Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes
Jinyoung Kim, Hwanju Cheon, Yeon Taek Jeong, Wenying Quan, Kook Hwan Kim, Jae Min Cho, Yu-Mi Lim, Seung Hoon Oh, Sang-Man Jin, Jae Hyeon Kim, Moon-Kyu Lee, Sunshin Kim, Masaaki Komatsu, Sang-Wook Kang, Myung-Shik Lee
Jinyoung Kim, Hwanju Cheon, Yeon Taek Jeong, Wenying Quan, Kook Hwan Kim, Jae Min Cho, Yu-Mi Lim, Seung Hoon Oh, Sang-Man Jin, Jae Hyeon Kim, Moon-Kyu Lee, Sunshin Kim, Masaaki Komatsu, Sang-Wook Kang, Myung-Shik Lee
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Research Article

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

Abstract

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.

Authors

Jinyoung Kim, Hwanju Cheon, Yeon Taek Jeong, Wenying Quan, Kook Hwan Kim, Jae Min Cho, Yu-Mi Lim, Seung Hoon Oh, Sang-Man Jin, Jae Hyeon Kim, Moon-Kyu Lee, Sunshin Kim, Masaaki Komatsu, Sang-Wook Kang, Myung-Shik Lee

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Figure 3

In vivo accumulation of hIAPP oligomer and amyloid.

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In vivo accumulation of hIAPP oligomer and amyloid. (A) Confocal microsc...
(A) Confocal microscopy after immunofluorescent staining of pancreas sections from 12-week-old mice using anti-insulin and anti-hIAPP oligomer Abs (I11). Arrowheads indicate colocalization of I11 and insulin immunostaining. Scale bar: 50 μm. (B) Confocal microscopy after immunofluorescent staining using anti-p62 and I11 Ab and subsequent DAPI staining to identify nuclei. The arrowhead indicates rare colocalization of I11 and p62 immunostaining. Scale bar: 50 μm. (C) Confocal microscopy after immunofluorescent staining of hIAPP+/+GFP-LC3+ mouse islets using A11 Ab. Line tracing performed along the white dashed line in the merged picture to visualize colocalization of A11-stained hIAPP oligomer and GFP-LC3+ autophagosomes shows overlapping of hIAPP fluorescence with GFP fluorescence. Scale bar: 5 μm. (D and E) Confocal microscopy after immunofluorescent staining of pancreas sections from 12-week-old mice using (D) anti-p62 Ab and thioflavin-S staining or (E) using anti-ubiquitin Ab and FSB staining, as described in the Methods. Arrowheads indicate amyloid stained with thioflavin-S (green) or FSB (blue). Scale bar: 5 μm.