Glucose intolerance and serum aminotransferase activities in Japanese men

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1 Journl of Heptology 38 (2003) Glucose intolernce nd serum minotrnsferse ctivities in Jpnese men Yumi Miyke 1, Hiroyuki Eguchi 1,2, Koichi Shinchi 3, Tkshi Od 3, Shizuk Sszuki 1, Suminori Kono 1, * 1 Deprtment of Preventive Medicine, Fculty of Medicl Sciences, Kyushu University, Fukuok , Jpn 2 Self-Defense Forces Fukuok Hospitl, Ksug, Fukuok, Jpn 3 Self-Defense Forces Kummoto Hospitl, Kummoto, Jpn Bckground/Aims: Elevted ctivities of serum minotrnsferse re commonly observed in ptients with dibetes mellitus. Few studies hve ddressed the reltion between glucose intolernce nd serum ctivities of minotrnsferse in free-living popultions. Methods: Using 75 g orl glucose tolernce test, we exmined the ssocition of impired fsting glycemi (IFG), impired glucose tolernce (IGT), nd type 2 dibetes mellitus with serum sprtte minotrnsferse (AST), lnine minotrnsferse (ALT), nd gmm-glutmyltrnsferse (GGT) mong 4621 men ged yers of the Jpn Self- Defense Forces. Sttisticl djustment ws mde for body mss index, wist-hip rtio, nd other possible confounding fctors. Results: Proportions of n elevted ALT (.50 IU/l) in men with norml glucose tolernce, IFG, IGT, nd newly dignosed dibetes mellitus were 3.5%, 9.5%, 7.7%, nd 18.0%, respectively. Adjusted odds rtios of n elevted ALT for IFG, IGT, nd newly dignosed dibetes mellitus were 2.2 (95% confidence intervl ), 1.7 ( ), nd 4.4 ( ), respectively. IGT nd dibetes mellitus were lso significntly positively ssocited with elevted AST (.40 IU/l) nd GGT (.50 IU/l). Conclusions: Glucose intolernce is ssocited with elevted serum minotrnsferse independent of obesity, but even mildly elevted ALT is reltively uncommon in free-living men with glucose intolernce. q 2002 Europen Assocition for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Serum minotrnsferse; Impired glucose tolernce; Dibetes mellitus; Jpnese men 1. Introduction Serum ctivities of sprtte minotrnsferse (AST) nd lnine minotrnsferse (ALT) re the most frequently used indictors of liver disese [1,2], nd elevted ctivities of serum minotrnsferse re commonly found in clinicl prctice nd helth screening [2 5]. Such bnormlities without either heptitis virus infection or hevy lcohol use hve recently drwn much ttention s non-lcoholic stetoheptitis [6,7]. Elevtions in serum minotrnsferse re frequently observed in ptients with dibetes mellitus [8 10], nd these chnges re mostly ttributed to ftty infiltrtion of the liver [9,10]. Obesity is lso known to be Received 21 Mrch 2002; received in revised form 27 August 2002; ccepted 12 September 2002 * Corresponding uthor. Tel.: ; fx: E-mil ddress: skono@phelth.med.kyushu-u.c.jp (S. Kono). ssocited with elevted ctivities of serum minotrnsferse, especilly with elevted ALT ctivity [4 6]. Becuse obesity is n importnt risk fctor for type 2 dibetes mellitus [11,12], the ssocition between dibetes mellitus nd elevted ctivities of AST nd ALT could be ttributble to obesity in ptients with dibetes mellitus. Few studies hve ddressed the reltion between dibetes mellitus nd elevted serum minotrnsferse in free-living popultions. In cross-sectionl study of the Hispnic Americn popultion [13], dibetes mellitus ws ssocited with elevted serum ALT independent of obesity. Another popultion study in the United Sttes [14] lso reported tht rised serum ALT ws independently ssocited with both obesity nd type 2 dibetes mellitus. In these popultion studies [13,14], only body mss index ws used s n index of obesity, nd bdominl obesity, which is more importnt in the development of type 2 dibetes mellitus /02/$20.00 q 2002 Europen Assocition for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. PII: S (02)

2 Y. Miyke et l. / Journl of Heptology 38 (2003) [11,12], ws not tken into considertion. We investigted the reltion of glucose tolernce sttus determined by the 75 g orl glucose tolernce test (OGTT) with serum AST nd ALT ctivities, controlling for not only body mss index but lso wist-hip rtio nd other fctors in Jpnese men. We lso exmined the ssocition with serum gmm-glutmyltrnsferse (GGT) becuse serum GGT my be correlte of hyperinsulinemi or insulin resistnce [15,16]. 2. Subjects nd methods 2.1. Study subjects Subjects were mle self-defense officils who received pre-retirement helth exmintion t the Self-Defense Forces (SDF) Fukuok Hospitl from Jnury 1991 to December 1994, t the SDF Kummoto Hospitl from Jnury 1991 to December 1994, t the SDF Spporo Hospitl from April 1992 to December 1994, or t the SDF Centrl Hospitl from Jnury 1993 to December In the consecutive series of 4883 men ged yers, 262 men were excluded for the following resons: insulin tretment (n ¼ 11), undetermined glucose tolernce due to lck of post-lod glucose mesurement (n ¼ 8), missing informtion on wist-to-hip rtio (n ¼ 3), known chronic heptitis or liver cirrhosis (n ¼ 87), positive test for heptitis C virus (HCV) ntibody (n ¼ 43), nd positive test for heptitis B virus surfce (HBs) ntigen (n ¼ 158); some men hd two or more conditions for exclusion. While HBs ntigen ws tested with ll the subjects, the test for HCV ntibody ws introduced in Thus, the study subjects (n ¼ 4621) included 2331 men of unknown sttus regrding HCV ntibody. Detils of the helth exmintion hve been described previously [17 20]. The study ws conducted in ccordnce with the Helsinki Declrtion, nd written informed consent ws obtined from ech subject Lbortory methods A 75 g OGTT ws done fter subjects fsted overnight. Glucose concentrtions were ssyed by the glucose oxidse method with commercil kit (Shino Test Co. Ltd., Tokyo) using plsm t the Fukuok, Spporo, nd Centrl Hospitls nd whole cpillry blood t the Kummoto Hospitl. On the bsis of the new criteri of the World Helth Orgniztion (WHO) in Ref. [21], subjects were clssified s hving norml glucose tolernce, impired fsting glycemi (IFG), impired glucose tolernce (IGF), nd type 2 dibetes mellitus. Men under dietry or drug tretment for dibetes mellitus were regrded s hving type 2 dibetes mellitus under tretment. Venus blood fter n overnight fst ws used for the determintion of serum ctivities of AST, ALT, nd GGT. The ssy ws done by the enzymtic method with n utonlyzer t ech hospitl using commercil regents [22,23]. Serum AST nd ALT vlues of greter thn 40 IU/l were defined s elevted AST nd ALT, respectively, nd serum GGT greter thn 50 IU/l ws defined s n elevted GGT, on the bsis of reference vlues provided by mnufcturers of the regents. HBs ntigen ws tested by reversed pssive hemgglutintion, nd HCV ntibody ws ssyed by pssive hemgglutintion (second genertion) using commercil kits (Dinbot Co. Ltd., Tokyo) Anthropometric nd lifestyle dt Body weight (kg) nd height (cm) were recorded, nd body mss index (kg/m 2 ) ws clculted s n index of overll obesity. Wist nd hip circumference were mesured to the nerest centimeter, with the prticipnt stnding in n erect position. Wist circumference ws mesured t the umbilicl point, nd hip circumference round the buttocks. Medicl history nd current mediction were elicited by wrd nurses nd physicins. Smoking hbit, lcohol use, nd other lifestyle chrcteristics were scertined by using self-dministered questionnire s described elsewhere in detil [18,20] Sttisticl nlysis The differences in mens nd proportions of confounding fctors ccording to glucose tolernce sttus were sttisticlly tested by one-wy nlysis of vrince nd chi-squre test, respectively. Anlysis of covrince ws used to clculte the mens of AST, ALT, nd GGT ccording to glucose tolernce sttus with djustment for possible confounding effects of hospitl, rnk in the SDF, cigrette smoking, lcohol use, coffee consumption, body mss index, nd wist-hip rtio. Becuse the distributions of vlues of the liver enzymes were skewed to the right side, the vlues were trnsformed to the scle of nturl logrithm so tht ech distribution ws pproximted to the norml distribution. Presented mens of AST, ALT, nd GGT re thus lwys geometric mens. Age ws in limited rnge from 49 to 59 yers, nd 99.3% were ged yers. Age ws thus omitted in the present nlysis. Repeted nlyses controlling for ge s continuos vrible produced essentilly the sme results s reported below. Rnk in the SDF ws ctegorized into three clsses (low, middle, nd high). Cigrette smoking ws ctegorized in five groups (never, pst, nd current smoking with consumption of,15, 15 24, or 25 1 cigrettes per dy), lcohol use ws in five ctegories (never, pst, nd current drinking with consumption of,30, 30 59, or 60 1 ml of lcohol per dy), nd coffee consumption ws in ctegories of 0, 1 2, 3 4, nd 5 1 cups per dy. Body mss index nd wist-hip rtio were ctegorized t the cutoff points of the 25th, 50th, nd 75th percentiles in ech distribution. Indictor vribles representing ctegories of the confounding fctors were included in the model s independent vribles. Multiple logistic regression nlysis ws used to exmine the reltion of glucose tolernce sttus to elevted ctivities of AST nd ALT in terms of odds rtio (OR) with djustment for the bove-mentioned confounding vribles. The 95% confidence intervl (CI) of OR ws estimted by using the stndrd error of logistic regression coefficient for ech indictor vrible. The trend of the ssocition between the degree of pthologic glucose tolernce nd elevtion in liver enzymes ws ssessed by using multiple liner regression for the mens nd by using multiple logistic regression for the ORs of elevted ctivities. In these nlyses, ordinl scores (0, 1, nd 2) were ssigned to the three ctegories of glucose tolernce (norml, IFG nd IGT combined, nd newly dignosed dibetes mellitus). P vlues (twosided) less thn 0.05 were regrded s sttisticlly significnt. All sttisticl nlyses were done by using the Sttisticl Anlysis System (SAS) version 6.12 (SAS Institute, Inc., Cry, NC). 3. Results Medins of serum AST, ALT, nd GGT were 19 IU/l (rnge IU/l), 16 IU/l (rnge IU/l), nd 27 IU/l (rnge IU/l), respectively. Numbers of men with elevted AST, ALT, nd GGT were 123 (2.7%), 223 (5.0%), nd 1065 (23.0%), respectively. Those hving two times the upper limit of norml numbered 16 (0.3%) for AST, 26 (0.6%) for ALT, nd 290 (6.3%) for GGT. Numbers of men by glucose tolernce sttus were s follows: norml, 3410; IFG, 116; IGT, 750; newly dignosed type 2 dibetes mellitus, 233; nd treted dibetes mellitus, 112. Tble 1 shows the mens of body mss index nd wisthip rtio s well s the prevlence of other potentil confounding fctors ccording to glucose tolernce sttus. Body mss index nd wist-hip rtio were greter in men with IFG, IGT, nd newly dignosed type 2 dibetes mellitus, but not in those with treted dibetes mellitus, thn in

3 20 Y. Miyke et l. / Journl of Heptology 38 (2003) Tble 1 Potentil confounding vribles ccording to glucose tolernce sttus (n ¼ 4621) Fctor Norml IFG IGT New type 2 dibetes Treted type 2 dibetes Overll P vlue Number of subjects Body mss index (men) Wist hip rtio (men) Current smoking (%) Hevy smoking (%) b Alcohol use (%) c Hevy lcohol use (%) d Dily use of coffee (%) b c d One-wy nlysis of vrince for men difference nd chi-squre test for the difference in proportions. Smoking 25 1 cigrettes per dy. Drinking t lest once per week. Drinking 60 1 ml of lcohol per dy. those with norml glucose tolernce. While the prevlence of cigrette smoking did not mterilly vry with glucose tolernce sttus, hevy smoking ws more frequent mong men with newly dignosed dibetes mellitus. Coffee use ws less frequent in those with dibetes mellitus whether they were under tretment or not. Tble 2 shows djusted geometric mens of serum AST, ALT, nd GGT with nd without djustment for body mss index nd wist-hip rtio. ALT levels were progressively higher for IFG, IGT, nd newly dignosed type 2 dibetes mellitus s compred with norml glucose tolernce. The vrition of ALT levels ccording to glucose tolernce sttus ws more profound thn tht of AST, but less mrked thn tht of GGT. Both AST nd ALT ctivities in the group of treted dibetes mellitus were lmost the sme s those in the group of norml glucose tolernce. Adjustment for body mss index nd wist-hip rtio slightly dwrfed the vrition in ctivities of the liver enzymes ccording to glucose tolernce sttus. The incresing trend of mens for more pthologic glucose tolernce (norml, IFG nd IGT combined, nd newly dignosed dibetes mellitus) ws highly significnt for ech of the three enzymes (trend P ¼ 0:0001). The proportions of elevted AST, ALT, nd GGT were higher in men with IFG, IGT, nd newly dignosed type 2 dibetes mellitus thn in those with norml glucose tolernce, nd the proportions were much higher mong men with newly dignosed dibetes mellitus thn mong those with IFG or IGT (Tble 3). With djustment for fctors other thn obesity indices, substntil increses in the prevlence odds of elevted AST, ALT, nd GGT were observed mong men with newly dignosed dibetes mellitus, s compred with those with norml glucose tolernce; the increse in the odds of elevted ALT ws slightly more profound. IGT ws lso ssocited with sttisticlly significntly increse in the odds of elevted ctivities of the liver enzymes. Treted dibetes mellitus ws unrelted to either elevted AST or ALT, but ws positively ssocited with n elevted GGT. Tble 4 shows djusted ORs of elevted AST, ALT, nd GGT in reltion to glucose tolernce sttus nd other covrites in the multivrite nlysis including body mss index nd wist-hip rtio. Increses in the djusted ORs of elevted AST, ALT, nd GGT ssocited with newly dignosed dibetes mellitus remined substntil, nd the trend Tble 2 Adjusted geometric mens nd 95% CIs (in prentheses) of serum AST, ALT, nd GGT ccording to glucose tolernce sttus Glucose tolernce sttus AST ALT GGT Adjusted geometric men Norml 18.7 ( ) 15.6 ( ) 27.6 ( ) IFG 19.5 ( ) 17.6 ( ) 29.9 ( ) IGT 20.3 ( ) 18.9 ( ) 35.7 ( ) New type 2 dibetes 20.7 ( ) 21.6 ( ) 45.7 ( ) Treted type 2 dibetes 17.4 ( ) 16.4 ( ) 35.8 ( ) Fully-djusted geometric men b Norml 18.8 ( ) 15.9 ( ) 28.1 ( ) IFG 19.1 ( ) 16.4 ( ) 28.1 ( ) IGT 20.0 ( ) 17.9 ( ) 33.9 ( ) New type 2 dibetes 20.3 ( ) 20.1 ( ) 42.9 ( ) Treted type 2 dibetes 17.4 ( ) 16.4 ( ) 35.5 ( ) b Adjusted for hospitl, rnk, smoking, lcohol use, nd coffee consumption. Adjusted for body mss index nd wist-hip rtio in ddition to the bove fctors.

4 Y. Miyke et l. / Journl of Heptology 38 (2003) Tble 3 Numbers of men with elevted serum AST (.40 IU/l), ALT (.40 IU/l), nd GGT (.50 IU/l) nd djusted OR with 95% CIs ccording to glucose tolernce sttus Glucose tolernce sttus Elevted AST Elevted ALT Elevted GGT No. (%) OR (95% CI) No. (%) OR (95% CI) No. (%) OR (95% CI) Norml 62 (1.8) 1.0 (referent) 118 (3.5) 1.0 (referent) 663 (19.4) 1.0 (referent) IFG 5 (4.3) 2.1 ( ) 11 (9.5) 3.0 ( ) 32 (27.6) 1.3 ( ) IGT 33 (4.4) 2.5 ( ) 58 (7.7) 2.3 ( ) 220 (29.3) 1.6 ( ) New type 2 dibetes 21 (9.0) 4.7 ( ) 42 (18.0) 6.0 ( ) 115 (49.4) 4.0 ( ) Treted type 2 dibetes 2 (1.8) 0.9 ( ) 4 (3.6) 1.0 ( ) 35 (31.3) 2.0 ( ) Adjusted for hospitl, rnk, smoking, lcohol use, nd coffee consumption. for norml glucose tolernce, IFG nd IGT combined, nd newly dignosed dibetes mellitus ws gin highly significnt regrding ech of the liver enzymes (P ¼ 0:0001). Body mss index nd wist-hip rtio were sttisticlly significntly relted to incresed ORs of elevted ALT nd GGT, but not with elevted AST. On the other hnd, hevy lcohol use ws strongly ssocited with elevted AST nd GGT, nd not with elevted ALT. Smoking ws not mesurbly ssocited with either elevted AST or ALT. Coffee consumption ws ssocited with decresed OR of elevted AST, nd showed dose-dependent inverse ssocition with GGT. 4. Discussion The present study showed strong, positive ssocition between type 2 dibetes mellitus nd elevted ctivities of serum AST nd ALT independent of body mss index, wist-hip rtio, nd other confounding fctors. The findings consolidte the previous observtion tht dibetes mellitus ws ssocited with elevted ALT independent of obesity [13,14]. The increse in the odds of elevted ALT ssocited with type 2 dibetes mellitus ws much greter in the present study thn in these previous studies; djusted ORs for dibetes mellitus compred with non-dibetes Tble 4 Adjusted ORs nd 95% CIs of elevted serum AST (.40 IU/l), ALT (.40 IU/l), nd GGT (.50 IU/l) in multivrite nlysis Fctor Ctegory Elevted AST Elevted ALT Elevted GGT Glucose tolernce Norml 1.0 (referent) 1.0 (referent) 1.0 (referent) IFG 1.8 ( ) 2.2 ( ) 1.1 ( ) IGT 2.2 ( ) 1.7 ( ) 1.4 ( ) New type 2 dibetes 3.8 ( ) 4.4 ( ) 3.4 ( ) Treted type 2 dibetes 0.8 ( ) 0.9 ( ) 1.9 ( ) Body mss index b, (referent) 1.0 (referent) 1.0 (referent) ( ) 0.7 ( ) 1.0 ( ) ( ) 1.3 ( ) 1.1 ( ) ( ) 2.6 ( ) 1.5 ( ) Wist hip rtio b, (referent) 1.0 (referent) 1.0 (referent) ( ) 2.2 ( ) 1.6 ( ) ( ) 3.1 ( ) 1.8 ( ) ( ) 4.1 ( ) 2.6 ( ) Cigrette smoking (no./dy) None 1.0 (referent) 1.0 (referent) 1.0 (referent) Former 1.2 ( ) 0.9 ( ) 1.2 ( ), ( ) 1.2 ( ) 1.2 ( ) ( ) 0.9 ( ) 1.4 ( ) ( ) 0.8 ( ) 1.4 ( ) Alcohol use (ml/dy) None 1.0 (referent) 1.0 (referent) 1.0 (referent) Former 2.3 ( ) 1.5 ( ) 1.4 ( ), ( ) 0.7 ( ) 2.4 ( ) ( ) 0.7 ( ) 4.9 ( ) ( ) 0.8 ( ) 8.4 ( ) Coffee use (cups/dy) (referent) 1.0 (referent) 1.0 (referent) ( ) 0.9 ( ) 0.8 ( ) ( ) 1.0 ( ) 0.7 ( ) ( ) 0.8 ( ) 0.6 ( ) The multivrite model included indictor vribles for hospitl, rnk, smoking, lcohol use, coffee use, body mss index, wist-hip rtio, nd glucose tolernce. b Ctegorized t qurtiles.

5 22 Y. Miyke et l. / Journl of Heptology 38 (2003) were reported to be two or three [13,14]. In these studies, however, IFG nd IGT were not exmined seprtely, nd the physicin s dignosis of dibetes mellitus ws combined with unknown (newly dignosed) dibetes mellitus. The present study demonstrted tht both IFG nd IGT were lso significntly ssocited with pproximtely two-fold increses in the odds of elevted ALT. Further, it is noteworthy tht treted dibetes mellitus ws unrelted to serum minotrnsferse ctivities. Filure to differentite IFG nd IGT from norml glucose tolernce nd dibetes mellitus under tretment from newly dignosed dibetes mellitus necessrily underestimtes the effect of dibetes mellitus on serum minotrnsferse ctivities. The present study lso showed strong, positive ssocition between type 2 dibetes mellitus nd GGT. A greter elevtion in the geometric men ws observed for GGT thn for ALT mong men with type 2 dibetes mellitus, nd even men under tretment for dibetes mellitus showed nerly two-fold, sttisticlly significnt increse in the OR of n elevted GGT. Serum GGT hs been implicted s mrker of insulin resistnce [15,16], nd elevted levels of GGT were lso shown to be predictive of the occurrence of type 2 dibetes mellitus [16]. The present findings on GGT re consistent with those of the previous studies [15,16]. Severl importnt confounding fctors were tken into ccount in the present study. Not only body mss index but lso wist-hip rtio ws controlled for. It hs consistently been shown tht bdominl obesity is more importnt s predictor for type 2 dibetes mellitus thn body size [11,12]. In fct, the wist-hip rtio ws more strongly ssocited with elevted ALT thn body mss index. The importnce of bdominl obesity for elevted ALT ws lso noted in men, but not in women, in cross-sectionl study in Denmrk [24]. Severl studies hve shown n incresed risk of type 2 dibetes mellitus ssocited with high lcohol intke [25,26] nd smoking [27], nd thus we included these fctors s possible confounding fctors. While lcohol use ws positively ssocited with serum ALT [13,14] s well s with serum AST [28,29] in other popultion studies, lcohol use ws virtully unrelted to elevted ALT in the present study. We hve no cler explntion for the lck of positive ssocition between lcohol consumption nd serum ALT. No mteril ssocition ws noted between smoking nd either serum AST or ALT, nd the findings re consistent with results in other studies [13,28,29]. Coffee drinking ws recently shown to be inversely ssocited with serum minotrnsferse ctivities [13,20]. In the present study popultion, coffee use ws less frequent in men with type 2 dibetes mellitus. It is known tht liver dysfunction ssocited with chronic heptitis or liver cirrhosis results in glucose intolernce [30]. In this respect, subjects with chronic heptitis or liver cirrhosis were excluded in the present nlysis. Men with positive test for HBs ntigen or HCV ntibody were lso excluded, but the ltter condition ws not tested in hlf of the study subjects. If HCV infection is positively ssocited with glucose intolernce, positive ssocitions of glucose intolernce with serum ALT nd AST my hve been overestimted. However, there ws no mteril vrition in the positive rte of HCV ccording to the ctegory of glucose tolernce. In men whose HCV ntibody ws tested (n ¼ 2320), the proportions of HCV ntibody positivity mong men with norml glucose tolernce, IFG, IGT, nd newly dignosed dibetes mellitus were 1.0%, 3.0%, 1.4%, nd 1.6%, respectively. The positive rte ws slightly higher in only those with treted dibetes mellitus (7.3%). It my be rgued tht men serving for the SDF until retirement my differ from those of the generl popultion in vrious chrcteristics nd tht the findings my not be generlized. However, the prevlence of IGT nd type 2 dibetes mellitus on the bsis of the older WHO criteri [31] did not differ much from the rtes reported in other studies in Jpn [32,33]. The prevlence rtes of IGT rnged from 13% to 17%, nd those of type 2 dibetes mellitus were from 9% to 14% mong middle-ged men in these studies; the corresponding figures in the present popultion were 16.5% nd 7.0%, respectively. Mny studies hve shown tht hyperinsulinemi or insulin resistnce is ssocited with non-lcoholic stetoheptitis [34 41]. In some of these studies [39,41], virtully ll ptients with non-lcoholic stetoheptitis were found to hve insulin resistnce. A positive ssocition between insulin resistnce nd non-lcoholic stetoheptitis ws observed even in those without dibetes mellitus [35,40]. The present study provides confirmtory evidence tht insulin resistnce is ssocited with liver pthology s indicted by rised trnsminses. However, it should be noted tht even mildly elevted ALT ws reltively uncommon in men with glucose intolernce; less thn 10% of those with IFG or IGT nd no more thn 18% of those with newly dignosed type 2 dibetes mellitus hd n elevted ALT. As lso suggested in nother popultion study [14], liver pthology seems to occur in only minority of ptients with insulin resistnce or glucose intolernce. Finlly, becuse the present study ws cross-sectionl, the observed ssocition of glucose intolernce with elevted minotrnsferse ctivities does not necessrily indicte cusl reltionship. Although the finding tht treted dibetes mellitus ws unrelted to elevted serum minotrnsferse ctivities suggests tht tretment of dibetes mellitus my reverse liver pthology, insulin resistnce nd glucose intolernce could be result of obesity-relted ftty liver s well s contributory cuses. Acknowledgements This study ws supported by Grnts-in Aid for Scientific Reserch (B) ( ) from the Jpn Society for the Promotion of Science, nd for Scientific Reserch on Priority Ares ( ) from the Ministry of Eduction, Culture, Sports, Science nd Technology, Jpn.

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