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Cited by 830Endoplasmic Reticulum Stress and DiseasePancreatic function and diabetesIon Channels and Receptors

Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes

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Laybutt, D. R., Preston, A. M., Åkerfeldt, M. C., Kench, J. G., Busch, A. K., Biankin, A. V., Biden, T. J.·2007·Diabetologia
DOI 10.1007/s00125-006-0590-z
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Abstract

Aims/hypothesis Increased lipid supply causes beta cell death, which may contribute to reduced beta cell mass in type 2 diabetes. We investigated whether endoplasmic reticulum (ER) stress is necessary for lipid-induced apoptosis in beta cells and also whether ER stress is present in islets of an animal model of diabetes and of humans with type 2 diabetes. Methods Expression of genes involved in ER stress was evaluated in insulin-secreting MIN6 cells exposed to elevated lipids, in islets isolated from db/db mice and in pancreas sections of humans with type 2 diabetes. Overproduction of the ER chaperone heat shock 70 kDa protein 5 (HSPA5, previously known as immunoglobulin heavy chain binding protein [BIP]) was performed to assess whether attenuation of ER stress affected lipid-induced apoptosis. Results We demonstrated that the pro-apoptotic fatty acid palmitate triggers a comprehensive ER stress response in MIN6 cells, which was virtually absent using non-apoptotic fatty acid oleate. Time-dependent increases in mRNA levels for activating transcription factor 4 (Atf4), DNA-damage inducible transcript 3 (Ddit3, previously known as C/EBP homologous protein [Chop]) and DnaJ homologue (HSP40) C3 (Dnajc3, previously known as p58) correlated with increased apoptosis in palmitate- but not in oleate-treated MIN6 cells. Attenuation of ER stress by overproduction of HSPA5 in MIN6 cells significantly protected against lipid-induced apoptosis. In islets of db/db mice, a variety of marker genes of ER stress were also upregulated. Increased processing (activation) of X-box binding protein 1 (Xbp1) mRNA was also observed, confirming the existence of ER stress. Finally, we observed increased islet protein production of HSPA5, DDIT3, DNAJC3 and BCL2-associated X protein in human pancreas sections of type 2 diabetes subjects. Conclusions/interpretation Our results provide evidence that ER stress occurs in type 2 diabetes and is required for aspects of the underlying beta cell failure.

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  • Elevated proinsulin levels and proinsulin/C-peptide ratios may lead to endoplasmic reticulum stress and failure of pancreatic beta cells.

    “Elevated proinsulin levels and proinsulin/C-peptide ratios may lead to endoplasmic reticulum stress and failure of pancreatic beta cells [16].”

    From Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1). (2023) · cites this paper as [16]

    The Discussion links ER stress to beta-cell apoptosis and describes a proinsulin folding mutation as one possible trigger. The paper does not say that elevated proinsulin levels or proinsulin/C-peptide ratios cause ER stress or beta-cell failure; its experiments instead examine lipid-induced stress. The cited passages have section labels but no page numbers in our copy. (LLM, conf=0.88)

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  1. Harding HP, Ron D (2002) Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51:S455-S461

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Authors
Laybutt, D. R., Preston, A. M., Åkerfeldt, M. C., Kench, J. G., Busch, A. K., Biankin, A. V., & Biden, T. J.
Affiliations
Garvan Institute of Medical Research (AU)
Corresponding author
Biden, T. J.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2007-02-01
Volume
50
Issue
4
Pages
752-763
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-006-0590-z
OpenAlex
W2089894176
Cited by
830
References
2
Citations by year
2026: 18 · 2025: 19 · 2024: 29 · 2023: 40 · 2022: 43 · 2021: 41 · 2020: 27 · 2019: 40 · 2018: 32 · 2017: 37 · 2016: 40 · 2015: 45 · 2014: 57 · 2013: 49 · 2012: 66
FWCI
25.38
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Diabetes Australia Research Trust
  • Diabetes Australia
  • Cancer Institute NSW
  • Medical Research Council
  • National Health and Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
endoplasmic reticulum stress, beta-cell apoptosis, type 2 diabetes, palmitate, oleate, GRP78, BiP, ATF4, CHOP, DNAJC3, XBP1 splicing, beta-cell failure, beta-cell mass, db/db mice, MIN6 cells
MeSH terms
Endoplasmic Reticulum Chaperone BiP, Animals, Cell Line, Diabetes Mellitus, Type 2, Endoplasmic Reticulum, Gene Expression Regulation, Heat-Shock Proteins, Humans, Lipids, Mice, Inbred C57BL, RNA, Messenger, Blotting, Western, Apoptosis, Oxidative Stress, Molecular Chaperones, Insulin-Secreting Cells, Mice

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