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1 J Korean Diabetes 2016;17: Vol.17, No.4, 2016 ISSN 백진경을지대학교식품영양학과 Application of Nutrigenomics in Diabetes Jean Kyung Paik Department of Food and Nutrition, Eulji University, Seongnam, Korea Abstract Diabetes mellitus (DM) is considered a global pandemic and its incidence continues to grow worldwide. The most common treatments for controlling diabetes focus on glucose control as a means to reduce long-term complications. Major changes in diet have taken place over the past 10,000 years since the beginning of the Agricultural Revolution: however, human genes have not changed. We now live in a nutritional environment that differs from that for which our genetic constitution was selected. Nutrients and dietary patterns are central issues in the prevention, development and treatment of DM. Nutritional genomics studies generally focus on dietary patterns according to genetic variations, the role of genenutrient interactions, gene-diet-phenotype interactions and epigenetic modifications caused by nutrients; these studies facilitate an understanding of the early molecular events that occur in DM and contribute to the identification of better biomarkers and diagnostic tools for the disease. In particular, this approach will help develop tailored diets that maximize the use of nutrients and other functional ingredients present in food, which will aid in the prevention and delay of DM and its complications. Here, we provide an understanding of the role of gene variants and nutrient interactions, and discuss the importance of nutrients and dietary patterns on gene expression. Keywords: Diabetes mellitus, Nutrigenomics, Phenotype, Single nucleotide polymorphism Corresponding author: Jean Kyung Paik Department of Food and Nutrition, Eulji University, 553 Sanseong-daero, Sujeong-gu, Seongnam 13135, Korea, jkpaik@eulji.ac.kr Received: Mar. 10, 2016; Accepted: Mar. 11, 2016 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright c 2016 Korean Diabetes Association 266 The Journal of Korean Diabetes

2 백진경 서론 역사적으로영양소의부족으로인한영양실조가일부질병의원인이되었지만최근에는영양소의과잉으로인한대사성질환이늘어나면서오늘날의영양학은영양소및식이와같은환경적요인과유전자변이및발현등유전적요인과의상호작용을연구함으로써개인의유전형에따른식이와생활방식등을제안하여만성질환에대한예방및건강증진을도모하고자하는것이다. 특히식이는평생에걸쳐서직 간접적으로연관된유일한환경인자중하나이며 [1] 질병의예방차원에서영양소-유전자간의관련성연구는중요해지고있다. 신체적조건과생활환경이동일한사람에게똑같은음식을섭취하게하더라도그결과가모든사람에게같은효과를보이는것은아니다. 이유는이사람의외부환경은동일할지라도유전적요인은동일하지않기때문이다. 이것은개인별유전적요인에따라대사과정에차이가생기고, 그결과인체에서의반응이다르게나타나기때문이다. 이러한영양소및식품구성성분이특정유전자에미치는영향은물론개인의유전적차이까지연구하는학문을영양유전체학이라한다. 유전자의다형성 (polymorphism) 에따라영양소대사의차이를연구하는분야인 nutrigenomics 와대용량의유전체정보를손쉽게측정할수있는고효율실험기법과여러오믹스분석등의분자생물학적분석기술을이용하여유전자의발현을조절하는기전을연구하는분야인 nutrigenetics로분류하기는하지만용어를명확하게구분짓지는않는다. 영양유전체학은 유전체학이발달하면서대량고속유전체분석도구를이용한기술이영양학에도입되면서영양소와유전자의상호작용을시스템생물학적접근방법으로이해하고자하는응용학문 [2,3], 질병에관하여유전자와영양소의상호작용을통해연구하는학문 [4,5], 식품및그구성성분과유전체의분자적, 세포적, 계통적수준에서의기능적상호작용을연구하여궁극적으로식이를이용하여질병을예방또는치료를위한학문 [6] 등으로정의되곤한다. 그러나실제로우리가섭취하는대부분의식이는복합물질이고들어있는영양성분도소량이기때문에특정유전자에이르러작용하기에는매우약한신호전달물질이고장기간에걸쳐노출이되어야지만우리몸에영향을줄수있게된다. 그럼에도불구하고영양유전체학에대한연구가활발히진행되고있는이유는인간유전자지도의완성과분자생물학의발달로다량의유전자통합분석이가능하고첨단분석기술의발달에힘입었기때문이다 [7]. 오늘날식이관련만성질환들에관한연구가다양해지고특정영양소가만성질환에잠재적요소로작용한다는것이알려지면서 [8], 바람직한건강을위한식이는영양소의양적균형뿐아니라, 체내에서의구체적인대사에관여하여특정한역할을수행할수있는구체적성분들의섭취가중요해졌다. 그리하여최근에는특정질환의발병률과상관관계가높은유전자다형성을밝혀내어환경적인요인과개인의유전자다형성과질환유병률과의상관관계를밝히고자하는연구들이활발하게진행되고있는것이다. 본론 당뇨병의유전적요인은매우복잡하며수많은당뇨유발성의대립유전인자들의조합에의해발병되고, 식이등환경적요인에의해서도영향을받는다 [9]. 당뇨관련감수성유전자 proliferator-activated receptor gamma (PPARγ), transcription factor-7-like 2 (TCF7L2), 체지방과비만관련단백질 (FTO) 유전자, APOA5 등은식이영양과의상호관련성을보여주었다. 1. 제2형당뇨관련감수성유전자 PPARγ Gouda 등의연구 [10] 에의하면 PPARγ에서 (Pro12Ala, rs ) Ala12 변이형은제2형당뇨의위험을감소시키고인슐린민감성에관련있음을보여주었다. 또한, Lazar 의연구 [11] 에따르면불포화지방산과같은특정영양인자가 PPARγ 조절증가와관련있는것으로조사되었으며, 267

3 Ala12 변이형은 Pro12 동형접합체와비교하여혈당항상성유지에있어불포화지방의유익한효과에더민감하고총지방과포화지방의안좋은영향에덜민감한것으로나타났다 [12,13]. 2. 제2형당뇨관련감수성유전자 TCF7L2 Ruchat 등의연구 [14] 에서는 TCF7L2 (rs ) 와식이지방섭취의상호관련성이인슐린민감성과내당능에영향을미치는것을보여주었으며, Nurses Health Study 에서는 [15] 제2형당뇨환자 1,114명과대조군 1,915명을대상으로 TCF7L2 (rs ) 에대한유전자형과, 반정량적식품섭취빈도설문을통한식이섭취량을평가한결과, 당질식이의질적, 양적변화에따라인슐린요구도의변화로제2형당뇨병의위험이달라진다는것을보여주었다. 3. 제2형당뇨관련감수성유전자 FTO FTO 유전자는비만위험과관련이있는유전자로제2형당뇨병과비만위험대립유전자사이의관계는논란의여지가있어왔다. 이와관련하여, FTO (rs ) 변이형에서지중해식식이요법과의유전자 -식이상호작용에관하여체질량지수 (body mass index, BMI) 에차이가없는대상자를대상으로환자-대조군연구를 ( 제2형당뇨환자군 3,430명, 대조군 3,622명 ) 수행한결과, 낮은지중해식식이시대립유전자변이형에서제2형당뇨의위험성이더높았으나, 높은지중해식식이시에는이러한관련성이사라지는결과를보였다 [16]. 또한, Steemburgo 등의연구 [17] 에서는, FTO (rs ) AA 유전자형을가진제2형당뇨환자군에서 BMI와는독립적으로높은지방섭취와낮은섬유소섭취와의관련된결과를보였다. 특히, AA 유전자형을가진여성은 TT, AT 유전자형을지닌여성에비해높은지방섭취와낮은섬유소섭취와의관련이있는것으로나타났다. 4. 제2형당뇨관련감수성유전자 APOA5 Apolipoprotein A5 (apo A-V) 는혈중중성지방농도와밀접한관련이있는것으로알려져있다. Kang 등 [18] 은공복혈당장애및제2형당뇨병환자에서전곡류의섭취가중성지방과 apo A-V 농도의혈중농도를조절하는 APOA5-1131T>C의유전적효과에미치는영향에관하여연구하였다. 또한, Kim 등 [19] 도공복혈당장애와제2형초기당뇨환자에서 APOA5-1131T>C 단일염기다형성이 3년간의당질과식이섬유소관련식이요법에따라혈중 apo A-V 농도와중성지방수치변화영향에관하여연구하였다. 3년간의식이요법후, TC, CC 유전자형의그룹에서 apoa-v 농도가감소하였고, 중성지방수치는 TT 유전자형그룹이식이요법이전보다감소한결과를보였다. 포도당, 인슐린, 인슐린저항성지표, 유리지방산모두 TT 유전자형그룹에서만감소됨을밝혔다. 이러한연구를통하여, 공복혈당장애와제2형초기당뇨환자에서식이요법의효과가유전자형에따라다름을확인할수있다. 결론 최근질환발생에관여하는유전적정보에대한많은연구가진행되고있지만, 이때간과하지말아야하는사실은이들질환연관유전자와영양소간의상호작용규명이꼭필요하다는것이다. 식이요인을포함한환경인자의영향이고려되지않을경우에때로는인종간에유의한차이를보이는유전자다형형조차도그영향이달라질수있고같은인종내에서도환경인자에의한영향및임상적의의에대한영향력에매우큰차이를보이게된다. 그러므로건강상의유익에대한영양유전체관련연구에서얻어진정보를사용함에신중해야할것이며, 이는각각의사례에따라평가되고검토되어야할것이다. 또한질병에대한위험도를약간상승시키는유전적소인 268

4 백진경 이있는유전자를가지고있다는것이마치그질환이발생할예비자인것처럼인식되면곤란하다. 따라서특정질병과의연관성을언급할때에는자세한정보를제공하여불필요한오해를줄일수있도록해야할것이다. 영양유전체학은앞으로전사체학, 단백체학, 대사체학라는학문들을통해앞으로각각의개개인의유전자에적합한음식을섭취함으로써식품을통하여질환을예방하여건강하게장수하는시대를열수있을것으로기대된다. REFERENCES 1. Simopoulos AP. Genetic variation and dietary response: Nutrigenetics/Nutrigenomics. Asia Pacific J Clin Nutr 2002;11:S van Ommen B, Stierum R. Nutrigenomics: exploiting systems biology in the nutrition and health arena. Curr Opin Biotechnol 2002;13: Elliott R, Ong TJ. Nutritional genomics. BMJ 2002;324: Chávez A, Muñoz de Chávez M. Nutrigenomics in public health nutrition: short-term perspectives. Eur J Clin Nutr 2003;57 Suppl 1:S Kritchevsky D. Diet and cancer: what's next? J Nutr 2003;133(11 Suppl 1):3827S-9S. 6. Ordovas JM, Corella D. Nutritional genomics. Annu Rev Genomics Hum Genet 2004;5: Müller M, Kersten S. Nutrigenomics: goals and strategies. Nat Rev Genet 2003;4: DeBusk R. Diet-related disease, nutritional genomics, and food and nutrition professionals. J Am Diet Assoc 2009;109: Diamond J. The double puzzle of diabetes. Nature 2003;423: Gouda HN, Sagoo GS, Harding AH, Yates J, Sandhu MS, Higgins JP. The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol 2010;171: Lazar MA. PPAR gamma, 10 years later. Biochimie 2005;87: Lamri A, Abi Khalil C, Jaziri R, Velho G, Lantieri O, Vol S, Froguel P, Balkau B, Marre M, Fumeron F. Dietary fat intake and polymorphisms at the PPARG locus modulate BMI and type 2 diabetes risk in the D.E.S.I.R. prospective study. Int J Obes (Lond) 2012;36: Luan J, Browne PO, Harding AH, Halsall DJ, O'Rahilly S, Chatterjee VK, Wareham NJ. Evidence for genenutrient interaction at the PPARgamma locus. Diabetes 2001;50: Ruchat SM, Elks CE, Loos RJ, Vohl MC, Weisnagel SJ, Rankinen T, Bouchard C, Pérusse L. Evidence of interaction between type 2 diabetes susceptibility genes and dietary fat intake for adiposity and glucose homeostasis-related phenotypes. J Nutrigenet Nutrigenomics 2009;2: Cornelis MC, Qi L, Kraft P, Hu FB. TCF7L2, dietary carbohydrate, and risk of type 2 diabetes in US women. Am J Clin Nutr 2009;89: Ortega-Azorín C, Sorlí JV, Asensio EM, Coltell O, Martínez-González MÁ, Salas-Salvadó J, Covas MI, Arós F, Lapetra J, Serra-Majem L, Gómez-Gracia E, Fiol M, Sáez-Tormo G, Pintó X, Muñoz MA, Ros E, Ordovás JM, Estruch R, Corella D. Associations of the FTO rs and the MC4R rs polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low. Cardiovasc Diabetol 2012;11: Steemburgo T, Azevedo MJ, Gross JL, Milagro FI, Campión J, Martínez JA. The rs polymorphism 269

5 in the FTO gene is associated with fat and fiber intakes in patients with type 2 diabetes. J Nutrigenet Nutrigenomics 2013;6: Kang R, Kim M, Chae JS, Lee SH, Lee JH. Consumption of whole grains and legumes modulates the genetic effect of the APOA5-1131C variant on changes in triglyceride and apolipoprotein A-V concentrations in patients with impaired fasting glucose or newly diagnosed type 2 diabetes. Trials 2014;15: Kim M, Chae JS, Kim M, Lee SH, Lee JH. Effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein A-V levels in patients with impaired fasting glucose or new-onset type 2 diabetes as a function of the APOA T > C polymorphism. Nutr J 2014;13:

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract