812 482
PPAR
ၡāāࢋ
TZD PPAR 1997
TZD
TZD
TZD
TZD TZD
PPAR
ᙯᔣෟĈ PPAR ə( Peroxisome proliferator activated receptor-ə)
फ৵ܡԩّ ( Insulin resistance )
۹ࡪ፬৵ ( Adipocytokine )
ᎤԌঽඪঽត ( Diabetic nephropathy )
݈֏
ҋଂௐ˘࣎ thiazolidinedione ( TZD ) ۞ᘽ ۏĂჍࠎ troglitazone Ăٺ 1997 ѐд઼࡚གྷ FDA ( Food and Drug AdministrationĂࢴݡᘽۏგநԊ ) ८ࣞ˯ξ̝ޢ1ĂᎤԌঽ۞˾ڇᘽۏڼᒚᔙˢ˞
˘࣎၈າ۞ࡔ̮ćЯࠎଂ֤ॡ࣏ฟؕĂ̙ಏΪߏ д༊ॡࣧѣ۞ sulfonylureas ( ᒥ㈢Ԍ৵ᙷ )ă
biguanides ( ᗕ᷻ᙷ )ăᄃɗ-glucosidase inhibitors ( ɗ-ཬᎤྋ Ժט ) ̝γĂ˫к˞˘̂ᙷ
۞˾ڇࢫҕᎤᘽۏĂࢦࢋ۞ຍཌྷߏдٺᖣϤ TZDᙷफ৵ᆧୂ ( insulin sensitizer ) ۞ࡁ
൴ĂдᎤԌঽ۞ڼᒚ͞ࢬĂԧࣇጾѣ˞˘࣎Б າүϡ፟ט۞ᘽۏĂ˵ಶߏགྷϤו፬߿̼ PPAR ə ( peroxisome proliferator activated receptor-ə )Ă አଠ۹̈́ᔝᙷᔁ۞࠹ᙯૄЯĂซ҃Լචफ
৵ܡԩّ ( insulin resistance )Ă྿זࢫҲҕᎤ۞ϫ ᇾ2,3Ą
ᐌ PPAR ə agonist ۞˯ξֹϡĂ၆ٺιٙ
ѣ۞дࢫҕᎤͽγ۞кࢦड़ᑕ ( pleiotropic ef- fects )â̙ۡᕝజࡁտଣĄᔵௐ˘۞
TZDᘽۏ troglitazone д˯ξ̙˳̝ޢӈЯࠎᚑ ࢦ۞քّ߲҃ٺ 2000 ѐజ༰ֹͤϡ1ĂҭϤٺҋ 1999ѐ८ࣞ۞ௐ˟ TZD ĂΒ߁ pioglitazone ( Actos® ) rosiglitazone ( Avandia® ) ̪ᇃھᑕ ϡٺᓜԖ˯ᎤԌঽ۞ڼᒚĂЯѩѣᙯ TZD ၆ٺ Һࠪࡪă۹ࡪ፬৵ ( adipocytokines )ăᄃ ҕგ̰ϩࡪ۞አଠүϡඈĂ̙გߏдૄᖂٕᓜ Ԗ͞ࢬ۞ࡁտĂϒтܥޢߋඎਠгซҖćੵ˞
ૄᖂᗁጯࡁտౙᜈᙋ၁˞ T Z D ѣ۞ԩ൴ۆ ( anti- inflammation )үϡ̝γ4Ăࣃ˘೩۞ߏд ADOPT ( A Diabetes Outcome Progression Trial ) study̚Ăᙋ၁˞ᓜԖ˯ͽಏቢ˾ڇᘽۏڼᒚᎤ Ԍঽܜ྿αѐͽ˯۞ॡมĂ rosiglitazone ځពᐹ ٺ metformin glyburide ĂΞͽഴቤ beta cell Αਕ ಉεᄃԼචफ৵ୂຏّ ( insulin sensitivity )Ă֭
ͷՀѣड़г྿זҕᎤଠטϫᇾ5Ą
ώ͛ϫ۞дٺώ໖ĂࢵА੫၆૱֍۞
າౘᔁ়ঽĂ˵ಶߏᎤԌঽĂͽҺࠪͅᑕጱ
ၙّ൴ۆ۞៍ᕇ̷ˢĂྋᛖঽ፟ᖼćซ҃ᛚ
ᑕϡ PPAR ə agonist Ăӈ TZD ᙷᘽۏĂт ңԼචफ৵ܡԩّĂ˫ਕТॡࣘᜪԩ൴ۆ۞ड़ ڍĄޢĂ֭পҾ੫၆ PPAR ə agonist ၆ٺᎤԌ ঽඪঽត۞ᇆᜩΐͽ̬Ą
າౘᔁᄃҺࠪ፟ט۞࠹̢ᙯܼᄃ አଠЯ̄
ଂϠۏႊ̼۞៍ᕇ҃֏Ă࣎វ۞х߿ѣᏥٺ ઉБ۞Һࠪͅᑕͽٯԩຏߖ࣒֭ೇ๋चĂТॡ˵
υืጾѣ։р۞າౘᔁΑਕͽᐼхਕณֻ֭ᑕ
ٙื6ćధкఈႬᄋăࡪ፬৵ă็ᅍੈि۞క ϨኳăᖼᛌЯ̄ ( transcription factor )ăϠۏ
߿ّ۞ኳౌТॡፉЇ˞າౘᔁᄃҺࠪͅᑕ۞
֎Ғ֭Ϲ̢አଠĂ҃࣎វઉ۞ჯӈѣᏥٺາ ౘᔁᄃҺࠪր۞ӮᏊྻᖼĄ҃༊͇࣎π εᏊ۞ॡ࣏ĂಶົயϠ̙࣎Т۞ໂბଐԛć˘
ߏˠᙷΫ˯൴Ϡᛞਣٕߏ࣎វᒉዳ̙։۞ېڶĂ
ҺࠪΑਕྫྷ˭ࢫĂֹٯԩ˧मăઉೋ̼7-9ć
҃д͇πΩ˘ბߏԆБ࠹ͅĂ˵ಶߏдϫ݈А ซ઼छĂΒ߁έ៉ĂϤٺࢴҘ̼ᄃϠ߿ݭၗԼ តĂౄјᒉዳ࿅౺۞ଐԛĂЧၙّঽ൴Ϡத̙
ᕝᘆ̿ĂΒ߁۲ࡡăᎤԌঽă۹քăજਔർ
̼ăᄃ͕ҕგ়ঽඈĂ࠰ߏᛳٺវ̰ᜈҲޘ൴ ۆٙጱ۞ၙّঽ6ĄЯѩĂ֗វઉѣᏥٺઉ Б۞Һࠪրᄃޮؠ۞າౘᔁΑਕĄ
̂ࡗ 1 0 ѐк݈Ă൴ۆͅᑕາౘᔁεᏊ
۰̝ม۞ᙯᓑĂࢵޘజᙋ၁ć۲ࡡ۞ˠĂ۹
ᖐົயϠ̂ณ TNF-ɗ࣎൴ۆࡪ፬৵ ( in- flammatory cytokine )Ăጱ۲ࡡ۞ˠயϠफ৵
ܡԩ6 , 1 0ĄΩ˘͞ࢬĂ۹ࡪ̶کѣາౘ
ᔁΑਕ۞ࡪ፬৵Ă˵Тॡਕૉአ༼ҺࠪүϡĂ т leptin ӈߏć leptin ۞ഴ͌ĂΞͽྋᛖᒉዳ̙
։ֹҺࠪΑਕజԺט۞ࣧЯ11ćည adiponectin, resistin, visfatin˵ౌߏϤ۹ࡪᄦౄĂͷ˫ણ ᄃҺࠪͅᑕ۞ࡪ፬৵6Ą
၁ଂ۹ࡪ ( adipocyte ) ᄃλጥࡪ ( macrophage ) ۰఼̢ѣă࠹̢አଠ۞ன෪ֽ
ྋᛖՀᒢ ( ဦ˘ )Ăλጥࡪົᄦౄ۹
ࡪ̶ک۞ fatty acid-binding protein ( FABP ) aP2 ᄃ PPARə6,12Ă҃۹ࡪ˵ਕᄦౄTNF-ɗĂIL-6 Ă ᄃ MMPs ( matrix metalloproteinases ) 6,10,13ć۹
ࡪᖣᛖٸኳΝአଠ൴ۆͅᑕĂᇆᜩҺࠪү ϡć҃λጥࡪົд۹ᖐჸะĂགྷϤӌጥ
֭ᐼхкዶኳᖼតࠎڽڰࡪ ( foam cell )Ăΐ
ి൴ۆͅᑕซҖĂซ͔҃൴˘ాҚາౘᔁ়
ဦ˘Ĉλጥࡪᄃ۹ࡪдЧҋయ۞൴ۆͅᑕᄃ
ᔁүϡ̝γĂ˫࿅Вѣ۞አ༼Я̄யϠ̙Ξ
̶۞ᙯᓑ
ঽćٙͽᄲࡪౌТॡѣҺࠪᄃᔁᗕ ࢦΑਕ6,14Ą
யϠफ৵ܡԩ۞Һࠪአ༼Я̄ᄃ үϡ፟ᖼ
ࠎңၙّ൴ۆͅᑕᄃफ৵ܡԩ۞யϠѣᙯ
ĉдफ৵үϡ࿅̚Ăѣ˘࣎ޝࢦࢋ۞Վ
ូĂಶߏ insulin receptor substrate ( IRS ) ࣎
ࡪ̰కϨኳ۞ tyrosine జᒤᅕ̼Ă༊࣎Վូ൴ ϠౝĂயϠफ৵ܡԩ6Ą˯೩ז TNF-ɗ
ౄјफ৵ܡԩĂಶߏགྷϤ serine kinase ۞үϡ ΝԺט IRS ᒤᅕ̼15ćΩγĂ SOCS ( suppressor of cytokine signaling ) Тᇹߏүϡд IRS ҃Ժט
फ৵ΑਕĂ̙࿅ι۞፟ᖼ̙Тٺ TNF-ɗĂߏᖣ Ϥ proteosome ̶ྋ IRS6Ą
ϫ݈̏ۢົ̒ᕘ IRS үϡ۞ᅔ৵Ăѣᓝ
֖ᅅࢦгҜ۞ಶߏ JNK ( c-Jun amino-terminal ki- nase )Ă IKK-ɘ( inhibitor of nuclear factor-ɠB ( NF-ɠB ) kinase-ɘ)Ă̈́ PKC ( protein kinase C )Ą ࡁտ൴னĂֱᅔ৵ົ߿̼ AP-1 ( activator pro- tein-1 ) complexes NF-ɠB Ăአ̿ᄃ൴ۆͅᑕѣ ᙯ۞ૄЯܑன16Ą
ࢵА೩ז JNK Ă JNK ۞߿ّд۲ࡡ۰វ̰
۞۹ᖐăքăٕࠤҌ˭ෛĂౌӔனព
˯̿16Ą JNK ۞߿̼Ăҋٺ۲ࡡ͔൴۞ TNF-
ɗ˯̿ăഫᗓ۹ᅕᆧΐăᄃ̰ኳშ ( endoplas- mic reticulumĂ ER ) ᔁᑅ˧˯̿ ( ဦ˟ )6Ąд જۏሀݭ̏ᙋ၁ૄЯౝౄј J N K ͻ۞ҁ ဂĂ̙ົயϠफ৵ܡԩّĂ֭ҺٺயϠ۹ք ᄃᎤԌঽ17ĄϏֽĂԺט JNK ߿ّΞਕᑕϡٺڼ ᒚᎤԌঽ16Ą
ГֽĂ IKK-ɘ˵ߏᄃயϠफ৵ܡԩѣᙯ
۞ᅔ৵Ąдҁဂሀݭ̏ᙋ၁Ăѣ IKK-ɘࡎត۞
ҁ ဂ ̙ ົ ѣ फ ৵ ܡ ԩ Ă ҃ ϡ ณ ͪ ᅕ ( salicylates ) Ժט IKK-ɘਕԼචफ৵߿ّ18Ą ࡁտϺ൴னĂ IKK-ɘٙᇆᜩ۞າౘᔁүϡ
ࢋะ̚дք19Ą
ତࢋኘ۞ߏ P K C ĂιТᇹણᄃ˞൴ۆᄃ
ᔁ۰̝ม۞ధкϹ̢ͅᑕć۹ᅕ۞ᔁۏ
̚Ăည fatty acyl coenzyme A ᄃ diacylglyceride Ă
ົΝ߿̼҉҇ᖐ۞ PKC-ɞٕߏքᖐ̚۞
P K C -ɚĂ҃Ժטफ৵߿ّ1 6ćΩ˘͞ࢬĂ PKC-ɞ˵ົ߿̼ࣣ೩ז۞ IKK ĂᖣϤѩ˘፟ᖼ ጱफ৵ܡԩ16Ąϫ݈̏ۢ۞˩˟ PKC ளၹ ۏ̚Ă PKC-ɘᇃھхдٺҕგᖐĂ࿃ѣҕ Ꭴېڶಶజ߿̼Ă͔ధкࡪ፬৵˯̿Ăт TGF-ɘ ( transforming growth factor-ɘ )ă VEGF ( vascular endothelial growth factor )ă endothelin-1 ă
ICAM ( intercellular adhesion molecules ) ۞ᆧ ΐ20Ăౄј൴ۆͅᑕ˯̿҃ᇆᜩϒ૱າౘᔁΑ ਕćன̫ࡁ൴̚۞ᘽۏ ruboxistaurin Ăӈ PKC- ɘԺטĂ̏Ԇј phase II ۞ᓜԖྏរล߱Ăᙋ ၁ΞͽࢫҲᎤԌঽඪঽតଈ۰۞కϨԌăഴቤᎤ Ԍঽෛშቯঽត۞ซणăᄃԼචᎤԌঽˠฉᙝৠ གྷঽត۞াې21,22Ą
ࠎ̦ᆃၙّ൴ۆͅᑕົдາౘᔁεᏊ۞۲ ࡡ۰វ̰జୁજĉܕֽજۏሀݭ۞ࡁտඕڍĂ ពϯ̰ኳშ ( endoplasmic reticulum, ER ) ᔁᑅ
˧۞ᆧΐߏୁજ൴ۆᄃᔁεᏊ۞ฟბćдᔁ ள૱۞ଐڶ˭Ă̰ኳშົ߿̼Ⴭࠎ UPR ( unfold- ed protein response ) ۞ኑᗔͅᑕĂͽቁ̰ܲኳშ ϒ૱ྻүć҃ၹј U P R ۞ੈि็ᅍ̶̄ࢋ
ѣĈ IRE1 ( inositol-requiring enzyme 1 )Ă PERK ( PKR-like endoplasmic-reticulum kinase )Ăᄃ ATF6 ( activating transcription factor 6 )16ć༊̰ኳ შᔁᑅ˧ᆧΐົ߿̼ IRE-1 ᄃ PERK Ăତ๊
ဦ˟Ĉࡪ̰యአଠ൴ۆͅᑕᄃᔁүϡ۞̶̄ੈि
็ᅍྮश ( ER: endoplasmic reticulum, FFA: free fatty acid )
̼ JNK ̈́ AP-1 ă IKK ̈́ NF-ɠB ٙણᄃ۞൴ ۆͅᑕ ( ဦ˟ )Ăጱफ৵ܡԩĂᐌޢᄵ൴Հ кၙّ൴ۆͅᑕĂດΐೋ̼फ৵ܡԩĂາౘ
ᔁΑਕດߏᔌٺεᏊĂೋّೈᒖٺԛј16Ą
PPARəٙણᄃ۞फ৵ᆧୂүϡᄃ
࠹ᙯ۞Һࠪ̈́ᔁአ༼Я̄
ࠎ˞ᑕ;ᒉዳ̙։ٕ࿅౺ăާّຏߖٕၙّ
൴ۆ۞ள૱ېڶĂˠវ̰хдአଠ፟טĂͽዼ฿
ҺࠪᄃᔁͅᑕซҖĂჯࡪϒ૱Αਕć҃
इአଠ፟ט̶ࠎ̂ᙷâߏϤᷴ ( peptide ) య
۞አଠྮशĂᷴ ۞ߏࡪ፬৵ ( cytokines )ă
̼ጯ፬৵ ( chemokines ) ඈĂΩ˘፟טߏϤኳ ( lipid ) యአଠ۞ͅᑕĂΒ߁ኳăഫᗓ۹ ᅕăᄃࡪ८̰۞ఈႬᄋצጡඈĂ҃ PPARs ӈߏ ᛳٺ˘ᙷ2 3Ą P PA R s ߏࡪ८̚۞ੈिତצ ۰Ăధк۹ᅕౌߏ PPARs ̰Ϡّ۞ତЪૄ ( en- dogenous ligand )ĂΞͽ PPARs ඕЪĂଂૄЯᆸ
৺Νአଠᔝᙷ̈́۹ᔁ24ć҃ PPARs གྷϤ
̙Т፟טֽአଠૄЯᖼᐂ ( transcription )âߏᖼ
߿̼ ( transactivation )Ă۞ߏତЪૄᄃ PPARs ඕ Ъ̝ޢĂд cofactor ۞םӄ˭Гᄃ retinoid X re- ceptor ( RXR ) ԛј˘ኑЪۏĂޢాତٺᇾ۞ૄ
Я۞ PPAR response elements ćΩ˘፟טߏᖼԺט ( transrepression )Ă۞ߏ PPARs ᄃତЪૄඕЪ̝
ޢĂົ̒ᕘߙֱੈि็ᅍྮशĂт NF-ɠB ۞ੈ
ि็ᅍྮशĂซ҃Ժטᄃ൴ۆͅᑕѣᙯЯ̄۞ૄ
Яᖼᐂ3,23Ą PPAR əߏϫ݈̏ۢ۞ˬ PPARs ̝
˘ĂࠎPPARɗPPARɘ( ٕPPARɚ)4Ą
݈۞ڼᒚᎤԌঽᘽۏ TZD Ăӈࠎ PPAR ə۞ܳ
ड़ ( agonist )Ą
PPARəࢋхдٺ۹ᖐĂт
ɘࡪăҕგ̰ϩࡪăᄃλጥࡪඈĂ˵ౌ
ѣ PPAR əхд3Ą PPAR əࢦࢋΑਕдٺయ
۹ࡪ۞̶̼ᄃᆧതĂᔘѣ۹ᅕ۞Ӏϡᄃ ᐼхć߇ଯኢ TZD ۞फ৵ᆧୂүϡ˜ߏٺ
ۡତᄃมତ၆۹ᖐ۞አଠĄۡତүϡӈٙ
Ꮬ۞ "۹ᅕᕩҜ" ᄲ ( "fatty acid steal" hy- pothesis )Ă˵ಶߏܳซ۹ᅕд۹ᖐ۞ӛќ ᄃᐼхĂٺߏ۹ಶזιᑕྍхд۞۹
ᖐ྆ᐼхĂ̙҃ົӨ᎕дι̙ྍхд۞г͞Ă
т҉҇ᖐăքăٕߏĂͽᔖҺ፧ޘ
۞ഫᗓ۹ᅕПचֱᖐ3ć T Z D ۞มତү ϡĂߏᇆᜩ۹ࡪ፬৵ ( adipocytokine ) ۞ ᛖٸĂт adiponectin р۞۹፬৵፧ޘົ˯
̿Ăᖣѩᆧΐफ৵ୂຏّĂ҃дҁဂሀݭ̚Ă TZDࢫҲ TNF-ɗă resistin ă 11ɘ-hydroxys- teroid dehydrogenase 1۞፧ޘĂֱۏኳౌజᙋ၁
ົ͔൴फ৵ܡԩّ3Ą
ֹϡ PPAR ə agonist ၆ٺᎤԌঽඪ ঽត۞ᓜԖຍཌྷᄃᘽந፟ᖼ
ௐ 2 ݭᎤԌঽдБߏҖத͟႙ᘆ̿۞ၙ
ّঽĂ҃ᎤԌঽౄј۞ᎤԌঽඪঽតĂࠎϫ݈
Аซ઼छ߾ඪ۞ࢋࣧЯćЯѩĂтң֨Ꭴ Ԍঽඪঽត۞൴ϠĂ˜ߏ˘࣎ג̙टቤ۞ࢦࢋኝ ᗟĄ TZD ˘ᙷڼᒚᎤԌঽ۞ᘽۏĂ࿅ࢫҲ
फ৵ܡԩّ҃ࢫҲҕᎤĂҋ 1 9 9 7 ѐયξͽ ޢĂధк۞ᓜԖࡁտ̏གྷᙋ၁˞ TZD ၆ٺࢫҲ ௐ 2 ݭᎤԌঽˠϨకϨԌ۞Αड़ć҃дனѣ۞
ԩᎤԌঽ˾ڇᘽۏ̚ĂϤٺ TZD ۞ᘽۏᔁ
ࢋдքĂٙͽ TZD ̙ҭΞͽϡٺڼᒚЪ׀ඪ ঽត۞ᎤԌঽˠ25Ă҃ͷ˫ਕ࿅ͽ˭ֱ፟ᖼ
྿ז᜕ܲඪ۞ϫ۞ ( ܑ˘ )26Ĉ
ܑ˘Ĉ T Z D ࢫҲϨకϨԌଵณᄃԼචᎤԌঽඪঽ ត۞үϡ፟ᖼ
ࢫҲҕᎤᄃफ৵፧ޘ
ഴ͌फ৵ٙౄј۞ඪකมኳࡪᆧϠ ࢫҲҕᑅ
ࢫҲϹຏৠགྷ߿ّ
ഴ͌ҕგπ҉ࡪ̰۞ถᗓ̄፧ޘ Լච̰ϩࡪΑਕ
೩چ˘উ̼ധ ( NO ) дඪ۞፧ޘ ԩᆧϠүϡ
ࢫҲ TGF-ɘă PAI-1
ԺטมኳࡪᄃࡪγૄኳకϨᆧϠ ԩ൴ۆүϡ
ࢫҲinterleukin ( IL )-1ăIL-6ăTNF-ɗăCRP ( C-reactive protein )
̒ᕘඪ৵-ҕგΐᑅ৵ր ( renin-angiotensin system ) ഴ͌ҕგΐᑅ৵ I II
ഴ͌ඪࡪ̰۞ኳુ᎕
೩چඪක۞ LXR-ɗܑனͽᆧΐᓙዔଵ
ࢫҲ̰ϩ৵ ( endothelin ) -1 ፧ޘ
˘ăࢫҲҕᎤᄃफ৵፧ޘĈҕᎤົౄј protein kinase C ( PKC ) ߿̼Ă֭ซ˘Վጱඪක
Αਕε૱ćֹϡ TZD ĂΞͽࢫҲҕᎤ҃Ժט P K C߿̼Ăͷᐌफ৵፧ޘࢫҲĂಶਕഴ͌
फ৵ٙౄј۞ඪකมኳࡪᆧϠĂ֭ࢫҲඪ
ᖐ̚ᙷफ৵Я̄ ( insulin-like growth factor )
۞፧ޘĂ྿ז᜕ܲඪ۞ड़ڍĄ
˟ăࢫҲҕᑅĈϤٺ TZD ΞͽԼච̰ϩ
ࡪΑਕăࢫҲϹຏৠགྷ߿ّă̈́ഴ͌ҕგπ
҉ ࡪ ̰ ۞ ถ ᗓ ̄ ፧ ޘ Ă ߇ ѣ ᅅ ࢫ ҕ ᑅ ड़ ڍĂͷᔵࢫҲ۞ҕᑅࣃϏ྿ࢍमளĂ၆ٺ
ϨకϨԌಶ̏གྷѣពԼචĄΩγĂ TZD ᔵ ਕࢫҲҕᑅĂҭݒֹវ୵˯̿Ăϫ݈ᄮࠎ T Z D
ົүϡдะЪგ ( collecting duct ) ˯၆ amiloride ѣୂຏّ۞ทᗓ఼̄Ăᆧΐทᗓ̄ГӛќĂ
͔វ୵႖ᄃវࢦᆧΐĂѩ˜ֹϡ TZD ࠎ
ྛঽ̝27Ą
ˬăԼච̰ϩࡪΑਕĈᎤԌঽ۞̂̈ҕგ ঽតᄃ̰ϩࡪΑਕள૱ѣᙯĂ҃फ৵ܡԩّ
ᄃ̰ϩࡪΑਕε૱˵хд̷ᙯᓑĄᓜԖ˯Ă
ϨకϨԌϒߏඪҕგঽត۞ѝഇࢦࢋܑᇈĂ
༊ֹϡ T Z D дௐ 2 ݭᎤԌঽˠॡĂιੵ˞Լච
फ৵ܡԩّĂ˫ਕᆧซ̰ϩࡪΑਕćΩγĂ જۏ၁រϺ൴ன TZD ົ೩چ˘উ̼ധ ( NO ) дඪ
۞፧ޘĂֹˢ̈જਔᄃ̈જਔᕖૺĂࢫ Ҳඪකᑅ˧Ă֭ഴ͌Ԍ୵̚ϨకϨଵณĄ αăԩᆧϠүϡĈధкϠܜЯ̄ᄃயϠᎤԌ ঽඪঽតѣᙯĂ҃ TGF-ɘߏдֱ̏ۢϠܜ Я̄̚ࢦࢋ۞˘࣎Ą TZD ЯࠎΞͽԼච
फ৵ҕাĂ߇ਕૉਗ਼ᖼफ৵ౄј۞ TGF-ɘᆧ ΐĂ֭ซ҃Ժטมኳࡪ ( mesangial cell ) ᆧϠᄃ
ࡪγૄኳకϨ ( extracellular matrix protein ) ᆧ ΐĄѩγĂдᎤԌঽҁဂሀݭ̚Ă TZD ົഴቤ MMP-2 ( matrix metalloproteinases-2 ) ࢫҲ۞
ޘĂ᜕ܲඪකҺٺ collagen IV ુ᎕ćΩ˵೩ זĂ TZD ਕഴ͌ PAI-1 ( plasminogen activator in- hibitor type 1 ) ҕ̚፧ޘĂ҃ PAI-1 ϒߏౄјᖐ ញჯ̼۞Я̄Ąࡪ၁រ̚Ăᙋ၁ T Z D ۞ p i - oglitazoneົ߿̼֖ࡪ ( podocyte ) ̰۞ PPAR- əĂഴ֖͌ࡪᗼѪ ( necrosis )Ă֭ܳซ֖ࡪ
̶̼28Ą
̣ăԩ൴ۆүϡĈ߹Җঽጯ۞ࡁտᙋ၁ඪΑ ਕੜᄃ൴ۆᇾ̝ม۞࠹ᙯّĂ҃ᎤԌঽඪঽ តᄃ൴ۆͅᑕ༊˵̙Ξ̶Ąࡪ၁រඕڍព ϯĂ T Z D ົԺטܳඓېർ̼۞൴ۆࡪ፬৵ ( proatherogenic inflammatory cytokine ) ᄦౄĂт interleukin ( IL )-1ă IL-6 ăᄃ TNF-ɗඈĂ֭ࢫҲ C-ͅᑕకϨ ( C-reactive protein )ćѩγĂ rosigli- tazoneдඪมኳࡪ ( renal mesangial cell )
ົഴ͌ N F - ɠ B ߿̼ᄃ M C P - 1 ( m o n o c y t e chemoattractant protein-1 ) ᄦౄĂҁဂ၁រϺᙋ၁ pioglitazoneົүϡٺඪක̰ϩࡪ ( glomeru- lar endothelial cell ) ˯۞ PPAR-əĂԺט NF-ɠB ߿
̼Ăഴ͌ ICAM ( intercellular adhesion molecule )-1
ܑனĂ֨ͤλጥࡪჸะ29ĄϤٺ TZD ѣֱ
ԩ൴ۆүϡĂ߇ਕૉഴ͌൴ۆͅᑕ၆ඪ۞๋
चĄ
̱ă̒ᕘඪ৵-ҕგΐᑅ৵ր ( renin-an- giotensin system )Ĉࡁտពϯ TZD Ξͽഴ͌ϩ˭
۹ࡪᄦౄ۞ҕგΐᑅ৵ I II Ăдҕგπ
҉Ă TZD ਕૉአࢫҕგΐᑅ৵ I ତצጡ ( an- giotensin I receptor ) ۞ mRNA ᄃకϨኳ̝ᄦౄĄ
˛ăഴ͌ඪࡪ̰۞ኳુ᎕Ĉҕள૱
ߏֹඪঽតᜈೋ̼۞ࢦࢋᙯᔣĂ҃ኳુ᎕
ᄃڽڰࡪ ( foam cell ) ԛјĂߏኳౄјඪක
ᄃ ඪ ̈ გ ม ኳ ๋ च ۞ ̂ ঽ ந প ᇈ ć ֹ ϡ TZDĂΞͽ࿅၆ IL-1 ɘ۞ԩĂᆧซኳᏮ
Ăซ҃ഴ͌ኳુ᎕ٺඪĄΩγĂࣧώ̏ۢ
хдٺλጥࡪ۞ liver-X-receptor-ɗ( LXR-ɗ )Ă ߏአ༼ᓙዔᏮ۞צጡĂܕֽ൴னι˵хдٺ ඪක۞มኳࡪ ( mesangial cell )ć҃ TZD ਕૉ
ព೩چඪක۞ LXR-ɗܑனĂᆧΐᓙዔଵ
Ą
ˣăࢫҲ̰ϩ৵ ( endothelin ) -1 ፧ޘĈᓜԖ
˯៍၅ௐ 2 ݭᎤԌঽЪ׀ϨకϨԌ۞ঽˠĂ̰
ϩ৵-1 ۞፧ޘځពᆧΐĂ Яѩଯኢ̰ϩ৵-1 ણ ᄃ˞ᎤԌঽඪঽត۞ঽ࿅Ą̰ϩ৵ߏ˘ҕ გќᒺ৵Ăົֹඪҕ߹ณഴ͌Ăඪක࿅ᕭ த˭ࢫĂܕֽ၁រពϯιົ߿̼ PKC Ăֹมኳ
ࡪᆧϠćֹϡ TZD ΞͽԺט PKC ĂࢫҲ̰ϩ
৵-1 ۞߿ّĂᔖҺ̰ϩ৵-1 ၆ඪ۞๋चĂ྿ז
᜕ܲඪ۞ड़ڍĄ
ඕኢ
ҋ 1997 ѐ˯ξ۞ TZD Ă࿅ᄃ PPAR əඕ ЪĂଂૄЯᆸ৺ΐͽአଠ۹̈́ᔝᙷᔁĂι۞
ᘽந፟ᖼੵ˞Լචफ৵ܡԩ۞າౘᔁүϡ̝
γĂТॡ˵ᇆᜩధк൴ۆͅᑕ۞አ༼Я̄Ăٙͽ ၆ٺညᎤԌঽᙷၙّҲޘ൴ۆౄј۞າౘᔁ
়ঽĂֹϡ T Z D ڼᒚĂ۞ቁߏдࢫҲҕᎤ̝
γĂ˫೩ֻ˞кࢦԩ൴ۆड़ڍĄ
҃Ăܕᙯٺ rosiglitazone pioglitazone
۞̂ݭᓜԖࡁտ̚5,30Ăݒຍγ൴ன˞ TZD ົᆧ ΐௐ 2 ݭᎤԌঽ̃۞ฉᙝԶ፟தćѩγĂд 2007ѐ̱͡ NEJM ۞˘ቔ meta-analysis ̚31Ăጯ ۰ᕩৼֹϡ rosiglitazone ົពᆧΐ͕҉ୟ
൴ϠதĂͷЯ͕ҕგ়ঽѪ˸۞ּͧѣ˯̿ᔌ ๕ćᐌӈΩ˘ጯ۰д˛͡Њ۞ NEJM ̚32Ăॲፂ
˘నࢍԆච۞ᓜԖࡁտ RECORD ( Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes ) studyΐͽᅺϋĄϫ݈Ăᔵ
ͻ֖ૉ۞၁ᙋᗁጯॲፂઇޢؠኢĂҭ˵೩ ᏹ˞ᓜԖᗁरдֹϡ TZD ᙷᘽۏॡĂυืᖰ ຕ҂ᇋ۞˘ֱሕдઘүϡĄ
ଂ၁ᗁጯ۞֎ޘĂԧࣇ̙ਕӎᄮĂ̙გߏ rosiglitazoneٕ pioglitazone ۞ᘽநүϡĂ۞ቁౌ
ࣘᜪ˞າౘᔁᄃ൴ۆүϡ۰̝ม۞םአĂឰ ԧࣇͽ˘ܜഇҲޘ൴ۆጱၙّ͛ځঽ۞
Ă่̙णன˞ᘽۏڼᒚᎤԌঽ۞າݵ፟Ă˵
ֽ˞ଂૄώঽ፟ᖼ͘ؼቤᄃ֨ᎤԌঽၙّ
׀൴া۞˘ቢᑨЍĊ
ણ҂͛ᚥ
1.Nathan DM. Finding new treatments for diabetes--how many, how fast... how good? N Engl J Med 2007; 356: 437-40.
2.ͳڼ̮Ăૺ͇ธĄफ৵ᆧୂᘽۏ thiazolinedione ڼᒚௐ 2 ݭᎤԌঽ̝၁ᙋᗁጯᙋፂĄ̰ࡊጯᄫĄ 2007; 18: 11-9.
3.Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351:
1106-18.
4.Brown JD, Plutzky J. Peroxisome proliferator-activated recep- tors as transcriptional nodal points and therapeutic targets.
Circulation 2007; 115: 518-33.
5.Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-43.
6.Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes.
J Clin Invest 2005; 115: 1111-9.
7.Khovidhunkit W, Kim MS, Memon RA, et al. Effects of infec- tion and inflammation on lipid and lipoprotein metabolism:
mechanisms and consequences to the host. J Lipid Res 2004;
45: 1169-96.
8.Chandra RK. Nutrition, immunity and infection: from basic knowledge of dietary manipulation of immune responses to practical application of ameliorating suffering and improving survival. Proc Natl Acad Sci U S A 1996; 93: 14304-7.
9.Blackburn GL. Pasteur's Quadrant and malnutrition. Nature 2001; 409: 397-401.
10.Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose ex- pression of tumor necrosis factor-alpha: direct role in obesity- linked insulin resistance. Science 1993; 259: 87-91.
11.Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998;
394: 897-901.
12.Sun L, Nicholson AC, Hajjar DP, Gotto AM, Jr., Han J.
Adipogenic differentiating agents regulate expression of fatty acid binding protein and CD36 in the J744 macrophage cell line.
J Lipid Res 2003; 44: 1877-86.
13.Bouloumie A, Sengenes C, Portolan G, Galitzky J, Lafontan M.
Adipocyte produces matrix metalloproteinases 2 and 9: in- volvement in adipose differentiation. Diabetes 2001; 50: 2080- 6.
14.Charriere G, Cousin B, Arnaud E, et al. Preadipocyte conver- sion to macrophage. Evidence of plasticity. J Biol Chem 2003;
278: 9850-5.
15.Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced in- sulin resistance. Science 1996; 271: 665-8.
16.Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-7.
17.Liu G, Rondinone CM. JNK: bridging the insulin signaling and inflammatory pathway. Curr Opin Investig Drugs 2005; 6: 979- 87.
18.Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkɘ. Science 2001; 293: 1673-7.
19.Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin re- sistance resulting from hepatic activation of IKK-ɘ and NF-ɠ B. Nat Med 2005; 11: 183-90.
20.Casellini CM, Barlow PM, Rice AL, et al. A 6-month, random- ized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-ɘ inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic pe- ripheral neuropathy. Diabetes Care 2007; 30: 896-902.
21.Kelly DJ, Buck D, Cox A, Zhang Y, Gilbert RE. Effects of pro- tein kinase C-ɘ inhibition on glomerular endothelial cells in ad- vanced experimental diabetic nephropathy. Am J Physiol Renal Physiol 2007. (In press)
22.Williams ME. New potential agents in treating diabetic kidney disease: the fourth act. Drugs 2006; 66: 2287-98.
23.Lehrke M, Lazar MA. The many faces of PPARə. Cell 2005;
123: 993-9.
24.Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol 2005; 288: H1037-43.
25.Iglesias P, Diez JJ. Peroxisome proliferator-activated receptor gamma agonists in renal disease. Eur J Endocrinol 2006; 154:
613-21.
26.Sarafidis PA, Bakris GL. Protection of the kidney by thiazo- lidinediones: an assessment from bench to bedside. Kidney Int 2006; 70: 1223-33.
27.Semenkovich CF. TZDs and diabetes: testing the waters. Nat Med 2005; 11: 822-4.
28.Kanjanabuch T, Ma LJ, Chen J, et al. PPAR-ə agonist protects podocytes from injury. Kidney Int 2007; 71: 1232-9.
29.Ohga S, Shikata K, Yozai K, et al. Thiazolidinedione amelio- rates renal injury in experimental diabetic rats through anti-in- flammatory effects mediated by inhibition of NF-ɠ B activa- tion. Am J Physiol Renal Physiol 2007; 292: F1141-50.
30.Hampton T. Diabetes drugs tied to fractures in women. JAMA 2007; 297: 1645.
31.Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
N Engl J Med 2007; 356: 2457-71.
32.Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes-an interim analysis.
N Engl J Med 2007; 357: 28-38.
Role of PPAR ə for Immuno-Metabolic Influences and Impacts on Diabetic Nephropathy
Wei-Wen Hung, Shyi-Jang Shin1, and Jer-Ming Chang
As an antidiabetic agent introduced in 1997, PPARə agonist, or thiazolidinediones (TZD), has received much attention not only in clinical research but also in basic study about its mechanism behind the clinical ef- fects. Evidence from clinical study of TZD use in type 2 diabetes with microalbuminuria had proved that TZD treat- ment significantly reduced urine albumin excretion (UAE). In this article, we intended to discuss the basic patho- physiology of diabetes from an immuno-metabolic viewpoint in the beginning. Then we tried to analyze the im- pacts on immuno-metabolic systems with regards to TZD treatment, and describe in detail about its insulin-sen- sitizing and anti-inflammatory effects. Finally, we went on to explore the actions of TZD on the reduction of UAE and attenuation of renal injury. As diabetic nephropathy being the leading cause of end-stage renal disease world- wide, the exploration of PPARə would be promising for the development of drugs to delay or prevent diabetic nephropathy. ( J Intern Med Taiwan 2008; 19: 121- 127 )
Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital;
1Division of Endocrinology and Metabolism,
Department of Internal Medicine, Kaohsiung Medical University Hospital
