Alternative Methods of Insulin Sensitivity Assessment in Obese Children and Adolescents

Transcription

1 Diabetes Cae Publish Ahead of Pint, published online Januay 17, 2008 Altenative Methods of Insulin Sensitivity Assessment in Obese Childen and Adolescents Sophia M Rössne, MD, (1); Matin Neovius, PhD, (2); Scott M Montgomey, PhD, (3,4,5); Claude Macus, MD, PhD, (6); Svante Nogen, MD PhD, (1) 1. Division of Pediatics, Depatment of Woman and Child Health, Kaolinska Institute, Stockholm, Sweden 2. Depatment of Medicine, Kaolinska Institute, Stockholm, Sweden 3. pincipal eseach fellow, Clinical Epidemiology Unit, Kaolinska Institute, Stockholm Sweden; 4. Clinical Reseach Cente, Öebo Univesity Hospital, Sweden; 5. Depatment of Pimay Cae and Social Medicine, Chaing Coss Hospital, Impeial College, London, UK 6. National Childhood Obesity Cente, Depatment fo Clinical Science, Intevention and Technology, Division of Pediatics, Kaolinska Institute, Stockholm, Sweden Running Title: Validation study of fasting indices Coesponding Autho: D. Sophia Rössne, B57, Kaolinska Univesitetssjukhuset Huddinge, SE Stockholm, Sweden sophia.ossne@kaolinska.se Received fo publication 22 August 2007 and accepted in evised fom 4 Januay Copyight Ameican Diabetes Association, Inc., 2008

2 ABSTRACT Objective: To validate fasting indices against minimal model analysis of the fequently sampled intavenous glucose toleance test (FSIVGTT-MMOD) in an obese pediatic population. Reseach Design and Methods: FSIVGTT-MMOD esults wee compaed to HOMA-IR and fasting insulin with sample statified by sex, pubety and S i median in 191 childen (82 males; 13.9±2.9y, BMI 36.9±6.2 kg/m 2, BMI-SDS 6.1±1.6). Results: Acoss pubetal goups coelation coefficients between S i and HOMA-IR anged fom to in males, and fom to in females (age and BMI adjusted, p<0.05 in all instances). Simila esults wee seen fo fasting insulin. In females the elationship was significantly weake in moe insulin esistant subjects. Conclusions: The validity of fasting indices in explaining S i was sex dependent, vaied with pubetal stage, and in females influenced by degee of insulin sensitivity. In obese pediatic populations we geneally discouage the use of fasting indices, although the validity vaies within subgoups. 2

3 O besity in childen and adolescents (1-6) with the complication of insulin esistance equies accuate methods fo insulin sensitivity assessment. Minimal model analysis of the fequently sampled intavenous glucose toleance test (FSIVGTT-MMOD) (7) is a well validated method. Howeve, altenative methods fo outine clinical use have been developed using fasting plasma glucose and insulin concentations, such as HOMA-IR (8) and QUICKI (9). In obese childen and adolescents, the use of fasting indices has been pomoted (10; 11) as well as discouaged (12). We pefomed FSIVGTT-MMOD among obese paticipants anging fom childen to young adults and compaed esults with fasting indices, aiming to evaluate these as suogate measues of insulin sensitivity in an obese pediatic population. RESEARCH DESIGN AND METHODS The study included 191 oveweight o obese Swedish paticipants, anging fom childen to young adults. Patients with mental, endocine o metabolic disodes (except mild dyslipidemia), wee excluded. Anthopometic and pubetal assessments wee pefomed (13; 14), BMI-SDS calculated (15) and DEXA scan pefomed (16). The study potocol was appoved by the local Ethics Committee, and witten infomed consent obtained. FSIVGTT was pefomed accoding to standad potocol (7; 16; 17) with sensitivity index (S i ) calculated by compute pogam MINMOD vesion 3.0 (Richad Begman, 1994). Fasting insulin and glucose wee analysed using standad laboatoy techniques, and HOMA-IR and QUICKI calculated as peviously descibed (8; 9). Results ae epoted as mean ± SD. Fasting indices and S i wee tansfomed logaithmically. Analyses wee sex statified and the sample divided into goups of pepubetal (Tanne 1), pubetal (Tanne 2-3) and post-pubetal (Tanne 4-5)(13; 14). Patial coelation coefficients wee calculated with adjustment fo BMI and age. To exploe the effect of insulin esistance on the elationship between S i and fasting indices, a vaiable denoting high/low S i was tested in egession models (detemined as above/below median). An inteaction tem between indices and the high/low vaiable was included to investigate potential effect modification. When testing fo inteaction, adjustment was made fo main effects. P- values of <0.05 wee consideed statistically significant. As QUICKI and HOMA-IR showed consistently highly simila esults, only HOMA-IR esults will be epoted. RESULTS The study included 191 oveweight o obese paticipants (82 males, age 13.9±2.9 yeas (14.0; yeas [median; ange]), BMI 36.9±6.2 kg/m 2 (35.8; kg/m 2 ), BMI-SDS 6.1±1.6 (6.0; ), DEXA 45.7±5.2% (45.6%; %). Tanne stage (I/II/III/IV/V) fo males was 37.8/14.6/12.2/14.6/20.7% and fo females 8.3/9.2/2.8/16.5/46.8%, espectively. Males wee heavie (3.1 kg; p=0.001), talle (2.9 cm; p<0.001), had highe fasting glucose (0.1 mmol/l; p=0.022) and wee less adipose (2.6 %; p=0.001). Statistically significant diffeences in Tanne stage wee found (p<0.001). DEXA esults showed that 99% wee above the 98 th pecentile in body fat pecentage (age and sex adjusted) (18). The elationships between HOMA-IR, fasting insulin and S i ae pesented in Table 1, statified by sex and pubetal status. The female pepubetal goup was too small to povide any eliable esults (n=6). In both sexes, the pubetal goup had the highest coelation coefficients. When including the high/low S i vaiable in egession analysis, in females the elationship appeaed to vay with degee of insulin sensitivity; while vaiations in HOMA-IR explained 33.7% of the vaiation in S i fo subjects with high S i (p<0.001), the coesponding numbe fo subjects with low S i was only 3.2% (p=0.197). Fasting insulin explained 14.1% 3

4 of the vaiation in S i in female subjects with high S i (p<0.004), with coesponding numbe fo subjects with low S i being 0.3% (p=0.715). In males, no such inteactions wee detected eithe gaphically (paallel lines) o in egession analysis. Peason coelation coefficient of HOMA-IR to fasting insulin was 0.81 (males 0.87, females 0.78, p<0.001 in all instances). CONCLUSIONS We found sex dependent diffeences in the explanatoy powe of fasting indices, with consistently bette ability to explain the vaiation in S i among males. In both sexes the explanatoy powe vaied with pubetal status, supisingly showing highest coelations in the pubetal goups, whee insulin sensitivity is known to be low (19). When statifying fo high/low S i, the elationship was significantly weake in the moe insulin esistant females, in which fasting indices exhibited vitually no explanatoy value at all. HOMA-IR yielded little additional explanatoy value compaed to fasting insulin alone. The validity of fasting indices in childen and adolescents has been investigated with coelations of HOMA-IR and clamp o FSIVGTT anging fom (10; 20-23). Conwell et al found fasting indices to coelate stongly with S i of the FSIVGTT-MMOD, concluding that these ae valid tools in obese childen and adolescents (10). The high coelation seen in the Conwell study of 18 individuals in thee epeated tests (=-0.9 fo HOMA-IR and S i, p<0.001) is not found in ou lage study although the coelation in pubetal males is easonably high. The esults in most of ou sub-goups ae in bette ageement with the study by Cutfield et al, in which fasting indices exhibited only weak coelation with the S i of the FSIGVTT- MMOD (=-0.4, p<0.001 fo HOMA-IR and S i ) (24). Bandou et al, who examined fasting indices in obese and lean childen at vaying stages of pubety, found no coelation between HOMA-IR o QUICKI and S i (12). Also, in the pesent study fo each given value of the fasting indices thee was a wide spead in S i, which waants caeful intepetation. In summay, we have shown the validity of HOMA-IR and fasting insulin in explaining S i as detemined by the FSIVGTT in obese childen and adolescents to be sex dependent as well as influenced by pubetal stage and in females by level of insulin sensitivity. In pubetal males, HOMA-IR and fasting insulin coelated easonably well with FSIVGTT-MMOD, wheeas in pe- and postpubetal subgoups the coelation was low. In females the stength of the association was geneally weake, especially among the most insulin esistant paticipants. Thus, in obese pediatic populations, especially those at isk of alteed glucose homeostasis, we discouage the use of these measues. ACKNOWLEDGMENTS This wok was suppoted by gants fom Stiftelsen Samaiten, the Fimuae Banhuset Foundation, Stockholm City Council and the Swedish Medical Reseach Council (9941). 4

5 REFERENCES 1. Obesity: peventing and managing the global epidemic.. In Wold Health Ogan Tech Rep Seies Geneva, Wold Health Oganisation, 2000, p Dietz WH: Oveweight in childhood and adolescence. N Engl J Med 350: , Ebbeling CB, Pawlak DB, Ludwig DS: Childhood obesity: public-health cisis, common sense cue. Lancet 360: , Kimm SY, Obazanek E: Childhood obesity: a new pandemic of the new millennium. Pediatics 110: , Lobstein T, Felut ML: Pevalence of oveweight among childen in Euope. Obes Rev 4: , Haslam DW, James WP: Obesity. Lancet 366: , Begman RN: Lilly lectue Towad physiological undestanding of glucose toleance. Minimal-model appoach. Diabetes 38: , Matthews DR, Hoske JP, Rudenski AS, Naylo BA, Teache DF, Tune RC: Homeostasis model assessment: insulin esistance and beta-cell function fom fasting plasma glucose and insulin concentations in man. Diabetologia 28: , Katz A, Nambi SS, Mathe K, Baon AD, Follmann DA, Sullivan G, Quon MJ: Quantitative insulin sensitivity check index: a simple, accuate method fo assessing insulin sensitivity in humans. J Clin Endocinol Metab 85: , Conwell LS, Tost SG, Bown WJ, Batch JA: Indexes of insulin esistance and secetion in obese childen and adolescents: a validation study. Diabetes Cae 27: , Guzzaloni G, Gugni G, Mazzilli G, Moo D, Moabito F: Compaison between beta-cell function and insulin esistance indexes in pepubetal and pubetal obese childen. Metabolism 51: , Bandou F, Bun JF, Mecie J: Limited accuacy of suogates of insulin esistance duing pubety in obese and lean childen at isk fo alteed glucoegulation. J Clin Endocinol Metab 90: , Mashall WA, Tanne JM: Vaiations in patten of pubetal changes in gils. Ach Dis Child 44: , Mashall WA, Tanne JM: Vaiations in the patten of pubetal changes in boys. Ach Dis Child 45:13-23, Rolland-Cachea MF, Sempe M, Guilloud-Bataille M, Patois E, Pequignot-Guggenbuhl F, Fautad V: Adiposity indices in childen. Am J Clin Nut 36: , Kamel A, Nogen S, Elimam A, Danielsson P, Macus C: Effects of gowth homone teatment in obese pepubetal boys. J Clin Endocinol Metab 85: , Saad MF, Steil GM, Riad-Gabiel M, Khan A, Shama A, Boyadjian R, Jinagouda SD, Begman RN: Method of insulin administation has no effect on insulin sensitivity estimates fom the insulin-modified minimal model potocol. Diabetes 46: , McCathy HD, Cole TJ, Fy T, Jebb SA, Pentice AM: Body fat efeence cuves fo childen. Int J Obes (Lond) 30: , Hoffman RP, Vicini P, Sivitz WI, Cobelli C: Pubetal adolescent male-female diffeences in insulin sensitivity and glucose effectiveness detemined by the one compatment minimal model. Pediat Res 48: , Gungo N, Saad R, Janosky J, Aslanian S: Validation of suogate estimates of insulin sensitivity and insulin secetion in childen and adolescents. J Pediat 144:47-55, Keskin M, Kutoglu S, Kendici M, Atabek ME, Yazici C: Homeostasis model assessment is moe eliable than the fasting glucose/insulin atio and quantitative insulin sensitivity check index fo assessing insulin esistance among obese childen and adolescents. Pediatics 115:e ,

6 22. Uwaifo GI, Fallon EM, Chin J, Elbeg J, Paikh SJ, Yanovski JA: Indices of insulin action, disposal, and secetion deived fom fasting samples and clamps in nomal glucosetoleant black and white childen. Diabetes Cae 25: , Lee JM: Insulin esistance in childen and adolescents. Rev Endoc Metab Disod 7: , Cutfield WS, Jeffeies CA, Jackson WE, Robinson EM, Hofman PL: Evaluation of HOMA and QUICKI as measues of insulin sensitivity in pepubetal childen. Pediat Diabetes 4: ,

7 TABLE 1. Patial coelation coefficients of ln S i to ln HOMA-IR and ln fasting insulin espectively, adjusted fo age and BMI. Ln HOMA-IR Ln fasting insulin Females Males Females Males Pepubetal p=0.839 p=0.028 p=0.393 p=0.053 n=6 n=28 n=6 n= Pubetal p=0.004 p<0.001 p=0.049 p<0.001 n=26 n=28 n=26 n= Postpubetal p<0.001 p=0.004 p=0.002 p=0.019 n=77 n=26 n=77 n= Total p<0.001 p<0.001 p<0.001 p<0.001 n=109 n=82 n=109 n=82 7