prekomerna teŽina, gojaznost i metaboliýki sindrom...

70 MEDICINSKI GLASNIK / str. 70-80

Sandra Stankovi * 1, Saša Živi 1, Ljiljana Šaranac1,Vesna Cvetkovi 1, Ivana Marinkovi 1, Aleksandra Topalovi 2

PREKOMERNA TEŽINA, GOJAZNOST I METABOLI KI SINDROM KOD DECE I ADOLESCENATA SA DIJABETES MELITUSOM TIP 1

Sažetak: Broj studija koje se bave problemom gojaznosti u populaciji dece i adolescenata sa dijabetesom tip 1 je ograni en.

Cilj: Cilj ovog istraživanja je da se odredi zastupljenost preuhranjenih, gojaznih i osoba sa metaboli kim sindromom u grupi dece i adolescenata sa dijabetes melitusom tip 1 i da se utvrdi povezanost uhranjenosti sa drugim faktorima rizika za razvoj kardiovaskularnih bolesti.

Metod: U istraživanje je uklju eno 197 pacijenata (94 de aka i 103 devoj-ice). Prose na starost svih pacijenata je 12,71±4,89. Analizirani su njihovi

podaci o telesnoj masi, telesnoj visini, indeksu telesne mase, nivou ukupnog holesterola, LDL i HDL holesterola, GHbA1c, o dnevnoj dozi insulina, hipertenziji, uzrastu u kojem je bolest zapo ela, dužini bolesti.

Rezultati: U ispitivanoj grupi bilo je 77,2% dece koja su bila normalno uhranjena, 14,2% preuhranjenih, 3,4% gojaznih i 5,2% dece i adolesce-nata koja su razvila metaboli ki sindrom. Utvr ena je statisti ki zna ajna povezanost izme u poreme aja uhranjenosti i ukupnog holesterola, tri-glicerida, arterijske hipertenzije, dužine bolesti i dnevne doze insulina.

Zaklju ak: S obzirom na rastu u u estalost i gojaznosti i dijabetes me-litusa tip 1, njihovo me usobno preplitanje, kao komorbiditeta i/ili me-usobnih faktora rizika, od velike je važnosti pratiti stepen uhranjenosti

i prevenirati pojavu gojaznosti dece i adolescenata sa dijabetesom tip 1 kroz kontinuiranu edukaciju i optimalizaciju insulinskog režima.

Klju ne re i: dijabetes tip 1, deca, gojaznost, metaboli ki sindrom

* Sandra Stankovi , De ija interna klinika, Klini ki centar Niš, stankovi [email protected], tel +38162393225.

1 Klinika za de je interne bolesti, Klini ki centar Niš2 Centar za medicinsku statistiku, Medicinski fakultet Niš

71PREKOMERNA TEŽINA, GOJAZNOST I METABOLI KI SINDROM KOD DECE I...

Uvod

Gojaznost je multifaktorsko, složeno oboljenje koje nastaje kao posledica dugotrajnog prekomernog energetskog unosa uz podršku genetskih i faktora spoljne sredine (1,2). Predstavlja naj eš i poreme aj ishrane u industrijalizovanim zemljama i udružena je sa porastom morbiditeta i mortaliteta od metaboli kih, endokrinih, respiratornih, kardiovaskularnih, ortopedskih i drugih bolesti i po-reme aja (3).

Polaze i od de nicije da telesna masa iznad P85 za pol i uzrast zna i preu-hranjenost, a iznad P95 gojaznost, evidentno je da postoji dramati an porast inci-dence poreme aja uhranjenosti u svim uzrasnim grupama i me u svim etni kim zajednicama (4). Gojaznost se epidemijski pojavljuje u sve ranijem uzrastu. Pro-cenjuje se da svake godine oko 1.3 miliona dece u Evropi postaje preuhranjeno, a 35 000 novih gojazno. U Srbiji se prevalencija gojaznosti kod dece i adolescenata procenjuje na 19% (5,6).

Masno tkivo nije samo prost organ za skladištenje masti – ono je aktivan endokrini organ i deo uro enog imunog sistema koji uti e na mnoge ziološke i patološke mehanizme, kakvi su homeostaza glukoze, in amacija, angiogeneza, elijska proliferacija i diferencijacija (7). Ovu endokrinu ulogu ostvaruju pre svega

sami adipociti ali i aktivirani makrofagi in ltrovani u masno tkivo. Promenjena ekspresija adipokina udružena sa gojaznoš u dovodi do indukcije sistemske in a-macije niskog stepena i dislipidemije koje zajedno mogu da dovedu do ubrzane i rane ateroskleroze (8).

Dijabetes melitus tip 1 predstavlja naj eš i endokrino-metaboli ki poreme-aj u detinjstvu i adolescenciji i tako e pokazuje rastu u incidencu (9). Uprkos

napretku koji je napravljen u le enju dece i adolescenata sa dijabetes melitusom tip 1, ovi pacijenti i dalje imaju nekoliko puta ve i rizik za razvoj koronarne, cerebrovaskularne i periferne arterijske bolesti u ranom odraslom dobu (10,11). Dijabetesna makrovaskulopatija je posledica strukturnih i funkcionalnih promena u krvnim sudovima koje nastaju kao posledica brojnih pato zioloških poreme aja. Me u njima centralno mesto ima hiperglikemija, koja dovodi do neenzimske gli-kozilacije, pove anog oksidativnog stresa i aktivacije proin amatornih signalnih puteva (12,13). U loše regulisanom dijabetesu dolazi do kvantitativnih i kvali-tativnih poreme aja lipida u smislu pove anja koncentracije slobodnih masnih kiselina, triglicerida, holesterola, lipoproteina niske gustine (LDL), a smanjenja lipoproteina visoke gustine (HDL), kao i glikozilacija lipoproteina i peroksidacije LDL. Ovi poreme aji izazivaju endotelnu disfunkciju sa poreme ajem ravnoteže izme u vazokonstriktora i vazodilatatora, prokoagulantnih i antikoagulantnih medijatora, kao i faktora koji stimulišu i usporavaju rast i samim tim dovode do ranijeg i eš eg nastanka ateroskleroze, koja kod dijabeti ara pokazuje bržu evo-luciju i teži klini ki tok (14).


Sve više studija ukazuje na direktnu povezanost rastu e incidence gojaznosti i rastu e incidence oba osnovna tipa dijabetes melitusa (tip 1 i 2) (15). Oba navedena tipa dijabetesa nastaju po patogenetskom modelu in amacije. U tipu 1 posredi je hro-ni na in amacija unutar pankreasnih ostrvaca sa detektibilnim autoimunim antitelima na periferiji, dok se u tipu 2 dijabetesa radi o modelu prave sistemske in amacije sa reaktantima akutne faze zapaljenja u cirkulaciji. Gojaznost preko patološke aktiva-cije NF- B može biti odgovorna za nastanak i beta elijske destrukcije i insulinske rezistencije, ime se potvr uje teza o povezanosti epidemije gojaznosti u mladih sa nastankom novog tipa dijabetesa: i 1 i 2 – „duplog“ ili „hibridnog“ (16).

Prema rezultatima studije SEARCH for Diabetes in Youth, procenat preuhra-njenosti (ne gojaznosti) u grupi dece sa dijabetom tip 1 je ve i u odnosu na zdravu kontrolnu grupu, sugerišu i postojanje razli itih mehanizama koji doprinose pore-me aju uhranjenosti u ovoj populaciji (17). Pored sedentarnog na ina života, deluju i ostali faktori poput prekomerne insulinizacije u cilju optimalizovanja glikoregulacije tokom intenzivirane insulinske terapije ili pove anog kalorijskog unosa zbog estih hipoglikemijskih epizoda i nutritivne liberalizacije (18).

Etiologija i pato ziološki mehanizam nastanka preuhranjenosti (ne gojaznosti) su razli iti kod dece i adolescenata sa dijabetesom tip 1 u odnosu na opštu popula-ciju. Preuhranjenost i gojaznost, kao faktori rizika i kao komorbiditeti u dijabetesu mladih, bile su predmet istraživanja nekoliko studija, koje su pokazale kontradik-torne rezultate (18,19). Me utim, DCCT studija je pokazala da preuhranjenost dece i adolescenata predstavlja zna ajan kardiometaboli ki rizik (20).

Povezanost gojaznosti i rezistencije na insulin, hipertenzije, dislipidemije, tipa 2 dijabetesa, kao i drugih metaboli kih abnormalnosti udruženih s rizikom od aterosklerotske kardiovaskularne bolesti kod odraslih, Reaven i saradnici 1988. godine su opisali kao „metaboli ki sindrom“ (sinonimi: sindrom rezistencije na insulin, dismetaboli ki sindrom ili sindrom X) (21). Danas se smatra da je osnovni poreme aj u metaboli kom sindromu rezistencija tkiva na delovanje insulina koja dovodi do kompenzatorne hiperinsulinemije, sekundarnog poreme aja koncentracija lipida u plazmi i porasta krvnog pritiska (22). Za dijagnozu metaboli kog sindro-ma u detinjstvu i adolescenciji mogu se upotrebiti isti kriterijumi koji se koriste za dijagnozu ovog sindroma kod odraslih uz neophodnost prilago avanja svakog od kriterijuma za uzrast i pol ispitanika (23,24). Imaju i u vidu razlike kod dece i adolescenata razli itog uzrasta i pola, de nicija metaboli kog sindroma prema kriterijumima Internacionalne federacija za dijabetes (IDF) podeljena je na razli-ite dobne grupe: 6 – <10, 10 – <16 i iznad 16 godina (25) (tabela 1). Kod dece i

adolescenata sa dijabetes melitusom tip 1 metaboli ki sindrom se javlja sa sli nom incidencom kao i u opštoj populaciji.

S obzirom na injenicu da su osobe sa dijabetes melitusom tip 1 pod visokim rizikom za razvoj vaskularnih komplikacija, prevencija, rana detekcija i le enje svih kardiometaboli kih faktora rizika su imperativ (26).


Tabela 1. Usaglašeni IDF kriterijumi za de niciju metaboli kog sindroma kod dece i adolescenata

Uzrast

Gojaznost 90. percentila de nisana na osnovu obima

struka

Trigliceridi HDL Krvni pritisak Glikemija

6 – 10 g 90. percentil

Druga ispitivanja se preduzimaju na osnovu anamnesti kih podataka o metaboli kom sindromutipu 2 dijabetesa, dislipidemiji, hipertenziji, kardiovaskularnoj bolesti ili gojaznosti u porodici

Uzrast 10 – 16 g 90. percentil 1,7 mmol/l <1.03 mmol/l

Sistolni pritisak 130 ili

dijastolni 85 mmHg

5,6 mmol/l ili tip 2 dijabetesa melitusa

Uzrast > 16 g Upotrebiti kriterijume za odrasle

Cilj ovog istraživanja je da se odredi zastupljenost preuhranjenih, gojaznih i osoba sa metaboli kim sindromom u grupi dece i adolescenata sa dijabetes melitusom tip 1 i da se utvrdi povezanost uhranjenosti sa drugim faktorima rizika za razvoj kardi-ovaskularnih bolesti kao što su dislipidemija, glikoregulacija, povišen krvni pritisak, doza insulina, uzrast obolevanja, dužina bolesti.

Metod rada

Istraživanje je obavljeno na Endokrinološkom odeljenju De ije interne klinike u Nišu. Ispitivanjem je obuhva eno 197 dece i adolescenata sa dijabetes melitusom tip 1 u trajanju od najmanje godinu dana. U istraživanje je uklju eno 197 pacijenata (94 de aka i 103 devoj ice). Prose an uzrast pacijenata je bio 12,71±4,89 godina.

Retrospektivnom analizom dobijeni su podaci o telesnoj masi, telesnoj visini, izra unat je BMI prema formuli kg/m2. Standardnim laboratorijskim postupcima odre ivani su ukupni holesterol, LDL i HDL holesteroli, AST, GHbA1c, uvidom u medicinsku dokumentaciju, dobijeni su podaci o dnevnoj dozi insulina, kao i tipu insulinske terapije, uzrastu u kojem je bolest zapo ela, dužini bolesti, eventualnom postojanju mikrovaskularnih komplikacija (mikroalbuminurija, retinopatija, neuro-patija) i hipertenzije.

Ispitanici su u odnosu na stepen uhranjenosti podeljeni u 4 grupe:Grupa (N=152) obuhvatala je ispitanike sa BMI ispod 85. percentila,1.


Grupa (N=28) obuhvatala je ispitanike koji su bili preuhranjeni, odnosno 2. koji su imali BMI ve i od 85. percentila, a manji od 95. percentila.Grupa (N=7) N obuhvatala je ispitanike koji su bili gojazni, odnosno imali 3. BMI preko 95. percentila za uzrast i pol,Grupa (N=10) obuhvatala je ispitanike koji su prema IDF referencama (tabela 4. 1) imala ispunjene kriterijume za metaboli ki sindrom (MS).

Statisti ka obrada

Podaci su prikazani u vidu aritmeti ke sredine i standardne devijacije, odnosno u vidu apsolutnih i relativnih brojeva. Kolmogorov-Smirnov test koriš en je za testiranje distribucije podataka. Ukoliko je zadovoljena normalna distribucija za testiranje stati-sti ki zna ajne razlike izme u više grupa koriš ena je ANOVA sa post hoc analizom, ukoliko nije zadovoljena normalna distribucija koriš en je Kruskal-Wallisov test, a kao post hoc analiza u tom slu aju koriš en je Mann-Whitnijev U test. Statisti ka hipoteza testirana je na nivou signi kantnosti za rizik od = 0.05, tj. razlika me u uzorcima smatra se zna ajnom ako je p < 0.05. Za analizu podataka koriš en je SPSS 16.0 programski paket.

Rezultati

U istraživanje je uklju eno 197 pacijenata (94 de aka i 103 devoj ice). Antro-pometrijske karakteristike ispitanika date su u tabeli 2. Nije bilo statisti ki zna ajne razlike u polu me u ispitivanim grupama (p=0,847). Prose na starost svih pacijenata je 12,71±4,89 godina. Postoji statisti ki zna ajna razlika u starosti me u ispitivanim grupama (p=0,023). Postoji statisti ki zna ajna razlika u starosti izme u ispitivanih grupa: prva vs.

etvrta (p=0,029), druga vs. treca (p=0,039) i treca vs. etvrta (p=0,007). Nije bilo statisti ki zna ajne razlike me u ispitivanim gru-

pama u telesnoj visini.Statisti ki zna ajna razlika me u ispitivanim grupama postoji u telesnoj masi

(p<0,001), BMI-u (p<0,001), percentile BMI-a (p<0,001), holesterola (p=0,039). Utvr eno je da statisti ki zna ajna razlika u TM postoji izme u slede ih grupa: prva vs.

etvrta (p=0,029), druga vs. tre a (p=0,039), tre a vs etvrta (p=0,007). Prose ne vrednosti BMI se statisti ki zna ajno razlikuju u

slede im grupama: prva vs druga (p<0,001), prva vs tre a (p=0,044), prva vs etvrta (p<0,001) i druga vs etvrta (p=0,005). Statisti ki zna ajna razlika u percentile BMI-a postoji izme u svih grupa (p<0,001), osim izme u tre e i etvrte.


Tabela 2. Antropometrijske karakteristike ispitanika

BMI <P85n=152 (77,2%)

BMI <P95n=28 (14,2%)

BMI >P95n=7 (3,4%)

MSn=10 (5,2%)

p

Starost 14.13±3.31 10.68±5.88 9.93±4.02 15.69±4.88 0,023*

Pol (M/Ž) 74/78 12/16 4/3 4/6 0,847

TV 148,96±24,97 155,18±22,19 142,40±24,52 158,19±13,47 0,307

TVP 55,68±28,63 56,79±31,15 74,43±16,11 44,80±34,02 0,252

TM 42,42±17,92 54,05±17,54 45,64±19,14 64,00±15,89 <0,001*

BMI 18,78±3,76 22,04±3,14 21,47±3,81 25,37±3,36 <0,001*

BMI P 45,09±23,79 82,36±21,22 96,57±2,22 94,60±2,91 <0,001*

Koncentracija holesterola se statisti ki zna ajno razlikuje me u ispitivanim grupama (p=0,039), i to izme u: prve i etvrte grupe (p=0,004), druge i etvrte (p=0,016). Pokazano je da postoji statisti ki zna ajna razlika u prisustvu hipertenzije me u ispitivanim grupama (p<0,001). Koncentracija triglicerida bila je statisti ki zna ajno ve a u grupi dece sa metaboli kim sindromom. Razlika u koncentraciji LDL i HDL holesterola me u ispitivanim grupama nije bila statisti ki zna ajna (tabela 2).

Tabela 3. Kardiometaboli ki faktori rizika

BMI P85 P85 BMI P95 BMI P95 MS p

Ukupni holesterol (mmol/l) 4,38±0,88 4,49±1,05 4,53±1,27 5,61±1,33* 0,039*

HDL-holesterol (mmol/l) 1,41±0,38 1,58±0,84 1,43±0,21 1,37±0,24 0,407

LDL-holesterol (mmol/l) 2,51±0,66 2,65±0,79 2,66±0,58 2,87±0,45 0,224

Trigliceridi (mmol/l) 0,93±0,47 0,86±0,51 0,71±0,14 1,26±0,49* 0,050*

Uzrast obolevanja (g) 8,41±4,32 8,42±3,82 5,71±4,27 5,85±4,22 0,137

Arterijska hipertenzija % 2,6 14,3 28,6 70 <0,001*

Prose na dužina bolesti bila je 4,39±4,08. Analiza je pokazala da statisti ki zna ajna razlika u dužini bolesti postoji me u slede im grupama: prva vs etvrta (p=0,001), druga vs etvrta (p=0,009), tre a vs etvrta (p=0,025) (gra kon 1)


a – BMI<P85 vs metaboli ki sindrom, p<0,01,b – BMI<P95 vs metaboli ki sindrom, p<0,05,c – BMI>P95 vs metaboli ki sindrom, p<0,05

Gra kon 1. Dužina bolesti u ispitivanim grupama

Prose na doza insulina bila je 38,62±35,58. Postoji statisti ki zna ajna razlika u dozi insulina me u ispitivanim grupama (p=0,005), dalja analiza je pokazala da statisti ki zna ajna razlika u dozi insulina postoji me u slede im grupama: prva vs druga (p=0,022) i prva vs etvrta (p=0,005) (gra kon 2).

a – BMI<P85 vs BMI<P95, p<0,05,b - BMI<P85 vs metaboli ki sindrom, p<0,01

Gra kon 2. Doza insulina u ispitivanim grupama


Me u ispitivanim grupama nije bilo statisti ki zna ajno velike razlike u gliko-regulaciji (Gra kon 3)

Gra kon 3. Hba1c u ispitivanim grupama

U tabeli 4 je prikazana distribucija kasnih komplikacija me u ispitivanim grupama. U grupi sa metaboli kim sindromom je naj eš a, a u grupi BMI<P85 se najre e javlja. Distribucija mikroalbuminurije se statisti ki zna ajno razlikuje me u ispitivanim grupama (p=0,001). Naj eš a je kod dece koja imaju metaboli ki sindrom. Prisustvo retinopatije se statisti ki zna ajno razlikuje me u ispitivanim grupama (p=0,017). Naj eš a je kod pacijenata sa metaboli kim sindromom.

Tabela 4. Kasne komplikacije u ispitivanim grupama

BMI<P85n=152 (%)

BMI<P95n=28 (%)

BMI>P95n=7 (%)

Metaboli ki syn=10 (%) p

Mikroalbuminurija 7 (4,6) 6 (21,4) 0 4 (40) 0,001*Retinopatija 3 (1,9) 1 (3,6) 0 3 (30) 0,017*

Diskusija

Uticaj gojaznosti na kardiometaboli ko zdravlje u opštoj populaciji je široko ispitivan, ali je mali broj studija koje se bave problemom gojaznosti u populaciji dece i adolescenata sa dijabetesom tip 1.

Rezultati ukazuju da je zastupljenost preuhranjenosti/gojaznosti u grupi dece i adolescenata sa dijabetesom 22,8%, što se poklapa sa rezultatima drugih autora (27).

Analiziraju i prose nu starost po grupama prime uje se statisti ki zna ajno stariji uzrast dece sa manifestnim metaboli kim sindromom, što govori u prilog injenici da se sa starijim uzrastom pojavljuje sve ve i broj kardiometaboli kih faktora rizika (28).

S obzirom na razli itu etiologiju i pato ziologiju preuhranjenosti/obeziteta kod dece i adolescenata, koja mahom nastaje zbog prekomerne insulinizacije, rezultati naše studije ukazuju na niži nivo triglicerida i viši nivo HDL holesterola, mada bez statisti ke zna ajnosti kod dece koja su preuhranjena, u odnosu na decu normalne telesne težine. Sli ni rezultati dobijeni su u studiji belgijskih autora (29).

Posmatraju i uticaj uhranjenosti na kvalitet glikoregulacije, nismo uo ili stati-sti ki zna ajnost. U grupama dece koja su bila preuhranjena/gojazna, prime uje se ak i niži procenat glikoziliranog hemoglobina.

Smatra se da je mla i uzrast obolevanja nezavisan kardiovaskularni faktor rizika kod dece i adolescenata sa dijabetes melitusom tip 1 (30). Rezultati našeg istraživanja


ukazuju da su deca i adolescenti koji su gojazni i imaju manifestan metaboli ki sindrom oboleli u nešto ranijem uzrastu, u odnosu na normalno uhranjenu decu.

Pokazano je da adolescenti sa razvijenim metaboli kim sindromom imaju du-žinu bolesti statisti ki zna ajno ve u, u odnosu na ostale grupe, što je pokazano i u ranijim studijama (31).

Ukupna dnevna doza insulina, kao i vrsta insulinske terapije ne razlikuju se statisti ki u ispitivanim grupama.

Pokazano je da postoji statisti ki zna ajna razlika u prisustvu hipertenzije me u ispitivanim grupama (p<0,001). U grupi sa metaboli kim sindromom je naj eš a, a u grupi dece koja su normalno uhranjena se najre e javlja. Dobijeni rezultati koreliraju sa rezultatima drugih autora (28).

O ekivano, mikroalbuminurija i retinopatija kao hroni na komplikacija su naj-eš e kod dece koja boluju od metaboli kog sindroma.

Zaklju ak

S obzirom na rastu u u estalost i gojaznosti i dijabetes melitusa tip 1, njihovo me usobno preplitanje, kao komorbiditeta i/ili me usobnih faktora rizika, od velike je važnosti pratiti stepen uhranjenosti i prevenirati pojavu gojaznosti dece i adoles-cenata sa dijabetesom tip 1 kroz kontinuiranu edukaciju i optimalizaciju insulinskog režima.

Literatura

Aoi N, Soma M, Nakayama T, et al. Variable number of tandem repeatof the 5- anking 1. region of type C- human natriuretic peptid receptor gene in uences blood pressure le-vels in obesity associated hypertension. Hypertension research, 2004; Vol. 27, No 10, pp711-716.Kosuge K, Soma M, Nakayama T, Human uncapling protein 2 and 3 genes are associated 2. with obesity in Japanese. Endocrine, 2008; Vol. 34, No 1-3, pp 87-95.Sowers J.R. Obesity as a kardiovascular risk factor. The American Journal of Medicine, 3. 2003; Vol 115, No 8 pp 37-41.Živi S., iri V., Stankovi S. Epidemiolške karakteristike i etiopatogeneza gojaznosti 4. dece i adolescenata. Medicinski glasnik 2009,41-49.Zdravkovi D., Bani evi M., Bogdanovi R. Prevencija i le enje gojaznosti kod dece i 5. adolescenata u Srbiji. Udruženje pedijatara Srbije i Institut za štitastu žlezdu i metaboli-zam Zlatibor, 2007:5–7.Zdravkovi D, Bani evi M, Petrovi . 6. Novi standardi rasta i uhranjenosti dece i adoles-cenata. Udruženje pedijatara Srbije, 2009:42–4.Rasouli N et al. Adipocytokines and the metabolic complications of obesity. J Clin En-7. docrinol Metab 2008;93:64-73.


Mici D. Gojaznost, dijabetes i ateroskleroza: in amacija kao mehanizam povezivanja. 8. Medicinski glasnik 2011:36-38.Soltesz G, Patterson C, Dahlquist G. IDF Diabetes Atlas 49. th edition. Diabetes in the Young: a Global Perspective 2010;1-36.Dahl-Jørgensen K, Larsen JR, Hanssen KF. Atherosclerosis in childhood and adolescent 10. type 1 diabetes: early disease, early treatment? Diabetologia 2005;48:1445–1453.Margeirsdottir HD, Larsen JR, Brunborg C, Overby NC, Dahl-Jørgensen K, Norwegian 11. Study Group for Childhood Diabetes. High prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes: a population-based study. Diabetologia 2008;51:554–561.Bownlee M. Glycation and diabetic complications. Diabetes; 1994, 43: 836-841. 12. Rahman S, Rahman T, Al-Sha Ismail, Rahman A. Diabetes associates macrovasculopaty: 13. pathophysiology and pathogenesis. Diab, Obes and Metab. 2006, 0, 1-14.Wadwa P, Kinney G, Maahs D et al. Awareness and treatment of dyslipidemia in young 14. adults with type 1 diabetes. Diabetes Care 2006;28:1051-1056.Verbeeten, K. C., Elks, C. E., Daneman, D. and Ong, K. K. (2011), Association between 15. childhood obesity and subsequent Type 1 diabetes: a systematic review and meta-analysis. Diabetic Medicine, 28: 10–18.Pozzilli P, Guglielmi C, Pronina E et al. Double or hybrid diabetes associated with 16. an increase in type 1 and type 2 diabetes in children and youth. Pediatric Diabetes 2007;8(9):88-95.Liu LL, Lawrence JM, Davis C, Liese AD, Pettitt DJ, Pihoker C, Dabelea D, Hamman 17. R, Waitzfelder B, Kahn HS (2009). Prevalence of overweight and obesity in youth with diabetes in USA: the SEARCH for Diabetes in Youth Study. Pediatr Diabetes 11:4–11.Holl RW, Grabert M, Sorgo W, Heinze E, Debatin KM. Contributions of age, gender and insu-18. lin administration to weight gain in subjects with IDDM. Diabetologia 1998;41:542–547.van Vliet M, Van der Heyden JC, Diamant M, Schindhelm RK, von Rosenstiel I, Aanstoot 19. J, Veeze HJ (2010), Overweight is highly prevalent in children with type 1 diabetes and ssociates with cardiometabolic risk. J Pediatr 156:923–929Lešovi , S. i Saji S. „Metaboli ka kontrola i uhranjenost dece i adolescenata obolelih od 20. diabetes mellitusa tip 1”. Medicinski glasnik, Specijalna bolnica za bolesti štitaste žlezde i bolesti metabolizma Zlatibor 14.30 (2009): 56-66.Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD (1998) 21. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. JAMA 280:140–146 Reaven GM. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes. 22. 1988;37:1595-607.Goran MI, Ball GDC, Cruz ML. Obesity and risk of type 2 diabetes and cardiovascular 23. disease in children and adolescents. J Clin Endocrinol Metab. 2003;88:1417-27.Rodriguez-Moran M., Salazar-Vazquez B., Violante R., Guerrero-Romero F. Metabolic 24. syndrome among children and adolescents aged 10-18 years. Diabetes Care, 2004, 27, 2516-2517.


Zimmet P, Alberti KGMM, Kaufman F, Tajima N, Silink M, Arslanian S, et al. The me-25. tabolic syndrome in children and adolescents – an IDF consensus report. Pediatr Diab. 2007;8:299-306. Lipsy R. J. The National Cholesterol Education Program Adult Treatment Panel III 26. guidelines.J. Manag. Care Pharm., 2003, 9, suppl. 1, 2-5. Luczy ski 27. W, Szypowska A, Bossowski A, Ramotowska A, Re ko P, Rembi ska M, Tercjak M, Blecharczyk B, Lachowska U, Sucho P, Wi niewska K, Bernatowicz P, G owi ska-Olszewska B.Overweight, obesity and metabolic syndrome in children with type 1 diabetes melllitus. Pediatr Endocrinol Diabetes Metab. 2010;16(2):83-8.Schwab K28. O, Doerfer J, Hecker W, Grulich-Henn J, Wiemann D, Kordonouri O, Beyer P, Holl RW; DPV Initiative of the German Working Group for Pediatric Diabetology. Spec-trum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: cross-sectional data from the German diabetes documentation and quality management system (DPV). Diabetes Care. 2006;29(2):218-25.van Vliet M, van der Heyden J C, Diamant M et al. Overweight children with type 1 29. diabetes have a more favourable lipid pro le than overweight non-diabetic children. Eur J Pediatr. 2012; 171:493–498.Dalla Pozza R, Bechtold S, Bon g W et al. Age of onset of type 1 diabetes in children and 30. carotid intima medial thickness. J Clin Endocrinol Metab 2007, 92(6):2053-2057.Orchard TJ, Costacou T, Kretowski A, Nesto RW. Type 1 diabetes and coronary artery 31. disease. Diabetes Care 2006, 29:2528–2538.

81OVERWEIGHT, OBESITY AND METABOLIC SYNDROM IN CHILDREN AND ADOLESCENTS...

Sandra Stankovi *1, Saša Živi 1, Vesna Cvetkovi 1, Ivana Marinkovi 1, Aleksandra Topalovi 2

OVERWEIGHT, OBESITY AND METABOLIC SYNDROM IN CHILDREN AND ADOLESCENTS WIT TYPE 1 DIABETES MELLITUS

Abstract: The in uence of obesity on cardiometabolic health in the general population has been widely studied, but few studies are dealing with the problem of obesity in children and adolescents with type 1 diabetes.Aim: The aim of this study was to determine the presence of overweight, and obese persons with metabolic syndrome in children and adolescents with type 1 diabetes and to determine the conection of nutritional status with other risk factors for cardiovascular disease, such as dyslipidemia, glycoregulation, high blood pressure , insulin dose, age, illness, length of illness.Methods: The study included 197 children and adolescents with type 1 diabetes mellitus (103 females, 94 males). The average age of respon-dents was 12,71 years. Data on body weight, height, BMI was calculated according to the formula kg/m2. Standard laboratory procedures were determined, total cholesterol, LDL and HDL cholesterol, AST, GHbA1c, data on a daily dose of insulin, and type of insulin therapy, age at which the disease began, duration of disease, the possible existence of micro-vascular complications (microalbuminuria, retinopathy, neuropathy) and hypertension were obtained.Results: There were 77,2% patients had normal weight, 14,2% were overweight, 3,4% were obese and 5,2% nutritional had metabolic syn-drome. We found statisticaly signi cant conection between nutritional impairment and total cholesterol, tryglycerides, hypertension, lenght of disease and daily insuline dose.

* Sandra Stankovi , Children Clinic, Clinical Center Niš, stankovi [email protected], tel +38162393225

1 Children Clinic, Clinical Center Niš2 Center for Mediacl Statistics, Medical Faculty Niš


Conclusion: Due to the fact that people with type 1 diabetes are at high risk for the development of vascular complications, prevention, early detection and treatment of nutritional impairment as well as other car-diometabolic risk factors are imperative.

Key words: diabetes type 1, children, obesity, metabolic syndrome

Introduction

Obesity is a multifactorial, complex disease that occurs as a result of chronic excessive energy intake supported by genetic and environmental factors (1.2). Is the most common nutritional disorder in industrialized countries and is associated with increased morbidity and mortality from cardiovascular disease (3).

Starting from the de nition of the weight above the P85 for age and sex means overnutrition and obesity over the P95, it is evident that there is a dramatic increase in the incidence of nutritional disorders in all age groups and among all ethnic com-munities (4). Obesity epidemically occurs in all younger age. It is estimated that each year about 1.3 million of children becoming overweight in Europe and 350 thousand new obese. In Serbia, the prevalence of obesity is estimated at 19% (5.6).

Adipose tissue is not only a simple body to store fat - it is an active endocrine organ and part of the innate immune system that affects many physiological and pat-hological mechanisms, such as glucose homeostasis, in ammation, angiogenesis, cell proliferation and differentiation (7). This endocrine role are carrying adipocytes and activated macrophages in ltrated in adipose tissue. Altered expression of adipokines associated with obesity leads to the induction of systemic in ammation and a low de-gree of dyslipidemia, which together can lead to rapid and early atherosclerosis (8).

Diabetes mellitus type 1 is the most common endocrine metabolic disorder in childhood and adolescence, and also shows the increasing incidence (9). Despite the progress that has been made in the treatment of children and adolescents with type 1 diabetes, these patients still have a few times higher risk of developing coronary, cerebrovascular and peripheral arterial disease in early adulthood (10,11). Diabetic macrovasculopthy is a result of structural and functional changes in blood vessels that occur as a result of numerous pathophysiological disorders. Among them hyper-glycemia has a central role, which leads to nonenzymatic glycosylation, increased oxidative stress and activation of proin ammatory signaling pathways (12,13). In poorly controlled diabetes it leads to quantitative and qualitative lipid disorders by increasing the concentration of free fatty acids, triglycerides, cholesterol, low-density lipoprotein (LDL) and decrease in high density lipoprotein (HDL), and lipoprotein glycation and peroxidation of LDL. These disorders cause endothelial dysfunction with a disturbance of the balance between vasoconstrictor and vasodilator, anticoagulant and procoagulant mediators, as well as the factors that stimulate or slow down growth and


thus lead to earlier and more frequent occurrence of atherosclerosis in diabetic patients, which shows the evolution of faster and more dif cult clinical course (14) .

The in uence of obesity on cardiometabolic health in the general population has been widely studied, but few studies are dealing with the problem of obesity in children and adolescents with type 1 diabetes.

Increasing number os studies suggest a direct link between the growing incidence of obesity and the increasing incidence of the two main types of diabetes mellitus (type 1 and 2) (15). Both of these types of diabetes are caused by pathogenic model of in ammation. In type 1 it is an chronic in ammation within the pancreatic islets from autoimmune antibodies detectable in the periphery, whereas in type 2 diabetes is a true model of systemic in ammation with acute phase reactants of in ammation in the circulation. Pathological obesity through activation of NF-kappaB may be respon-sible for the development and beta cell destruction and insulin resistance, con rming the hypothesis on the connection between obesity epidemic in young people with the emergence of a new type of diabetes: 1 and 2 - “double” or “hybrid” (16 ).

According to the study, SEARCH for Diabetes in Youth, the percentage of over-nutrition (not obesity) in the group of children with type 1 diabetes is higher than in the healthy control group, suggesting the existence of different mechanisms that con-tribute to nutritional disorder in this population (17). Besides sedentary lifestyle, and other factors such as excessive insulin supply to optimalise glycemic control during intensi ed insulin therapy or increased caloric intake because of frequent episodes of hypoglycemia and nutritional liberalization (18).

Etiology and pathogenetic mechanisms of overnutrition (not obesity) are different in children and adolescents with type 1 diabetes compared to the general population. Over-nutrition and obesity as risk factors and comorbidities were the subject of several studies, which have shown contradictory results (18,19). However, the DCCT study showed that overnutrition in children and adolescents is a signi cant cardiometabolic risk (20).

Relationship between obesity and insulin resistance, hypertension, dyslipide-mia, type 2 diabetes and other metabolic abnormalities associated with the risk of atherosclerotic cardiovascular disease in adults (Reaven et al 1988) was described as the “metabolic syndrome” (synonymous: the insulin resistance syndrome, dismeta-bolical syndrome or syndrome X) (21). Today it is considered that the basic distur-bance in metabolic syndrome tissue resistance to the action of insulin, which leads to compensatory hyperinsulinemia, secondary disorders plasma lipids and increased blood pressure (22). For the diagnosis of the metabolic syndrome in childhood and adolescence can be used the same criteria used for the diagnosis of this syndrome in adults with the need to adjust any of the criteria for age and sex of respondents (23,24). Given the differences in children and adolescents of different ages and sexes new de nition of the metabolic syndrome according to the criteria of the International Diabetes Federation (IDF) is divided into different age groups: 6 - <10, 10 - <16 and over 16 (25) (Table 1).


Table 1. The IDF consensus de nition of metabolic syndrome in children and adolescents

Age group [years] Obesity (WC) Triglycerides HDL-Ch Blood pressure Glucose

6-10 90 percentile

Metabolic syndrome cannot be diagnosed, but further measurements should be made if there is a family history of metabolic syndrome, T2DM, dyslipidemia, cardiovascular disease, hypertension and/or obesity

10-16 90

1,7 mmol/l <1.03 mmol/l

systolic 130 mmHg /

diastolic 85 mmHg

5.6 mmol/l

16 Use existing IDF criteria for adults

Due to the fact that people with type 1 diabetes are at high risk for the development of vascular complications, prevention, early detection and treatment of cardiometabolic risk factors is imperative (26).

The aim of this study was to determine the presence of overweight, and obese persons with the metabolic syndrome in children and adolescents with type 1 diabe-tes and to determine the nutritional status of connections with other risk factors for cardiovascular disease, such as dyslipidemia, glycoregulation, high blood pressure , insulin dose, age, illness, length of illness.

Methods

The study was conducted at Children’s endocrinology department of Children clinic in Niš. The study included 197 children and adolescents with type 1 diabetes mellitus. The average age of respondents was 12,7 years.

By using retrospective analysis, we obtained data on body weight, height, BMI was calculated according to the formula kg/m2. Standard laboratory procedures were deter-mined, total cholesterol, LDL and HDL cholesterol, AST, GHbA1c, after reviewing the medical records, data were obtained on a daily dose of insulin, and type of insulin therapy, age at which the disease began, duration of disease, the possible existence of microvascular complications (microalbuminuria, retinopathy, neuropathy) and hypertension.

Respondents were divided into 4 groups:1. First group (N154) included patients with BMI below the 85th percentile,2. Second group (N=28) included patients who were overweight or who had a

BMI greater than the 85th percentile and less than 95th percentile3. Third group (N=7) N obuvatala the respondents who were obese or had a BMI

over the 95th percentile for age and sex4. Fourth group (N=10) is comprised of those who are references to the IDF

(Table 1) had met criteria for the metabolic syndrome (MS)


Statistical processing

Data are presented as mean and standard deviation, or in the form of absolute and relative numbers. Kolmogorov-Smirnov test was used to test the data distributi-on. It was done to test the normal distribution of statistically signi cant differences between several groups we used ANOVA with post hoc analysis, if the normal normal distribution was not satis ed we Kruskal-Wallis test as a post hoc analysis, in this case we used the Mann-Whitny’s U test. The statistical hypothesis was tested at the risk of signi cancy for = 0.05, ie. difference between samples is considered signi cant if p <0.05. For the analysis we used SPSS 16.0 software package.

Results

The study included 197 patients (94 boys and 103 girls). There were no signi cant statistical differences in sex among the groups (p = 0.847). The average age of all patients was 12.71 ± 4.89. There was a statistically signi cant difference in age among the groups (p = 0.023). There was a statistically signi cant difference in age between the groups: rst vs. fourth (p = 0.029), second vs. third (p = 0.039) and third vs. fourth (p = 0.007). No statistically signi cant differences among the groups in height.

Statistically signi cant difference among the groups exist in the TM (p <0.001), BMI (p <0.001), BMIP (p <0.001), cholesterol (p = 0.039). It was found that a sta-tistically signi cant difference exists in TM between the following groups: rst vs. fourth (p = 0.029), second vs. third (p = 0.039), third vs. fourth (p = 0.007). The average BMI are signi cantly different in the following groups: rst vs. second (p <0.001), rst vs. third (p = 0.044), rst vs. fourth (p <0.001) and second vs. fourth (p = 0.005). Statistically signi cant difference in BMIP exists between all groups (p <0.001), except between the third and fourth (Table 2).

Table 2. Anthropometrical characteristics

BMI <P85n=152 (77,2%)

BMI <P95n=28 (14,2%)

BMI >P95n=7 (3,4%)

MSn=10 (5,2%)

p

Age 14.13±3.31 10.68±5.88 9.93±4.02 15.69±4.88 0,023*Sex (M/Ž) 74/78 12/16 4/3 4/6 0,847Height 148,96±24,97 155,18±22,19 142,40±24,52 158,19±13,47 0,307Height P 55,68±28,63 56,79±31,15 74,43±16,11 44,80±34,02 0,252Weight 42,42±17,92 54,05±17,54 45,64±19,14 64,00±15,89 <0,001*BMI 18,78±3,76 22,04±3,14 21,47±3,81 25,37±3,36 <0,001*BMI P 45,09±23,79 82,36±21,22 96,57±2,22 94,60±2,91 <0,001*

Cholesterol is statistically signi cantly different among the groups (p = 0.039), and between: the rst and fourth groups (p = 0.004), the second and fourth (p = 0.016).


It is shown that there is a statistically signi cant difference in the presence of hypertension among the groups (p <0.001). In the group with metabolic syndrome is the most common, and in group BMI <P85 can occur quite rarely (Table 2).

Table 3. Cardiometabolic risk factors

BMI P85 P85 BMI P95 BMI P95 MS p

Total cholesterol (mmol/l) 4,38±0,88 4,49±1,05 4,53±1,27 5,61±1,33* 0,039*

LDL-cholesterol (mmol/l) 1,41±0,38 1,58±0,84 1,43±0,21 1,37±0,24 0,407

HDL-cholesterol (mmol/l) 2,51±0,66 2,65±0,79 2,66±0,58 2,87±0,45 0,224

Triglycerides(mmol/l) 0,93±0,47 0,86±0,51 0,71±0,14 1,26±0,49* 0,050*

Age of set up (g) 8,41±4,32 8,42±3,82 5,71±4,27 5,85±4,22 0,137

Arterijska hipertenzija % 2,6 14,3 28,6 70 <0,001*

The average length of illness was 4.39 ± 4.08. There was a statistically signi -cant difference in the duration of disease among the groups (p = 0.002). The analysis showed no statistically signi cant difference in the length of the disease among the following groups: rst vs. fourth (p = 0.001), second vs. fourth (p = 0.009), third round, fourth (p = 0.025) (Gra c 1).

a – BMI<P85 vs metabolic syndrome, p<0,01,b - BMI<P95 vs metabolic syndrome, p<0,05c - BMI>P95 vs metabolic syndrome, p<0,05

Gra c 1. Lenght of diseaseThere was not signi cant difference in glycoregulation between study group

(Gra c 2).


Gra c 2. Hba1c levelThe average insulin dose was 38.62 ± 35.58. There was a statistically si-

gni cant difference in the dose of insulin among the groups (p = 0.005), further analysis showed no statistically signi cant difference in insulin dose exists among the following groups: rst vs. second (p = 0.022) and the rst round, fourth (p = 0.005) (Gra c 3).

a – BMI<P85 vs BMI<P95, p<0,05,b - BMI<P85 vs metaboli ki sindrom, p<0,01

Gra c 3. Insuline dose

Table 4 shows the distribution of late complications between the groups. Distribu-tion of microalbuminuria are signi cantly different among the groups (p = 0.001). It is the most common in children who suffer from the metabolic syndrome. The presence of retinopathy is signi cantly different among the groups (p = 0.017). Outbreaks in patients with metabolic syndrome.

Tabela 4. Microvascular complication

BMI<P85n=152 (%)

BMI<P95n=28 (%)

BMI>P95n=7 (%)

Metabolic syndromen=10 (%)

p

Mikroalbuminury 7 (4,6) 6 (21,4) 0 4 (40) 0,001*

Retinopaty 3 (1,9) 1 (3,6) 0 3 (30) 0,017*


Discussion

The in uence of obesity on cardiometabolic health in the general population has been widely studied, but few studies are dealing with the problem of obesity in children and adolescents with type 1 diabetes

Results indicate that the prevalence of overnutrition / obesity in children and adolescents with diabetes is 22.8%, which coincides with the results of other authors (27).

Analyzing the average age in the group observes a signi cantly older age of the children with manifest metabolic syndrome, which speaks to the fact that in older age appears a growing number of cardiometabolic risk factors (28).

Due to the different etiology and pathophysiology of overnutrition / obesity in children and adolescents, mostly caused by excessive insulin supply, the re-sults of our study indicate lower triglyceride levels and higher HDL cholesterol levels, although not statistically signi cant in children who were overweight, compared with children normal weight. Similar results were obtained in a study by Belgian (29).

Looking at the impact on the nutritional quality of glycemic control, we did not nd it statistically signi cant. In the group of children who were overweight / obese, it is noticed even lower percentage of glycosylated hemoglobin.

It is established that the younger age of disease is an independent cardi-ovascular risk factor in children and adolescents with diabetes mellitus type 1 (30). Our ndings indicate that children and adolescents who are overweight and have a manifest metabolic syndrome, patients are in a younger age, compared to normal weight children.

It is shown that adolescents with established metabolic syndrome have a duration of illness signi cantly higher, compared to the other groups, as shown in previous studies (31).

The total daily dose of insulin, and type of insulin therapy did not differ statistically in the two groups.

It is shown that there is a statistically signi cant difference in the presence of hypertension among the groups (p <0.001). In the group with metabolic syndrome is the most common, and in the group of children who were of normal weight are the rarest occurs. The results correlate with the results of other authors (28).

As expected, microalbuminuria and retinopathy as the most common chronic complications in children who suffer from the metabolic syndrome.


Conclusion

Due to the fact that people with type 1 diabetes are at high risk for the development of vascular complications, prevention, early detection and treatment of nutritional impairment as well as other cardiometabolic risk factors are imperative.

Literature

Aoi N, Soma M, Nakayama T, et al. Variable number of tandem repeatof the 5- anking region 1. of type C- human natriuretic peptid receptor gene in uences bood pressure levels in obesity associated hypertension. Hypertension research, 2004; Vol. 27, No 10, pp711-716.Kosuge K, Soma M, Nakayama T, Human uncapling protein 2 and 3 genes are associated 2. with obesity in Japanese. Endocrine, 2008; Vol. 34, No 1-3, pp 87-95.Sowers J.R.. Obesity as a kardiovascular risk factor. The Amecican Journal of Medicine, 3. 2003; Vol 115, No 8 pp 37-41.Živi S, iri V, Stankovi S. Epidemiloške karakteristike i etiopatogeneza gojaznosti 4. dece i adolescenata. Medicinski Glasnik 2009,41-49.Zdravkovi D., Bani evi M., Bogdanovi R. Prevencija i le enje gojaznosti kod dece i 5. adolescenata u Srbiji. Udruženje pedijatara Srbije i Institut za štitastu žlezdu i metaboli-zam Zlatibor, 2007:5–7.Zdravkovi D, Bani evi M, Petrovi . 6. Novi standardi rasta i uhranjenosti dece i adoles-cenata. Udruženje pedijatara Srbije, 2009:42–4.Rasouli N et al. Adipocytokines and zhe metabolic complications of obesity. J Clin En-7. docrinol Metab 2008;93:64-73.Mici D. Gojaznost, dijabetes i ateroskleroza: in amacija kao mehanizam povezivanja. 8. Medicinski Glasnik 2011:36-38.Soltesz G, Patterson C, Dahlquist G. IDF Diabetes Atlas 49. th edition. Diabetes in the Young: a Global Perspective 2010;1-36.Dahl-Jørgensen K, Larsen JR, Hanssen KF. Atherosclerosis in childhood and adolescent 10. type 1 diabetes: early disease, early treatment? Diabetologia 2005;48:1445–1453.Margeirsdottir HD, Larsen JR, Brunborg C, Overby NC, Dahl-Jørgensen K, Norwegian 11. Study Group for Childhood Diabetes. High prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes: a population-based study. Diabetologia 2008;51:554–561.Bownlee M. Glycation and diabetic complications. Diabetes.; 1994, 43: 836-841. 12. Rahman S, Rahman T, Al-Sha Ismail, Rahman A. Diabetes associates macrovasculopaty: 13. pathophysiology and pathogenesis. Diab, Obes and Metab. 2006, 0, 1-14.Wadwa P, Kinney G, Maahs D et al. Awareness and treatment of dyslipidemia in young 14. adults with type 1 diabetes.Diabetes Care 2006;28:1051-1056.Verbeeten, K. C., Elks, C. E., Daneman, D. and Ong, K. K. (2011), Association between 15. childhood obesity and subsequent Type 1 diabetes: a systematic review and meta-analysis. Diabetic Medicine, 28: 10–18.


Pozzilli P, Guglielmi C, Pronina E et al. Double or hybrid diabetes associated with 16. an increase in type 1 and type 2 diabetes in children and youth. Pediatric Diabetes 2007;8(9):88-95.Liu LL, Lawrence JM, Davis C, Liese AD, Pettitt DJ, Pihoker C, Dabelea D, Hamman 17. R, Waitzfelder B, Kahn HS (2009). Prevalence of overweight and obesity in youth with diabetes in USA: the SEARCH for Diabetes in Youth Study. Pediatr Diabetes 11:4–11Holl RW, Grabert M, Sorgo W, Heinze E, Debatin KM. Contributions of age, gender and 18. insulin administration to weight gain in subjects with IDDM. Diabetologia 1998;41:542–547.van Vliet M, Van der Heyden JC, Diamant M, Schindhelm RK, von Rosenstiel I, Aanstoot 19. J, Veeze HJ (2010) Overweight is highly prevalent in children with type 1 diabetes and ssociates with cardiometabolic risk. J Pediatr 156:923–929Lešovi , S., i S. Saji . “Metaboli ka kontrola i uhranjenost dece i adolescenata obolelih od 20. diabetes mellitusa tip 1.” Medicinski glasnik Specijalna bolnica za bolesti štitaste žlezde i bolesti metabolizma Zlatibor 14.30 (2009): 56-66.Purnell JQ, Hokanson JE, Marcovina SM, Steffes MW, Cleary PA, Brunzell JD (1998) 21. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial. JAMA 280:140–146 Reaven GM. Banting Lecture 1988: role of insulin resitance in human disease. Diabetes. 22. 1988;37:1595-607.Goran MI, Ball GDC, Cruz ML. Obesity and risk of type 2 diabetes and cardiovascular 23. disease in children and adolescents. J Clin Endocrinol Metab. 2003;88:1417-27.Rodriguez-Mor24. an M., Salazar-Vazquez B., Violante R., Guerrero-Romero F.: Metabolic syndrome among children and adolescents aged 10-18 years. Diabetes Care, 2004, 27, 2516-2517.Zimmet P, Alberti KGMM, Kaufman F, Tajima N, Silink M, Arslanian S, et al. The me-25. tabolic syndrome in children and adolescents – an IDF consensus report. Pediatr Diab. 2007;8:299-306. Lipsy R.J.: The National Cholesterol Education Program Adult Treatment Panel III 26. guidelines.J. Manag. Care Pharm., 2003, 9, suppl. 1, 2-5. Luczy ski 27. W, Szypowska A, Bossowski A, Ramotowska A, Re ko P, Rembi ska M, Tercjak M, Blecharczyk B, Lachowska U, Sucho P, Wi niewska K, Bernatowicz P, G owi ska-Olszewska B.Overweight, obesity and metabolic syndrome in children with type 1 diabetes melllitus. Pediatr Endocrinol Diabetes Metab. 2010;16(2):83-8.Schwab K28. O, Doerfer J, Hecker W, Grulich-Henn J, Wiemann D, Kordonouri O, Beyer P, Holl RW; DPV Initiative of the German Working Group for Pediatric Diabetology. Spec-trum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: cross-sectional data from the German diabetes documentation and quality management system (DPV). Diabetes Care. 2006;29(2):218-25.van Vliet M, van der Heyden J C, Diamant M et al.Overweight children with type 1 29. diabetes have a more favourable lipid pro le than overweight non-diabetic children. Eur J Pediatr. 2012; 171:493–498.


Dalla Pozza R, Bechtold S, Bon g W et al. Age of onset of type 1 diabetes in children and 30. carotid intima medial thickness. J Clin Endocrinol Metab 2007, 92(6):2053-2057.Orchard TJ, Costacou T, Kretowski A, Nesto RW. Type 1 diabetes and coronary artery 31. disease. Diabetes Care 2006, 29:2528–2538.

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