1、非酒精性脂肪肝与非酒精性脂肪肝与2 2型糖尿病型糖尿病1人类对脂肪肝与糖尿病的认识人类对脂肪肝与糖尿病的认识1906年：年：“Hepatogenous diabetes” 肝源性糖尿病肝源性糖尿病 肝硬化患者中多发糖尿病肝硬化患者中多发糖尿病1980年：年： Ludwig et al.首次提出首次提出“非酒精性脂肪性肝炎非酒精性脂肪性肝炎NASH”的命名的命名 20例、几乎不饮酒、其中例、几乎不饮酒、其中19例肥胖例肥胖/超重、多伴有糖尿病超重、多伴有糖尿病 肝活检病理：肝脂肪变性、小叶炎症、灶性坏死、炎症细肝活检病理：肝脂肪变性、小叶炎症、灶性坏死、炎症细 胞浸润、胞浸润、Mallory小体
2、、纤维化小体、纤维化、甚至肝硬化，其形态学改变与甚至肝硬化，其形态学改变与 酒精脂肪肝非常相似酒精脂肪肝非常相似1999年：年：Matteoni 等，根据肝活检和长期观察的结局性研究证据，发现等，根据肝活检和长期观察的结局性研究证据，发现 非酒精性脂肪肝严重程度不同，是一组从单纯性脂肪肝到脂肪非酒精性脂肪肝严重程度不同，是一组从单纯性脂肪肝到脂肪性性 肝炎以致纤维化的疾病谱，首次提出肝炎以致纤维化的疾病谱，首次提出NAFLD的定义的定义Ludwig J, et al. Mayo Clin Proc 1980; 55:434 438 Paola Loria， et al. Hepatology
3、Research 2013; 43: 5164 Perseghin G, et al. Hepatology 2000; 31: 694703. Alina Pascaleet al.J Gastrointestin Liver Dis 2010 Vol.19 No 4, 415-423 Matteoni CA, et al. Gastroenterology 1999; 116:14131419 2非酒精性脂肪性肝病是一个疾病谱非酒精性脂肪性肝病是一个疾病谱Cohen JC , et al. Science 2011, 332:1519-1523. 3ALT as a Predictor o
4、f Type 2 Diabetes A prospective study in Pima Indians605040302010005101520years of follow-up incidence type 2 diabetesUpper tertile of ALT (59 mU/l)Lower tertile of ALT (21 mU/l)Vozarova B, Diabetes 51:18891895,20024肝酶升高预测糖尿病前期和肝酶升高预测糖尿病前期和2型糖尿病的发生型糖尿病的发生The Bogalusa Heart Study（follow up over 16 ye
5、ars ）Diabetes Care. 2011 Dec;34(12):2603-7and al coholdri nki ng (yes/ no) observedsi nce basel i ne as l ongi t udi nalcat egori calvari abl esand BM I,M AP,H DL chol est erol ,LDL chol est erol ,t ri gl yceri des,and H O M A-IR asl ongi t udi nalcont i nuousvari abl es,aswel lasALT and GGT (m odel
6、1 and 2,re-spect i vel y),adj ust edf orst udyyear,age,agesquared,race,sex,and sex byracei nt erac-ti on,as appl i cabl e.O dds rati os are ex-pressed per1-SD i ncrem enti n BM I,M AP,H DL chol est erol ,LDL chol est erol ,t ri gl y-ceri des,H O M A-IR,ALT,and GGT.N on-si gni f i cantt erm s(P . 0.
7、05)wererem ovedf rom t hem odelbybackward st epwi sepro-cedure.To eval uat e t he di scri m i nat ory ca-pabi l i t yoft hem odel susi ngt heareaundert herecei veroperat i ng charact eri st i c(RO C)curve(C st at i st i c),t hem ul t i vari at eC st at i s-t i c l ogi st i c regressi onswere perf or
8、m ed ont heassoci at i onoft hebasel i nel i verf unct i onenzym esand gl ucosehom eost asi svari abl es(gl ucose,i nsul i n,and H O M A-IR)wi t h pre-di abet esordi abet esst at usatt hef ol l ow-upi n adul t hood adj ust ed f or age,race,sex,sm oki ng,dri nki ng,BM I,M AP,H DL cho-l est erol ,LDL
9、chol est erol ,and t ri gl yceri des.RO Cs(C val ues)weret est ed f orequal i t ybydi abet esst at usand bypai rwi secom pari sonofeach m odelwi t h t herest .R ESU LTS d M ean l evel s of ant hropo-m et ri c,hem odynam i c,m et abol i c,and l i verf unct i on enzym e vari abl es atbasel i ne arepre
10、sent ed i n Tabl e1 byf ol l ow-up di abet esst at us.The predi abet i c group,versus t henorm ogl ycem i c group,di spl ayed si gni f i -cantl y hi gher systol i c bl ood pressure,M AP,LDL chol esterol ,gl ucose,i nsul i n,H O M A-IR,and ALT.The di abet i c group,versus the norm ogl ycem i c group,
11、di s-pl ayed hi gherBM I,syst ol i cbl ood pressure,di ast ol i c bl ood pressure,M AP,LDL cho-l esterol ,tri gl yceri des, gl ucose,i nsul i n,H O M A-IR, ALT, and G G T and low erH DL chol est erol .The f ol l ow -up preval ence rat e ofdi -abet es status af t er a 16-year i ntervalbyquart i l es
12、of basel i ne ALT and GGT i sshown i n Fi g.1.Si gni f i cantadverset rendsofALT and GGT werenot ed f orbot h pre-di abet i c(P, 0. 01)and di abet i c(P, 0. 05)groups.Tabl e 2 show sthe resul t sofa m ul t i -vari abl e adj usted l ongi tudi nall ogi sti cre-gressi on m odelt hati ncl uded BM I,M AP
13、,H DL chol esterol ,LDL chol esterol ,tri gl y-ceri des,and H O M A-IR al ong w i th ALT(m odel1)and GGT (m odel2)asam ul t i pl erepeat ed-m easurem entst andardi zed vari -abl e (z scores)and sm oki ng (yes/ no)andal coholdri nki ng (yes/ no)asal ongi t udi nalrepeat ed-m easurem entcat egori calv
14、ari abl eobserved si ncebasel i ne.Af t eradj ust i ngf orst udy year,age,race,sex,and race by sexi nt eracti on (as appl i cabl e),expressed per1-SD i ncrease,H O M A-IR showed asi gni f -i cantoddsrat i o of1. 70 (P , 0. 0001)f ordevel opi ng f ol l ow -up predi abetesaf t eranaverage of16 yearsof
15、f ol l ow -up.N ei t herALT norGGT show ed si gni f i cantoddsra-t i osi n t hi sregard.W i t h respectt o devel -opi ng f ol l ow -up di abetes,t he oddsrat i osper1-SD i ncreasewere1. 16 (P = 0. 05)f orALT and 1. 20 (P , 0. 01)f orGGT.BM I,tri gl yceri des, and H O M A-IR di spl ayedodds rat i os
16、of1. 77,1. 26,and 1. 57,re-spect i vel y (P , 0. 05);BM Iand t ri gl ycer-i desshow ed oddsrat i osof2. 23 and 1. 36,respect i vel y,i n m odel2 (P , 0. 001).N osi gni f i cantracedi f f erencei n t hepredi cti veval ue ofl i ver f unct i on enzym es was ob-served f or ei t her predi abetes or di ab
17、etes(dat a notshow n).In t erm s ofdi scri m i nati ve val ues ofdi f f erentbasel i ne l i verf unct i on enzym esand gl ucose hom eostasi s vari abl es (gl u-cose,i nsul i n,and H O M A-IR)(Tabl e 3),t hepredi cti vem odel sproduced C val uesFigure 1d Prevalence off ol low-up di abetes status by q
18、uarti les ofbasel ine ALT and G G Tl evel si n theBogal usa H eartStudy.ALT and G G T val uesby quarti l esw ere, 13. 0 U I/ L and, 10U I/ L f orquarti l e1;f rom 13to18U I/ L and10to14U I/ L f orquarti l e2;from 19to28U I/ Land 15 to 22 U I/L f orquartil e 3;and f rom 29 to 126 U I/L and 23 to 476
19、U I/L f orquarti le4,respecti vel y.care. di abetesj ournal s. orgDIABETESCARE,VO LUM E34,DECEM BER20112605N guyen and Associ atesand al coholdri nki ng (yes/ no) observedsi nce basel i ne as l ongi t udi nalcat egori calvari abl esand BM I,M AP,H DL chol est erol ,LDL chol est erol ,t ri gl yceri d
20、es,and H O M A-IR asl ongi t udi nalcont i nuousvari abl es,aswel lasALT and GGT (m odel1 and 2,re-spect i vel y),adj ust edf orst udyyear,age,agesquared,race,sex,and sex by racei nt erac-ti on,as appl i cabl e.O dds rati os are ex-pressed per1-SD i ncrem enti n BM I,M AP,H DL chol est erol ,LDL cho
21、l est erol ,t ri gl y-ceri des,H O M A-I R,ALT,and GGT.N on-si gni f i cantt erm s(P . 0. 05)wererem ovedf rom t hem odelbybackward st epwi sepro-cedure.To eval uat e t hedi scri m i nat ory ca-pabi l i t yoft hem odel susi ngt heareaundert herecei veroperat i ngcharact eri st i c(RO C)curve(C st at
22、 i st i c),t hem ul t i vari at eC st at i s-t i c l ogi st i c regressi onswere perf orm ed ont heassoci at i onoft hebasel i nel i verf unct i onenzym esandgl ucosehom eost asi svari abl es(gl ucose,i nsul i n,and H O M A-I R)wi t h pre-di abet esordi abet esst at usatt hef ol l ow-upi n adul t ho
23、od adj ust ed f or age,race,sex,sm oki ng,dri nki ng,BM I,M AP,H DL cho-l est erol ,LDL chol est erol ,and t ri gl yceri des.RO Cs(C val ues)weret est ed f orequal i t ybydi abet esst at usand bypai rwi secom pari sonofeach m odelwi t h t herest .R ESU LTS d M ean l evel s of ant hropo-m et ri c,hem
24、 odynam i c,m et abol i c,and l i verf unct i on enzym e vari abl es atbasel i ne arepresent ed i n Tabl e1 byf ol l ow-up di abet esst at us.The predi abet i c group,versus t henorm ogl ycem i c group,di spl ayed si gni f i -cantl y hi gher systol i c bl ood pressure,M AP,LDL chol esterol ,gl ucose
25、,i nsul i n,H O M A-I R,and ALT.The di abet i c group,versus the norm ogl ycem i c group,di s-pl ayed hi gherBM I,syst ol i cbl ood pressure,di ast ol i c bl ood pressure,M AP,LDL cho-l esterol ,tri gl yceri des, gl ucose,i nsul i n,H O M A-IR, ALT, and G G T and l ow erH DL chol est erol .The f ol
26、l ow -up preval ence rat e ofdi -abet es status af t er a 16-year i ntervalbyquart i l es of basel i ne ALT and GGT i sshown i n Fi g.1.Si gni f i cantadverset rendsofALT and GGT werenot ed f orbot h pre-di abet i c(P, 0. 01)and di abet i c(P, 0. 05)groups.Tabl e 2 show sthe resul t sofa m ul t i -v
27、ari abl e adj usted l ongi tudi nall ogi sti cre-gressi on m odelt hati ncl uded BM I,M AP,H DL chol esterol ,LDL chol esterol ,tri gl y-ceri des,and H O M A-IR al ong w i th ALT(m odel1)and GGT (m odel2)asam ul t i pl erepeat ed-m easurem entst andardi zed vari -abl e (z scores)and sm oki ng (yes/
28、no)andal coholdri nki ng (yes/ no)asal ongi t udi nalrepeat ed-m easurem entcat egori calvari abl eobserved si ncebasel i ne.Af t eradj ust i ngf orst udy year,age,race,sex,and race by sexi nt eracti on (as appl i cabl e),expressed per1-SD i ncrease,H O M A-IR showed asi gni f -i cantoddsrat i o of1
29、. 70 (P , 0. 0001)f ordevel opi ng f ol l ow -up predi abetesaf t eranaverage of16 yearsoff ol l ow -up.N ei t herALT norGGT show ed si gni f i cantoddsra-t i osi n t hi sregard.W i t h respectt o devel -opi ng f ol l ow -up di abetes,t he oddsrat i osper1-SD i ncreasewere1. 16 (P = 0. 05)f orALT an
30、d 1. 20 (P , 0. 01)f orGGT.BM I,tri gl yceri des, and H O M A-IR di spl ayedodds rat i os of1. 77,1. 26,and 1. 57,re-spect i vel y (P , 0. 05);BM Iand t ri gl ycer-i desshow ed oddsrat i osof2. 23 and 1. 36,respect i vel y,i n m odel2 (P , 0. 001).N osi gni f i cantracedi f f erencei n t hepredi cti
31、 veval ue ofl i ver f unct i on enzym es was ob-served f or ei t her predi abetes or di abetes(dat anotshow n).In t erm s ofdi scri m i nati ve val ues ofdi f f erentbasel i ne l i verf unct i on enzym esand gl ucose hom eostasi s vari abl es (gl u-cose,i nsul i n,and H O M A-IR)(Tabl e 3),t hepredi
32、 cti vem odel sproduced C val uesFi gure 1d Prevalence off ol l ow-up di abetes status by quarti l es ofbasel ine ALT and G G Tl evel si n theBogal usa H eartStudy.ALT and G G T val uesby quarti l esw ere , 13. 0 U I/ L and, 10U I/ L f orquarti l e1;from 13 to18U I/ L and10to14 U I/ L f orquarti l e
33、2;from 19to28U I/ Land 15 to 22 U I/L forquartil e 3;and from 29 to 126 U I/L and 23 to 476 U I/L f orquarti le4,respecti vel y.care. di abetesj ournal s. orgDIABETESCARE,VO LUM E34,DECEM BER20112605N guyen and Associ ates5NAFDL是2型糖尿病发生的预测因素Sung KC, Kim SH, J Clin Endocrinol Metab2011; 96:10931097 F
34、arrell GC , J Gastroen terol Hepatol 2011; 26:510 516 Ortiz-Lopez C,.,Cusi K Diabetes Care 2012; 35:873 878 Kim SW, Diabetes Care 2011; 34:727729 Musso G，et al. Ann Med. 2011 Dec;43(8):617-49Williams et al. Endocr Rev. 2013 Feb;34(1):84-129韩国：韩国：Sung KC : 11091例基线糖代谢正常受试者例基线糖代谢正常受试者 随访随访5年，年， NAFLD发
35、生发生T2DM 风险风险 OR 5.05 (CI, 2.08 12.29)Kim SW: 2049例非例非DM受试者，受试者， 随访随访4年，年， 基线存在基线存在NAFLD和和IFG患者发生患者发生2型糖尿病型糖尿病 风险风险 HR8.95 ( CI, 6.49 12.35) 意大利：意大利： Musso G：荟萃分析三个平均随访：荟萃分析三个平均随访4-10年的社区队列研究结果，年的社区队列研究结果， NAFLD患者未来新发糖尿病风险是非脂肪肝患者的患者未来新发糖尿病风险是非脂肪肝患者的3.51倍倍6从脂肪肝到从脂肪肝到2 2型糖尿病型糖尿病Hepatology Research 2013
36、; 43: 5164 7为什么肝脏脂肪沉积可以引起糖代谢异常为什么肝脏脂肪沉积可以引起糖代谢异常1Departm ent of I nternal M edi ci ne, Yal e Uni versi ty School of M edi ci ne, N ew H aven, Connecti cut 06520, USA. 2VA Connecti cut H eal thcare System W est H aven, Connecti cut 06516, USA. 3N ovo N ordi sk Foundati on Center f or Basi c M etabol
37、i c Research, Uni versi ty of Copenhagen, Copenhagen DK-2200, Denm ark. 4Departm ent of Cel l ul ar and M ol ecul ar Physi ol ogy, Yal e Uni versi ty School of M edi ci ne, N ew H aven, Connecti cut 06520, USA. 5H ow ard H ughes M edi cal I nsti tute, Yal e Uni versi ty School of M edi ci ne, N ew H
38、 aven, Connecti cut 06535-8012, USA. Modern gl obal heal t h care f aces chal l enges t hat are drast i cal l y di f f erent f rom past generat i ons, l argel y owi ng t o t he i ncreas-i ng worl dwi de preval ence of obesi t y. Thi s i s exem pl i f i ed by a change i n f ocus t o cent re on obesi
39、t y-rel at ed l i ver di sease. Al t hough vi ral hepat i t i s cont i nues t o be an i m port ant heal t h concern, non-al cohol i c f at t y l i ver di sease (NAFLD) i s t he now m ost com m on l i ver di sorder i n t he W est ern worl d, where t he rat es of adul t and paedi at ri c obesi t y hav
40、e soared t o an est i m at ed 20 30% of t he U S popul at i on1, 2. In east and sout h Asi an com m uni t i es, NAFLD i s al so on t he ri se, wi t h est i m at es t hat i t s preval ence reaches as hi gh as 60% i n urban areas3, 4. St art l i ngl y, NAFLD has been f ound t o be hi ghl y preval ent
41、am ong young l ean sout h Asi an Indi ans5, 6.A st rong associ at i on bet ween NAFLD and t ype 2 di abet es has been dem onst rat ed: m ore t han 90% of obese pat i ent s wi t h t ype 2 di abet es have NAFLD7. I nsul i n resi st ance i s com m on i n bot h condi t i ons5. Pat i ent s wi t h NAFLD a
42、l m ost uni versal l y have hepat i c i nsul i n resi st ance, whi ch i ncreases t he ri sk of i m pai red f ast i ng gl ucose and t ype 2 di abet es5, 8 11. In addi t i on, a subset of pat i ent s wi t h NAFLD wi l l devel op non-al cohol i c st eat ohepat i t i s (NASH ) wi t h hi st ol ogi cal ch
43、anges such as st eat osi s, l obu-l ar i nf l am m at i on and/ or hepat ocel l ul ar bal l ooni ng12. Around 20% of pat i ent s wi t h NASH wi l l progress t o l i ver ci rrhosi s and l i ver f ai l ure13, 14. NASH -associ at ed ci rrhosi s i s now t he t hi rd m ost com m on i ndi cat i on f or l
44、i ver t ranspl ant at i on i n t he Uni t ed St at es15. Heal t h pol i ci es t hat can prevent NAFLD and new t reat m ent s t hat can reverse t he di sease wi l l of f er t rem endous benef i t s, i n t erm s of bot h l i ves saved and heal t h-care cost s.Thus, i n t hi s Perspect i ve we wi l l d
45、i scuss t he l i nk bet ween hepat i c l i pi d accum ul at i on and hepat i c i nsul i n resi st ance and f ocus on t he rol e of di acyl gl ycerol , a l i pi d m et abol i t e t hat act i vat es novel prot ei n ki naseC i so-f orm s (PKCs) and t hereby i m pai rs i nsul i n si gnal l i ng, i n t h
46、e pat hogenesi s of l i pi d-i nduced hepat i c i nsul i n resi st ance. Al t hough several ot her m echa-ni sm s have been proposed t o expl ai n t hi s associ at i on, t hese al t ernat i ves have been revi ewed el sewhere16. As we wi l l di scuss here, di acyl gl ycerol -i nduced novel PKC act i
47、vat i on has em erged as a com m on m echani sm t o expl ai n t he devel opm ent of i nsul i n resi st ance i n l i ver and skel et al m uscl e i n a vari et y of experi m ent al and cl i ni cal m odel s.M M o ol l e ec cu ul l a ar r m m e ec ch ha an ni i s sm m o of f l l i i p pi i d d- -i i n n
48、d du uc ce ed d i i n ns su ul l i i n n r re es si i s st ta an nc ce e I nsul i n act i on requi res a coordi nat ed, i nt ri cat e rel ay of i nt racel l ul ar si g-nal s, i nvol vi ng m ost l y phosphoryl at i on and dephosphoryl at i on event s. I n t he canoni cal vi ew of hepat i c i nsul i n
49、 si gnal l i ng, i nsul i n bi nds and act i vat es t he i nsul i n recept or t yrosi ne ki nase (IRTK), whi ch i n t urn pro-m ot es t yrosi ne ki nase phosphoryl at i on of i nsul i n recept or subst rat es (I RS), m ost i m port ant l y I RS2 i n t he l i ver (Fi g. 1)17. Phosphoryl at i on of IR
50、S2 generat es bi ndi ng si t es f or Src hom ol ogy 2 dom ai n prot ei ns, i ncl udi ng phosphat i dyl i nosi t ol -3-O H ki nase ( PI ( 3) K)18. The bi ndi ng of PI(3)K t o IRS2 recrui t s phosphat i dyl i nosi t ol -3, 4, 5-t ri sphosphat e (Pt dI ns(3, 4, 5)P3), whi ch i n t urn recrui t s Akt19.
