The Metabolic Syndrome is Associated with Increased Risk of Colorectal Adenoma Development: The Self-Defense Forces Health Study

Transcription

1 The Metolic Syndrome nd Colorectl Adenom Development RESEARCH COMMUNICATION The Metolic Syndrome is Associted with Incresed Risk of Colorectl Adenom Development: The Self-Defense Forces Helth Study Tkko Morit 1, Shinji Tt 1, 2, Msmichi Mineshit 3, Tetsuy Mizoue, 1 Mlcolm A Moore, 1 Suminori Kono 1 Astrct The metolic syndrome, cluster of metolic normlities linked to insulin resistnce, hs ttrcted much interest s risk fctor for crdiovsculr disese nd type 2 dietes. Hyperinsulinemi is lso postulted iologicl risk fctor for colorectl crcinogenesis. We therefore here exmined the reltion etween the metolic syndrome nd colorectl denom development. The study sujects were 756 cses of colorectl denom nd 1751 controls with no polyps who underwent totl colonoscopy during the period Jnury 1995 to Mrch 2002 t two Self Defense Forces (SDF) hospitls in Jpn. The metolic syndrome ws defined with reference to dominl oesity in comintion with ny two of the following conditions: elevted triglycerides ( 150 mg/dl); lowered HDL cholesterol (<40 mg/dl); elevted lood pressure (systolic lood pressure 130 mmhg nd/or distolic lood pressure 85 mmhg); nd rised fsting glucose ( 110 mg/dl). Adominl oesity ws defined s wist circumference of 85cm or more(jpnese criterion) or 90cm (Asin criterion). Sttisticl djustment ws mde for ge, hospitl, nd rnk in the SDF. The metolic syndrome ws found to e ssocited with modertely incresed risk of colorectl denoms whether either of the Jpnese nd Asin criteri ws used; djusted odds rtios with the Jpnese nd Asin criteri were 1.38 (95% confidence intervl [CI] ) nd 1.48 (95% CI ), respectively. Incresed risk ws more evident for proximl thn distl colon or rectl denoms, nd ws lmost exclusively oserved for lrge lesions ( 5mm in dimeter). Thus the metolic syndrome ppers to e n importnt entity with regrd to the prevention of colorectl cncer, s well s crdiovsculr disese nd type 2 dietes. Key Words: Adominl oesity metolic syndrome colorectl denom Jpnese men Asin Pcific J Cncer Prev, 6, Introduction The metolic syndrome hs recently drwn much ttention in connection with the emerging glol epidemic of oesity nd type 2 dietes mellitus (Hslm nd Jmes, 2005; King et l., 1998). The syndrome is constelltion of metolic normlities including glucose intolernce, hypertriglyceridemi, nd hypertension which increses the risk of crdiovsculr disese s well s type 2 dietes mellitus (Eckel et l., 2005). The pthophysiology of the metolic syndrome is considered to e primrily ttriutle to insulin resistnce ssocited with oesity nd physicl inctivity. In this context, dominl rther thn sucutneous ft ppers of prticulr concern ecuse viscerl ft leds to high influx of undnt free ftty cids nd proinflmmtory cytokines into the liver, therey ccentuting insulin resistnce nd locl nd systemtic proinflmmtory stte (Eckel et l., 2005; Hslm nd Jmes, 2005). Thus dominl oesity is currently considered s core component of metolic syndrome, with two or more comorid conditions of normlities of serum triglycerides, serum HDL cholesterol, fsting lood glucose, nd lood pressure s criteri for dignosis (Alerti et l., 2005). Oesity nd physicl inctivity re lso consistently relted to n incresed risk of colon cncer (IARC, 2002), with hyperinsulinemi ssocited with insulin resistnce s one of the postulted underlying mechnisms (McKeown- Eyssen, 1994; Giovnnucci, 1995; Moore et l., 1998). 1 Deprtment of Preventive Medicine, Fculty of Medicl Sciences, Kyushu University, Fukuok, Jpn. 2 Self Defense Forces Fukuok Hospitl, Ksug-shi, Jpn. 3 Self Defense Forces Kummoto Hospitl, Kummoto, Jpn. Address for correspondence: S Kono, Deprtment of Preventive Medicine, Fculty of Medicl Sciences, Kyushu University, Higshi-ku, Fukuok , Jpn. Fx: , E-mil: skono@phelth.med.kyushu-u.c.jp Asin Pcific Journl of Cncer Prevention, Vol 6,

2 Tkko Morit et l Insulin hs een shown to promote colorectl crcinogenesis (Corpet et l., 1997; Trn et l., 1996) nd severl studies hve shown n incresed risk of colon or colorectl cncer with dietes (Weiderpss et l., 1997; Wideroff et l., 1997; Hu et l., 1999). Dietes mellitus hs lso een shown to e ssocited with n incresed risk of colon denom development (Kono et l., 1998; Nishii et l., 2001; Mrugme et l., 2002). It is thus nturlly of interest whether the metolic syndrome is relted to colorectl crcinogenesis. In this pper, we therefore exmined links etween the metolic syndrome nd colorectl denom, well-estlished precursor lesion for colorectl cncer (O Brien et l., 1990), in popultion of middle-ged Jpnese men. Mterils nd Methods Sujects Study sujects were mle officils in the Self-Defense Forces (SDF) who received preretirement helth exmintion t the SDF Fukuok Hospitl from Jnury 1995 to Mrch 2002 or t the SDF Kummoto Hospitl from My 1996 to Mrch The preretirement helth exmintion is ntionwide progrm offering comprehensive medicl exmintion to those retiring from the SDF, detils of which hve een descried elsewhere (Kono et l., 1999; Toyomur et l., 2004). Colonoscopy ws routine procedure mong others during 5-dy dmission. The study ws pproved y the ethicl committee of Kyushu University. The present investigtion included 756 cses of histologiclly confirmed colorectl denoms nd 1751 controls with no polyps mong 3552 men who underwent totl colonoscopy successfully. In consecutive series of 4219 men during the ove-mentioned period, 8 refused to prticipte in the survey, nd 659 did not undergo successful totl colonoscopy (no colonoscopy, 126; poor results, 11; nd prtil colonoscopy, 522). Of the 3552 undergoing totl colonoscopy, 324 were excluded ecuse of history of colectomy (n = 20), colorectl polypectomy (n = 283), mlignnt neoplsms (n = 36), or inflmmtory owel disese (n = 3). In the remining 3228 men, colonoscopic findings were clssified s colorectl cncer (n = 2), polyp (n = 1471), non-polyp enign lesions such s diverticul (n = 207), nd norml (n = 1548). Of the 1755 controls with norml or non-polyp enign lesions, 1751 were used s controls fter exclusion of 4 men for whom the wist ws not mesured. Of the 1471 men with colorectl polyps, 756 were found to hve denoms without in situ or invsive crcinom, nd they were used s cses for the present study. Numers of cses hving denoms of the proximl colon lone, distl colon lone, nd rectum lone were 258, 294, nd 79, respectively. Proximl colon included cecum, scending colon nd trnsverse colon. A totl of 125 cses hd denoms t multiple sites. Cses with denoms sized of <5, 5 9, nd 10 mm (the lrgest size for multiple denoms) numered 460, 243, nd 49, respectively. Size of denom ws not recorded with 4 cses. In the present 486 Asin Pcific Journl of Cncer Prevention, Vol 6, 2005 study, denoms of 5 mm or greter dimeter ws clssified s lrge, while lesions mesuring less thn 5 mm in dimeter were defined s smll denoms. Clinicl nd Lortory Dt Venous lood ws drwn fter n overnight fst for the determintion of serum lipids nd other iochemicl mesurements. Serum triglycerides nd HDL-cholesterol were ssyed enzymticlly t ech hospitl lortory using regents from different sources. Plsm glucose levels were ssyed y the glucose oxidse method using commercil kit (Shino Test, Co. Ltd., Tokyo) t ech hospitl lortory. A single lood pressure reding on the first dy of dmission ws used for the present study. Wist nd hip circumferences were mesured in the horizontl plne t the level of the umilicus nd t the lrgest circumference round the uttocks, respectively. Medicl history nd current mediction were scertined y wrd nurses nd physicins. Definition of the Metolic Syndrome In ccordnce with the dignostic criteri proposed y the Jpnese Committee of the Metolic Syndrome Dignostic Criteri (2005) nd the Interntionl Dietes Federtion (Alerti et l., 2005), the metolic syndrome ws defined s the comintion of dominl oesity with ny two of the following conditions: elevted triglycerides ( 150 mg/dl); lowered HDL cholesterol (<40 mg/dl); elevted lood pressure (systolic lood pressure 130 mmhg nd/or distolic lood pressure 85 mmhg); nd rised fsting glucose ( 110 mg/dl). Mediction for hypertension nd tretment for dietes mellitus were tken s evidence of rised lood pressure nd fsting glucose, respectively. Of the cses nd controls comined, 300 (12.0%) were under ntihypertensive mediction, 109 (4.3%) were under dietry or drug tretment for dietes mellitus. It hs een recommended y the Interntionl Dietes Federtion (Alerti et l., 2005) tht cutoff points for dominl oesity tke ccount of the ethnicity nd sex, nd wist circumference of 85cm hs een dopted s the definition for dominl oesity for Jpnese men ( 90cm for Jpnese women). However, cutoffs of 90 cm for men nd 80 cm for women hve lredy een specified for Chinese nd South Asins (Alerti et l., 2005). The clinicl significnce of the different cutoffs remins uncertin t the present, nd therefore we pplied oth 85 cm nd 90 cm (for men), s the Jpnese nd Asin definitions, respectively, for the present nlysis. Sttisticl Anlysis Odds rtios (ORs) nd 95% confidence intervls (CIs) were otined y logistic regression nlysis; the 95% CI ws derived from the stndrd error for the logistic regression coefficient. Sttisticl djustment ws mde for ge (continuous vrile), hospitl, nd rnk in the SDF. Twosided P vlues less thn 0.05 were regrded s sttisticlly significnt. All computtions were performed using SAS version 8.2 (SAS Institute Inc., Cry, NC).

3 The Metolic Syndrome nd Colorectl Adenom Development Tle 1. Reltion of Ech Component of the Metolic Syndrome to Colorectl Adenoms Vrile/ctegory Numer (%) OR (95% CI) Cses Controls Wist circumference (cm) < (50) 1034 (59) 1.00 (referent) (26) 417 (24) 1.31 ( ) (24) 300 (17) 1.66 ( ) Triglycerides (mg/dl) < (65) 1201 (69) 1.00 (referent) (35) 550 (31) 1.18 ( ) HDL (mg/dl) (93) 1605 (92) 1.00 (referent) <40 54 (7) 146 (8) 0.85 ( ) Elevted lood pressure ( ) 287 (38) 729 (42) 1.00 (referent) (+) 469 (62) 1022 (58) 1.16 ( ) Rised fsting glucose c ( ) 613 (81) 1435 (82) 1.00 (referent) (+) 143 (19) 316 (18) 1.06 ( ) Either systolic lood pressure 130 mmhg nd/or distolic lood pressure 85 mmhg or mediction for hypertension. c Either fsting plsm glucose 110 mg/dl or tretment for dietes mellitus. Results Ages rnged yers for the cses nd yers for the controls, with 99% in the rnge of yers in oth groups. Adominl oesity defined y the Jpnese criterion ( 85cm in wist circumference) ws oserved with 50% of of the cses nd 41% of the controls. Adominl oesity sed on the Asin criterion ( 90 cm) ws much less frequent, ut ws lso more prevlent in the cses (Tle 1). Prevlent odds of colorectl denom progressively incresed with higher vlues for wist circumference. Adjusted ORs for colorectl denom with dominl oesity s clssified y the Jpnese ( 85 cm versus <85 cm) nd Asin ( 90 versus < 90 cm) criteri were 1.45 (95% CI ) nd 1.52 (95% CI ), respectively. Hypertriglyceridemi, lowered HDL cholesterol, rised lood pressure, nd rised fsting glucose were evident in 31%, 8%, 58%, nd 18%, respectively, for the control group. None of these four components of the metolic syndrome ws mesurly ssocited with colorectl denom. Tle 2. Risk of Colorectl Adenoms in Reltion to the Metolic Syndrome Metolic syndrome Numer (%) OR (95% CI) Cses Controls Jpnese criteri ( ) 563 (74) 1403 (80) 1.00 (referent) (+) 193 (26) 348 (20) 1.38 ( ) Asin criteri ( ) 657 (87) 1588 (91) 1.00 (referent) (+) 99 (13) 163 (9) 1.48 ( ) The prevlence rtes for the metolic syndrome s defined y the Jpnese criteri were 26% in the cses nd 20% in the controls. The corresponding vlues on the sis of the Asin criteri were 13% nd 9% (Tle 2). The djusted OR for colorectl denoms ws modertely ut sttisticlly significntly incresed in individuls with the metolic syndrome, independent of the criteri pplied. When the nlysis ws conducted y tissue site (Tle 3), the ORs ssocited with metolic syndrome were consistently incresed for proximl colon denoms. A less evident increse in the OR of distl colon denom ssocited with metolic syndrome ws sttisticlly significnt only when the Jpnese definition ws used, while sttisticlly non-significnt increse in the OR of rectl denom ws more pronounced with the Asin definition. A positive ssocition with metolic syndrome ws oserved lmost exclusively for lrge denoms (Tle 4). Of the cses with proximl colon denom lone (n = 258), 85 cses were clssified s hving lrge denoms, nd denoms of the remining 173 cses were clssified s smll. Cses of lrge proximl colon denom with the metolic syndrome defined y the Jpnese nd Asin criteri numered 27 nd 12, respectively, resulting in n OR of 1.90 (95% CI ) for the Jpnese definition nd n OR of 1.70 (95% CI ) for the Asin definition. The ORs for smll proximl denoms were 1.42 (95% CI ) nd 1.61 (95% CI ), respectively. Discussion The present study reveled sttisticlly significnt Tle 3. Risk of Adenoms of the Proximl Colon, Distl Colon nd Rectum in Reltion to the Metolic Syndrome Proximl colon Distl colon Rectum Metolic syndrome No OR (95% CI) No OR (95% CI) No OR (95% CI) Jpnese criteri ( ) (referent) (referent) (referent) (+) ( ) ( ) ( ) Asin criteri ( ) (referent) (referent) (referent) (+) ( ) ( ) ( ) Numer of denom cses. Asin Pcific Journl of Cncer Prevention, Vol 6,

4 Tkko Morit et l Tle 4. Risks of Colorectl Adenom in Reltion to the Metolic Syndrome y Size of Adenom Metolic Smll denoms Lrge denoms syndrome No OR (95% CI) No OR (95% CI) Jpnese criteri ( ) (referent) (referent) (+) ( ) ( ) Asin criteri ( ) (referent) (referent) (+) ( ) ( ) Numer of denom cses. increse in the risk of colorectl denom ssocited with the metolic syndrome, most prevlent for the proximl colon rther thn the distl colon or rectum, nd prticulrly for lrge denoms. We were unle to rule out smll increse in the risk of distl colon or rectl denom ssocited with metolic syndrome, however. It should e noted tht the findings were consistent with oth the Jpnese nd Asin criteri for dominl oesity. Previously, to our knowledge, only one study hs exmined the reltion etween cluster of metolic normlities nd colorectl cncer (Trevisn et l., 2001). The focus ws on norml vlues for triglycerides, HDL cholesterol, nd fsting glucose (ech defined y the highest or lowest qurtile) nd hypertension (systolic pressure 140 mmhg nd/or 90 mmhg). Adominl oesity ws not tken into ccount, ut the cluster of metolic normlities ws ssocited with sttisticlly significnt 3-fold increse in mortlity from colorectl cncer (Trevisn et l., 2001). The present findings re in greement with the previous oservtions regrding dietes mellitus nd colon denoms in the SDF Helth Study. In erlier nlyses (Nishii et l., 2001; Mrugme et l., 2002), sed on some of the sujects included in the present nlysis, dietes mellitus ws ssocited with incresed risks of oth proximl nd distl colon denoms, ut ws more strongly ssocited with proximl colon denom nd with lrge denoms ( 5 mm in dimeter). The finding tht the metolic syndrome might lso e more strongly ssocited with lrge denoms indictes tht hyperinsulinemic sttus my e responsile for growth of denoms. Insulin my exert prolifertive effect on colonic tumor cells directly (Corpet et l., 1997; Trn et l., 1996) or vi the insulin-like growth fctor pthwy indirectly (Yu nd Rohn, 2000). Furthermore, incresed production of proinflmmtory cytokines nd decresed production of n nti-inflmmtory diponectin in dipocytes my e relevnt to the growth of denoms (Eckel et l., 2005). Recently, high plsm levels of diponectin were shown to e inversely relted to the risk of colon cncer (Wu et l., 2005). However, it is not cler why the metolic syndrome or dietes mellitus should e most strongly ssocited with proximl colon denom. Susite differences in the ssocition with dietes mellitus 488 Asin Pcific Journl of Cncer Prevention, Vol 6, 2005 hs lso een oserved s regrds colorectl cncer. At lest three studies hve exmined the reltion of dietes mellitus to susite-specific colorectl cncer risk. One of these studies showed n incresed risk ssocited with dietes mellitus for proximl colon cncer exclusively (Limurg et l., 2005), nd the other two found more evident increse in the risk of proximl colon cncer (Weiderpss et l., 1997; Hu et l., 1999). However, centrl oesity hs een reported to increse the risk in oth proximl nd distl sites (Moore et l., 2004) nd dietry zinc, protective ginst dietes, hs een linked with reduction in oth sites (Lee et l., 2004). The present study fetures methodologicl dvntges in tht totl colonoscopy ws performed lmost nonselectively in defined popultion nd tht the sence of polyp lesions could therey e confirmed in the controls. However, the study sujects were not representtive of Jpnese men in the generl popultion. Thus the present findings my not e generlized. Another importnt spect is tht firly lrge numer of the sujects (n = 283) hd previously undergone colorectl polypectomy, nd consequently cses with smll denom ccounted for lrge proportion of the totl denom cses. If the metolic syndrome is most relevnt to the growth of denoms, the oserved ssocition my hve een underestimted. In the present study, physicl ctivity nd other fctors ssocited with colorectl denom nd cncer were not tken into considertion. Physicl inctivity is one of the most importnt lifestyle fctors relted to the metolic syndrome, s well s to colon cncer development (Moore et l., 1998). In ddition, moderte lcohol use is relted to incresed insulin-sensitivity (Fcchini et l., 1994; Dvies et l., 2002) while smoking exerts n opposite effect (Fcchini et l., 1992). Both lcohol use nd cigrette smoking re ssocited with incresed risk of colorectl denom (Giovnnucci et l., 1993; Giovnnucci nd Mrtinez 1996; Toyomur et l., 2000). Adjustment for these fctors (except lcohol) proly cuses overdjustment which necessrily tends to msk ny ssocition etween the metolic syndrome nd colorectl denom. In fct, nlysis llowing for physicl ctivity, lcohol use, nd cigrette smoking only ttenuted the ssocition to limited extent with our sujects; ORs for denoms t the colorectum, proximl colon, distl colon, nd rectum with the Jpnese definition were thus 1.31 (95% CI ), 1.47 (95% CI ), 1.34 (95% CI ), nd 1.16 ( ), respectively. It could e rgued tht controlling for such fctors is not pproprite when the im is to ddress the role of the metolic syndrome per se in the occurrence of colorectl denomd. In summry, the present resonly lrge cross-sectionl study in popultion of middle-ged Jpnese men showed n incresed risk of colorectl denoms, prticulrly of proximl colon denoms nd of lrge denoms, ssocited with the metolic syndrome. Thus the metolic syndrome cn e considered n importnt entity with regrd to prevention of colorectl cncer s well s circultory disese nd type 2 dietes.

5 Acknowledgments This work ws supported y Grnt-in-Aid for Scientific Reserch (B) ( ) from the Jpn Society for the Promotion of Science. The uthors grtefully cknowledge the supportive work y wrd nurses t the SDF Fukuok nd Kummoto Hospitls nd the ssistnce of Ms. Msumi Kog, Ms. Kumiko Arie, nd Ms. Hiroko Mizut. References Alerti KGMM, Zimmet P, Shw J, for the IDF Epidemiology Tsk Force Concensus Group (2005). The metolic syndrome - new worldwide definition. Lncet, 366, Corpet DE, Jcquinet C, Peiffer G, Tche S (1997). Insulin injections promote the growth of errnt crypt foci in the colon of rts. Nutr Cncer, 27, Dvies MJ, Ber DJ, Judd JT, et l (2002). Effects of moderte lcohol intke on fsting insulin nd glucose concentrtions nd insulin sensitivity in postmenopusl women: A rndomized controlled tril. JAMA, 287, Eckel RH, Grundy SM, Zimmet PZ (2005). The metolic syndrome. Lncet, 365, Fcchini F, Chen YD, Reven GM (1994). Light-to-moderte lcohol intke is ssocited with enhnced insulin sensitivity. Dietes Cre, 17, Fcchini FS, Holleneck CB, Jeppesen J, Chen YD, Reven GM (1992). Insulin resistnce nd cigrette smoking. Lncet, 339, Giovnnucci E (1995). Insulin nd colon cncer. Cncer Cuses Control, 6, Giovnnucci E, Mrtinez ME (1996). Tocco, colorectl cncer, nd denoms: review of the evidence. J Ntl Cncer Inst, 88, Giovnnucci E, Stmpfer MJ, Colditz GA, et l (1993). Folte, methionine, nd lcohol intke nd risk of colorectl denom. J Ntl Cncer Inst, 85, Hslm DW, Jmes WPT (2005). Oesity. Lncet, 366, Hu FB, Mnson JE, Liu S, et l (1999). Prospective study of dult onset dietes mellitus (type 2) nd risk of colorectl cncer in women. J Ntl Cncer Inst, 91, IARC (2002). Weight Control nd Physicl Activity. IARC Hndooks of Cncer Prevention Vol 6. IARC, Lyon, pp Jpnese Committee of the Metolic Syndrome Dignostic Criteri (2005). Definition nd dignostic criteri of metolic syndrome. Nihon Nik Gkki-shi (J Jpn Soc Int Med), 94, (in Jpnese). King H, Auert RE, Hermn WH (1998). Glol urden of dietes, : prevlence, numericl estimtes, nd projections. Dietes Cre, 21, Kono S, Hnd K, Hyuchi H, et l (1999). Oesity, weight gin nd risk of colon denoms in Jpnese men. Jpn J Cncer Res, 90, Kono S, Honjo S, Todoroki I, et l (1998). Glucose intolernce nd denoms of the sigmoid colon in Jpnese men (Jpn). Cncer Cuses Control, 9, Lee DH, Anderson KE, Hrnck LJ, Folsom AR, Jcos DR Jr (2004). Heme iron, zinc, lcohol consumption, nd colon cncer: Iow Women's Helth Study. J Ntl Cncer Inst, 96, The Metolic Syndrome nd Colorectl Adenom Development Limurg PJ, Anderson KE, Johnson TW, et l (2005). Dietes mellitus nd susite-specific colorectl cncer risks in the Iow Women s Helth Study. Cncer Epidemiol Biomrkers Prev, 14, Mrugme T, Lee K, Eguchi H, et l (2002). Reltion of impired glucose tolernce nd dietes to colorectl denoms in Jpn. Cncer Cuses Control, 13, McKeown-Eyssen G (1994). Epidemiology of colorectl cncer revisited: re serum triglycerides nd/or plsm glucose ssocited with risk? Cncer Epidemiol Biomrkers Prev, 3, Moore LL, Brdlee ML, Singer MR, et l (2004). BMI nd wist circumference s predictors of lifetime colon cncer risk in Frminghm Study dults. Int J Oes Relt Met Disord, 28, Moore MA, Prk CB, Tsud H (1998). Implictions of the hyperinsulinemi dietes cncer link for preventive efforts. Eur J Cncer Prev, 7, Moore MA, Prk CB, Tsud, H (1998). Physicl exercise: pillr for cncer prevention? Eur J Cncer Prev, 7, Nishii T, Kono S, Ae H, et l (2001). Glucose intolernce, plsm insulin levels, nd colon denoms in Jpnese men. Jpn J Cncer Res, 92, O Brien MJ, Winwer SJ, Zuer AG, et l (1990). The Ntionl Polyp Study: ptients nd polyp chrcteristics ssocited with high-grde dysplsi in colorectl denoms. Gstroenterology, 98, Toyomur K, Ymguchi K, Kwmoto H, et l (2004). Reltion of cigrette smoking nd lcohol use to colorectl denoms y susite: the self-defense forces helth study. Cncer Sci, 95, Trn TT, Medline A, Bruce WR (1996) Insulin promotion of colon tumors in rts. Cncer Epidemiol Biomrkers Prev, 5, Trevisn M, Liu J, Muti P, et l (2001). Mrkers of insulin resistnce nd colorectl cncer mortlity. Cncer Epidemiol Biomrkers Prev, 10, Wei EK, Giovnnucci E, Fuchs CS, Willett WC, Mntzoros CS (2005). Low plsm diponectin levels nd risk of colorectl cncer in men: prospective study. J Ntl Cncer Inst, 97, Weiderpss E, Gridley G, Nyren O, et l (1997). Dietes mellitus nd risk of lrge owel cncer. J Ntl Cncer Inst, 89, Wideroff L, Gridley G, Mellemkjer L, et l (1997). Cncer incidence in popultion-sed cohort of ptients hospitlized with dietes mellitus in Denmrk. J Ntl Cncer Inst, 89, Yu H, Rohn T (2000). Role of the insulin-like growth fctor fmily on cncer development nd progression. J Ntl Cncer Inst, 92, Asin Pcific Journl of Cncer Prevention, Vol 6,