Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article

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

  • Text
  • PDF
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

×

Figure 1

Development of diabetes in hIAPP+Atg7Δβcell mice.

Options: View larger image (or click on image) Download as PowerPoint
Development of diabetes in hIAPP+Atg7Δβcell mice.
(A) RT-PCR analysis of...
(A) RT-PCR analysis of hIAPP and Atg7 expression in primary islets. The residual expression of Atg7 in islets of hIAPP–Atg7Δβcell or hIAPP+Atg7Δβcell mice is probably due to non–β cells in primary islets. (B) Nonfasting blood glucose levels in male and female mice (n = 33~46 for male and 30~51 for female mice between 8 and 20 week of age; n = 10~16 for male and 10~19 for female mice before 8 weeks of age). (C) Body weight of male mice. Body weight of female mice was also not different between groups (data not shown). The numbers of mice in C are the same as those in B. (D) IPGTT after overnight fasting in 12- to 15-week-old male (n = 5~7) and female mice (n = 12~23). (E) Serum insulin levels in fasted 12- to 15-week-old male mice determined by ELISA (n = 10 each). (F) The insulinogenic index was calculated from 12- to 15-week-old male mice (n = 5~7). *P < 0.05, **P < 0.01, ***P < 0.001; #P < 0.05, ##P < 0.01, ###P < 0.001. (*, comparison with hIAPP+Atg7fl/fl mice; #, comparison with hIAPP–Atg7Δβcell mice in B and D.)

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts