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Peroxisomes and pancreatic beta-cell lipo-dysfunction

Lookup NU author(s): Dr Helen Porteous, Dr Cara Tomas, Dr Satomi Miwa, Professor Mark Walker

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Abstract

© 2020 Elsevier Inc.Aims: Pancreatic beta-cell lipo-dysfunction decreases insulin secretion and predisposes to the development of type 2 diabetes. Through targeted Pex11β knockdown and peroxisome depletion, our aim was to investigate the specific contribution of peroxisomes to palmitate mediated pancreatic beta-cell dysfunction. Methods: MIN6 cells were transfected with probes targeted against Pex11β, a regulator of peroxisome abundance, or with scrambled control probes. Peroxisome abundance was measured by PMP-70 protein expression. 48 h post transfection, cells were incubated with 250 μM palmitate or BSA control for a further 48 h before measurement of glucose stimulated insulin secretion and of reactive oxygen species. Results: Pex11β knockdown decreased target gene expression by >80% compared with the scrambled control (P<0.001). This led to decreased PMP-70 expression (p<0.01) and a 22% decrease in peroxisome number (p<0.05). At 25 mM glucose, palmitate treatment decreased insulin secretion by 64% in the scrambled control cells (2.54±0.25 vs 7.07±0.83 [mean±SEM] ng/h/μg protein; Palmitate vs BSA P<0.001), but by just 37% in the Pex11β knockdown cells. Comparing responses in the presence of palmitate, insulin secretion at 25 mM glucose was significantly greater in the Pex11β knockdown cells compared with the scrambled controls (4.04±0.46 vs 2.54±0.25 ng/h/μg protein; p<0.05). Reactive oxygen species generation with palmitate was lower in the Pex11β knockdown cells compared with the scrambled controls (P<0.001). Conclusion: Pex11β knockdown decreased peroxisome abundance, decreased palmitate mediated reactive oxygen species generation, and reversed the inhibitory effect of palmitate on insulin secretion. These findings reveal a distinct role of peroxisomes in palmitate mediated beta-cell dysfunction.

Publication metadata

Author(s): Blair HR, Tomas C, Miwa S, Heath A, Russell A, Ginkel M-V, Gunn D, Walker M

Publication type: Article

Publication status: Published

Journal: Journal of Diabetes and its Complications

Year: 2021

Volume: 35

Issue: 3

Print publication date: 01/03/2021

Online publication date: 31/12/2020

Acceptance date: 20/12/2020

ISSN (print): 1056-8727

ISSN (electronic): 1873-460X

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.jdiacomp.2020.107843

DOI: 10.1016/j.jdiacomp.2020.107843

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