Diabetes and Metabolism Journal

Korean Diabetes Association (대한당뇨병학회)
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Effects of Anti-Vascular Endothelial Growth Factor (VEGF) on Pancreatic Islets in Mouse Model of Type 2 Diabetes Mellitus

제2형 당뇨병 동물모델에서 항 혈관내피세포 성장인자(Anti-Vascular Endothelial Growth Factor (VEGF)) 투여 시 췌장에 대한 효과

Kim, Ji-Won;Ham, Dong-Sik;Park, Heon-Seok;Ahn, Yu-Bai;Song, Ki-Ho;Yoon, Kun-Ho;Yoo, Ki-Dong;Kim, Myung-Jun;Jeong, In-Kyung;Ko, Seung-Hyun
김지원;함동식;박헌석;안유배;송기호;윤건호;유기동;김명준;정인경;고승현

  • Published : 20090600
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Abstract

Background: Vascular endothelial growth factor (VEGF) is associated with the development of diabetic complications. However, it is unknown whether systemic VEGF treatment has any effects on the pancreatic islets in an animal model of type 2 diabetes mellitus. Methods: Anti-VEGF peptide (synthetic ATWLPPR, VEGF receptor type 2 antagonist) was injected into db/db mice for 12 weeks. We analyzed pancreatic islet morphology and quantified beta-cell mass. Endothelial cell proliferation and the severity of islet fibrosis were also measured. VEGF expression in isolated islets was determined using Western blot analysis. Results: When anti-VEGF was administered, db/db mice exhibited more severe hyperglycemia and associated delayed weight gain than non-treated db/db mice. Pancreas weight and pancreatic beta-cell mass were also significantly decreased in the anti-VEGF-treated group. VEGF and VEGF receptor proteins (types 1 and 2) were expressed in the pancreatic islets, and their expression was significantly increased in the db/db group compared with the db/dm group. However, the elevated VEGF expression was significantly reduced by anti-VEGF treatment compared with the db/db group. The anti-VEGF-treated group had more prominent islet fibrosis and islet destruction than db/db mice. Intra-islet endothelial cell proliferation was also remarkably reduced by the anti-VEGF peptide. Conclusion: Inhibition of VEGF action by the VEGF receptor 2 antagonist not only suppressed the proliferation of intra-islet endothelial cells but also accelerated pancreatic islet destruction and aggravated hyperglycemia in a type 2 diabetes mouse model. Therefore, the potential effects of anti-VEGF treatment on pancreatic beta cell damage should be considered.

연구배경: 대표적인 당뇨병성 합병증인 당뇨병성 신증과 망막병증은 공통적으로 혈관내피세포성장인자(Vascular endothelial growth factor, VEGF)가 합병증의 발생에 중요한 역할을 하는 것이 알려져 있으나 항 VEGF 치료가 췌도나 베타세포에 직접적으로 어떠한 영향을 주는지는 거의 알려진 바가 없다. 이에 당뇨병성 합병증 치료를 목적으로 하는 항 VEGF 치료가 췌장과 당뇨병의 경과에 미치는 영향을 관찰하고, 당뇨병이 진행되면서 나타나는 췌도 및 베타 세포의 변화에 있어서 VEGF의 역할을 규명하고 치료에 응용하고자 하였다. 방법: 이에 당뇨병 동물모델인 db/db mouse에 12주간 VEGF 수용체 type 2 antagonist (ATWLPPR, 5 mg/kg)를 복강 내 투여하여 혈당의 변화와 함께 췌장의 면역염색을 통하여 베타세포 질량 및 췌도의 형태적인 변화를 관찰하고 VEGF 의 췌도 내 발현 및 혈관신생 정도를 평가하였다. 결과: 12주간 항 VEGF peptide를 투여한 결과, 복강 내 당부하검사 시 db/db mouse 에 비해 항 VEGF 투여군에서 현저한 고혈당을 보였으며 고혈당이 심해지면서 항 VEGF 투여군에서 체중의 증가가 적었다. 췌장의 무게(db/dm vs. db/db vs. anti-VEGF group, 0.321 ${\pm}$ 0.05 vs. 0.206 ${\pm}$ 0.13 vs. 0.158 ${\pm}$ 0.12 g) 및 베타세포 질량(db/dm vs. db/db vs. anti-VEGF group, 4.08 ${\pm}$ 0.1 vs. 3.77 ${\pm}$ 0.2 vs. 2.89 ${\pm}$ 0.2 mg, P < 0.05) 역시 db/db군에 비해 항 VEGF 군에서 더 감소되었다. 또한 정상 췌도에 비해 당뇨병이 발생한 군에서 췌도 내 VEGF 발현이 증가되었으나, 항 VEGF 투여시 췌도 내 VEGF 단백의 발현이 감소하였고 (db/dm vs. db/db vs. anti-VEGF group, 3.63 ${\pm}$ 2.86 vs. 6.60 ${\pm}$ 3.56 vs. 2.74 ${\pm}$ 1.55%, * P < 0.05) 췌도의 크기가 감소하였으며, 췌도 내 섬유화 진행이 더 심하게 관찰되었고(db/dm vs. db/db vs. anti-VEGF group, 3.37 ${\pm}$ 1.51 vs. 13.96 ${\pm}$ 3.20 vs. 16.99 ${\pm}$ 4.96%, * P < 0.05) 췌도 내 내피세포의 증식이 더 감소되어 있었다. 결론: 제2형 당뇨병 동물모델에서 혈관내피세포 성장인자(VEGF)는 정상 췌도보다 당뇨병이 발생한 췌도에서 발현이 증가되므로 당뇨병의 발병 기전과 관련이 있을 것이며, 베타세포의 증식 및 췌도 변형에 중요한 역할을 하므로 당뇨병의 치료에도 응용할 수 있을 것으로 생각되고, 당뇨병성 미세혈관 합병증의 치료나 예방을 목적으로 제2형 당뇨병모델에 항 VEGF를 투여할 경우 고혈당 상태를 더 악화시키고 베타세포 증식을 억제하며 췌도 파괴를 가속화 시키므로, 항 VEGF 치료 시 이에 대한 충분한 고려가 필요할 것이다.

Keywords

References

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