American Diabetes Association
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Single-cell RNA sequencing reveals a role for reactive oxygen species and peroxiredoxins in fatty-acid-induced rat beta-cell proliferation

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posted on 2022-10-03, 22:10 authored by Alexis Vivoli, Julien Ghislain, Ali Filali-Mouhim, Zuraya Elisa Angeles, Anne-Laure Castell, Robert Sladek, Vincent Poitout

The functional mass of insulin-secreting pancreatic beta cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing beta cells. Type 2 diabetes appears when these compensatory mechanisms fail. Nutrients including glucose and fatty acids are important contributors to the beta-cell compensatory response, but their underlying mechanisms of action remain poorly understood. Herein, we investigated the transcriptional mechanisms of beta-cell proliferation in response to fatty acids.

Isolated rat islets were exposed to 16.7 mM glucose with or without 0.5 mM oleate (C18:1) or palmitate (C16:0) for 48 h. The islet transcriptome was assessed by single cell RNA-sequencing. Beta-cell proliferation was measured by flow cytometry.

Unsupervised clustering of pooled beta cells identified different subclusters, including proliferating beta cells. Beta-cell proliferation increased in response to oleate but not palmitate. Both fatty acids enhanced the expression of genes involved energy metabolism and mitochondrial activity. Comparison of proliferating vs. non-proliferating beta cells and pseudotime ordering suggested the involvement of reactive oxygen species (ROS) and peroxiredoxin signaling. Accordingly, N-acetyl cysteine and the peroxiredoxin inhibitor Conoidin A both blocked oleate-induced beta-cell proliferation.

Our study reveals a key role for ROS signaling through peroxiredoxin activation in oleate-induced beta-cell proliferation.


This study was supported by the National Institutes of Health (R01-DK-58096), the Canadian Institutes of Health Research (MOP 77686), and the Quebec Cardiometabolic Health, Diabetes and Obesity Research Network.