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T\u0130P 2 D\u0130YABET NED\u0130R?<\/h2>\n\n\n\n
Tip 2 diyabet ins\u00fclin direnci ya da ins\u00fclin yetersizli\u011fi sebebiyle y\u00fcksek kan \u015fekeri ile karakterize edilen bir metabolik bozukluktur. Diyabet vakalar\u0131n\u0131n y\u00fczde 90’\u0131 tip 2 diyabetten olu\u015fur. Klasik diyabet semptomlar\u0131 aras\u0131nda poli\u00fcri, polifaji, polidipsi, kilo kayb\u0131 gibi g\u00fcnl\u00fck hayatta k\u0131sa ve orta vadede fark\u0131na var\u0131labilecek anormallikler vard\u0131r. Ancak \u00e7o\u011fu insan diyabetin ilk y\u0131llar\u0131nda semptom g\u00f6stermez. Tip 2 diyabet hastalar\u0131n\u0131n kardiyovask\u00fcler hastal\u0131klara yakalanma olas\u0131l\u0131\u011f\u0131 sa\u011fl\u0131kl\u0131 insanlara g\u00f6re \u00e7ok daha fazlad\u0131r, bunun d\u0131\u015f\u0131nda v\u00fccut uzuv amp\u00fctasyonlar\u0131 riskleri de sa\u011fl\u0131kl\u0131 insanlara g\u00f6re \u00e7ok daha fazlad\u0131r. Tip 2 diyabet retinopati dolay\u0131s\u0131yla k\u00f6rl\u00fc\u011fe sebebiyet verebilmektedir ve geli\u015fmi\u015f \u00fclkelerdeki travma d\u0131\u015f\u0131 k\u00f6rl\u00fc\u011f\u00fcn en b\u00fcy\u00fck sebebidir. Nefropati, cinsel g\u00fc\u00e7s\u00fczl\u00fck ve bunama da tip 2 diyabet komplikasyonlar\u0131 aras\u0131ndad\u0131r. Tip 2 diyabet genellikle uygun ya\u015fam tarz\u0131 ve ila\u00e7 tedavileri ile kontrol alt\u0131na al\u0131nabilmektedir.<\/p>\n\n\n
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T\u0130P 2 D\u0130YABET\u0130N GENET\u0130K ALTYAPISI<\/h2>\n\n\n\n
GWAS (genome-wide association study) d\u00f6neminden \u00f6nce vaka kontrol, aile ve ba\u011flant\u0131 yakla\u015f\u0131mlar\u0131n\u0131 kullanan birka\u00e7 ba\u015far\u0131l\u0131 \u00e7al\u0131\u015fma yap\u0131lm\u0131\u015f ve PPARG, KCNJ11, TCF7L2 ve WFS1 genlerindeki varyantlar\u0131n; tip 2 diyabet ile ili\u015fkili oldu\u011fu tespit edilmi\u015ftir. Bug\u00fcn, Avrupa ve \u00e7oklu etnik gruplardan meydana gelen pop\u00fclasyonlarda 120’den fazla genetik lokusun tip 2 diyabet veya glukoz ve ins\u00fclin konsantrasyonlar\u0131 ile ili\u015fkili oldu\u011fu bulunmu\u015ftur. TCF7L2 genindeki genetik varyantlar\u0131n tip 2 diyabet riskini artt\u0131rd\u0131\u011f\u0131 mekanizmalar, a\u011f\u0131rl\u0131kl\u0131 olarak pankreas adac\u0131klar\u0131nda ve muhtemelen karaci\u011ferde etkiler g\u00f6steren \u00e7oklu doku modelini i\u00e7eriyor gibi g\u00f6r\u00fcnmektedir. Ara\u015ft\u0131rmac\u0131lar\u0131n \u00fczerinde durdu\u011fu di\u011fer bir gen ise ya\u011f k\u00fctlesi ve obezite ile ili\u015fkilendirilen FTO’dur. Geni\u015f epidemiyolojik Mendel randomizasyon \u00e7al\u0131\u015fmalar\u0131, bir FTO varyant\u0131n\u0131n tip 2 diyabet riski \u00fczerindeki nedensel etkilerini g\u00f6stermi\u015ftir. Bir \u00e7al\u0131\u015fma, FTO-IRX genlerinin obezite ve tip 2 diyabet riski \u00fczerindeki etkilerini g\u00f6stermi\u015ftir. Epidemiyolojik verilere bak\u0131ld\u0131\u011f\u0131nda geli\u015fmi\u015f \u00fclkelerde obezite ve tip 2 diyabet art\u0131\u015f\u0131 paralel seyretmektedir. Diyabet Genetik Giri\u015fimi taraf\u0131ndan ger\u00e7ekle\u015ftirilen ilk GWAS’ta , ins\u00fclinojenik ve e\u011filim indeksleri gibi nicel \u00f6zellikler analiz edilmi\u015ftir. Melatonin resept\u00f6r\u00fc 1B (MTNR1B) geninde (rs10830963), oral glukoz tolerans testi (OGTT) s\u0131ras\u0131nda glukoza kar\u015f\u0131 bozulmu\u015f erken ins\u00fclin yan\u0131t\u0131 ve gelecekteki tip 2 diyabet riskinin 1,1 kat artmas\u0131 ile ili\u015fkili ortak bir varyant belirlenmi\u015ftir. MTNR1B genindeki risk aleli, hem oral (ins\u00fclinojenik ve e\u011filim indeksi) yan\u0131t olarak bozulmu\u015f erken ins\u00fclin sal\u0131n\u0131m\u0131 \u00fczerinde b\u00fcy\u00fck bir etkiye sahip oldu\u011fu (etki b\u00fcy\u00fckl\u00fc\u011f\u00fc, beta \u00b1 SEM: -0.170 \u00b1 0.021, p = 5\u00d710-6, ve – 0.241 \u00b1 0.022, p = 5\u00d710-26, s\u0131ras\u0131yla) hem de intraven\u00f6z (birinci faz ins\u00fclin yan\u0131t\u0131) glukoz y\u00fcklemesi \u00fczerinde b\u00fcy\u00fck bir etkiye sahip oldu\u011fu g\u00f6r\u00fclm\u00fc\u015ft\u00fcr. (-0.065 \u00b1 0.023, p = 0.004). Ayr\u0131ca, risk alel ta\u015f\u0131y\u0131c\u0131lar\u0131 risksiz alel ta\u015f\u0131y\u0131c\u0131lar\u0131 ile kar\u015f\u0131la\u015ft\u0131r\u0131ld\u0131\u011f\u0131nda, 7 y\u0131ll\u0131k bir takip s\u00fcresi boyunca azalm\u0131\u015f ins\u00fclin sekresyonunu s\u00fcrd\u00fcrm\u00fc\u015ft\u00fcr (ba\u015flang\u0131\u00e7ta ins\u00fclinojenik indeks: -0.160 \u00b1 0.026, p = 6\u00d710-10 ve devam\u0131nda: -0.188 \u00b1 0.026, p = 1 \u00d710-12). Ayr\u0131ca Diyabet \u00d6nleme Program\u0131nda yap\u0131lan \u00e7al\u0131\u015fmalar, MTNR1B rs10830963 risk varyant\u0131 ta\u015f\u0131y\u0131c\u0131lar\u0131n\u0131n bir y\u0131ll\u0131k bir s\u00fcre boyunca erken ins\u00fclin sal\u0131n\u0131m\u0131nda s\u00fcrekli bir bozulma sergiledi\u011fini ve bu lokustaki etkinin ilerleyici bir k\u00f6t\u00fcle\u015fmeye i\u015faret etti\u011fini g\u00f6stermi\u015ftir. Avrupa k\u00f6kenli 10.000’den fazla diyabetik olmayan bireyde OGTT s\u0131ras\u0131nda ins\u00fclin sekresyonunun dinamik \u00f6l\u00e7\u00fcmlerini ara\u015ft\u0131ran GWAS meta-analizinde, birinci faz ins\u00fclin sekresyonu i\u00e7in MTNR1B rs10830963 en g\u00fc\u00e7l\u00fc sinyal olarak do\u011frulanm\u0131\u015ft\u0131r (ins\u00fclinojenik indeks, beta \u00b1 SEM: -0.17 \u00b1 0.16, p = 7\u00d710-28). Ayr\u0131ca MTNR1B mRNA’n\u0131n insan pankreas adac\u0131klar\u0131nda eksprese edildi\u011fi g\u00f6sterilmi\u015ftir. Daha spesifik olarak, risk aleli ta\u015f\u0131yan diyabetik olmayan bireyler (ortalama \u00b1 SEM, GG: 3.773 \u00b1 1.593, CG: 1.399 \u00b1 0.380, CC: 0.457 \u00b1 0.089, p = 0.001). tip 2 diyabetli hastalar (5.00 5 \u00b10.475’e kar\u015f\u0131 3.142) \u00b1 0.980, p = 0.14) resept\u00f6r\u00fcn artm\u0131\u015f ekspresyonunu g\u00f6sterir. Bu bulgular, insan pankreas adac\u0131klar\u0131n\u0131n geni\u015f bir gen ekspresyon analizi ile daha da do\u011frulanm\u0131\u015ft\u0131r. KCNQ1’in maternal alelinin hipermetilasyonunun, kom\u015fu, maternal olarak eksprese edilen protein kodlayan genlerin fetal pankreasta monoalelik aktivitesi ve yeti\u015fkin pankreas adac\u0131klar\u0131nda bialelik aktivite ile sonu\u00e7land\u0131\u011f\u0131 g\u00f6sterilmi\u015ftir, bu da genin erken pankreas geli\u015fimini etkiledi\u011fini d\u00fc\u015f\u00fcnd\u00fcrmektedir. B\u00f6ylece ya\u015fam\u0131n ilerleyen d\u00f6nemlerinde artan tip 2 diyabet riskine etki edebilece\u011fi d\u00fc\u015f\u00fcn\u00fclmektedir. 7q32.3 kromozomundaki KLF14 transkripsiyon fakt\u00f6r\u00fcn\u00fcn yukar\u0131 ak\u0131\u015f\u0131ndaki bir varyant, tip 2 diyabet ve HDL-kolesterol ile ili\u015fkilendirilmi\u015ftir. \u00c7al\u0131\u015fmalar, bask\u0131lanm\u0131\u015f b\u00fcy\u00fcme fakt\u00f6r\u00fcne ba\u011fl\u0131 protein 10 (GRB10) geninde azalm\u0131\u015f erken faz ins\u00fclin sekresyonu ile ili\u015fkili bir varyant tan\u0131mlam\u0131\u015ft\u0131r. Eksojen olarak uygulanan melatoninin kemirgenlerde ins\u00fclin sekresyonu \u00fczerindeki inhibit\u00f6r etkileriyle paralel olarak melatoninin INS-1 s\u0131\u00e7an beta h\u00fccrelerinde glukoza yan\u0131t olarak ins\u00fclin sal\u0131n\u0131m\u0131n\u0131 inhibe etti\u011fini g\u00f6sterilmi\u015ftir. MTNR1B genindeki varyantlar\u0131n ins\u00fclin salg\u0131lanmas\u0131 ve izole edilmi\u015f a\u00e7l\u0131k glukozu \u00fczerindeki etkilerine ek olarak hepatik glukoz \u00fcretimi ile de ili\u015fkili oldu\u011fu bildirilmi\u015ftir (n = 77, beta, %95 CI: 0.4 (0.07-0.6), p = 0.017).<\/p>\n\n\n\n
Tip 2 diyabetin genetik altyap\u0131s\u0131 \u015fimdiden \u00e7\u00f6z\u00fcmlenmeye ba\u015flam\u0131\u015ft\u0131r. Ancak halen \u00e7\u00f6z\u00fcmlenmesi gereken bir\u00e7ok biyolojik mekanizma vard\u0131r. Genellikle ins\u00fclin \u00fcreten beta h\u00fccreleri \u00fczerinde durulsa da glukagon \u00fcreten alfa h\u00fccreleri \u00fczerine de \u00e7al\u0131\u015fmalar yapmak faydal\u0131 olacakt\u0131r. Epidemiyolojik \u00e7al\u0131\u015fmalarda g\u00f6sterildi\u011fi gibi sirkadiyen ritimlerin d\u00fczenlenmesinde rol oynayan genlerin ke\u015ffi, farkl\u0131 beslenme d\u00fczenleri, uyku bozukluklar\u0131 ve tip 2 diyabet riski aras\u0131nda kurulu bir ba\u011flant\u0131y\u0131 a\u00e7\u0131klayabilir. Tip 2 diyabetin genetik mimarisinin molek\u00fcler olarak anla\u015f\u0131lmas\u0131 farkl\u0131 diyabet alt tiplerinin daha iyi s\u0131n\u0131fland\u0131r\u0131lmas\u0131na yol a\u00e7acak ve b\u00f6ylece altta yatan patofizyolojilere dayal\u0131 daha kesin t\u0131bbi tedavinin yolunu a\u00e7acakt\u0131r.<\/p>\n\n\n\n
<\/p>\n\n\n\n
KAYNAK\u00c7A<\/h2>\n\n\n\n
Diabetes Genetics Replication and Meta-Analysis (DIAGRAM) Consortium; Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium; South Asian Type 2 Diabetes (SAT2D) Consortium; Mexican American Type 2 Diabetes (MAT2D) Consortium; Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium. Mahajan A, Go MJ, Zhang W, Below JE, et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. <\/em>2014;46(3):234\u2013244. <\/p>\n\n\n\n Prasad RB, Groop L. Genetics of type 2 diabetes-pitfalls and possibilities. Genes (Basel). 2015 Mar 12;6(1):87-123. doi: 10.3390\/genes6010087. PMID: 25774817; PMCID: PMC4377835.<\/p>\n\n\n\n Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sj\u00f6gren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L. 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