Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes
Jinyoung Kim, … , Sang-Wook Kang, Myung-Shik Lee
Jinyoung Kim, … , Sang-Wook Kang, Myung-Shik Lee
Published July 18, 2014
Citation Information: J Clin Invest. 2014;124(8):3311-3324. https://doi.org/10.1172/JCI69625.
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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 6

Effects of autophagy enhancer on the glucose profile of hIAPP+ mice.

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Effects of autophagy enhancer on the glucose profile of hIAPP+ mice. (A)...
(A) Primary mouse islet cells were treated with 100 mM trehalose for 24 hours with or without 100 nM bafilomycin pretreatment to block lysosomal steps of autophagy. Cell lysates were subjected to Western blot analysis using anti-LC3 or anti-p62 Ab. (B) Trehalose (2 g/kg) was administered i.p. to 12-week-old GFP-LC3+ mice on HFD for 2 weeks, and frozen pancreas sections were prepared for confocal microscopy to examine LC3 puncta. Scale bar: 50 μm. (C) Trehalose (2 g/kg) was administered i.p. to 16- to 20-week-old hIAPP+ mice on HFD, and nonfasting blood glucose levels were monitored (n = 5). (D) IPGTT was performed after 4 weeks of trehalose administration to hIAPP+ mice on HFD (n = 5). (E) The insulinogenic index was calculated after 4 weeks of trehalose administration to hIAPP+ mice on HFD (n = 3). (F) After immunofluorescent staining using A11 Ab, the percentage of A11-stained cells among total DAPI+ islet cells was determined by confocal microscopy. Representative pictures are shown. Scale bar: 50 μm. (G) After FSB staining, mean fluorescence intensity per islet area was determined using the NIS-Elements AR 3.0 software (Nikon). Representative pictures are shown. Scale bar: 100 μm. *P < 0.05, **P < 0.01, ***P < 0.001; #P < 0.05, ##P < 0.01, ###P < 0.001. (*, comparison between hIAPP+/HFD + trehalose and hIAPP+/HFD + PBS groups; #, comparison between hIAPP+/HFD + PBS and hIAPP–/HFD + PBS groups in C and D.)