Obezite ve TIP 2 diyabet hastalıklarının patogenezinde yer alan insülin direncinin gelişiminde PIK3R1 (fosfotidilinositol 3 kinaz p85 alfa düzenleyici alt ünite 1) gen polimorfizmlerinin rolü
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2016
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Selçuk Üniversitesi Sağlık Bilimleri Enstitüsü
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Abstract
İnsülin direnci; başlıca yağ dokusu, iskelet kası ve karaciğer hücreleri gibi hedef dokularda insülinin azalmış etkisine bağlı olarak, glukozun hücre içine alımının azalması şeklinde tanımlanır ve hem obezite hem de T2DM'nin karakteristik özelliğidir. İnsülin direnci gelişiminde insülin sinyal mekanizmasını ilgilendiren postreseptör düzeydeki defektler önem kazanmaktadır. İnsülin reseptör substratının (IRS), fosfotidilinositol 3 kinaz (PI3K)'ın düzenleyici etkiye sahip p85α alt ünitesine bağlanması, PI3K aktivasyonu ile sonuçlanmakta ve Akt'nin de içinde yer aldığı yolakların aktivasyonu gerçekleşmektedir. Bu durum, insülinin metabolik etkileri kadar, hücre büyümesi çoğalması, farklılaşması ve mitojenik etkilerinin oluşması için de gereklidir. T2DM'li ve obez hastalarda, insülin reseptörünün aşağı yönündeki PI3K insülin sinyal sisteminin p85α alt ünitesinde oluşan değişikliklere bağlı olarak baskılanmasıyla yolak aktivasyonunun bozulduğu insülin direncininin tetiklendiği bilinmektedir. Çalışmamızda ilk kez Türk toplumunda 427 diyabetik (206 obez ve 221 nonobez) ve 413 diyabetik olmayan (138 obez ve 275 nonobez) olmak üzere toplam 840 bireyde, insülin sinyal yolunda anahtar protein olarak bilinen p85α alt ünitesini kodlayan PIK3R1 genindeki 6 tek nükleotid polmorfizminin (SNP), T2DM ve ilgili diğer fenotipik özellikler ile ilişkisi araştırılmıştır. Bu SNP'ler; rs3756668 (3' UTR), rs706713 (ekzon 1), rs3730089 (ekzon 6), rs7713645 ve rs7709243 (intron 1), rs1550805 (intron 6)'dır. Çalışmalarımızda, SNP rs706713, tip 2 diyabet ile önemli düzeyde ilişkili bulunmuştur. Ayrıca SNP rs706713'ün obez ve non-obez gruplar kendi içlerinde değerlendirildiğinde, özellikle non-obezlerde hastalıkla güçlü ilişkisinin varlığı ortaya konmuştur. SNP rs3730089 (Met326Ile) değişiminin tip 2 diyabet ile ilişkili olduğu gösterilmiştir. İntron 1'de lokalize SNP'lerden rs7709243 değişiminin obez bireylerde, SNP rs7713645 değişiminin ise non-obezlerde hastalıkla ilişkil olduğu tespit edilmiştir (p<0,05). rs1550805'in ise vücut kitle indeksi (p=0,007) ve serum c-peptid düzeyi (p=0,023) ile ilişkili olduğu ortaya konmuştur. Bu yönüyle çalışmamız; insülin sinyal akışında kritik öneme sahip önemli bir aday gen olan PIK3R1'in T2DM ve obezite gelişimindeki rolünü desteklemektedir.
Insulin resistance is mainly defined as decreased glucose uptake depending on reduced insulin effects on target tissues such as fat, skeletal muscle and liver, and it is characteristic feature of both obesity and T2DM. Postreceptor defects releated insulin signaling is important in developing insulin resistance. Binding insulin receptor substrate (IRS) to p85α regulator subunit of phosphoditilinositol 3 kinase (PI3K) results in PI3K activation and subsequently the activation of some pathway including Akt recruitment occurs. This case is necessary not only for metabolic effects of insulin but also cell growth, proliferation, differentiation and mitogenic effect. It is known that insulin resistance is trigered in obese and nonobese T2DM patients via the inhibition of downstream insulin receptor in PI3K signalling pathway due to the changes in PIK3R1 protein. For the first time in Turkey the relationship between 6 single nucleotide polymorphism (SNP) in PIK3R1, which is known key protein in insulin signaling pathway, and T2DM and T2DM-related phenotypic features was investigated on 427 diabetic and 413 non diabetic, totally 840 participants in our study. These were rs3756668 (3' UTR), rs706713 (exon 1), rs3730089 (exon 6), rs7713645 and rs7709243 (intron 1), rs1550805 (intron 6). As a resul of study, SNP rs706713 was found significantly related to T2DM, and when obese and non-obese groups were evaluated separately, a significant relation between rs706713 and the disease in non obese group was found. It was also found that SNP rs3730089 (Met326Ile) was related with T2DM. The other findings were while rs7709243C>T polymorphism localised intron 1 on PIK3R1 gene was related to disease in obese individuals, SNP rs7713645 changing was related to disease in non-obese individuals (p<0,05), and rs1550805 was significantly related with BMI (p=0,007) and serum c-peptide level (p=0,023). In this respect, our study supports the role of a significant candidate gene PIK3R1 which has critical importance in insulin signalling in obesity and T2DM incidence.
Insulin resistance is mainly defined as decreased glucose uptake depending on reduced insulin effects on target tissues such as fat, skeletal muscle and liver, and it is characteristic feature of both obesity and T2DM. Postreceptor defects releated insulin signaling is important in developing insulin resistance. Binding insulin receptor substrate (IRS) to p85α regulator subunit of phosphoditilinositol 3 kinase (PI3K) results in PI3K activation and subsequently the activation of some pathway including Akt recruitment occurs. This case is necessary not only for metabolic effects of insulin but also cell growth, proliferation, differentiation and mitogenic effect. It is known that insulin resistance is trigered in obese and nonobese T2DM patients via the inhibition of downstream insulin receptor in PI3K signalling pathway due to the changes in PIK3R1 protein. For the first time in Turkey the relationship between 6 single nucleotide polymorphism (SNP) in PIK3R1, which is known key protein in insulin signaling pathway, and T2DM and T2DM-related phenotypic features was investigated on 427 diabetic and 413 non diabetic, totally 840 participants in our study. These were rs3756668 (3' UTR), rs706713 (exon 1), rs3730089 (exon 6), rs7713645 and rs7709243 (intron 1), rs1550805 (intron 6). As a resul of study, SNP rs706713 was found significantly related to T2DM, and when obese and non-obese groups were evaluated separately, a significant relation between rs706713 and the disease in non obese group was found. It was also found that SNP rs3730089 (Met326Ile) was related with T2DM. The other findings were while rs7709243C>T polymorphism localised intron 1 on PIK3R1 gene was related to disease in obese individuals, SNP rs7713645 changing was related to disease in non-obese individuals (p<0,05), and rs1550805 was significantly related with BMI (p=0,007) and serum c-peptide level (p=0,023). In this respect, our study supports the role of a significant candidate gene PIK3R1 which has critical importance in insulin signalling in obesity and T2DM incidence.
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Diabetes mellitus, Obezite, Obesity, İnsülin direnci, Insulin resistance, PIK3R1
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Karadoğan, A. H. (2016). Obezite ve TIP 2 diyabet hastalıklarının patogenezinde yer alan insülin direncinin gelişiminde PIK3R1 (fosfotidilinositol 3 kinaz p85 alfa düzenleyici alt ünite 1) gen polimorfizmlerinin rolü. Selçuk Üniversitesi, Yayımlanmış doktora tezi, Konya.
