Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes

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 tr...

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Veröffentlicht in:The Journal of clinical investigation 2014-08, Vol.124 (8), p.3311-3324
Hauptverfasser: Kim, Jinyoung, Cheon, Hwanju, Jeong, Yeon Taek, Quan, Wenying, Kim, Kook Hwan, Cho, Jae Min, Lim, Yu-Mi, Oh, Seung Hoon, Jin, Sang-Man, Kim, Jae Hyeon, Lee, Moon-Kyu, Kim, Sunshin, Komatsu, Masaaki, Kang, Sang-Wook, Lee, Myung-Shik
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Sprache:eng
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Zusammenfassung: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI69625