eatic islet hor_mor~~)that 1s Involved m the regulation of body fuel metabohsm~nges­tion of protein appears to be the major stimplus to secretion of glucag~ Glucagon's principal target tissue is t..he liver. Like insulin,-glucagon is secreted first into the portal blood and is therefore anatomically "'Nell positioned to regulate hepatic metabolism.

Although the amino acids released by digestion of a protein meal appear to be the major glucagon secretagogue: glucagon's main ·actions on the liver appear to involve the regulation of carbohydrate and lipid metabolis;;J.:..t;lucagon is particularly important in stimulating glycogenolysis, glu­coneogenesis, and ketogenesis. Glucagon does not act solely on the liver, but also has glycogenolytic action on cardiac and skeletal muscle and lipolytic action on adipose tissue, and it promotes the breakdown of protein by several tissues.: However, these effects on protein tissue breakdown appeaF to be more prominent when tissues are exposed to pharma:,i cological concentrations of glucagon. At more physiological­concentration) the liver appears to be the major targe~ tissue. ~;.:

--- ---~--- - ....... -. - -.-- .. -.-. · .. ';""·~-:,---"':~-::--:~·?~:}.:::~'-"':: . '-":-~:-'...::·.~--- .. 4. ._ .... -.. ~~·'?'..:"':-<·.;~~.:::~?-- .. . .. . .,_., .· .. ,···~ . . .., .. r:'~.~.--~-=-:-.-:---~----·----. -·---·--

. r o) . -<.'--: \ ev _____ /,~~ ~ , :;:, Y~v---. . ·-------~~. .

ILPf{J.S I ~ \ L _!_=-_ __ j ____ : ____ I .

PARATI-1YRO l DS

--- ...,...... ~ -'C'"·

~ \

··-·--...;;. "'-<..:-,

I

..,..:__ v .. j . . ''\ c.\ I f'_pj-L_:_ . -\ . ;:-+=---~ ····- --·--/ .-· ~ ... -···· --··

~

~ ~~

;,

j. I i

; i I

I !

i ~}-

I

I ~~ f.--:

r k ~~·.

t: f K ::·· f'. I ,, 1:

fc •.. !..: f i

I ' ' ;

~..,

Thyroid gland __ _;,

Parathyroid glands (located on posterior side of the thyroid gland)

~" Chief cell

,,,., Oxyphil cell

G' ro~,~t Red blood cell

Figure 79-10 The four parathyroid glands lie immediately behind the thyroid gland. Almost all of the parathyroid hormone (PTH) is synthesized and secreted by the chief cells. The function of the oxyphil cells is uncertain, but they may be modified or depleted chief cells that no longer secrete PTH.

--.~-.~--- ..... -.~--.~-. -.-~.-...~. -~-.-·-·-··

!\

"i ' . ' q ·. -

1-The parathyroid glands develop at 5-14 weeks of gestation.

2- PTH is a single chain protein (9600 molecular weight) that contains 84 amino acids.

The biologic activity of the hormone resides within a.a.l-34. 3- PTH interacts with receptors on the surface

of the target cells increasing the formation of cAMP, IP & diacylglycerol.

1 !\ 4- PTH is free in plasma with half life 25 m. 5- PTH is essential for life, without it Ca++

falls in plasma neuromuscular excitability t, tetany & death occurs.

6- The dominant regulator ofPTH secretion is the plasma Ca++ level.

7- Ca++ also regulates the size & the number of \. parathyroid cells.

8- Hypomagnesemia stimulates PTH secretion such as Ca++ but less potent.

9- Arise in plasma phosphate concentration indirectly causes a transient t in PTH secretion.

10- 1,25 (OH)2 -D directly redues PTH 1 ~ secretion.

I 1 .----.------ ,.

------------- --------·---~--"---- ------------ --------------- - ------.,-~---:--<>--.;--.-~ .. ---

+ Plasma calcium

-+ Plasma PTH

-+Plasma t Urinary excretion of phosphate 1 ,25-(0Hb 03

+ Urinary excretion of calcium

-+ Release of calcium into plasma

+ Plasma phosphate + Plasma calcium

- - -·_' FIGURE 36.7

metabolism.

Effects of parathyroid hormone (PTH) on calcium and phosphate

-------

'0

'7'

!' 1 1

~ 1

~

\

.-.. ·.i.:.::;. -· . .., b~ ~ ,:, ... !t III('.J; ~!-· •... I .... ,... '!'f ~~

·- ... _,;;:;, 'i::;i !··tl:· ,, I j'< q.i~ -I • . .: j I . I I ·,,.\ ~~-., 1

I oj j•;,· ·:-: ·' ' ·,·i·., __ t .,. .. , . ~-. :·1 .. · .. ·.·. :

•. I < ...• ~ ~

:,; ·_.:. !

·'

.,

PTH .:.:;:::.

·~if, _: ~

............... ~-·;o,l -:. ....... .

. · .. I ·_'f,•)?~'-t Calcium Plaama ~ ~. --: .. =.·.·:-'.:~·; .:--~~.;;.

- .c. i . \

I

\

Kidney ,.

-- ·:·:·:: . ~ ·. ·. ~-~~ _·_·;

FIGURE 38-7 Overvie':" of parathyroid hormone (PTH) actions. PTH acts directly on bone and_:s~·i.~~ kidney to increase calcmm influx into plasma. By stimulating 1,25-(0Hh·D synthesls,.P'I:~.~!=U-.1-~B'-:'t rectly also increases calcium absorption from the gut. Thus plasma calcium level increases~:m.1~~;1:t· contrast, PTH inhibits renal tubular resorption of phosphate, thereby increasing urinary phos-.:h!f: phate excretion. This effect quantitatively offsets entry of phosphate from bone and gut, There~:.'~<;: fore plasma phosphate level decreases. :"· '

_-----.-.. ·....;··

~. .:.• .. ·:·: i·'··.' .. ,. '

. . . ~

• • - ·.I •.

. . :. ~ >·-~ ~ ..... -____ ,,._ , ___ ... - .. ---·---'-------

.. : ·_:+·;~;~~~ l

·.J.

"

~ -..... ·.· ..•. ... .- ,, .. ::,1 .. • · ·. · a ... ,t~t.:-

.. . ·_' · .. !;;:::·.h;~~w

'

\

UNDERACTIVITY of PARATHYROIIDS I .,·.,.:,

Atrophy or ·removal o(Ppra thyroid tisswz causes a fall; in :BLOOD CALClUty( lcz~e .nd incnas(ld ~citability. of Neuromuscular tisswz: .. ·-This !Clads: to: sev<ire :·;·::~< ... •: ...

· :, ;,;:·;.~· convulsive q~~order:::TETANY~: ·:--~;-;);:.:. I I ~~ -~- . ·•t . , ,.1:· ~,,,;~~:\_• ;,·;;:J ;~·~_:'(_·-~~:-·:·

Vsual Manif'rzst.stions;- ·. 1 • .,. ·' •

TWITCHINGS, - ..... . NERVOUSNESS,

'ARATHYROID.! --· .... ·-- ... .. -· . ~-·';"'.~~;";c 'tAr:-~~;~-~- n .. .l.·~:·:

I :·· • . . ' ' '. , .~ ,,·,:~.:~-: ;· -1 .... :! ----;I . - I ., ! I ' • '~~.· i ''''I ,;.J .:- ... ·_._ ... > . . ' I ---- ;; .-· ' i ... '. I I I I~--~--~: ~-!I .. : •,:··· ln"'~"qU"'"...,; · ··1 '"· -·- ---- · · -~·-";-~·:;:.' . c "" at..""' 'ol ' -•··· •• ,,, r

Prod ctlon __ of · .. 60N E ~ - (:~~;;:_:.H~·. PTH .... ._ f./) ·. ,-· .. ; .. t

........ R~tducrz.d ,· :·•: <·: .., "' L •/' ' ·" '· ·. ·. , .. ., moul/t.z~tton

1 · ..... ·; :'-' · !

.. , orCaandP '-,, ··i•·t;··.· .. i '£'/1 '"' .: :'·.-'·:/: ' "" ' ' ·:. :· ...:: "'') .... Increased · .:,;· ::·;·i;.::

.,_.1mounts o~ ' : ·1 :,, 1.--! :·.:.I - l:'.~~nd Pt'n ··. 1 ·.' l·.,:: :

OCCASIONAL SPASMS .. OF FACIAL A~ro . . ' LIMB MUSe ..........

"

bonas · 1 ._.

', • '• ,·' -~ '•1\ ,., : ., \ j' 'II I!'· .. , ''I_'' •

• 1:""\-\1'

\ TETANY ... :.~·}\1 ,• : t ~""fl"t"''•\ ' . ~:_~.._),\~. ··,~·,:. .

Vitamt'n D maiabolitas Dtin/m~h~dl \ . ·:.:\~U.~·J;;;r. notconvartcdto 1 b'!.r /, 1 · -r~·~,;\ 1•.,~··:: S J)J.ICC u u -a ' · ·''··· ·r•

1.-2 1 rgabsorption ofCs \ II' c;unc:.:ntr.»tt'on ·'.ol ·' · : .gncJ" ,/]\\\ \ 1 C~inb/oodr~//s.;,.,···,!~ 1 dacr<used ~ )tl \ 1 balow 6mr;/100m(

1j'·;!

1 phosph_ace /ncr~ase ' 1 • · p/&~mG! ·:'·:·r ·, 1 n '"""""ton · · · · ' 1 ·· ,~ .. ·1 , ..... 1 w.x .. , •'" tn ur;nary \ \ · _ .' · .,-.!·:,_~,: : \ Cc9 \ \ '· ':){\i\~?1;:; \ Ill \ \ ''·. ,. •w . .-... ·. ,'1~.-·~·-/,: ..

\ ' 'l·•·':,l:-:,;:.~ ' \ ...... , .... "•'\''. \ \ , ......... ,~ .. :;.: ..... ~_'"; ' ' . ',.' . .,. '

. "2.... GUT \\, Fall in Concczntration.:.~r/'/ · ~ -~ ' ~ · · d Cal 'urn '· .. )-.. :.:. · ·--,,~ ' .... ~ 10n1ze c1 • ./i'::,,:>·.

, Diminis(lgd ... .. .. # {Ris~ in p/crsma _! 7 :~?(' Hbsorptton of ... •• __ • _...... . phosphat~./- ,::;.;; 1''1"1\l\," d/rztory Ca · -- - - ---- -- _ ___ - .. _ · . , . : .::.·:.·.· ~ J =.':~-~::':(-

. ·- •,.

{Not• Ch• inv•rse rd.-tionshlp b.Cwaen plasma calcium end inorgamf: ph~ sph<> t~. ·. , .•. ·-1·•·, . --:.:j_';-~.:):·.~ ::. ...

Symptoms arrz nz/J~vad hy in;'rzct/on"oi Calcium, Jargrz. doses of a Vit.D colJ??iN:~ pound and Par.athorm.one. · · :-~~;·:nv:, .

. ..... ..-- ' .. ~-~-

·~

(,.::£ • :·

--- .. -.. -......... ·--------··-··--- ........ -··-··--··-··--· ---··.

!\

!\

\

~

\'

I ,. . ,. ';;· :·.

OVERACTIVITY of PARATHYROIDS ...

. ., : 1.! ,, : )·::: ". . .• . . . . ··, · ••

pvczractivity of the Parathyroi~s ( du~ often to tumo_ur) l~_ads ·tq riscz in ~LOOD CALCIUM l~vlil ;a·nd eventually to OSTEITIS FI6RQSA eySTICA . .'::~ ·:_

. ~. t !, i i • . . . . . ; . . I . I I I .. · • I : ... • • • 0

<;~~~·:;) : j ;,;,•, ~:;>i

·'jg',t •: . - • .-;. ~. -~ ·, ;:.~·:I

l: ··:\i /!~;·1; ·:~:t';<::-::··( ,_:;::_=:::·

PARATHYROID; .·<,:t'!; .. ; ;· 1 ,·,::.-:1•\.·.:1,~-:. GLANDS • • r _.,... ' ' . : :!'. . .. · ..

:~:~~.:: ,• I I !>; j.' :i, .. ';': ~~~. ;r. -_:;.~";~:-':~~.:', . Ov~rproduc~.i~~~,. ~ .. , . ·L~~:h)i·.~:.;:·

of PTH --------- BONE '"• · -- - ·'<::_:·.:_·.:: . ~ ~·_, -- ·;.~:;.:~ . . · ..... Greatly lncrrz~t~srzd :~: ·, ·:~--~

mo.6il/zatt'on or _,·_; -: .. C'O' cJnd P ,·· :·:·. ' ··

!!~ (After c:.n qy ASIIf.IUR.sr.) - . : ·:: ·.

\_.~ . OSTEITIS Fl BROSA CYST! CA.!··.:··_. ~~ t . ~~ ~ . ~ ~ Ev~usl .SorctZning· ~,-• ~':I ... : and djrormity or bon~s_,;:· ... ::. · ..

···l·~·-w·~····, ~ GreCitly incrrr,as12d)

t-utJv.lar ,.1/.-.,..._ rqabs9.rpt,.on of ca c;nd (Ybular.~.

srzcnzt'ion ii}J\: t 1 : 25 DHCC ~!!i!Y \\

Gnzat/oss arPin

Vrin12

II

~'ih ~ -···.·

'~ ::;;; .· .. ·.

Great incrq,as!l in Con~ntration

(Plasma Ca may/;~ orv 16mt]/IOOml o+lncr~as¥Zd

of Ca in Blood 1 r- t · .. - . """' ____/ Viscosity of Pta~ma.) vrea rncraosa. tn . . . . .

''ttht e1bsorption or Deposition .of Calc1um 1n

''---~1ert4ry c8 Unusu~l Sitczs e.Q •. K.idney:...,. ., .. , .. ,, .... "'':.::.··"··.... S1gns ofTox1c1ty ....-- .. ·

. . . - (/7-;u.LJ~ifl.~vomitinq,/ass of.;;ppetitrz, etc.)

• Thrz incrrzasczd fqvel of blood calcium eventually lczaCfs.to -exci'ssivcz:-~os­- :-_of CALCIUM .in.URINE(in splt<Z of t reabso:·ption) .:.md also of WATER since thcz. salt -~ excrczted in solution. POLYURIA and THIJ:<ST result. · · ·

Excision of th-e overactiv(Z Parathyroid tissue a.boli'shrzs syndromrz .. ~ ·-·- ---····-··-·.

~ .. <:·.;.;i.-~i / u ,! .. : ~ '·--~ ;<~~~~-~i·:';~ffi\ ~( / ·: .. ·;., '··:r.,~!\1. ~

. ':I·· ........ l,,;s.~~~ r;~ : ·.. '•·F!t·· .• ~~-'·~~. '.- llf~ · · .:. ·: .': •,.',~·\· rl>~4~f:.: '~~: :r: ,

. :. , •.· ., ... ·.~ ;· . ! j !

··---·---

• .. :~::--·:: . ." I ..

'

- ... UL.W- ;;.;:,-f---~-;....j~~~~!i~;;;r;::i --~- ':::-=-:. _: : .'::~;_c~~-~----- -~ ---~------ -- ... ---· ~-···-..-......... ·----~--~---~--

Preosteoclasts

PTH Vitamin D

\I

(

Acid secretion Lysosome

Ruffled membrane Osteoblast

~. ~

~steocytes

Figure 79-5 Bone reso:pt!o:1 by osteoda~ts. Parathyroid hor­mone (PTH) binds to rEceptors on osteobla:::ts, causing them to release osteoprotegerin ligand (OPGL), \·vh!ch binds to receptors on preosteodast celts. This causes thE: cells to differentiate into mature osteodasts. The osteoclasts then develop a ruffled bor­der and release enzymes from lysosomes, as well as acids that promote bone resorption. Osteocytes a:·e osteoblasts that have become encased in bone matrix- du:ing b2tne tissue~ production;

. the osteocytes form a system of inte;-c_:;:·::-,::cted cells that spreads all through the bone.

~

~

"'- ·.• ~'-:011 ' ,_,

• ....... ---.. :---=--- .- - --·-- ~- -

r' '

·•:. • .,Jl ....

~~vifamfn · o Vitamin ··n, in conjunction with PTH, is the sec­

ond major regulatory hormone for Ca2-r and phos­

phate metabolism. The roles of PTH and vitamin D can be distinguished as follows. The role of PTH is to maintain the plasma Ca2 + concentration, and its actions are coordinated to increase the ionized Ca2 +

concel)tr_~tion t.owardnormaL-The role of vitamin D is to promote mineralization of new . bone, ·and its actions are coordinated to increase both Ca2 + and . . phosphate concentrations in pla~ma so that these ~lements can be deposited in new bone mineraL

-- ····------------ """:"

o Bone. In bone, 1,25-dihydroxyrcholecalciferol acts synergistically with PTH to stimulate osteo-. clast activity and bone re:;urption. This· action . may seem paradoxical, since the overall action of 1,25-dihydroxycholecalciferol is to promote bone mineralization. Hovvever, mineralized "old, bone is resorbed to provide n1ore Ca:! +

and phosphate to ECF so that "ne\v" bone can ~ . be mineralized (bone remodeling). _.

.. ,_

(£

~

-' __ c.. :·- -~-" _:::., ______ ...,...;.~~- --' -~~=~i ---;··.·";'·";-

._-,--.,... ----- ~

-... :-: · ---:---·.-:--:- ~--::---:-:-.~-....~~-\3-T/·:--:-: -~···-":'"':~-~--;':-- -- .•.

---.--~-::-~1.:.-~-0'..,~~3:'~~0:1-~....,... ....... ______ . .., ......... -.- ·----------- ---------..-----. ~-

Vitamin D & its Metabolism

1. Vitamin D, is a major regulator of calcium & phosphate metabolism.

2. Vitamin D is a hormone in the sense that it is synthesized in the body, although not by an endocrine gland; after

further processing, it is transported via the circulation to act on target cells.

3. It is a vitamin in the sense that when it cannot be synthesized in sufficient quantities, it must be ingested in

minimal amounts for health to be maintained.

4. Deficiency ofvitatnin D causes failure of bone mineralization & results in the classic disease of rickets in children & softening ofthe bones (osteomalacia) in ad11.!ts.

5. The sterol structure of the synthesized form of vitamin D (D3) differs slightly from the form usually ingested (D2).

6. Vitamins D3 & D2 are essentially prohormones that undergo identical processing that converts them to molecules with identical qualitative & quantitative actions.

7. Once vitamin D enters the circulation from the skin or the gut, it is concentrated in the liver. There it is hydroxylated to 25-0H-D. this molecule is transported to the kidney where it undergoes alternative fates. i ·

8. 24,25-(0H)rD is only 1/20th as potent as 1,25-(0H)2-D & main1y serves to dispose of excess vitamin D.

9. Vitamin D, 25-0H-D & 1,25-(0H)rD circulate bound to a protein carrier. 1,25-(0H)rD has by far the lowest

concentration & the shortest half-life of the three.

..

~

:\

!\

!\

+ Plasma calcium

+Plasma PTH

t + Renal 1 a.-hydroxylase activity

+Urinary excretion of phosphate

t + 1 ,25-(0H)2 0 3 formation

t +Plasma

1 ,25-(0H)2 03

+ Urinary excretion of calcium

+ Plasma calcium

FIGURE 36.9 Effects of 1, 2 5-dihydroxycholecalcifcr•t [t;25-(0H)2 0 3 ] on calcium and pho_

phate metabolism .

/

. '

, ..

------- •.• ---··- •• , ~- -:----~·-:-- -- ... -·--- ., --~. -··. -- -- --- • ' • --.- • "·'7 ., -------- ------7---- ·.· . -. -- . - -~ -~---------- -- --- .. -··-- ----

1--

• ~ ~

i .I

~ J ·!

. . ~

.. •t'· :•! ;_ .

. ,, .....

.... .I '

··~ -f : •• 1 I

. ;- ~ .:..: ..

Dietary suurce · · Intestine · · '''"'~ =~-~-~··1'-~·~"'·~~ .. \~c\fil_:-'

7 Dehydrocholesterol . ' Skiri,· UV light ._ ....

.. _:. '·

; ' :: ! li;; f; p .,J, I ,·,.

\. I~Hiii II ::, .. , ; i:! I I I l·t I\ I ~ I I. >l! J .--- i :: ,f!!!• I

I ;I'! :f.L~}.' i:! '!I

lfl(-Hy r.troxrt~s~

Calcium excess '----....

Phosphate exceu '-----'

_ 24,25-(0H)l-D

~~ il·~~ :·~ ·~', ~~~ ., . ) ,' 'l) :: ; '

- • ,- - --'·- -1

·''• 'o I

1\'; ' ,oi!, ,,,

o o ' ' • 1' ' I , :~ :l -. '.1:' (.-;;~~e>~~ 0

' ,.,, •:·1· ' \II I !·, ll h· I'IL!-~..rl ' ' '; ; ... ·,I.,' ' : ,;·•': \'.1;''-·.~_.!;l ,I ' i 'I' ·i I' 1-•' •,' I' I •J:, II I ·I'.·!~ I ' . . . ' ' I ol '·II.· ··I

. - . . ""' - I . -- •• ! ';.: · .. ·-~I ~- . .

·:

... '1 ~'- .' ;:

; .. ·,i,.

1 1 ,. ~'I

.:: ~ '_-: :' :: .·:.f.\·· '• ... ~--:

,,

;j ' . , I

·-... :,::H::b:· Kidney

Q44hdrdi(Vl§'4

.' l I , < •> 1 ~~;.~=~~~)! ' ' ' .. , ,:•J.\.,;.{, ,· \_;~Qii;it

' -· ·-·:·-v '"'~l:ih,itk'f:J} 0 '~',I ··:.·~-J~ft~?=.-

.·,1~;:c~/ . :],. ··­·:·.

~ Vitamin D deficiency

Calc:lum deflc:lency •

Phosphalo deHclency

Parathyroid hormone

1,25·(0H)2-D _,

FIGURE 38-B Vitamin D metabolism: Whether synthesized ln the skin or absorbed from the d vitamin D under~oes ~5 hydroxylation in tho .:;var. In t.!:e kidney, it is further hydroxylated in 1 position when more biological activity is required or in the 24 position when.. leas b1olc activity Is required.

-~- ---

/--~

~ .. .J~,, .. ,.._1··.;··r ....... ,·:ii'i-'i;:~·.r~l

. . ~:~~~;:-~;I.:

-----;::=..:,....;.. .. ~:::::=::-

---- .... ~-

. · ;~: ~:~ti :L3;:;l.;,;;~~f:'~?<, :, '3;{:'>:A~i~f~\~~~~~;~::~', ':;.' ~;;:s;~;.g~~:iB~~~i:.t~tff'.· f f .I· i

---------·-- ··- -·...;~:~_·.:._a ----.... ----

• TABLE 51-2. Vitamin D: metabolism in humans

1.25.-(0Hh-D3 24,25-(0H)2-D j 25-0H-D3

Plasma concentration (~giL)

0.03 2

20

·- ..... - ___ ...... -. ··-- --. -··---- ...... ---- ··--- ....

·,

J

~ ~

Plasma half-life (days)

1 to 3 15 to 40 5 to 20

~

~ ... ---···--.

....

Estimated production rare (~g!day)

1-1

10

~-

~

~ ......

I

:.\

I: I !'.

i:' !j

l I. I

I.

I

I ~ I

~

-f Plasma calcium

+Plasma PTH

~ + Renal1 a-hydroxylase activity

~ + 1 ,25-(0H)2 0 3 formation

Kidneys

t Phosphate '. reabsorption

t Urinary excretion of phosphate

~ +Plasma

1 ,25-(0H)2 03

t Urinary excretion ofcalcium-

+ Plasma calcium

-. FIGURE 36.9 ·

EH<!cts of 1, 2 5-dihydroxycholecalciferot. [t ,25-(0H)2 0 3 ] on calcium and ph<

phate metabolism.

-.----- .... -~~~.-.-----~.-.-~----·--------------------.---- ·---·----T··----·---- -- ---.------ . .., ___ --- -·---. ··----~- -·-:·· . .,..-., .... ------ --·

fll\:.l·"·''ii'l·'-/(" l · . .- ·".~· -~ ·~'

~ ~ I . '

'

·. ,:/. .. ~ .. ·_ .~. -· ·- .. _.:. ....

J·---·-··

Endocrine Modulation

Pituitary Pancreas Parathyr;oids

\~

Insulin . -. -..=::. ~: ~ ·.

-·

25(0H)D ____ .,... MAMM:.'.Y GlAND

PLACENTA

SKIN

. ·• ·.:".ff:_;=; ~:.1;~:: ~~-AVIAN SHELL GlArlO

···-.-:-;:-.· ... .=-:.:-.~·~:-·.· --

MINERAL TRANSFER

Intestine Kidney Bona I

Mineral Homeostasis ; ' . I

Figu~r· 8A1. Function and regulation of 1 ,25-(0H)2D. (From Haussler and McCain, 1977.) '

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. T_able 7.5 Caus~s of deficiency of 1 : 25-dihydroxycalciferol ·

··Failure to-synthesize chpletalciferol in the skin {this occurs in dar:k-skinned . pe.opfe in a temperature. cli_inate)

Dietary deficiency of c~olecalciferol (relatively unimportant)

Failure to hydroxylate chole~alciferol in the 2? position (this· occurs in chronic liver disease; hepatic· osteodystrophy)

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2. Involved h1 triggering the rel~ase, of· acetylcholine frotn;nerve endings .at the neuro1nuscular junction · .. ·. . ' · .

3. Involved h1 excitation-contraction coupling in· muscle cells ·

4. Serves as an intracellular signal' for some horn1ones

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1. Calcitonin, a straight-chain peptide of 3 2 amino acids, has a molecular weight of3400.

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2. The biologically active core of the n1olecule probably resides in its central region.

3. Calcitonin is secreted by thyroid parafollicular cells known as "C" cells.

4. Calcitonin, (CT), decreases plasma calcium-levels by antagonizing the actions of PTH on bone.

5. Calcitonin is also present in nervous tissue, where ·it may function as a neurotnodulator.

6. The major stimulus to CT secretion is a rise in plasma calcium concentration.

7. The hypocalcemic acti~n is caused by ~ibition both of osteocytic osteolysis & osteoclastic bone resorption particularly when these are stimulated by PTH.

8. However, with respect to phosphate, it has the san1e net effect as PTH; that is, CT decreases plasma phosphate concentration & increases urinary phosphate excretion slightly.

9. The importantfof CT in humans is controversial CT deficiency does not lead to hypercalcetnia & CT hypersecretion does not produce hypocalcemia. It may be that abnormal CT secretion is easily compensated for by adjustment in PTH & vitamin D levels.

1 0. Is degraded within the liver & kidney, after half-life of 3 0-60 minutes.

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By the 1920s, investigators recognized that dietary deficiency of a fat-soluble vitamin Wa5 responsible for the childhood disease rickets. This disorder is characterized clinically by hypocalcemia and multiple skeletal abnormalities. Dietary replacement of vitamin D corrects this disorder and has led to the practice of adding vitamin D to milk, bread, and other products. This practice has greatly reduced the prevalence of this previously common disorder. ~ Our understanding of the involvement of vitamin D in

the regulation of plasma [Ca''J and skeletal physiology has been clarified only over the past 2 decades. Vitamin D exists in the body in two forms, vitamin D3 and vitamin D, (Fig. 52-9). Vitamin D3 can be synthesized from the ?-dehydro­cholesterol that is present in the skin, provided sufficient ultraviolet light is absorbed. This observation explains why nutritional rickets had been a much more prevalent problem in northern countries, where clothing covers much of the ~kin a~ where individuals remain indoors much more of the year. Vitamin D3 is also available from several natural sources, including cod and halibut liver, eggs, and fortified ~tamin D2 is obtained only from the diet, largely from vegetables. Vitamins D3 (Fig. 52-9A) and vitamin D, (Fig. 52-93) differ only in the side chains of ring D. The side chain in vitamin D3 (cholecalciferol) is characteristic of choles­terol, whereas that of vitamin D, (ergocalciferol) is charac­teristic of plant sterols.

Vitamin D (i.e., either D, or D3) is fat soluble but water insoluble. Its absorption from the intestine depends on its solubilization by bile salts (see Chapter 45). In the circula­ti-cn, vitamin D is found either solubilized with chylomi­cwns (see Chapter 46) or associated with a plasma binding

protein. Most of the body stores of vitamin D are located in body fat. The body's pools of vitamin D are large, and only 1% to 2o/o of the body's vitamin D is turned over each

'""da?' Therefore, several years of very low dietary intake (as well as diminished endogenous synthesis) is required before the endogenous pools are depleted and deficiency develops. ~ In addition to vitamins D2 and D3 and their respeaive

j 25-hydroxy and 1,25-dihydroxy metabolites, more than IS other metabolites of vitamin D have been identified in plasma. However, the specific physiological function of these

. metabolites, if any, is unclear.

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Osteomalacia ID . .

*Osteomalacia is rickets in adults and is frequently called "adult rickets." . .

Normal adults rarely have a serious dietary deficiency of vitamin D or calcium because large quantities of calciu& are not needed for bone growth as in children. However, a seri­~ deficiency of both vitamin D and calcium occasForuiTiy OCcurs as a result of steatorrhea (failure to absorb fat), for vitamin D is fat-soluble, and calcium tends to form insolu­ble soaps with fat;,· consequently, in steatorrhea ~.pth vita­min D and calcium tend to pass into the feces:-D_lli4rr these conditions an adult occasionally has such poor carcium and phosphate absorption that adult rickets can occur, though this almost never proceeds to the stage of tetany-but very often is a cause of severe bone disability.

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fliCKETS ·. CD . ~~occurs nwinly in children as a result o~ calcium or phosphate~eficiency in the extracellular fluid~- Yet, ordi­narily rickets is due to lack of vitarnin D, rather than a

. dietary lack of calciutn or phosphate. If the child is-properly exposed to sunlight, the 7-dehydrocholesterol in the skin becmnes activated by the ultraviolet rays and forms vitamin D3 , which prevents rickets by promoting calcium and phos­phate absorption fron1 the intestines, as discussed earlier in the chapter. .

6)Chi1Jren. who rernain indoors through the winter in gen­era1 do not receive adequate quantities of vitaliffin D without son1e suppletnentary therapy in the diet~i2Kets tends to occur especially in the spring months because vitamin D fanned during the preceding summer· is stored in the liver ancl is still available for use during the early winter months. Also, calciuxn and phosphate absorption from the bones can prevent clinical signs of rickets for the first few months of vitmnin D deficiency.

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