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

作者：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^*

来源：Journal of Clinical Investigation, 2014, 124(8): 3311-3324.

DOI：10.1172/JCI69625

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 beta cell-specific expression of hIAPP to evaluate the contribution of autophagy in T2D-associated accumulation of hIAPP. In mice with beta 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 MAPP-expressing animals resulted in hIAPP oligomer and amyloid accumulation in pancreatic islets, leading to increased death and decreased mass of beta cells. Expression of hIAPP in purified monkey islet cells or a murine beta 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 MAPP-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.

• 出版日期2014-8