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Inhibition of NADPH oxidase-1 preserves beta cell function
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Journal Article
Inhibition of NADPH oxidase-1 preserves beta cell function
2015
Overview
Aims/hypothesis
Upregulation of the reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX)-1 in islets and beta cells follows acute exposure to inflammatory cytokines and is concomitant with beta cell dysfunction. NOX-1 is a candidate mediator of inflammation-induced beta cell dysfunction. This study aimed to determine whether selective inhibition of NADPH oxidase-1 presents a new strategy to preserve beta cell function.
Methods
Induced beta cell dysfunction was studied in primary human donor islets, isolated mouse islets and murine beta cell lines. Islets and beta cells were stimulated with inflammatory cytokines (TNF-α, IL-1β, IFN-γ). NOX-1 activity was blocked by the selective inhibitor ML171.
Results
Cytokine induction of intracellular ROS was reduced 80% with 1 μmol/l ML171 in murine beta cell lines (
p
< 0.01). Cytokine-induced apoptosis, measured by caspase-3 activation or quantified fluorescence microscopy, was prevented in islets and beta cell lines up to 100% with ML171 in a concentration-dependent manner (
p
< 0.05). Functionally, glucose-stimulated insulin secretion was abolished by cytokine exposure but preserved by ML171 in isolated mouse islets and murine beta cell lines. A feed-forward regulation of NOX-1 in islets and beta cell lines was disrupted by ML171.
Conclusions/interpretation
Stimulation of NOX-1 activity is a major component of inflammatory cytokine-induced beta cell dysfunction. Significant protection of beta cells is conferred with selective inhibition of NOX-1. Suppression of NOX-1 activity may present a new therapeutic strategy to preserve and protect beta cell function in diabetes.
Publisher
Springer Berlin Heidelberg,Springer Nature B.V
Subject
/ Cells
/ Cytoprotection - drug effects
/ Diabetes
/ Enzyme Inhibitors - pharmacology
/ Enzymes
/ Glucose
/ Humans
/ Inflammation - prevention & control
/ Insulin
/ Insulin-Secreting Cells - drug effects
/ Insulin-Secreting Cells - physiology
/ Interferon-gamma - adverse effects
/ Interleukin-1beta - adverse effects
/ Male
/ Medicine
/ Mice
/ NADH, NADPH Oxidoreductases - antagonists & inhibitors
/ Phenothiazines - pharmacology
/ Rats
