The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice
2015 (English)In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 49, no 11, 1308-1318 p.Article in journal (Refereed) Published
In type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) overactivity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet or HFD-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose- and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In long-term experiments (1-3 days), high-glucose-induced human islet cell reactive oxygen species (ROS) production and death were prevented by GLX351322. We propose that while short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4 activity, for example, during conditions of high-fat feeding, promotes ROS-mediated beta-cell dysfunction. Thus, selective NOX inhibition may be a therapeutic strategy in type 2 diabetes.
Place, publisher, year, edition, pages
2015. Vol. 49, no 11, 1308-1318 p.
NOX inhibitor; human islet; reactive oxygen radical; NADPH oxidase; insulin release; beta-cell death; glucose intolerance
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-273312DOI: 10.3109/10715762.2015.1067697ISI: 000369892600003PubMedID: 26118714OAI: oai:DiVA.org:uu-273312DiVA: diva2:894708