Diabetes and Metabolism Journal

Korean Diabetes Association (대한당뇨병학회)
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Oxidative Stress Causes Vascular Insulin Resistance in OLETF Rat Through Increased IRS-1 Degradation

OLETF 쥐에서 산화스트레스가 IRS-1 degradation을 통한 혈관성 인슐린저항성의 유발

Park, Jung-Lae;Lee, Young-Sil;Kim, Bo-Hyun;Kang, Yang-Ho;Kim, In-Ju;Kim, Yong-Ki;Son, Seok-Man;Son, Seok-Man
박정래;이영실;김보현;강양호;김인주;김용기;손석만;손석만

  • Published : 20070100
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Abstract

-Backgroud: Insulin resistance and oxidative stress have been reported to play essential pathophysiological roles in diabetic cardiovascular complication. The relationship between insulin resistance and oxidative stress in vasculature remains unclear. The study was conducted to assess whether oxidative stress induce vascular insulin resistance in OLETF rat, a model of type 2 diabetesMethods: We used OLETF rats (20/30/40 weeks, n = 5/5/5), as models of type 2 DM, and LETO rats (20/30/40 weeks, n = 5/5/5) as controls. Aortas of each rats were extracted. Superoxide anion production was detected by NBT assay and lucigenin assay. 8-hydroxyguanosine (OHdG) and nitrotyrosine were detected as markers of oxidative stress in 20 and 40 weeks groups. The glucose uptake of aortas was measured by detecting 2-deoxyglucose uptake in both groups. The expression of IR, IRS-1, PI3-K and Akt/PKB were detected by immuno precipitation and immunoblotting in 20, 30 and 40 weeks groups Results: Superoxide anion production and markers of oxidative stress (8-OHdG, nitrotyrosine) were significantly increased in aortas of OLETF rats compared with controls. Aortas of OLETF rats exhibited decreased IRS-1 content and increased phosphorylation of IRS-1 at Ser307 compared with LETO rats. There were no significant differences in expressions of IR, PI3-K and Akt/PKB between two groups Conclusion: These results suggest that oxidative stress induces insulin resistance in vasculature of OLETF rat specifically through increasing serine phosphorylation of IRS-1 and its degradation by a proteasome-dependent pathway, providing an alternative mechanism that may explain the association with insulin resistance and diabetic vascular complications. (J Kor Diabetes Assoc 31:22~32, 2007)

연구배경: 당뇨병환자와 당뇨병 동물모델에서 산화스트레스가 증가하며 이러한 산화스트레스가 당뇨병에서 혈관합병증의 발생에 중요한 원인임이 밝혀지고 있고, 혈관조직의 인슐린저항성에 관여한다고 알려져 있다. 따라서, 본 연구에서는 제2형 당뇨병 모델인 OLETF 쥐에서 산화스트레스가 혈관조직에서 인슐린저항성을 유도하는 기전을 알아보고자 하였다.방법: OLETF 쥐 수컷 20주 5마리, 30주 5마리와 40주 5마리를 사용하였고, 대조군으로 LETO 쥐 수컷 20주 5마리, 30주 5마리와 40주 5마리를 사용하였고, 각 군의 대동맥을 적출하여 20주와 40주군의 superoxide 음이온, 8-OHdG, nitrotyrosine 생성량을 측정하였고, 각 군의 포도당 섭취률을 2-deoxyglucose 이용해 측정하였으며 20주, 30주, 40주군의 IR, IRS-1, PI3K, Akt/PKB의 발현 정도, Akt/PKB의 인산화와 IRS-1 Ser307의 인산화를 비교해 보았다.결과: Superoxide 음이온과 8-OHdG, nitrotyrosine같은 산화스트레스의 표지자가 대조군에 비해 OLETF 쥐의 대동맥 조직에서 현저히 증가되어 있었고, NBT 염색을 했을때 OLETF 쥐의 대동맥 중막의 염색은 LETO 쥐에 비해 감소되어 있는 결과를 보였으나, 외막에서는 LETO 쥐에 비해 현저히 염색이 증가되어 있는 결과를 보였다. 또한 2-deoxyglucose의 섭취가 OLETF 쥐의 대동맥 조직에서 현저히 감소되어 있었으며 OLETF 쥐의 대동맥 조직에서 IR, PI3-K, Akt/PKB의 발현과 인산화에는 차이가 없었으나, IRS-1의 발현이 LETO에 비해 감소되어 있었고, IRS-1의 Ser307의 인산화가 증가되어 있는 결과를 보였다.

Keywords

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