Hype r ur i c e mi a i n Hypot hyr oi di s m:I s I t As s oc i at e d wi t h Pos t - I ns ul i n I nf us i on Gl yc e mi c Re s pons e?

Hype r ur i c e mi a i n Hypot hyr oi di s m:I s I t As s oc i at e d wi t h Pos t - I ns ul i n I nf us i on Gl yc e mi c Re s pons e?

N

D

,G

A

,A

B

Ç

,H

H

and G

B

Depar tment of Physiology, Depar tment of Biochemistr y, Cer r ahpas

a Medical Faculty, I stanbul Univer sity, Depar tment of Car diology, Flor ance Nightingale Hospital, Kadir Has Univer sity, Depar tment of Inter nal Medicine, Cer r ahpas

a Medical Faculty, I stanbul Univer sity, I stanbul, Tur key

D

,N. ,A

,G. ,Ç

,A. B. ,H

,H.and B

,G.

Hyper ur icemia in Hypothyr oidism: Is It Associated with Post-Insulin Infusion Glycemic Response ? Tohoku J .Exp.Me d. ,2 0 0 3 ,1 9 9( 2 ) ,5 9 -6 8 Thi s e xpe r i - me nt al s t udy was de s i gne d t o e xami ne whe t he r hype r ur i c e mi a i n hypot hyr oi di s m i s as s oc i at e d wi t h i ns ul i n r e s i s t anc e . For i nduc t i on of hypot hyr oi di s m,r abbi t s ( n＝1 2 )we r e admi ni s t e r e d me t hi maz ol e or al l y( 7 5 mg/1 0 0 g f ood)f or 3 0 days . T , T and TSH val ue s me as ur e d i n pl as ma pr i or t o and at t he e nd of t he e xpe r i me n- t at i on pe r i od r e ve al e d t he e s t abl i s hme nt of hypot hyr oi di s m. I n t he e ut hyr oi d and hypot hyr oi d s t at e s of r abbi t s ,c r ys t al l i ne por c i ne i ns ul i n was admi ni s t e r e d( 0 . 1 uni t /kg body we i ght )i nt r ape r i t one al l y and pl as ma gl uc os e was me as ur e d at 0 , 1 5 , 3 0 , 4 5 and 6 0 mi nut e s . Sum of pos t i ns ul i n i nf us i on gl uc os e val ue s was c ons i de r e d t o r e fle c t i ns ul i n r e s i s t anc e . Cr e at i ni ne c l e ar anc e( GFR)and ur i c ac i d c l e ar anc e ( C )we r e de t e r mi ne d. Addi t i onal l y,t r i gl yc e r i de s we r e me as ur e d i n pl as ma and Mg bot h i n e r yt hr oc yt e s and i n pl as ma. Due t o hypot hyr oi di s m: i )The gl yc e mi c r e s pons e t o i ns ul i n was not al t e r e d. i i )GFR and C we r e bot h de c r e as e d but C / GFR unc hange d. i i i )Tr i gl yc e r i de s i n pl as ma de c r e as e d. i v)Mg c onc e nt r at i on i nc r e as e d i n pl as ma whe r e as de c r e as e d i n e r yt hr oc yt e s . Se ve r al as s oc i at i ons we r e obs e r ve d be t we e n t he var i abl e s on c or r e l at i on anal ys i s . On t he bas i s of our dat a,i t c oul d be s ugge s t e d t hat i ns ul i n r e s i s t anc e doe s not e xi s t i n hypot hyr oi di s m.

Hype r ur i c e mi a obs e r ve d i n hypot hyr oi di s m s houl d be c ons i de r e d t o be s e c ondar y t o de c r e as e d r e nal e xc r e t i on but not as an i ndi c at or of i ns ul i n r e s i s t anc e .

hypot hyr oi di s m;hype r ur i c e mi a;pos t i ns ul i n i nf us i on gl yc e mi c r e s pons e ;t r i gl yc e r - i de s ;magne s i um

2 0 0 3 Tohoku Uni ve r s i t y Me di c al Pr e s s

Recei ved Sept ember 25,2002;r evi s i on accept ed f or publ i cat i on Febr uar y 12,2003.

Addr es s f or r epr i nt s :Nur an Dar ı yer l i ,Depar t ment of Phys i ol ogy,Cer r ahpa a Medi cal Facul t y, I s t anbul Uni ver s i t y,Bos na bul var ı At a 2 Si t es i ,Er guvan cad.79/7 Çengel koy,Us kudar ,I s t anbul ,Tur key.

e- mai l :dar i yer l i ＠yahoo. com

59

Hype r ur i c e mi a and i ns ul i n r e s i s t anc e ar e s t r i ki ngl y as s oc i at e d,as obs e r ve d i n obe s i t y, hype r t r i gl yc e r i de mi a,i mpai r e d gl uc os e t ol e r - anc e and hype r t e ns i on. Addi t i onal l y,hype r ur - i c e mi a and i ns ul i n r e s i s t anc e ar e bot h mor e c ommon i n me n t han i n pr e me nopaus al wome n ( Mi kke l s on e t al .1 9 6 5 ;Modan e t al .1 9 8 7 ) . Re c e nt l y, hype r ur i c e mi a has be e n s ugge s t e d as a s i mpl e mar ke r of i ns ul i n r e s i s t anc e i n non- di abe t i c s ubj e c t s e ve n i n t he abs e nc e of s i gns and s ympt oms of gout( Vuor i ne n- Mar kkol a and Yki - J ar vi ne n 1 9 9 4 ) . Ear l i e r s t udi e s have s hown t hat bot h abnor mal c ar bohydr at e t ol e r anc e ( Shah e t al .1 9 7 5 )and hype r ur i c e mi a( Er i c ks on e t al .1 9 9 4 ;Yokogos hi and Sai t o 1 9 9 6 )e xi s t i n pat i e nt s wi t h hypot hyr oi di s m. Howe ve r ,i t i s unknown whe t he r hype r ur i c e mi a pr e di c t s i ns u- l i n r e s i s t anc e i n hypot hyr oi di s m. I n t hi s c on- t e xt ,t he pr e s e nt s t udy was de s i gne d t o e xami ne whe t he r hype r ur i c e mi a i n hypot hyr oi di s m i s as s oc i at e d wi t h t he r e s pons e t o i nt r ave nous l y admi ni s t e r e d i ns ul i n as me as ur e d by pl as ma gl uc os e l e ve l s( Shah e t al .1 9 7 5 ) . Addi t i onal l y c ons i de r i ng t he ke y r ol e of i nt r ac e l l ul ar Mg i n i ns ul i n me di at e d gl uc os e upt ake( Paol i s s o and Ravus s i n 1 9 9 5 ) ,whe t he r e r yt hr oc yt e Mg c on- c e nt r at i on i s as s oc i at e d wi t h t he gl yc e mi c r e s pons e t o admi ni s t e r e d i ns ul i n i n hypot hyr - oi di s m was al s o de t e r mi ne d.

To i nve s t i gat e t he s e as s oc i at i ons i n a we l l de fine d s ys t e m we c hos e t o s t udy i n a r abbi t mode l of hypot hyr oi di s m i nduc e d by me t hi m- az ol e . Thus obe s i t y unt r e at e d hype r t e ns i on, e l e vat e d t r i gl yc e r i de s and i mpai r e d gl uc os e t ol - e r anc e r e l at e d t o hype r ur i c e mi a on one hand and hype r i ns ul i ne mi a on t he ot he r ar e be i ng avoi de d and di r e c t l y hypot hyr oi di s m i nduc e d i nt r ai ndi vi dual c hange s c oul d be s hown up ( Vuor i ne n- Mar kkol a and Yki - J ar vi ne n 1 9 9 4 ) .

M ATERI ALS AND M ETHODS

Animals and exper imental design

Twe l ve r abbi t s ,1 mont h ol d and 1 . 8 -2 kg body we i ght we r e obt ai ne d f r om t he Labor at or y Ani mal Se r vi c e of t he Uni ve r s i t y of I s t anbul .

The r abbi t s c ar e d f or i n ac c or danc e wi t h t he Gui de f or t he Car e and Us e of Labor at or y Ani mal s( 1 9 9 6 )we r e pe r mi t t e d ad l i bi t um ac c e s s t o f ood and dr i nki ng wat e r f or 1 0 days pr i or t o e xpe r i me nt al pr oc e dur e . Rabbi t s we r e t r e at e d wi t h me t hi maz ol e f or 3 0 days ( 7 5 mg/1 0 0 g f ood) . Pr i or t o me t hi maz ol e t r e at me nt and at t he e nd of t he e xpe r i me nt at i on pe r i od t he f ol - l owi ng we r e done :

Twe nt y f our hour ur i ne c ol l e c t i on:Pr i or t o ur i ne c ol l e c t i on,t he ur i nar y bl adde r was fir s t e mpt i e d c ompl e t e l y t hr ough an i ndwe l l i ng s t e r - i l e c at he t e r and t he n t he r abbi t put i nt o t he s pe c i al pl e xi gl as s c age f or 2 4 hour s . At t he e nd of t hi s pe r i od t he bl adde r was r e - e mpt i e d and t hi s por t i on was adde d t o t hat c ol l e c t e d i n t he c age .

Bl ood s ampl i ng:Af t e r an ove r ni ght f as t , be t we e n 9 -1 1 a. m. he par i ni z e d bl ood s ampl e s we r e t ake n f r om e ac h e xpe r i me nt al ani mal by he ar t punc t ur e f or t he anal ys i s of bi oc he mi c al par ame t e r s .

Me as ur e me nt of pos t - i ns ul i n i nf us i on gl yc e mi c r e s pons e :For t he de t e r mi nat i on of t he gl yc e mi c r e s pons e t o admi ni s t e r e d i ns ul i n,c r ys - t al l i ne por c i ne i ns ul i n( 0 . 1 uni t /kg body we i ght ) was r api dl y admi ni s t e r e d i nt r ape r i t one al l y.

He par i ni z e d bl ood was obt ai ne d vi a t he e ar ve i n at 1 5 mi nut e s i nt e r val s f or 6 0 mi nut e s and pl as ma gl uc os e i mme di at e l y me as ur e d. Sum of 0 , 1 5 , 3 0 , 4 5 and 6 0 mi nut e s pos t - i ns ul i n i nf u- s i on gl uc os e l e ve l s ( gl yc e mi c r e s pons e )was c ons i de r e d as t he me as ur e of t he r e s pons e t o i ns ul i n,t he hi ghe r t he gl yc e mi c r e s pons e t he mor e i ns ul i n r e s i s t ant t he s ubj e c t( Shah e t al . 1 9 7 5 ) . The t e s t s we r e pe r f or me d at t he s ame t i me of t he day i n al l c as e s t o avoi d c i r c adi an fluc t uat i ons .

Biochemical analysis

Pl as ma,s e par at e d pr ompt l y by l ow s pe e d

c e nt r i f ugat i on and ke pt at 4 ° C was anal ys e d f or

T ,T ,TSH,ur i c ac i d,c r e at i ni ne and t r i gl yc e r -

i de s and ur i ne f or ur i c ac i d and c r e at i ni ne .

Mg was anal ys e d bot h i n t he pl as ma and t he

e r yt hr oc yt e s . The e r yt hr oc yt e s af t e r be i ng was he d t hr e e t i me s wi t h 9 g/l i t e r NaCl we r e he mol ys e d by di l ut i on wi t h f our f ol d wat e r and e r yt hr oc yt e Mg e xpr e s s e d as mg/g Hb. T , T and TSH anal ys e s we r e pe r f or me d by RI A.

Ur i c ac i d,c r e at i ni ne ,t r i gl yc e r i de ,Mg ,gl uc os e was me as ur e d by s pe c t r ophot ome t r i c al me t hods us i ng t he r e s pe c t i ve ki t s( Randox,Cr uml i n,UK) and he mogl obi n anal ys i s .

Statistical analysis

The i ndi vi dual c hange s i nduc e d by me t hi m- az ol e we r e s t at i s t i c al l y e val uat e d by St ude nts pai r e d t - t e s t . Pe ar s on- Br avi s c or r e l at i on c of - f i c i e nt was de t e r mi ne d t o de fine t he r e l at i on- s hi ps among t he var i abl e s me as ur e d.

R ^ESULTS

Pr i or t o admi ni s t r at i on of me t hi maz ol e , t he bas e l i ne pl as ma val ue s of T ,T and TSH we r e f ound t o be 6 3 . 0 8 ±1 2 . 0 0 ng/1 0 0 ml ,2 . 4 4 ±0 . 4 8 μg/1 0 0 ml and 0 . 0 2 ±0 . 0 1μI U/ml ,r e s pe c t i ve l y.

At t he e nd of t he e xpe r i me nt al pe r i od t he me as ur e d val ue s f or T ,T and TSH we r e ( 4 7 . 2 4 ±1 0 . 6 8 ng/1 0 0 ml ) ( 1 . 5 2 ±0 . 5 2μg/1 0 0 ml ) and ( 0. 07 ±0. 02μI U/ml ) , r es pect i vel y. A s i gni fic ant de c r e as e i n bot h T ,and T but a s i gni fic ant i nc r e as e i n TSH c onfir me d t he e s t ab-

l i s hme nt of pr i mar y hypot hyr oi di s m i n t he ani - mal s( Tabl e 1 ) .

As s hown i n Tabl e 1 due t o t he e s t abl i s he d hypot hyr oi di s m,ur i c ac i d c onc e nt r at i on was f ound t o be s i gni fic ant l y( p＜0 . 0 0 1 )i nc r e as e d i n t he pl as ma( Fi g. 1 a)whe r e as( p＜0 . 0 5 )de c r e as e d s i gni fic ant l y i n t he ur i ne( Fi g. 1 b) . Ur i c ac i d c l e ar anc e was f ound t o be s i gni fic ant l y( p＜0 . 0 0 1 )de c r e as e d due t o hypot hyr oi di s m ( Fi g. 1 c ) . Gl ome r ul ar fil t r at i on r at e was al s o f ound t o be l owe r i n t he hypot hyr oi d s t at e whe n c ompar e d t o t he e ut hyr oi d s t at e( p＜0 . 0 5 ) . Howe ve r , f r ac - t i onal e xc r e t i on of ur i c ac i d as de t e r mi ne d by C /gl ome r ul ar fil t r at i on r at e( C /GFR)was f ound t hat not t o be al t e r e d( Fi g. 1 d) . Sum of 0 , 1 5 , 3 0 , 4 5 and 6 0 mi nut e s pos t i ns ul i n i nf us i on gl uc os e l e ve l s we r e f ound not t o be al t e r e d due t o t he i nduc t i on of hypot hyr oi di s m ( Fi g. 1 e ) . Pl as ma t r i gl yc e r i de c onc e nt r at i on was f ound t o be de c r e as e d( p＜0 . 0 1 )due t o hypot hyr oi di s m ( Fi g. 1 f ) . Pl as ma Mg c onc e nt r at i on was f ound t o be i nc r e as e d( p＜0 . 0 1 )whe r e as e r yt h- r oc yt e Mg de c r e as e d( p＜0 . 0 1 )due t o hypot h- yr oi di s m ( Fi gs . 1 g and 1 h) .

As t o our findi ngs on c or r e l at i on anal ys i s ( Tabl e s 2 and 3 ) :Pos t i ns ul i n i nf us i on s um gl u- c os e val ue s we r e f ound t o be c or r e l at e d wi t h TSH val ue s i n t he hypot hyr oi d s t at e( r＝0 . 7 6 ,

T

1. The Labor ator y data in euthyr oid and hypothyr oid states of exper imental animals

Par amet er Eut hyr oi d Hypot hyr oi d T ( ng/100 ml ) 63. 08±12. 00 47. 24±10. 68 T ( μg/100 ml ) 2. 44±0. 48 1. 52±0. 52 TSH ( μI U/ml ) 0. 02±0. 01 0. 07±0. 02 Ur i c aci d( pl as ma) ( mg/100 ml ) 0. 55±0. 17 0. 84±0. 20 Ur i c aci d( ur i ne) ( mg/100 ml ) 10. 51±2. 68 7. 81±1. 93 Cl ear ence of ur i c aci d( C ) ( ml /mi n. ) 1. 93±0. 56 0. 97±0. 48 Cl ear ence of cr eat i ni ne( GFR) ( ml /mi n. ) 5. 77±3. 20 2. 90±2. 31

C /GFR 0. 60±0. 07 0. 77±0. 07

Sum Gl ucos e 409±79. 4 352. 3±71. 9 Tr i gl ycer i des( mg/100 ml ) 76. 75±23. 20 42. 24±14. 86 Mg Pl as ma( mg/100 ml ) 1. 90±0. 4 2. 5±0. 5 Mg Er yt hr oyct e( mg/g Hb) 0. 70±0. 1 0. 50±0. 2

Dat a ar e t he means ±

.( n＝12) .

p ＜0. 05. p ＜0. 01. p ＜0. 001.

Fi g.1. Hypot hyr oi di s m i nduced i nt r ai ndi vi dual changes i n t he par amet er s .

a,Pl as ma ur i c aci d;b,Ur i nar y ur i c aci d;c,Cl ear ance of ur i c aci d;d,C /GFR;e,Sum

gl ucos e;f ,Tr i gl ycer i des ;g,Pl as ma magnes i um;h,Er yt hr ocyt e magnes i um.

p＜0 . 0 1 ) . Pos t i ns ul i n i nf us i on s um gl uc os e val ue s we r e f ound t o be c or r e l at e d wi t h GFR i n t he hypot hyr oi d s t at e( r＝0 . 7 5 ,p＜0 . 0 0 1 ) . Tr i g- l yc e r i de val ue s we r e f ound t o be i nve r s e l y c or - r e l at e d wi t h T val ue s i n t he hypot hyr oi d s t at e ( r＝−0 . 6 0 ,p＜0 . 0 5 )and c or r e l at e d wi t h TSH val ue s i n t he e ut hyr oi d s t at e( r＝0 . 6 1 ,p＜0 . 0 5 ) . Pl as ma ur i c ac i d c onc e nt r at i on was f ound t o be c or r e l at e d t o T val ue s bot h i n t he hypot hyr oi d and e ut hyr oi d s t at e s( r＝0 . 7 2 ,p＜0 . 0 1 ,r＝0 . 5 8 , p＜0 . 0 5 ) ,r e s pe c t i ve l y. Pl as ma Mg val ue s we r e f ound t o be c or r e l at e d wi t h e r yt hr oc yt e Mg val ue s i n t he e ut hyr oi d s t at e( r＝0 . 6 1 ,p＜

0 . 0 5 ) . Pl as ma and e r yt hr oc yt e Mg val ue s we r e f ound t o be i nve r s e l y c or r e l at e d wi t h GFR val ue s i n t he e ut hyr oi d s t at e( r＝−0 . 5 9 p＜0 . 0 5 , r＝−0 . 7 0 p＜0 . 0 1 ) ,r e s pe c t i ve l y. Pl as ma and e r yt hr oc yt e Mg val ue s we r e bot h f ound t o be i nve r s e l y c or r e l at e d wi t h T val ue s i n t he e ut h- yr oi d s t at e( r＝−0 . 6 5 p＜0 . 0 5 ,r＝−0 . 7 5 p＜0 . 0 1 ) ,r e s pe c t i ve l y. Er yt hr oc yt e Mg val ue was f ound t o be i nve r s e l y c or r e l at e d wi t h T val ue i n t he hypot hyr oi d s t at e ( r＝−0 . 6 3 , p＜0 . 0 5 ) . Er yt hr oc yt e Mg val ue was f ound t o be c or - r e l at e d wi t h pl as ma ur i c ac i d val ue i n t he e ut h- yr oi d s t at e( r＝0 . 5 9 ,p＜0 . 0 5 ) .

D I SCUSSI ON

Lowe r e d l e ve l s of T , T and e l e vat e d TSH s how t hat hypot hyr oi di s m has be e n e s t abl i s he d i n r abbi t s ,admi ni s t e r e d me t hi maz ol e f or 3 0 days . I n r abbi t s as t he nor mal r ange of pl as ma ur i c ac i d c onc e nt r at i on i s 0 . 5 8 -0 . 7 8 mg/1 0 0 ml our findi ngs c l e ar l y s how t he de ve l opme nt of hype r ur i c e mi a due t o t he i nduc t i on of hypot hyr - oi d s t at e( Akde mi r e t al .2 0 0 1 ) . Hype r ur i c e mi a i n hypot hyr oi di s m i s a we l l - e s t abl i s he d phe nom- e non. I n c ompar i s on t o t he pr e val e nc e r e por t - e d i n t he ge ne r al popul at i on,a s i gni fic ant i nc r e as e of bot h hype r ur i c e mi a and gout has be e n r e por t e d i n t he hypot hyr oi d pat i e nt s i n nume r ous c l i ni c al s t udi e s( Gi or dano e t al .2 0 0 1 ) . Pl as ma ur i c ac i d c onc e nt r at i on i nc r e as e s due t o an i nc r e as e i n ur i c ac i d pr oduc t i on and/or a de c r e as e i n ur i c ac i d e xc r e t i on( Fac c hi ni e t al .

1 9 9 1 ) . Si nc e t he e xc r e t e d amount of ur i c ac i d i n ur i ne has be e n f ound t o de c r e as e due t o hypot hyr oi di s m, we c ons i de r t hat hype r ur i c e mi a doe s not r e s ul t f r om ove r pr oduc t i on but f r om de c r e as e d c l e ar anc e i n t he hypot hyr oi d s t at e . As t he f r ac t i onal e xc r e t i on of ur i c ac i d( C / GFR)was f ound t o be s i mi l ar i n hypot hyr oi d and e ut hyr oi d s t at e s ,i t appe ar s t hat de c r e as e d GFR ac c ount s f or t he de c r e as e d ur i c ac i d c l e ar - anc e obs e r ve d i n t he hypot hyr oi d s t at e . Hype r - ur i c e mi a as s oc i at e d wi t h hypot hyr oi di s m has al s o be e n s hown t o be due t o t he de c r e as e d r e nal ur i c ac i d c l e ar anc e i n e ar l i e r s t udi e s( Yokogos hi and Sai t o 1 9 9 6 ;Gi or dano e t al .2 0 0 1 ) . Fur t he r , we obs e r ve d t hat T i s pos i t i ve l y c or r e l at e d t o pl as ma ur i c ac i d bot h i n t he e ut hyr oi d and hypot hyr oi d s t at e s( r＝0 . 5 8,r＝0 . 7 2 ) ,r e s pe c - t i ve l y. Thi s s ugge s t s t hat t he de c r e as e i n me t abol i c r at e and ATP t ur nove r i s gr e at e r t han t he de c r e as e i n gl ome r ul ar fil t r at i on wi t h de pr e s s i on i n T i n bot h t he e ut hyr oi d and hypot hyr oi d s t at e s .

As t o pos t i ns ul i n i nf us i on s um gl uc os e

val ue s ,r e gar de d as a me as ur e of t he r e s pons e t o

i ns ul i n,we obs e r ve d no s i gni fic ant di f f e r e nc e

be t we e n t he e ut hyr oi d and hypot hyr oi d s t at e s of

r abbi t s . Howe ve r t hough non- s i gni fic ant t he

pos t - i ns ul i n i nf us i on s um gl uc os e val ue was

f ound t o be l owe r e d t o a c ons i de r abl e e xt e nt

due t o i nduc t i on of hypot hyr oi di s m. The i n-

duc e d l e ve l of hypot hyr oi d s t at e mi ght have

be e n obs e r ve d t o c aus e a s i gni fic ant de c r e as e

wi t h hi ghe r numbe r of ani mal s t han us e d i n t hi s

s t udy. Thi s s ugge s t i on i s c ons i s t e nt wi t h t he

f ac t t hat s e ns i t i vi t y t o e xoge nous i ns ul i n mi ght

be i nc r e as e d due t o s l owe r de gr adat i on of i ns u-

l i n i n hypot hyr oi di s m ( I ngbor 1 9 8 5 ) . Shah and

Ce r c hi o ( 1 9 7 3 )s ugge s t e d t hat gl uc os e i nt ol e r -

anc e of t he hypot hyr oi d s t at e i s due t o di mi ni -

s he d i ns ul i n s e c r e t i on r at he r t han t o r e s i s t anc e .

Shah e t al .( 1 9 7 5 )e xami ne d t he pos s i bi l i t y of

i ns ul i n r e s i s t anc e i n hypot hyr oi d pat i e nt s and

r e por t e d t he abs e nc e of any e vi de nc e of r e s i s -

t anc e t o t he ac t i on of e xoge nous l y admi ni s t e r e d

i ns ul i n i n hypot hyr oi d pat i e nt s but an i nc r e as e d

s e ns i t i vi t y t o i ns ul i n. Ac c or di ngl y,t he pos i t i ve c or r e l at i on of pos t - i ns ul i n i nf us i on s um gl uc os e wi t h GFR ( r＝0 . 7 5 )whi c h was f ound t o be l owe r e d due t o hypot hyr oi di s m i ndi r e c t l y s up- por t s t he de c r e as e i n s um gl uc os e val ue s ,

r e fle c t i ng i nc r e as e d s e ns i t i vi t y t o e xoge ne ous i ns ul i n i n hypot hyr oi di s m.

On t he ot he r hand,t he pr e s e nc e of a pos i - t i ve c or r e l at i on be t we e n TSH and s um gl uc os e val ue s i n t he hypot hyr oi d s t at e ( r＝0 . 7 6 )

T

2. Cor r elation coefficients among

T T TSH Ur i c aci d ( pl as ma)

Ur i c aci d ( ur i ne)

T 1 0. 21 −0. 04 0. 42 0. 38

T 1 0. 26 0. 58 0. 06

TSH 1 0. 06 0. 44

Ur i c aci d( pl as ma) 1 0. 30

Ur i c aci d( ur i ne) 1

Cl ear ance of ur i c aci d( C ) Cl ear ance of cr eat i ni ne( GFR) CuA/GFR

Sum gl ucos e Tr i gl ycer i des Mg Pl as ma Mg Er yt hr ocyt e

T

3. Cor r elation coefficients among

T T TSH Ur i c aci d ( pl as ma)

Ur i c aci d ( ur i ne)

T 1 0. 64 −0. 17 0. 50 0. 36

T 1 −0. 05 0. 72 0. 34

TSH 1 0. 21 0. 46

Ur i c aci d( pl as ma) 1 0. 56

Ur i c aci d( ur i ne) 1

Cl ear ance of ur i c aci d( C ) Cl ear ance of cr eat i ni ne( GFR) CuA/GFR

Sum gl ucos e

Tr i gl ycer i des

Mg Pl as ma

Mg Er yt hr ocyt e

mi ght appe ar c ont r adi c t or y t o above . How- e ve r ,t he we l l - e s t abl i s he d dos e - de pe nde nt dual ac t i ons of t hyr oi d hor mone s on var i ous me t a- bol i c e ve nt s s houl d be c ons i de r e d. I n r e l at i on t o gl uc os e ut i l i s at i on t hyr oi d hor mone s bot h

pot e nt i at e t he ac t i ons of i ns ul i n and al s o e nhanc e t he de gr adat i on of i t . The de c r e as e i n pot e nt i at i on of i ns ul i n,by t hyr oi d hor mone s may ac c ount f or t he pos i t i ve c or r e l at i on be t we e n TSH and s um gl uc os e s e e n i n t he the par ameter s in euthyr oid state

Cl ear ance of ur i c aci d

Cl ear ance of

cr eat i ni ne CuA/GFR Sum gl ucos e Tr i gl ycer i des Mg Pl as ma Mg Er yt hr oci t e

−0. 01 0. 04 0. 18 −0. 43 0. 14 −0. 26 −0. 41

−0. 26 0. 46 −0. 13 −0. 46 0. 54 −0. 65 −0. 75

−0. 12 −0. 25 0. 41 −0. 26 0. 61 −0. 19 0. 20

−0. 36 0. 45 0. 17 −0. 50 0. 32 −0. 33 0. 59 0. 35 0. 02 0. 51 0. 05 0. 11 0. 31 −0. 05

1 0. 12 0. 30 0. 34 −0. 39 0. 39 −0. 08

1 0. 08 0. 03 0. 37 −0. 59 −0. 70

1 −0. 26 0. 07 0. 21 0. 13

1 −0. 10 0. 45 0. 54

1 −0. 29 −0. 27

1 0. 61

1

the par ameter s in hypothyr oid state

Cl ear ance of ur i c aci d

Cl ear ance of

cr eat i ni ne CuA/GFR Sum gl ucos e Tr i gl ycer i des Mg Pl as ma Mg Er yt hr oci t e

0. 07 −0. 45 −0. 04 −0. 33 −0. 60 −0. 07 −0. 63

−0. 24 0. 28 0. 12 −0. 53 −0. 43 −0. 05 −0. 40 0. 16 0. 54 −0. 47 0. 76 0. 21 −0. 52 0. 002

−0. 10 0. 02 0. 15 −0. 33 −0. 19 0. 05 −0. 40 0. 01 −0. 44 0. 41 −0. 39 0. 11 −0. 30 −0. 29 1 0. 20 −0. 10 0. 11 0. 10 −0. 22 −0. 32

1 −0. 31 0. 75 0. 37 0. 02 0. 47

1 −0. 35 −0. 02 0. 001 0. 01

1 0. 49 −0. 36 0. 40

1 −0. 11 0. 51

1 0. 31

1

p ＜0. 05. p ＜0. 01.

hypot hyr oi di s m- i nduc e d ani mal s .

We obs e r ve d t hat de ve l opme nt of t he hypot hyr oi d s t at e was ac c ompani e d by a de c r e as e i n t r i gl yc e r i de c onc e nt r at i on of t he pl as ma. I n ac c or danc e wi t h t hi s findi ng Dor y and Rohe i m ( 1 9 8 1 )and Ros e nqvi s t e t al .( 1 9 8 1 ) al s o r e por t e d r e duc t i on i n pl as ma t r i gl yc e r i de s i n e xpe r i me nt al hypot hyr oi di s m. Pl as ma t r i g- l yc e r i de c onc e nt r at i on de c r e as e s due t o a de c r e as e i n pr oduc t i on and s e c r e t i on of VLDL f r om l i ve r and/or an i nc r e as e i n l i popr ot e i n l i pas e( LPL)ac t i vi t y. I n t he hypot hyr oi d s t at e t he de c r e as e i n pl as ma t r i gl yc e r i de c onc e nt r a- t i on c oul d be due t o t he de c r e as e d de l i ve r y of VLDL t o t he c i r c ul at i on. As hype r t r i gl yc e r - i de mi a i s ge ne r al l y as s oc i at e d wi t h i ns ul i n r e s i s - t anc e de c r e as e d t r i gl yc e r i de s i n t hi s s t udy,i n- di r e c t l y s uppor t t he abs e nc e of i ns ul i n r e s i s t anc e i n t he i nduc e d l e ve l of hypot hyr oi d s t at e . On ot he r hand,i n t he hypot hyr oi d s t at e we obs e r - ve d an i nve r s e c or r e l at i on be t we e n T and t r i g- l yc e r i de c onc e nt r at i ons . Whi c h i mpl i e s t hat s e r um t r i gl yc e r i de s t e nd t o i nc r e as e as hypot h- yr oi d s t at e be c ome s mor e s e ve r c e . I n t he e ut h- yr oi d s t at e i n l i ne wi t h t hi s c or r e l at i on,we obs e r ve d a pos i t i ve c or r e l at i on be t we e n TSH and t r i gl yc e r i de . The s e findi ngs ar e agai n c on- s i s t e nt wi t h t he dos e - de pe nde nt dual ac t i ons of t hyr oi d hor mone s . Bot h t he s ynt he s i s and de g- r adat i on of l i pi ds ar e de pr e s s e d i n s t at e s of t hyr oi d hor mone de fic i e nc y. Howe ve r ,as t he l at t e r i s e s pe c i al l y de pr e s s e d t he ne t e f f e c t i s an i nc r e as e i n t he s t or e s of mos t l i pi ds and us ual l y t he i r c onc e nt r at i ons i n pl as ma. Ac c or di ngl y I ngbor e t al .( 1 9 8 5 )r e por t e d t hat hype r t r i gl yc e r - i de mi a i n hypot hyr oi di s m i s due t o l owe r e d l i popr ot e i n l i pas e ac t i vi t y whi c h ne c e s s i t at e s avai l abi l i t y of ade quat e t hyr oi d hor mone s .

As t o Mg ,t he i nduc t i on of hypot hyr o- i di s m c aus e d an i nc r e as e i n pl as ma c onc e nt r a- t i on,whe r e as a de c r e as e i n t he e r yt hr oc yt e c onc e nt r at i on. We have pr e vi ous l y al s o r e por t - e d an i nc r e as e i n pl as ma Mg c onc e nt r at i on on hypot hyr oi di s m i nduc t i on(i m e k e t al .1 9 9 7 ) . Our findi ngs ar e c ons i s t e nt wi t h t hat t hyr oi d

hor mone s by i nc r e as i ng r e nal pl as ma flow and GFR and al s o by ac t i vat i ng t he r e ni n- al dos t e r one s ys t e m c aus e i nc r e as e d Mg e xc r e - t i on and t hus l owe r t he pl as ma c onc e nt r at i on (i m e k e t al .1 9 9 7 ) . The i nve r s e l y c or r e l at e d pl as ma Mg c onc e nt r at i on wi t h bot h GFR ( r＝−0 . 5 9)and T ( r＝−0 . 6 5)i n t he e ut hyr oi d s t at e ar e c ons i s t e nt wi t h t he s e ac t i ons of t hyr oi d hor mone s . Er yt hr oc yt e Mg c onc e nt r at i on was al s o f ound t o be i nve r s e l y c or r e l at e d t o GFR ( r＝−0 . 7 0 )and T ( r＝−0 . 7 5 )i n t he e ut hyr oi d s t at e . The s e findi ngs t oge t he r wi t h t he c or r e l at e d pl as ma and e r yt hr oc yt e Mg val ue s( r＝0 . 6 1)s ugge s t s t hat c hange s i n e r yt h- r oc yt e Mg ar e t o a c e r t ai n e xt e nt ,s e c ondar y t o t he c hange s i n pl as ma Mg i n t he e ut hyr oi d s t at e . Si mi l ar t o t hat obs e r ve d i n t he e ut hyr oi d s t at e ,we obs e r ve d t hat e r yt hr oc yt e Mg c on- c e nt r at i on was i nve r s e l y c or r e l at e d wi t h T ( r＝−0 . 6 3)i n t he hypot hyr oi d s t at e .

I n ac c or danc e wi t h our findi ngs Zumkl e y and Le hne r t( 1 9 8 4 )al s o r e por t e d l owe r e d e r yt h- r oc yt e Mg c onc e nt r at i on i n t he hypot hyr oi d s t at e as c ompar e d t o t he e ut hyr oi d s t at e . I t i s i mpor t ant t o not e t hat f or i nt e r pr e t at i on of dat a on e r yt hr oc yt e Mg i n t he hypot hyr oi d s t at e , t he l owe r e d me t abol i c ac t i vi t y of t he e r yt h- r oc yt e and t he de c r e as e d r e nal e xc r e t i on s houl d bot h be c ons i de r e d ( I ngbor 1 9 8 5 ) . Wi t h t he i nduc t i on of hypot hyr oi di s m t he l owe r e d me t a- bol i c ac t i vi t y i n t he e r yt hr oc yt e mi ght have l e d t o t he de c r e as e d i nt r ae r yt hr oc yt i c c onc e nt r a- t i on. Wi t h t he pr ogr e s s i on of t he hypot hyr oi d s t at e ,t he de c r e as e d Mg e xc r e t i on mi ght have c aus e d an i nc r e as e i n Mg c onc e nt r at i on of pr i mar i l y pl as ma and s e c ondar i l y of e r yt h- r oc yt e s( Shi but ani e t al .1 9 8 9 ) . The i nve r s e c or r e l at i on t hat we obs e r ve d be t we e n T and e r yt hr oc yt e Mg i n t he hypot hyr oi d s t at e mi ght be i nt e r pr e t e d i n f avor of t hi s s ugge s t i on.

Addi t i onal l y,t he pos i t i ve c or r e l at i on of e r yt h-

r oc yt e Mg wi t h pl as ma ur i c ac i d i n t he e ut hyr -

oi d s t at e( r＝0 . 5 9)i mpl y t he s i mi l ar pat t e r n of

c hange i n t he s e par ame t e r s ,t he maj or de t e r mi -

nant s ac t i ng r e c i pr oc al l y,be i ng r e nal e xc r e t i on

and me t abol i c ac t i vi t y.

I mpor t ant l y,bot h hype r ur i c e mi a and de - c r e as e d i nt r ac e l l ul ar Mg have be e n as s oc i at e d wi t h i ns ul i n r e s i s t anc e i n r e l at i on t o agi ng, hype r t e ns i on and obe s i t y i n nume r ous e xpe r i - me nt al and c l i ni c al s t udi e s( Paol i s s o e t al .1 9 9 0 , 1 9 9 5 ; Re s ni c k e t al . 1 9 9 0 ;Paol i s s o and Bar bagol l o 1 9 9 7 ) . Howe ve r on t he bas i s of our dat a on pos t - i ns ul i n i nf us i on s um gl uc os e and t r i gl yc e r i de s ,we obs e r ve d t hat i ns ul i n r e s i s t anc e di d not de ve l op i n t he hypot hyr oi d s t at e i nduc e d i n t hi s e xpe r i me nt al s t udy. I n t hi s r e gar d,we al s o obs e r ve d t hat t he c ons i de r at i on of dos e - de pe nde nt dual ac t i ons of t hyr oi d hor mone s i s i mpor t ant .

To c onc l ude t he i nc r e as e i n pl as ma ur i c ac i d obs e r ve d due t o hypot hyr oi di s m i s c ons i d- e r e d t o be s e c ondar y t o de c r e as e d r e nal e xc r e - t i on. As c l e ar l y e vi de nt f r om t hi s s t udy,hype r - ur i c e mi a of hypot hyr oi di s m s houl d not be r e gar - de d as an i ndi c at or of i ns ul i n r e s i s t anc e . I mpor t ant l y,t he me as ur e d l e ve l s of bi oc he mi c al par ame t e r s af f e c t e d by bot h me t abol i c ac t i vi t y and r e nal e xc r e t i on mus t be i nt e r pr e t e d wi t h c aut i on i n t hyr oi d hor mone di s or de r s .

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