Low Fasting Triglycerides: Hallmark of the Healthy Large Hip?

Transcription

1 nture publishing group rticles Low Fsting Triglycerides: Hllmrk of the Helthy Lrge Hip? Johnnes B. Ruige 1 nd Luc F. Vn Gl 2 Body ft distribution modultes risk for type 2 dibetes mellitus. We evluted potentilly involved metbolic risk fctors. In popultion of 282 mle nd 157 femle helthy subjects (dt from the Sn Antonio nd the Europen Group of Insulin Resistnce (EGIR) study cohorts), we evluted ssocitions between body ft distribution (ssessed by wist nd hip circumference) nd prmeters of lipid- nd glucose metbolism, including clmp mesurements of insulin sensitivity. After strtifiction for BMI, fsting triglycerides were lower in the presence of lrge hip, nd higher in lrge wist. Persons with the lrgest BMI (3rd tertile) showed difference in triglyceride levels of 1.5 vs. 2.4 mmol/l in lrge vs. smll hip circumference groups (P < 0.038), nd difference of 1.5 vs. 1.2 mmol/l in lrge vs. smll wist circumference groups (P < 0.025). A similr nlysis did not revel difference in insulin sensitivity. Liner regression nlyses confirmed the findings; they reveled negtive ssocitions between triglycerides nd hip, nd (for women borderline sttisticlly significnt) positive ssocitions between triglycerides nd wist, fter djustment for BMI, mutul confounding, nd ge (β ± s.e.; men: 0.48 ± 0.005,, nd 0.21 ± 0.005, P < 0.05; women: 0.78 ± 0.007,, nd 0.24 ± 0.005, P < 0.065), respectively. Liner regression nlyses reveled similr opposite ssocitions with high-density lipoprotein (HDL)-cholesterol, though not with glucose, insulin, or insulin sensitivity s mesured with the clmp method. In our study popultion of helthy persons, body ft distribution is ssocited with fsting triglycerides nd HDL-cholesterol, nd not with insulin sensitivity. Metbolic risk of unfvorble body ft distribution my be modulted by lower triglyceride storge cpcity. Obesity (2009) 17, doi: /oby Introduction Obesity increses risk for crdiovsculr disese nd dibetes mellitus, but the increse in risk is not liner with the BMI. So clled ndroid obesity (pple shpe) hs remrkbly different risk thn gynoid obesity (per shpe). Apprently, distribution of ft modultes risk. Abdominl obesity, cliniclly ssessed by the wist circumference, is strongly ssocited with crdiovsculr disese nd dibetes mellitus (1 3), wheres hip circumference ppered to be protective (4). The wist circumference is regrded s the centrl feture of the metbolic syndrome (Interntionl Dibetes Federtion 2005 criteri), which together with hypertension, lipid disturbnces (incresed triglycerides nd decresed high-density lipoprotein (HDL)-cholesterol), nd impired fsting glucose (feture of insulin resistnce), precedes type 2 dibetes mellitus nd crdiovsculr disese (5,6). In contrst, the hip circumference is ssocited with decresed incidence in crdiovsculr disese (7,8), dibetes mellitus (9,10), nd might even predict helth nd longevity, especilly in women (4). Becuse dibetes mellitus is preceded by insulin resistnce nd lipid disturbnces, we evluted ssocitions between body ft distribution (ssessed by wist nd hip circumference) nd components of glucose metbolism, including clmp mesurements of insulin sensitivity, triglyceride concentrtions, nd HDL-cholesterol. Methods nd Procedures We nlyzed dt from the Europen Group of Insulin Resistnce (EGIR) dtbse (which comprises nondibetic Cucsin Europens) nd the Sn Antonio Metbolism Study cohort (which includes non-hispnic white Cucsin, nd Hispnic residents of Sn Antonio, TX), including mesurements of insulin sensitivity obtined with the use of the euglycemic insulin clmp technique (with n infusion rte of 240 pmol/min/m for 2 h). Detils on the study cohort, the protocol, experimentl nd nlyticl methods hve been published previously (11 16). Approvl of the protocol by the locl Ethics Committee nd informed consent from ll subjects ws obtined before the studies t ech geogrphicl centre. For the purpose of the present study, insulin sensitivity ws tken to be the stedy-stte totl body insulin-medited glucose disposl rte (M LBM ), expressed s µmol per min per kg of ft-free (or len body) mss (µmol/min/kg/lbm). Blood smples were collected in the fsting stte for the mesurement of fsting plsm glucose, fsting plsm insulin, fsting plsm triglyceride, nd HDL-cholesterol. Plsm glucose ws mesured by the glucose oxidse method. Plsm insulin concentrtions were mesured by rdioimmunossy. Serum lipid levels were 1 Ghent University Hospitl, Deprtment of Endocrinology, Ghent, Belgium; 2 Antwerp University Hospitl, Deprtment of Dibetology, Metbolism, nd Clinicl Nutrition, Antwerp, Belgium. Correspondence: Luc F. Vn Gl (luc.vn.gl@uz.be) Received 5 My 2008; ccepted 19 Jnury 2009; published online 26 Februry doi: /oby obesity VOLUME 17 NUMBER 8 ugust

2 ssyed by stndrd enzymtic ssys. Ft mss (hence len body mss) ws mesured by different techniques: underwter weighing, electricl bio-impednce, nd trcer wter. The results were generlly in greement, but for homogeneity it ws decided to use the sex-specific Hume s formul throughout. For the purpose of the present study, subjects without dibetes or impired glucose tolernce were selected on bsis of the vilbility of the nthropometric prmeters BMI, wist, hip circumference, nd insulin sensitivity; the stedy-stte totl body insulin-medited glucose disposl rte (M), expressed s µmol per min per kg of ft-free mss (µmol/min/ kg len body mss). Only subjects with complete dt were nlyzed (n = 439). Noneligible subjects of the dtbse were in generl younger nd hd slightly lower BMI. Sttisticl nlyses Dt re given s mens (± s.d.) or medins nd their rnge, if distributions were skewed. Distributions of BMI, hip nd wist circumference were divided into tertiles to provide insight into their mutul reltionships nd their reltionship with insulin sensitivity nd triglycerides, with the help of 3D grphs. Cut-points were clculted for mle nd femle subjects seprtely, nd the tertile-groups combined fterwrds, to improve sttisticl power. Cut-points were 101 nd 112 cm for hip circumference in femle subjects (tertile-groups; lowest through 101, 101 through 112, 112 through highest), 99 nd 104 cm for hip circumference in mle subjects, 86 nd 96 cm for wist circumference in femle subjects, 90 nd 98 cm for wist circumference in mle subjects, 26 nd 31 kg/m 2 for BMI in femle subjects, nd 25 nd 28 kg/m 2 for BMI in mle subjects. Differences between groups were nlyzed by mens of the Mnn Whitney U-test. Liner regression nlysis ws pplied to djust for mutul confounding (hip nd wist circumference), BMI, nd ge. Results were expressed s stndrdized coefficients (β) nd R 2, the proportion of vrition explined by the independent vribles. If pproprite, distributions were trnsformed into their nturl logrithm to fulfill ssumption criteri. A P vlue <0.05 ws regrded sttisticlly significnt. Anlyses were performed with the SPSS-PC softwre pckge, version (SPSS, Chicgo, IL). Results Tble 1 shows popultion chrcteristics of 157 women nd 282 men, selected from the EGIR nd Sn Antonio study cohorts. The subjects hd wide rnge in ge, BMI, wist nd hip circumference. Dt were provided in mens (± s.d.) or medin vlues nd rnges, if distributions were skewed. Except for 44 Hispnics, subjects were Cucsins. Performing the nlyses without the Hispnic popultion did not essentilly chnge the results. Two women nd 13 men hd triglyceride concentrtions >5.6 mmol/l nd were excluded from nlyses concerning triglycerides, though inclusion did not essentilly chnge the results (dt not shown). Triglyceride levels >5.6 mmol/l re cliniclly regrded s very high, nd might be cused by specific lipid disorders (6). Tble 1 showed further wide rnge in BMI; performing nlyses without subjects with BMI >40 kg/m 2 did lso not essentilly chnge the results (dt not shown). Figure 1 shows tht wist nd hip circumference were strongly ssocited with BMI. BMI is lowest in subjects with smll hip nd smll wist circumference (1st tertile of both; 23 kg/m 2 ) s compred to smll wist (1st tertile) nd lrge hip circumference (3rd tertile; 29 kg/m 2, ), or smll hip (1st tertile) nd lrge wist circumference (3rd tertile; 27 kg/m 2, ), etc. In the following nlyses, ll tertiles of BMI, wist nd hip circumference Tble 1 Study popultion chrcteristics, nthropometric mesurements nd biochemistry Women Men N Cucsin Hispnic Age (yers) 41 (33 53) 50 (35 65) BMI (kg/m 2 ) 28.9 ± ± 4.8 Wist circumference (cm) 92 ± ± 12 Hip circumference (cm) 108 ± ± 11 Fsting plsm glucose (mmol/l) 5.0 ± ± 0.5 Fsting plsm insulin (pmol/l) 72 (55 115) 69 (46 96) Insulin sensitivity (µmol/min/kg len body mss) 40.9 ( ) 45.9 ( ) Triglycerides (mmol/l) 1.10 ( ) 1.39 ( ) HDL-cholesterol (mmol/l) 1.3 ± ± 0.4 Systolic blood pressure (mm Hg) 125 ( ) 124 ( ) Distolic blood pressure (mm Hg) 82 (75 90) 81 (74 90) Dt re numbers, men vlues ± s.d. or medin vlues (interqurtile rnges). HDL, high-density lipoprotein. Two women nd 13 men hd fsting triglyceride concentrtions >5.6 mmol/l nd were excluded from nlyses contining triglycerides. Men BMI (kg/m 2 ) Tertiles of hip were clculted seprtely for mle nd femle subjects (see Methods nd Procedures), nd fterwrds combined to improve sttisticl power. In helthy subjects with lrge BMI (3rd tertile), fsting triglyceride concentrtions ppered to be lower in the presence of lrge hip s compred to smll hip circumference (3rd vs. 1st tertile; 1.5 vs. 2.4 mmol/l, P < 0.038; Figure 2). And, in subjects with similr BMI (3rd tertile), fsting triglyceride concentrtions were higher in the presence of lrge wist circumference vs. smll wist circumference (3rd vs. 1st tertile; 1.5 vs. 1.2 mmol/l, P < 0.025, Figure 2b). A similr nlysis with respect to insulin sensitivity (clmp method), fsting glucose, fsting insulin, or HDL-cholesterol could not revel such divergent ssocitions of body ft Tertiles of wist Figure 1 Associtions between BMI, hip nd wist circumference in helthy subjects. BMI is lowest in subjects with smll hip nd wist circumference (1st tertile of both; 23 kg/m 2 ) s compred to smll wist (1st tertile) nd lrge hip circumference (3rd tertile; 29 kg/m 2, ) or smll hip (1st tertile) nd lrge wist circumference (3rd tertile; 27 kg/ m 2, ). (BMI, hip nd wist tertiles were clculted for mle nd femle subjects seprtely) VOLUME 17 NUMBER 8 ugust

3 Medin triglycerides (mmol/l) b Medin triglycerides (mmol/l) P < Tertiles of BMI 1.5 Tertiles of BMI distribution (dt not shown, except for insulin sensitivity), i.e., in helthy subjects hving lrge BMI (3rd tertile), insulin sensitivity ws not sttisticlly different compring smll hip circumference vs. lrge hip circumference (1st vs. 3rd tertile; 42 vs. 33 µmol/min/kg lbm, P < 0.373; Figure 3), lso insulin sensitivity ws not sttisticlly different compring smll wist circumference vs. lrge wist circumference (1st vs. 3rd tertile; 40 vs. 33 µmol/min/kg lbm, P < 0.099; Figure 3b). The divergent ssocition of fsting triglyceride concentrtions nd body ft distribution ws confirmed by use of liner regression nlyses, llowing djustment for BMI, mutul confounding (hip nd wist circumference) nd ge. Anlyses were performed for women nd men seprtely, becuse body ft distribution generlly shows distinct gender differences. Women showed n inverse ssocition between fsting triglyceride concentrtions nd hip circumference (β ± s.e.: 0.78 ± 0.007, ), nd (borderline sttisticlly significnt) positive ssocition between fsting triglycerides nd wist circumference (β ± s.e.: 0.24 ± 0.005, P < 0.065), fter djustment for BMI, mutul confounding, nd ge (Tble 2). Similrly, men showed n inverse ssocition between fsting triglyceride concentrtions nd hip circumference (β ± s.e.: 0.48 ± 0.005, ), 2.4 P < Tertiles of hip Tertiles of wist Figure 2 Body ft distribution nd triglycerides. () Assocition between triglycerides nd hip circumference in helthy subjects. Triglyceride concentrtions re lower in subjects with lrge hip circumference (3rd tertile; 1.5 mmol/l) s compred to subjects with smll hip circumference (1st tertile; 2.4 mmol/l, P < 0.038), fter strtifiction for BMI (hip nd BMI tertiles were clculted for mle nd femle subjects seprtely). (b) Assocition between triglycerides nd wist circumference in helthy subjects. Triglyceride concentrtions re higher in subjects with lrge wist circumference (3rd tertile; 1.5 mmol/l) s compred to subjects with smll wist circumference (1st tertile; 1.2 mmol/l, P < 0.025), fter strtifiction for BMI. (Wist nd BMI tertiles were clculted for mle nd femle subjects seprtely). Medin insulin sensitivity (µmol/min/kg lbm) P < b P < Medin insulin sensitivity (µmol/min/kg lbm) Tertiles of hip Tertiles of wist nd positive ssocition between fsting triglycerides nd wist circumference (β ± s.e.: 0.21 ± 0.005, P < 0.05), fter djustment for BMI, mutul confounding, nd ge. Liner regression nlyses did lso revel divergent ssocition between HDL-cholesterol nd body ft distribution. Women showed positive ssocition between HDL-cholesterol nd hip circumference (β ± s.e.: 0.39 ± 0.005, P < 0.05), nd n inverse ssocition between HDL-cholesterol nd wist circumference (β ± s.e.: 0.35 ± 0.004, P < 0.01), fter djustment for mutul confounding, ge, nd BMI. Similrly, men showed positive ssocition between HDL-cholesterol nd hip circumference (β ± s.e.: 0.36 ± 0.004, ), nd n inverse ssocition between HDL-cholesterol nd wist circumference (β ± s.e.: 0.32 ± 0.004, ), fter djustment for mutul confounding, ge, nd BMI (Tble 2). Liner regression nlyses, seprted for women nd men, did not revel n ssocition between insulin sensitivity nd body ft distribution, though positive ssocitions were shown in women for fsting glucose concentrtions nd wist circumference (β ± s.e.: 0.51 ± 0.005, ), nd positive ssocitions Tertiles of BMI Tertiles of BMI Figure 3 Body ft distribution nd insulin sensitivity (clmp). () Assocition between insulin sensitivity nd hip circumference in helthy subjects. A sttisticlly significnt difference in insulin sensitivity (clmp) could not be estblished between subjects with smll hip circumference (1st tertile; 42 µmol/min/kg lbm) s compred to subjects with lrge hip circumference (3rd tertile; 33 µmol/min/kg lbm, P < 0.373), in the presence of lrge BMI (3rd tertile). (Hip nd BMI tertiles were clculted for mle nd femle subjects seprtely). (b) Assocition between insulin sensitivity nd wist circumference in helthy subjects. A sttisticlly significnt difference in insulin sensitivity (clmp) could not be estblished between subjects with smll wist circumference (1st tertile; 40 µmol/min/kg lbm) s compred to subjects with lrge wist circumference (3rd tertile; 33 µmol/min/kg lbm, P < 0.099), in the presence of lrge BMI (3rd tertile) (Wist nd BMI tertiles were clculted for mle nd femle subjects seprtely). obesity VOLUME 17 NUMBER 8 ugust

4 Tble 2 Independent contributions of wist nd hip circumference to components of lipid nd glucose metbolism Fsting triglycerides Hip circumference (β ± s.e.) Wist circumference (β ± s.e) R 2 of model (%) Women 0.78 ± 0.007* 0.24 ± Men 0.48 ± 0.005* 0.21 ± 0.005*** 19 HDL-cholesterol Women 0.39 ± 0.005*** 0.35 ± 0.004** 28 Men 0.36 ± 0.004* 0.32 ± 0.004** 11 Insulin sensitivity (clmp) Women 0.33 ± ± Men 0.15 ± ± Fsting glucose Women 0.15 ± ± 0.005* 8 Men 0.03 ± ± Fsting insulin Women 0.29 ± ± 0.005*** 32 Men 0.01 ± ± 0.004*** 31 Adjusted for mutul confounding (hip or wist circumference), ge, nd BMI. HDL, high-density lipoprotein. Proportion of vrince explined by the model, including BMI, wist nd hip circumferences nd ge. *. **P < ***P < were lso shown for fsting insulin nd wist circumference in women (β ± s.e.: 0.28 ± 0.005, P < 0.05), nd men (β ± s.e.: 0.21 ± 0.004, P < 0.05) (Tble 2). Replcement of BMI-liner by BMI-ctegorized showed essentilly similr opposite ssocitions for triglycerides nd HDL-cholesterol, wheres it did not revel opposite ssocitions for glucose, insulin, or insulin sensitivity with body ft distribution. Furthermore, subnlyses of the Europen Group of Insulin Resistnce (EGIR) dtbse vs. the Sn Antonio Metbolism Study cohort did not essentilly chnge the results, prt from loss of sttisticl power. Repeting liner regression nlyses, with combined dt of men nd women, did revel positive ssocition between insulin sensitivity nd hip circumference, though no sttisticlly significnt (P < 0.05) ssocition with wist circumference, fter djustment for BMI, mutul confounding (hip nd wist circumference), ge, nd gender. Further explortion, by evluting effect modifiction in this model, reveled sttisticlly significnt interction between BMI nd ge on insulin sensitivity, which, however, did not essentilly chnge the ssocitions between hip nd wist circumference nd insulin sensitivity (dt not shown). Yet, the vrition (R 2 ) of insulin sensitivity explined by hip circumference in these models ws t mximum 1%. Replcement of insulin sensitivity by triglycerides in this model including the combined dt of men nd women, confirmed the findings of the seprte nlyses s provided in Tble 2, nd showed highly significnt inverse ssocition between triglycerides nd hip circumference, s well s highly significnt positive ssocition between triglycerides nd wist circumference. The vrition (R 2 ) of triglycerides explined by hip circumference ws 9.5% nd by wist circumference 6.5% (dt not shown). Evlution of effect modifiction between BMI nd ge in the ltter model ws not sttisticlly significnt. Evlution of effect modifiction between BMI nd hip or wist circumference, which might be suspected by the nlyses depicted in Figure 2, ws lso not sttisticlly significnt (dt not shown). Discussion We report here on link between fsting triglyceride concentrtions nd body ft distribution in helthy persons. In persons generlly regrded s hving incresed metbolic risk; the ones with lrge BMI, triglyceride concentrtions were lower in the presence of lrge thigh (hip circumference), nd higher in the presence of lrge wist. The study is one of the first studies in humns to suggest, without proving, tht dipocyte dysfunction precedes deteriortion of muscle insulin sensitivity in obesity-relted metbolic disturbnces. The finding suggests difference in triglyceride storge cpcity between thigh nd bdominl ft. This cpcity to dequtely store triglycerides my modulte the beneficil effects of gynoid obesity, nd seems to ply more principl role thn insulin sensitivity, in view of the fct tht we did not find link with insulin sensitivity in these helthy subjects, despite the use of the gold stndrd method to ssess insulin sensitivity (17). Thigh ft my contin dipose tissue better cpble of buffering lipid-excess thn bdominl ft (18). Recently, it ws shown tht women with lrge thigh more efficiently stored their mel ft thn women with lrge mount of viscerl ft (19). Mssen et l. nticipted tht the buffering function of dipose tissue my depend on number nd ctivity of mitochondri within dipocytes, contributing to the threshold t which ftty cids re relesed into the circultion, nd, if deficient, leding to insulin resistnce nd type 2 dibetes mellitus (20,21). Preferentil prtitioning of lipid-excess into glutel femorl ft my directly ffect glucose metbolism by reducing hrmful effects of circulting free ftty cids on the bility of insulin to suppress heptic glucose production (22), nd it my lso protect endothelil function (23). The present nlyses lso reveled opposite ssocitions between HDL-cholesterol nd body ft distribution, fter djustment for confounding. Agin, lrge thigh ws ssocited with fvorble HDL-cholesterol concentrtions wheres lrge wist ws ssocited with low cholesterol concentrtions. HDLcholesterol ppers to ply n importnt role with respect to the development of type 2 dibetes mellitus s well s crdiovsculr disese (24,25). Triglycerides nd HDL-cholesterol re inversely ssocited, though triglycerides my more clerly explin their contribution to the development of metbolic disturbnces (26). The findings on triglyceride- nd HDL levels re somehow in greement with former reports, though the bsence of sttisticlly significnt opposite ssocition between insulin sensitivity nd body ft distribution in the sme persons with similr nlytic techniques mkes the present study distinctive (27 30). Of course, if more persons hd been included in 1624 VOLUME 17 NUMBER 8 ugust

5 the study opposite ssocitions with insulin sensitivity could hve been reveled, though the finding tht opposite ssocitions with triglycerides re fr stronger nd lredy detectble in simple strtified nlyses (Figure 2), s well s the fct tht 16% of vrition in triglycerides (R 2 ) ws explined by hip nd wist circumference vs. t mximum 1% of vrition of insulin sensitivity (R 2 ) by hip circumference lone (in liner regression models), supports primry role for triglycerides in the metbolic risk difference between hip nd wist circumference, nd is in line with recent prospective study in helthy young men, reporting prediction of dibetes by n increse in triglyceride level over time (31). Other studies on the topic showed vrible findings. One study showed fvorble ssocitions between leg ft nd prmeters of insulin resistnce, s clculted by vlues of glucose nd insulin fter n orl glucose tolernce test (28). Another study showed positive ssocition between lower-body ft mss nd insulin sensitivity s estimted by the Mtsuds index; they concluded tht this effect could prtly be explined by vritions in serum diponectin levels (29). They reported lso lower serum insulin in subgroup of men selected for lrge lower-body ft mss concentrtion s compred to subgroup of men selected with smll lower-body ft mss, mtched for trunkl ft mss. Given tht we used most precise mesurements of insulin sensitivity in helthy popultion (17), the better ssocitions with triglycerides nd HDL-cholesterol s compred to insulin sensitivity suggest n initil disturbnce of lipid metbolism, which prtly depend on body ft distribution, though longitudinl studies re required to find out whether disturbnces in lipid metbolism precede insulin resistnce. Thus, prt of the discrepncy might be explined by different techniques to ssess insulin sensitivity nd by different study-popultions, with consequently different stges in the pthogenic pthwy. One study ws performed in helthy postmenopusl women (28), nd nother in rndomly selected men in combintion with juvenile onset obese men (29). Two lrge studies showed opposite effects on triglycerides nd HDL-cholesterol of wist vs. hip circumference in greement with our results (27,30), though both studies showed lso consistently opposite effects on glucose nd insulin. One of these studies included ptients with dibetes (27), nd the other study included subjects with impired glucose tolernce (30). Consequently, the rnge of glucose nd insulin is much lrger in these popultions thn in our helthy popultion (without dibetes nd impired glucose tolernce), which fcilittes detection of n ssocition. The bsence of n opposite ssocition of insulin sensitivity with body ft distribution in the present study might therefore be even more intriguing, becuse the rnge in insulin sensitivity is lrge in the present helthy study popultion (11). Definite conclusions cnnot be mde with respect to cusl interference, becuse most of the vilble dt re crosssectionl (27 30), nd mesurements of one prospective study re limited (31). It is further not completely cler whether the ssocition between the lipids nd body ft distribution is liner or more explicit in subjects with lrge BMI; further studies in lrge helthy popultions re needed. Another potentil limittion of the present study is tht hip circumference ws not seprted into peripherl muscle, ft msses, nd pelvic size, becuse peripherl muscle trophy might influence insulin sensitivity (32). Smll differences between women nd men hve not been evluted; they might be explined by regionl differences in dipocyte metbolism with respect to lipoprotein lipse ctivity nd lipolysis, or different effects of drenl hormones nd sex steroids (33). In conclusion, hip nd wist circumference show divergent effects with respect to fsting triglycerides nd HDLcholesterol. The findings support protective role by gynoid diposity through better triglyceride storge cpcity, preventing hrmful lipid exposure. Acknowledgments We re thnkful for the generous permission of E. Ferrnnini nd R.A. Defronzo to conduct the present study with dt of the Europen Group for the Study of Insulin Resistnce (EGIR) nd Sn Antonio. Disclosure The uthors declred no conflict of interest The Obesity Society REFERENCES 1. Hffner SM, Tegtmeyer H. Epidemic obesity nd the metbolic syndrome. Circultion 2003;108: Len MJ, Hn TS. Wist worries. Am J Clin Nutr 2002;76: Whrenberg H, Hertel K, Leijonhufvud BM et l. Use of wist circumference to predict insulin resistnce: retrospective study. BMJ 2005;330: Lissner L, Bjorkelund C, Heitmnn BL, Seidell JC, Bengtsson C. Lrger hip circumference independently predicts helth nd longevity in Swedish femle cohort. Obes Res 2001;9: World Helth Orgniztion. Definition, Dignosis nd Clssifiction of Dibetes Mellitus nd its Complictions: Report of WHO Consulttion. Genev, WHO/NCD/NCS Ntionl Cholesterol Eduction Progrm (NCEP) Expert Pnel on Detection, Evlution, nd Tretment of High Blood Cholesterol in Adults (Adult Tretment Pnel III). Third Report of the Ntionl Cholesterol Eduction Progrm (NCEP) Expert Pnel on Detection, Evlution, nd Tretment of High Blood Cholesterol in Adults (Adult Tretment Pnel III) finl report. Circultion 2002;106: Tnko LB, Bgger YZ, Alexndersen P, Lrsen PJ, Christinsen C. Peripherl diposity exhibits n independent dominnt ntitherogenic effect in elderly women. Circultion 2003;107: Heitmnn BL, Frederiksen P, Lissner L. Hip circumference nd crdiovsculr morbidity nd mortlity in men nd women. Obes Res 2004; 12: Seidell JC, Hn TS, Feskens EJ, Len ME. Nrrow hips nd brod wist circumferences independently contribute to incresed risk of non-insulin-dependent dibetes mellitus. J Intern Med 1997;242: Snijder MB, Dekker JM, Visser M et l. Associtions of hip nd thigh circumferences independent of wist circumference with the incidence of type 2 dibetes: the Hoorn Study. Am J Clin Nutr 2003;77: Ruige JB, Mertens IL, Brtholomeeusen E et l. Fsting-bsed estimtes of insulin sensitivity in overweight nd obesity: criticl pprisl. Obesity 2006;14: Ntli A, Toschi E, Cmstr S et l. Determinnts of postbsorptive endogenous glucose output in non-dibetic subjects. Europen Group for the Study of Insulin Resistnce (EGIR). Dibetologi 2000;43: Ferrnnini E, Ntli A, Cpldo B et l. Insulin resistnce, hyperinsulinemi, nd blood pressure: role of ge nd obesity. Europen Group for the Study of Insulin Resistnce (EGIR). Hypertension 1997;30: Ferrnnini E, Ntli A, Bell P et l. Insulin resistnce nd hypersecretion in obesity. Europen Group for the Study of Insulin Resistnce (EGIR). J Clin Invest 1997;100: Ferrnnini E, Vichi S, Beck-Nielsen H et l. Insulin ction nd ge. Europen Group for the Study of Insulin Resistnce (EGIR). Dibetes 1996;45: obesity VOLUME 17 NUMBER 8 ugust

6 16. Bldeweg SE, Goly A, Ntli A et l. Insulin resistnce, lipid nd ftty cid concentrtions in 867 helthy Europens. Europen Group for the Study of Insulin Resistnce (EGIR). Eur J Clin Invest 2000;30: Ferrnnini E, Mri A. How to mesure insulin sensitivity. J Hypertens 1998; 16: Fryn KN. Adipose tissue s buffer for dily lipid flux. Dibetologi 2002;45: Votrub SB, Mttison RS, Dumesic DA, Koutsri C, Jensen MD. Mel ftty cid uptke in viscerl ft in women. Dibetes 2007;56: Mssen JA, Romijn JA, Heine RJ. Ftty cid-induced mitochondril uncoupling in dipocytes s key protective fctor ginst insulin resistnce nd bet cell dysfunction: new concept in the pthogenesis of obesityssocited type 2 dibetes mellitus. Dibetologi 2007;50: Mssen JA, t Hrt LM, Ouwens DM. Lessons tht cn be lerned from ptients with dibetogenic muttions in mitochondril DNA: implictions for common type 2 dibetes. Curr Opin Clin Nutr Metb Cre 2007;10: Boden G. Role of ftty cids in the pthogenesis of insulin resistnce nd NIDDM. Dibetes 1997;46: Ferreir AC, Peter AA, Mendez AJ et l. Postprndil hypertriglyceridemi increses circulting levels of endothelil cell microprticles. Circultion 2004;110: Fgot-Cmpgn A, Knowler WC, Nryn KM et l. HDL cholesterol subfrctions nd risk of developing type 2 dibetes mong Pim Indins. Dibetes Cre 1999;22: Rizzo M, Corrdo E, Coppol G et l. Prediction of crdio- nd cerebrovsculr events in ptients with subclinicl crotid therosclerosis nd low HDL-cholesterol. Atherosclerosis 2008;200: Lewis GF, Crpentier A, Adeli K, Gicc A. Disordered ft storge nd mobiliztion in the pthogenesis of insulin resistnce nd type 2 dibetes. Endocr Rev 2002;23: Seidell JC, Perusse L, Despres JP, Bouchrd C. Wist nd hip circumferences hve independent nd opposite effects on crdiovsculr disese risk fctors: the Quebec Fmily Study. Am J Clin Nutr 2001;74: Vn Pelt RE, Evns EM, Schechtmn KB, Ehsni AA, Kohrt WM. Contributions of totl nd regionl ft mss to risk for crdiovsculr disese in older women. Am J Physiol Endocrinol Metb 2002;282:E1023 E Buemnn B, Sorensen TI, Pedersen O et l. Lower-body ft mss s n independent mrker of insulin sensitivity the role of diponectin. Int J Obes Relt Metb Disord 2005;29: Snijder MB, Zimmet PZ, Visser M et l. Independent ssocition of hip circumference with metbolic profile in different ethnic groups. Obes Res 2004;12: Tirosh A, Shi I, Bitzur R et l. Chnges in triglyceride levels over tme nd risk of type 2 dibetes in young men. Dibetes Cre 2008;31: Koh-Bnerjee P, Wng Y, Hu FB et l. Chnges in body weight nd body ft distribution s risk fctors for clinicl dibetes in US men. Am J Epidemiol 2004;159: Fried SK, Russell CD, Gruso NL, Brolin RE. Lipoprotein lipse regultion by insulin nd glucocorticoid in subcutneous nd omentl dipose tissues of obese women nd men. J Clin Invest 1993;92: VOLUME 17 NUMBER 8 ugust