한빛사논문
- 조회3,757
Abstract
Jinyoung Kim1,2, Hwanju Cheon1, Yeon Taek Jeong1, Wenying Quan1, Kook Hwan Kim1, Jae Min Cho1, Yu-Mi Lim1, Seung Hoon Oh1, Sang-Man Jin1, Jae Hyeon Kim1, Moon-Kyu Lee1, Sunshin Kim3, Masaaki Komatsu4, Sang-Wook Kang5 and Myung-Shik Lee1,2
1Department of Medicine and
2Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
3New Experimental Therapeutics Branch, Korean National Cancer Center, Goyang, Republic of Korea.
4Department of Biochemistry, Niigata University School of Medicine, Niigata, Japan.
5Department of Biomedical Sciences, University of Ulsan, Seoul, Republic of Korea.
Address correspondence to: Myung-Shik Lee, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangam-gu, Seoul, Republic of Korea. Or to: Sang-Wook Kang, Department of Biomedical Sciences, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea.
Authorship note: Jinyoung Kim, Hwanju Cheon, and Yeon Taek Jeong contributed equally to this work.
Islet amyloid accumulation is a hallmark of human type 2 diabetes (T2D). In contrast to human islet amyloid polypeptide (hIAPP), murine islet amyloid polypeptide (mIAPP) does not exhibit amyloidogenic propensity. Because autophagy is important in the clearance of amyloid-like proteins, we studied transgenic mice with β cell?specific expression of hIAPP to evaluate the contribution of autophagy in T2D-associated accumulation of hIAPP. In mice with β cell?specific expression of hIAPP, a deficiency in autophagy resulted in development of overt diabetes, which was not observed in mice expressing hIAPP alone or lacking autophagy alone. Furthermore, lack of autophagy in hIAPP-expressing animals resulted in hIAPP oligomer and amyloid accumulation in pancreatic islets, leading to increased death and decreased mass of β cells. Expression of hIAPP in purified monkey islet cells or a murine β cell line resulted in pro-hIAPP dimer formation, while dimer formation was absent or reduced dramatically in cells expressing either nonamyloidogenic mIAPP or nonfibrillar mutant hIAPP. In autophagy-deficient cells, accumulation of pro-hIAPP dimers increased markedly, and pro-hIAPP trimers were detected in the detergent-insoluble fraction. Enhancement of autophagy improved the metabolic profile of hIAPP-expressing mice fed a high-fat diet. These results suggest that autophagy promotes clearance of amyloidogenic hIAPP, autophagy deficiency exacerbates pathogenesis of human T2D, and autophagy enhancers have therapeutic potential for islet amyloid accumulation-associated human T2D.
논문정보
- Research article
- 2014년 07월 (BRIC 등록일 2014-07-30)
- 국내(교신)+국외 연구진
- 의약학 > 면역의학
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